In this lecture, we review the physiology of cardiac contraction and the cellular mechanisms involved in that process, including adrenergic receptors. Multiple inotropic and vasoactive agents are discussed in detail. Clinical examples are provided at the end of the lecture

In this lecture, we review the physiology of cardiac contraction and the cellular mechanisms involved in that process, including adrenergic receptors. Multiple inotropic and vasoactive agents are discussed in detail. Clinical examples are provided at the end of the lecture

This is an overview of the different electrolytes in the human body, the pathologies associated with imbalances of them, and how to manage them clinically.

In the perioperative cardiac complications lecture, we describe multiple cardiac and non-cardiac complications of cardiac surgery; an anatomic and organ system approach is taken to describe the cardiac and non-cardiac issues, respectively. A special emphasis is placed on heparin-induced thrombocytopenia as well as intra-aortic balloon pumps. After this lecture, learners should feel significantly more comfortable in the cardio-vascular ICU.

Dr. Zaafran presents following topics: DefinitionClassificationDiagnosisTreatment

Dr. Travkina presents a case about Takotsubo. Takotsubo cardiomyopathy. Intracranial pathophysiology She discusses the course of action in the operating room. PACU ICU management Treatment

Dr. Zaafran provides overview of the most common medications used to affect the sympathetic nervous system and their clinical applications.

Dr. Zaafran explores the various types of medications used to treat arrythmia. While basic pharmacology and pathophysiology are discussed, he also goes into clinical signs and symptoms and the standard of care in treatment.

Dr. Tatayana Travkina, MD/Anesthesiologist presents following topics for shock and its management: 1. Normal Cardiac Functions 2. Hypovolemic Shock 3. Distributive Shock 4. Pharmacology of the Shock Management 5. Cardiogenic Shock 6. Obstructive Shock

By Ahmed Zaafran Etiology Classes Symptomology Work-up Labs Diagnosis Treatment

Dr. Travkina presents following topics: How to manage these patients intraoperatively? How to prevent these situations by risk stratifying a patient pre-operatively? A case based discussion for pre-operative cardiac risk assessment.

Presenter: Ahmed Zaafran M.D. In this video we discuss ST elevated myocardial infarction (STEMI) Diagnosis Treatment Key Labs ECG Analysis with corresponding anatomy Percutaneous coronary intervention Thrombolysis

Presenter: Ahmed Zaafran M.D. In this video we discuss following topics about myocardial ischemia: Coronary blood supply vs. cardiac demand for the blood. Pathophysiology and types of myocardial ischemia are discussed. Risk factors. Clinical Symptoms. Stable vs unstable angine.

Ahmed Zaafran MD presents clinical aspects of the chest pain including: How to approach the chief complaint of chest pain? History and physical examination of a patient with the chest pain. Differential diagnosis of the chest pain. EKG considerations. Lab tests, Troponin levels and CK-MB levels. Characteristics of the cardiac and non-cardiac chest pains.

Dr. Anam Tariq from the John Hopkins School of Medicine's department of nephrology discusses epidemiology for hypertension. This is the foundational lecture for the management of hypertension.

The agenda for this discussion is the following:

1. High level blood pressure (BP) pathophysiology.
2. BP as a risk factor for the chronic kidney disease.
3. Descriptive epidemiology
4. Trial evidence
   1. Effects of specific anti-hypertensive medications.

Presented by: Ahmed Zaafran, M.D. Dr. Zaafran presents the definition, management, and treatment of clinical hypertension.

This video presents the introductory concepts to understand heart failure. Following concepts are discussed:

• Chambers of a human heart.
• Structures of a human heart.
• Valves between various chambers.
• Why is our heart divided two pumps?
• What are the two circulatory circuits?
• What is Ejection Fraction?
• How to calculate ejection fraction?
• How to visualize ejection fraction?
• Clinical considerations for heart failure.
• Signs and Symptoms of left heart failure vs right heart failure.
• Major pathologies leading to heart failure.

Following terms are discussed:

• Atria
• Ventricles
• Mitral valve
• Tricuspid valve
• Ejection fraction
• Calculating the ejection fraction
• End systolic volume
• End diastolic volume
• Left heart failure
• Right heart failure
• Systemic circulation
• Pulmonary circulation
• Etiology of the heart failure
• Signs and symptoms of the left heart failure
• Signs and symptoms of the right heart failure
• Right heart failure vs left heart failure
• Primary reasons for the heart failure
• Heart failure as a disease of old age

Dr. Zaafran covers the key factors of anti hypertensive medications, their mechanisms, and how they are utilized in the clinical setting. Pharmacological principles are discussed for different types of agents, including:

- Adrenergic agents

- Angiotensin-converting enzyme (ACEI) inhibitors

- Angiotensin II receptor blockers

- Calcium channel blockers

- Diuretics

- Vasodilators

Dr. Anam Tariq continues the discussion about hypertension. In this session, Dr. Tariq discusses with Dr. Mobeen the management aspects of hypertension. Questions from the community members are used to address common clinical scenarios and potential approach to consider.

The topics discussed are related to the following questions:

Questions from René Gardner: With the new guidelines recommending <130/80. How aggressively are they with pursuing this? Especially in older patients.
Related questions:
Kathy RN AHA vs. JNC8 guidelines?
AHA: elevated BP >130/80, stage 1 >130/80

Dr. Tariq discusses the definition and stages of abnormal blood pressure, according to the American Heart Association (AHA).

Question from Kat Tugado: Good evening, I would like to hear her insights on the latest management in pediatric hypertension. Thank you.

Question from Bishal Baishya I have a question with 2 parts -
"When new JNC and AHA guidelines were modified to remove Prehypertension, and reduce the upper roof of normal limits.
1. How do clinicians and patient themselves target for a level of healthy BP and management of hypertension? Because new levels are more of just numbers a patient can just dream to reach. It does have a negative psychological impact that they shall be always be unfit.
2.Does it necessarily mean that they should touch this new lower levels to stay fit when by region and altitude they were acclimatise to 110 to 120 systolic and likewise near diastolic levels?"

Question from Robert Adams: Is there a common mistake you see more “rookie” practitioners make treating hypertension, and if so , how can we avoid it?

Question from DrAlkesh Patel: How u predict or judge intermediate htn or border line htn
And mostly what the causative agent what true managment
Marwan Hassan A Is it advisable to restrict table salt for HTN patients who are on a treatment plan?

Dr. Anam discusses the correct process of taking a person's blood pressure. We believe this is a process that is overlooked in the majority of clinical practice. We hope our audience will take special note of this process and make it routine for their clinical practice.

Dr. Tariq discusses the potential for precise medical practice by using ambulatory monitoring devices for hypertension.

Question from Robert Adams: Is there good data for non pharmacological treatments like diet, exercise and increased higher quality sleep ? And what sort of reduction benefit might we expect from lifestyle changes , and over what time frame?

Questions from Robert Adams: A patient comes to you with a bp of 225/110 , how long would be an acceptable amount of time to get control of their bp and what might a reasonable bp be for them ?

Questions from Khaty RN: Patient with BP of 225/110 needs close monitoring and observation to prevent microvascular damage. PCP or family cannot manage unstable patients in the outpatient. That is why we refer to ED or cardiology.

Questions from Lee Ann Summers: does this person need to be sent to ED or can I start management in the outpatient setting?

Questions from Marlene Torres: Is it in the best interest of the patient to get a medication that will lower the blood pressure fast but possible give them rebound HTN? Or should be just give the patient HTN medication based on their ethnicity and bring them back in 1 week, so on and so forth so their BP comes down slowly instead of giving a quick result. I ask because this has been a blazing dispute between some providers in my clinic face.

Questions from Robert Adams: if this is chronic then they are no less stable than when they walked into your clinic to though, and probably much less stable if you begin aggressively lowering their bp secondary to hypo perfusing their brain and kidneys , the sepsispam trial might be able to offer us guidance on this in the inpatient setting
https://www.wikijournalclub.org/wiki/SEPSISPAM

Questions from Abdi Razak Yousuf Kahin: Why beta blockers are not a first line drug for HTN ?

Questions from Mohammad Salman: Resistant hypertension etiology and treatment plan.
Hypertensive urgency , emergency plus malignant Hypertension management.

Questions from Katanje Phiri: The approach in management of stroke secondary to severe hypertension.....?

Questions from DrHaseeb Ubaid Ullah: Resistant recurrent hypertensive urgency treatment plan
And basic treatment plan of a patient with raised BP during early period of ischemic attack

Questions from Marlene Torres: There is an attributing factor of a patient having OSA will also lead to AFIB. But is OSA also an attributing factor of HTN?

Questions from Marlene Torres: There is an attributing factor of a patient having OSA will also lead to AFIB. But is OSA also an attributing factor of HTN?

Questions from Robert Adams: How does obstructive sleep apnea play a role in your treatment of a hypertensive patient? Do you screen and treat early or do you wait till later?

Questions from Robert Adams: I hope at this point we all know smoking is terrible for us, is vaping as bad? I’ve also read pot has 10x the nicotine as cigarettes, is nicotine the culprit and if so have we seen any changes in rates of atherosclerosis or hypertension in legalized vs non legalized states?

Questions from Robert Adams: Do you know of any new treatments, drug trials , implantable mechanical devices that are promising for hypertension?

Are you tucked in the bed? Listen to the medical bedtime stories with Dr. Syed. This story presents the first session on the management of hypertension and JNC8. (Disclaimer: every patient's situation needs to be assessed by you and your colleagues and managed as is appropriate. This information is to help you understand the management approaches and by itself does not consist of a prescription for any patient.)

Are you tucked in the bed? Listen to the medical bedtime stories with Dr. Syed. This story presents the second session on the management of hypertension and JNC8. Fables about: Drugs: ACE Inhibitors, ARBs Topics: Renin-Angiotensin System Aldosterone ADH (Disclaimer: every patient's situation needs to be assessed by you and your colleagues and managed as is appropriate. This information is to help you understand the management approaches and by itself does not consist of a prescription for any patient.)

Dr. Syed continues the fable about the management of the hypertension. Topics discussed are: High renin vs. low renin hypertension. Causes of the hypertension including: Cushing disease and cushing syndrome Parathyroid abnormalities Hypothyroidism and hyperthyroidism Cardiac conditions Coarctation of Aorta Vascular conditions Supra-renal conditions including, 11 betahydroxylase deficiency, primary aldosteronism and pheochromocytoma Chronic kidney disease Fibromuscular dysplasia Atherosclerosis and the ostia of the renal arteries

List of anti-hypertensive drugs. Principles of therapy JNC-8 lifestyle guidelines JNC-8 high-level summary JNC-8 algorithm Important notes about various anti-hypertensive drugs Traditional therapeutic approaches. Disclaimer: these are generalized and high-level points to inform the healthcare professionals. These messages do not consist of a prescription for an individual patient. Each patient needs to have a complete assessment with physical examination, labs, other tests, etc. before a therapeutic approach.

In this recording of the live presentation by Dr. Ahmed Zaafran, we present:
1. Etiology of congestive heart failure (CHF)
2. Functional classes of CHF
3. Understanding the diagnosis and treatment of CHF
4. Symptoms of CHF and how to identify it.
5. Work-up and management
6. Essential diagnostic tests for CHF

This video presents following topics about Atherosclerosis: Definition Epidemiology Risk factors Clinical aspects.

This video presents following topics about Atherosclerosis: Pathological progression and clinical outcomes. Including a discussion of the clinical horizon.

This video presents following topics about Atherosclerosis: Cellular and chemical mechaisms of the atherosclerotic plaque development. Mechanism of damage that starts/accelerates atherosclerosis Initiation of the atherosclerosis Progression of the atherosclerosis Complications of the atherosclerosis

This video presents following topics about the high output heart failure: Definition Factors that increase stroke volume e.g. hyperthyroidism. Factors that cause vasodilation e.g. wet beriberi. AV fistula e.g. in the knife wounds. Factors that reduce viscosity e.g. anemia.

This video presents following topics about the right heart failure: Definition Causes Morphology Clinical points Compensatory mechanisms

This video presents following topics about the left heart failure: Statastics of this leading cause of death. Definition Why is it called congestive heart failure? Pathogenesis: reduced compliance reduced contractility. Findings Clinical signs and symptoms

This video presents: Pathology phase shape type munuver location and radiation of various murmurs. Murmurs covered are: Aortic Stenosis Aortic Regurge Mitral/Tricuspid Regurge Mitral Stenosis Mitral Prolapse Ventral Septal Defect Patent Ductus Arteriosis

This video presents the physiological arrythmias namely: Sinus tachycardia Sinus bradycardia Sinsu arrythmia associated with respiration We will discuss the reflexes that result in the cardiac rhytm change

This video discusses SA nodal block with its pathogenesis ECG changes and clinical importance.

This video discusses AV nodal blocks with following topics: First and second degree heart blocks Mobitz type I and type II heart blocks. Hay block.

This video discusses: Third degree heart block Stoke adam syndrome Pathogenesis and ECG for these pathologies.

Cardiovascular System Pathology of Arrythmias: Electrical Alternans & Purkenje Block

This video discusses following: Difference between fibrillatoin and flutter. Causes of fibrillation and flutter Mechanism of the circus movements. Causes of the circus movements. Causes of the torsades de pointes

This video discusses: Atrial and ventricular proxysmal tachycardia. Atrial fibrillation Ventricular tachycardia and v-fib Pathogenesis of the tachcardia and v-fib Cirsuc movemens Wolff parkinson white syndrome ECG showing these pathologies

This video presents the premature beats or extrasystoles generated due to pathologies in the atria. We will also review the ECG changes associated with atrial premature beats.

This video presents the premature beats or extrasystoles generated due to pathologies in the AV nodes. These extrasystoles are also called junctional extrasystoles. We will also explain the junctional rhytm vs junctional beat. We will also review the ECG changes associated with junctional premature beats.

This video presents the premature beats or extrasystoles generated due to pathologies in the ventricular tissue. We will also review the ECG changes and explain the pathogenesis of the: Tall and wide QRS complexes. Inverted T waves Torsades De Pointes Long QT Syndrome

This video presents following topics:
Re-entry
Types of Supraventricular Tachycardia.
Mnemonic to remember supraventricular tachycardia.
Characteristics of Supraventricular Tachycardia.
AV Nodal Reentrant Tachycardia.
EKG changes
Pseudo R waves

This video discusses following: Primary diseases of the heart muscle. Diseases discussed are: Dilated cariac myopathies Hypertrophic cardiac myopathies Restrictive cardiac myopathies

This video presents following topics about hypertension: Defintion Classification Normal blood pressure controlling mechanisms Pathological mechanisms that result in the hypertension

This video presents the complications of the hypertension including:

Hyaline damage

Atherosclerosis due to shearing of the cells

Onion skinning due to cell damage under pressure

Charcot bouchard aneurysms

Changes observed during the fundoscopy

Hypertensive changes in the kidneys

This video presents: Ischemic heart disease (causes about half of the yearly deaths in western world.) Epidemiology Clinical progress Pathophysiology of the ischemic heart disease Types of angina and their properties

This video discusses following topics: Definition of MI Types of MI Clinical presentation and variations Pathophysiology

This video discusses following topics: Cellular and morphological events during the MI Diagnosis of an MI by the cardiac enzymes and EKG changes Management approach Complications including dressler's syndrome

How do we define a hypertensive emergency? How important is it? How would you manage it and what would be your treatment goals? This is a very short high yield summary on this topic!

In this talk, we will review folate, tetrahydrofolate, 4-10 methionine THF, homocysteine, s-adenosyl homocysteine, s-adenosyl methionine, and metabolisms. We will also go over the importance of the methionine tetrahydrofolate reductase (MTHFR) enzyme deficiency and its association with cardiovascular system pathologies, and fetal neurological developmental abnormalities. We will especially look at the increased association with clotting in individuals with MTHFR mutated enzyme. We will also see the two common mutations and their high-level epidemiology. We will discuss how vitamins B6, B9 (folate or folic acid) and B12 can help reduce homocysteine levels.

Homocysteine and MTHFR Mutations | Circulation
https://www.ahajournals.org/doi/10.1161/circulationaha.114.013311

preprints202303.0418.v2.pdf
file:///C:/Users/s_mob/Downloads/preprints202303.0418.v2.pdf

Folate, MTHFR Gene and Heart Health
https://www.gbhealthwatch.com/GND-Cardiovascular-Diseases-MTHFR.php

Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate - PMC
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

Frontiers | Prognostic Genetic Markers for Thrombosis in COVID-19 Patients: A Focused Analysis on D-Dimer, Homocysteine and Thromboembolism
https://www.frontiersin.org/articles/10.3389/fphar.2020.587451/full

Methylenetetrahydrofolate Reductase Deficiency - Medical Genetics Summaries - NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK66131/

Contribution of genotypes in Prothrombin and Factor V Leiden to COVID‐19 and disease severity in patients at high risk for hereditary thrombophilia - Kiraz - 2023 - Journal of Medical Virology - Wiley Online Library
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28457

Do MTHFR polymorphisms make you more susceptible to COVID-19? - MTHFR Support Australia
https://mthfrsupport.com.au/2021/08/do-mthfr-polymorphisms-make-you-more-susceptible-to-covid-19/

Acute Macular Neuroretinopathy Associated With COVID-19 Infection: Is Double Heterozygous Methylenetetrahydrofolate Reductase (MTHFR) Mutation an Underlying Risk Factor? - PMC
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968507/

Methylenetetrahydrofolate reductase - Wikipedia
https://en.wikipedia.org/wiki/Methylenetetrahydrofolate_reductase
 

Why do we measure cardiac electrical activity (ECG)? Conduction medium of the heart ECG measurement from the body surfaces Properties of the ECG voltmeter ECG Paper Normal ECG

A healthy individual's standard wave form ECG waves ECG intervals ECG segments Interpretation of the ECG waveform

This video presents the 12 ECG leads and Einthoven's triangle. Leads presented are: 3 Bipolar Limb Leads 3 Unipolar Augmented Leads 6 Chest Leads Earth lead

Dr. Syed presents the first chapter in the series of the EKG Interpretation lectures. This chapter contains:

1. EKG waves.

2. EKG segments.

3. EKG intervals.

4. Various shapes of the QRS complex and how to articulate them.

5. EKG paper properties.

Session 2 of the EKG interpretation.

Dr. Syed presents:

1. EKG leads setup.

2. Surfaces that the EKG leads look at.

3. Properties of QT interval.

4. QRS progression.

Dr. Syed presents:

The terminology used for the cardiac chamber enlargement.

Principles of the EKG changes when chamber enlargement is present.

Right atrial enlargement, EKG changes, diagnostic criteria, and the pathologies.

Left atrial enlargement, EKG changes, diagnostic criteria, and the pathologies.

Right ventricular enlargement, EKG changes, diagnostic criteria, and the pathologies.

Left ventricular enlargement, EKG changes, diagnostic criteria, and the pathologies.

Both ventricular enlargement, EKG changes, diagnostic criteria, and the pathologies.

This video presents the isoelectric lead method to determine the cardiac axis. (Digital media video)

This video presents the quadrant method to determine the cardiac axis. (Digital media video)

Lecture 2 Part 1.

Dr. Syed starts the set of talks on arrhythmias as part of the interpretation of the EKG series. Following topics are covered:

*How to detect arrhythmias?

*Types of arrhythmias.

*Sinus arrhythmias (first type) are presented as well.

Errata: Note the QRS complex duration is from 80ms to 120ms and not 1.2ms as I have incorrectly written.

Lecture 2 part 2

Dr. Syed continues the discussion of arrhythmias. In this talk he discusses:

Ectopic Rhythms

Identifying Atrial Ectopic Rhythms on the EKG

Identifying Junctional Ectopic Rhythms on the EKG

Identifying Ventricular Ectopic Rhythms on the EKG

Dr. Syed presents the first session in the series of supraventricular extrasystole. Topics covered are: Atrial Premature Beat/Premature Atrial Contraction (PAC) Junctional Premature Beat Difference between the Junctional Premature Beat and the Junctional Escape Beat Blocked Atrial Premature Beat

Dr. Syed presents following topics about Atrial Flutter

1. Definition and difference from atrial tachycardia.

2. Types of Atrial Flutter (Typical and atypical.)

3. EKG changes.

4. Interpreting atrial flutter on an EKG.

5. Pathogenesis.

6. Clinical presentation.

7. Management:

    a) Pharmacological

    b) Cardioversion

    c) Pacing

    d) Radiofrequency ablation

Differences between multifocal atrial tachycardia, paroxysmal atrial tachycardia, and atrial fibrillation.

10% of the US population of 80 years of age and above suffer from atrial fibrillation. Sometimes, the patient does not notice atrial fibrillation for a long time, which results in sufficient cardiac remodeling. This makes establishing a sinus rhythm very difficult. 

In this video, Dr. Syed discusses the definition, presentation, pathology, EKG, and salient points of management of the atrial fibrillation. The following aspects are discussed in detail:

1. Loss of atrial function during the episodes of the atrial fibrillation.
2. The risk of thrombus formation and duration of fibrillation where this risk increases significantly so that cardioversion is contra-indicated.
3. Atrial fibrillation caused by failing heart and ischemic injury.
4. Cardiac remodeling at a macro and cellular level during the long-standing atrial fibrillation and why cardioversion becomes difficult.
5. Development of the reentry circuits and the need for catheter ablation.
6. EKG interpretation of the atrial fibrillation.
7. JVP changes (absence of the A wave) during the atrial fibrillation.
8. The absence of the S4 heart sound due to the atrial fibrillation where this abnormal sound is expected.
9. Pharmacological management and cardioversion approaches.
10. Catheter ablation indication and possible methods.
11. Clinical types/stages of atrial fibrillation.

EKG – difference between MAT and PAT

Posted on July 31, 2017

MAT stands for multifocal atrial tachycardia.

PAT stands for Paroxysmal atrial tachycardia.
A student going through drbeen’s EKG interpretation lectuers asked us the difference between MAT (multifocal atrial tachycardia) and PAT (paroxysmal atrial tachycardia).

Here is a quick summary of the differences:

1.  PAT is usually an extra focus/reentrant circuit in the atria. It is similar in pathology to PSVT but the location could be anywhere instead of near the coronary sinus (study our lecture on atrial flutter.) Due to the focus being away from the SA node, the P wave’s shape can be different but consistent. Usually, there also is a warm-up and cooling-down period.
2. MAT is due to many reentrant circuits (but not as many as in the atrial fibrillation). Because of multiple foci present in many locations in the atria, you will find P waves of many shapes. To diagnose a MAT you must identify three different shapes of the P waves in the EKG.

One more difference of the MAT and PAT from the PSVT is that carotid massage does not affect the heart rate in these conditions. Note: study this lecture to understand why it is difficult to cure arrhythmia due to reentrant circuits. (Hint: structural changes.)

MAT and PAT both have the common presentation of 100 to 200 bpm heart rate.

Visit drbeen.com for more lectures: https://www.drbeen.com/

Management notes

10% of the US population of 80 years of age and above suffer from atrial fibrillation. Sometimes atrial fibrillation is not noticed by the patient for a long time resulting in sufficient cardiac remodeling that establishing a sinus rhythm becomes very difficult. 

In this video talk, Dr. Syed discusses the definition, presentation, pathology, EKG, and salient points of management of the atrial fibrillation. Following aspects are discussed in detail:

1. Considerations for the treatment of the atrial fibrillation (AF.)
2. Cardioversion.
3. Anticoagulants and antiplatelets.
4. Antiarrhythmic.
5. Rate control.
6. Surgical approaches.

Considerations for Management

• Patient’s age and symptoms.
• Hemodynamic effects of the AF (LV function compromise, HF).
• Duration since the onset of the fibrillation.
  • <48 hours, unknown, >48 hours.
• Clinical stage of fibrillation.
  • Paroxysmal, persistent, permanent.
• Comorbidities.
• Risk of a cardiac incident.
• Risk of bleeding/stroke.
• Existing medication.

Electrical Cardioversion

• New onset AF associated with severe hypotension, pulmonary edema, and angina can be managed with electrical cardioversion. Usually, up to 48h of AF can be approached with cardioversion.
  • Assess the risk of stroke before cardioverting. (Use CHA2DS2-VASc score for assessment.)
    • Patients with prior embolic events, rheumatic mitral stenosis, hypertrophic cardiomyopathy with marked left atrial enlargement may not be cardioverted before careful consideration for the risk of stroke.
  • 200 Joule (sedation or anesthesia.)
    • Greater shock energy and different electrode placement may be tried if the shock fails to terminate AF.
    • If AF terminates and restarts then antiarrhythmic drugs (ibutilide) can be administered and then cardioversion attempted again.
• AF of unknown duration or greater than 48 hours must not be cardioverted. Following two choices are useful in such situations:
  • Give anticoagulants for 3 weeks before then cardiovert and then continue anticoagulants for at least 4 weeks after.
  • Perform transesophageal echocardiogram to detect a thrombus in the left atrial appendage. Cardiovert if there is no thrombus. Administer anticoagulants for at least 4 weeks after the cardioversion.
• Some patients may need continuous anticoagulation therapy instead of stopping after 4 weeks of cardioversion.

Medical Management

• Oral anticoagulants:
  • Vitamin K inhibitors.
  • Newer anticoagulants like:
    • Thrombin inhibitors (dabigatran.)
    • Factor Xa inhibitors (rivaroxaban, apixaban.)
  • Older anticoagulants like Warfarin are less used nowadays.
  • Immediate administration with Heparin is useful. This should give enough window of time to decide other therapies.
• Antiplatelet (Aspirin, Clopidogrel) have not shown efficacy for AF patients.
• Rate control:
  • Beta blockers.
  • Ca++ channel blockers. (Diltiazem, Verapamil.)
  • Na+/K+ ATPase inhibitor (Digoxin.) Especially when AV nodal blocking agent cannot be used.
• Rhythm Control (antiarrhythmic):
  • Class I
  • Class III

Anticoagulants/Stroke Prevention

• CHA2DS2-VASc score. (Indication of anticoagulants at a score of 2 or greater.)
  • Clinical Features:
    • CHF/LV Dysfunction: 1
    • HTN: 1
    • DM: 1
    • History of stroke, TIA or thromboembolism: 2
    • Vascular pathologies. History of MI, aortic atherosclerosis, PVD: 1
  • Age:
    • 65-74: 1
    • >= 75: 2
  • Sex:
    • Male: 0
    • Female: 1
• You can skip anticoagulants and antiplatelet, or administer Aspirin for a score of 0.
• Anticoagulants are administered at a score of 2 or higher, or to patients with prior history of stroke.
  • Anticoagulant may be considered even at a score of 1.
• Patients with rheumatic mitral stenosis or mechanical heart valves must receive vitamin K antagonists (Warfarin).
• Patients who have previously not received newer anticoagulants (Thrombin blocker and Factor Xa blockers) must get vitamin K antagonists as well.
• Keep in mind that 1% of the patients get intracranial hemorrhage or major bleeding that requires transfusion of fresh frozen plasma and vitamin K. (Monitoring is very important especially with the older anticoagulants.)
• Risk factors for bleeding are age >65-75 y, heart failure, anemia, excessive alcohol consumption, NSAID drugs usage, coronary stent patients on aspirin and a thienopyridine.
• Warfarin is superior to antiplatelet therapy.
  • It takes several days to achieve PT time/INR of greater than 2. Monitoring is needed. Hence newer anticoagulants are favored.
• Newer anticoagulants (dabigatran, rivaroxaban, and apixaban):
  • Shown marginal superiority over Warfarin (0.4%-0.7%.)
  • Promptly achieve the anticoagulant effect. Don’t need much dosage adjustment.
  • These are excreted by kidneys, hence severe renal failure patients cannot use these. Dose adjustment needed for modest renal failure.
  • •P-glycoprotein inducers and inhibitors also influence the excretion.
• Approach to the patient with paroxysmal AF and persistent AF is the same.
• Warfarin can be reversed by administering fresh frozen plasma and vitamin K.
• Reversing agents for the newer anticoagulants are lacking. However, they are excreted within 12 hours.
• Antiplatelet agents (aspirin, clopidogrel) are inferior to warfarin for stroke prevention in AF. Clopidogrel with aspirin is better than aspirin alone but have greater bleeding risk than aspirin alone.
• Chronic anticoagulants are contraindicated with patients with bleeding risks. In such patients, surgical removal of the left atrial appendage or catheter ablation is indicated.

Chronic Rate Control

• Usual goal is resting heart rate of <80 bpm and <100 bpm with light exertion (walking).
  • Note: if rate control is difficult then up to 110 bpm resting heart rate is acceptable provided symptoms are tolerable and ventricular function is normal.
• Rate control is important to alleviate symptoms and prevent ventricular damage due to chronic tachycardia.
• Rate control is important to also reduce the pace of or to prevent cardiac remodeling.
• Beta blockers, calcium channel blockers, and digoxin are used. Sometimes in combination.
• Rate control is incorrect if the patient experiences exertion related symptoms.
• If rate control fails with medications then catheter ablation is indicated. Sometimes AV Junction is ablated with a pace maker to manage ventricular rate. Sometimes there may be dyssynchronous ventricular rate for which biventricular pacing will be indicated.

Rhythm Control

• Rhythm control strategy includes the decision to administer antiarrhythmic or catheter ablation.
• Patient’s preference in light of risk and benefits is the guiding principle.
• Usually, the strategy is selected for following patients:
  • Symptomatic paroxysmal AF.
  • First episode of symptomatic persistent AF.
  • AF with difficult rate control i.e. patients that have structural changes.
  • AF compromising ventricular function.
  • AF aggravating heart failure.
• AV-nodal blocking agents are used.
• B-Adrenergic blockers and calcium channel blockers are used.
• These drugs help maintain sinus rhythm, improve symptoms, and have a low-risk profile. These drugs, however, have low efficacy to prevent AF episodes.
• Class I Na+ channel blockers (flecainide, propafenone, disopyramide) can be used if there is no significant structural heart change.
  • These have negative inotropic and proarrhythmic effect. Cannot be used in patients with coronary artery disease or patients with heart failure.
• Class III (sotalol and dofetilide) can be given to the patients with coronary artery disease.
  • 3% patients can develop prolonged QT and induce torsades des pointes.
  • Dofetilide should only be administered in a hospital with ECG monitors. Many physicians take the same approach with sotalol.
  • Amiodarone maintains sinus rhythm better in two-thirds of the patients.
    • It is also used after the open heart surgery to prevent a sudden onset of AF. 2g given over 2 days.
    • p-glycoprotein inhibitor.
    • Contraindicated in patients with heart block or SA node dysfunction. (Due to its class IV like behavior.)

Surgical Approach

• In patients with long standing AF (usually > 1 year) enough structural changes occur to the atrial tissue that reentrant circuits become permanent. In such patients, cardioversion will fail. If patient’s symptoms are disrupting their quality of life with permanent reentry circuits then catheter ablation is used.
• Catheter ablation can be done in two ways:
  • Usually, the tissue around the pulmonary veins is ablated trapping the reentrant signals in these areas.
  • If the restructuring is extensive, then a maze like path is formed in the atrial tissue that guides the impulse travel and prevents re-entry.
• In rare cases, catheter ablation can cause cardiac tamponade, stroke, esophageal injury, SA node injury requiring a pacemaker, and death.

Disclaimer

• All information contained in and produced by the drbeen corp., is provided for educational purposes only. This information should not be used for the diagnosis or treatment of any health problem or disease.
• THIS INFORMATION IS NOT INTENDED TO REPLACE CLINICAL JUDGMENT OR GUIDE INDIVIDUAL PATIENT CARE IN ANY MANNER.

Dr. Mobeen discusses following topics in the context of multifocal atrial tachycardia.

• Terms and definition of abnormal rate
• Definition of MAT
• Causes of MAT
• EKG representation
• Diagnostic criteria
• Pathological mechanisms behind the causative factors
• Treatment

Abnormal Impulse Terms

• Automaticity

  • Change in the heart rate driven by the pacemaker cells.

  • Sinus Tachycardia
  • Sinus Bradycardia
  • Sick sinus syndrome (alternating sinus tachycardia and sinus bradycardia.)

• Drivers

  • Non-nodal cardiac tissue that incorrectly starts to generate new impulses without the need to be triggered by another impulse. These ectopic foci are called drivers instead of pacemakers.

• Reentry

  • Entrapment of an impulse originated somewhere else in a reentrant circuit.
  • As the impulse cycles in this reentrant circuit, it sends new impulses to the neighboring cells.

• Triggered activity

  • An impulse giving rise to further impulses due to the abnormal state of myocardial cells.
  • Note: these cells in the abnormal state cannot produce a new impulse on their own, they need an impulse acting as a trigger.
  • Drugs that prolong action potential duration (APD), e.g. class III antiarrhythmic, can cause triggered activity.
  • This triggered activity is called afterdepolarization (AD). It is of two types.
    • Early Atrial Depolarization (AED). Caused by slow activation and prolonged action potential.
    • Delayed afterdepolarization (DAD). Caused by the Ca++ overload.

MAT

(A type of Supraventricular Tachycardia)

• Irregular rhythm occurring at the rate of 100 to 200 bpm.
  • The rate can be less than 100 bpm somtimes. In such cases, the arrhythmia is called wandering atrial pacemaker (WAP) or multifocal atrial rhythm.
  • Wandering atrial pacemaker can be detected in healthy individuals too.
  • If the rate is lesser than or equal to 60 then the term is multifocal atrial bradycardia.
• MAT occurrs due to the random firing of several different atrial foci.
• Common in patients with severe lung disease.
  • Older people with the chronic obstructive pulmonary disease (COPD,) and hypoxia.
  • Theophylline toxicity can also cause MAT. (Given in COPD.)
• MAT can occur with myocardial infarction.
• Low blood magnesium levels1 (<1.5 mg/dl) can lead to MAT.
  • Diuretics can cause hypomagnesemia.
  • Mg acts similar to Ca++ channel blockers.
  • Mg depletion reduces Na+/K+ pump action, leading to intracellular K+ depletion.
• Hypokalemia can lead to MAT. (<3.5 mg/dl or severe hypokalemia <2.5 mg/dl.)
• Rarely, digitalis toxicity in patients with heart disease can cause MAT.
• Treatment is usually not needed other than fixing the underlying disease.
  • Carotid massage has no effect as the rate is not originating from a pacemaker.

Clinical Presentation

• Patients are often asymptomatic.
• Exacerbated underlying disease symptoms may be present.
  • Shortness of breath, wheezing, productive cough, or the symptoms of acute metabolic derangement.
• Irregular heart rate/pulse.
• Heart rate > 100 bpm.
• Can worsen the systemic oxygenation in patients with advanced COPD.
• Can worsen the cardiovascular dynamics in patients with coronary artery disease or heart failure.
  • Signs and symptoms of exacerbated heart disease may be observed e.g. angina, dyspnea, and orthopnea.

MAT’s Diagnostic Criteria

• As the P waves appear from many different sites in the atria. The shapes of the P waves vary.
• For diagnosing MAT:
  • One must find three morphologies (shapes) of the P waves.
  • Note: one shape of a P wave can appear for a few beats before another shape of the P wave appears.
  • P waves must be separated by isoelectric lines.
  • Varying PR intervals, R-R intervals duration, and R-R intervals are observed.
• QRS complexes are of narrow type (no problem in the ventricle.)
  • Unless there are ventricular conduction pathologies present too.
• MAT is observed in about 3 patients out of every 1000 hospitalized adults.

EKG Presentation

(Credit: By Jer5150 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20243829)

Note the varying shapes of the p waves in the v6 rhythm lead at the bottom of this EKG image. You have to find at least three different shapes of p waves.

Difference of MAT and Atrial Fibrillation

• MAT usually has easily identifiable P waves before the QRS complex.
• There are clear isoelectric intervals between the P waves. Atrial fibrillation either does not have easily discernable P waves, or the P waves appear on the EKG with a higher frequency than the QRS complexes without isoelectric intervals between them.
• In atrial fibrillation, there is no discernible association between the P waves and the QRS complexes.
• In MAT PR intervals vary in size. Depends on the distance of the impulse origin from the AV node.

Chronic obstructive pulmonary disease (COPD) and MAT

• Hypoxia causes cell depolarization.
  • Na+/K+ pump function decreases due to the lack of ATP.
    • Reduced levels of hyperpolarizing currents.
    • Reduced pump activity leads to increased extracellular K+ levels. Which initially cause hyperpolarization but then cause depolarization because of increase extracellular K+ concentration.
  • Reduced ATP also slows down Na+ channels which causes action potential duration (APD) to become variable.
• Hypoxia affects the L-type Ca++ channel’s function.
  • These channels are important for the plateau phase of the cardiac action potential.
  • Disturbance in these L-type Ca++ channel function can result in life threatening arrhythmia. This happens as some cells end up with longer action potential duration and some with shorter durations. (An abnormal function of the L-type Ca++ channels.)
• In patients of severe COPD hypercapnia causes vasodilatation.
  • This, in turn, causes low blood pressure and the release of norepinephrine. Elevated levels of norepinephrine can cause arrhythmia.
    • APD shortening, resting membrane potential hyperpolarization, development of early afterdepolarizations cause arrhythmias.
    • https://books.google.com.pk/books?id=moq9BAAAQBAJ&pg=PA46&lpg=PA46&dq=mechanism+adrenaline+induced+arrhythmia&source=bl&ots=dQG2U-1x2L&sig=L4639d7lmGbSVsAVjq6MFDelo-w&hl=en&sa=X&ved=0ahUKEwiVyKad3rrVAhVKvI8KHfEcCb44ChDoAQgpMAI#v=onepage&q=mechanism%20adrenaline%20induced%20arrhythmia&f=false
  • Norepinephrine acts on beta receptors and triggers cAMP dependent PK-A. PK-A, in turn, acts on the L-type Ca++ channels in the cell membrane to increase Ca++ influx. PK-A also acts on the sarcoplasmic reticulum to release Ca++. Both of these effects increase the cardiac cell contractility. (In the heart the action is predominantly via beta 1 receptors.)
  • Norepinephrine also increases heart rate by its action on the Ca++ channels in the nodal tissue.

Treatment of the multifocal atrial tachycardia (MAT)

• Treat the underlying cause.
• Electrical cardioversion has no effect.
• Carotid massage has no effect.
• The following therapy can be applied (if the tachycardia due to MAT is causing hemodynamic issues.)
  • Ca++ channel blockers (verapamil.)
    • Verapamil is negatively inotropic and a vasodilator. It can cause severe hypotension in patients with heart failure. Use with caution.
  • Beta blockers (metoprolol.)
    • Patients with severe lung disease often cannot tolerate beta blockers.
  • Verapamil and beta blockers should not be given to patients with sinus node dysfunction or existing second or third-degree block without a pacemaker.
  • In patients with pulmonary disease start with calcium channel blockers. Use beta blockers with lots of care.
  • In patients who do not have pulmonary disease, you can start with beta blockers.
  • Amiodarone is effective but dangerous.
    • Long-term therapy with amiodarone is avoided due to its toxicity, especially pulmonary fibrosis.
  • Oxygen
  • Simultaneously correct magnesium and potassium levels.
  • Radiofrequency ablation of the AV node with a pacemaker installation is indicated in patients who are not responding to the drug therapy or who cannot tolerate drug therapy.

Disclaimer

• All information contained in and produced by the drbeen corp., is provided for educational purposes only. This information should not be used for the diagnosis or treatment of any health problem or disease.
• THIS INFORMATION IS NOT INTENDED TO REPLACE CLINICAL JUDGMENT OR GUIDE INDIVIDUAL PATIENT CARE IN ANY MANNER.

Notes on Paroxysmal Atrial Tachycardia (PAT)/Focal Atrial Tachycardia (Focal AT.)

Focal atrial tachycardia is caused by enhanced automaticity or re-entrant circuits giving rise to a flutter like atrial and consequently ventricular tachycardia.

Dr. Mobeen discusses:

• Properties of the focal atrial tachycardia (Focal AT.)
• Different terms used in this class of disorders e.g. focal atrial tachycardia, paroxysmal atrial tachycardia, atypical atrial flutter, etc.
• Causes of Focal AT.
• Pathophysiology of Focal AT.
• Clinical presentation.
• EKG representation.
• Medical and surgical treatment.

Abnormal Impulse Terms1

• Automaticity

  • Normal Enhanced Automaticity:
    • Change in the heart rate driven by the pacemaker cells.
    • Sinus Tachycardia
    • Sinus Bradycardia
    • Sick sinus syndrome (alternating sinus tachycardia and sinus bradycardia.)
  • Abnormal Enhanced Automaticity:
    • An increased pacemaker like activity of cardiac myocytes and Purkinje cells.

• Drivers

  • Non-nodal cardiac tissue that incorrectly starts to generate new impulses without the need to be triggered by another impulse (become automatic.) These ectopic foci are called drivers instead of pacemakers.

• Reentry

  • Entrapment of an impulse, that originated somewhere else, in a reentrant circuit.
  • As the impulse cycles in this reentrant circuit, it sends new impulses to the neighboring cells.

• Triggered activity

  • An impulse giving rise to further impulses due to the abnormal state of myocardial cells.
  • Note: these cells in the abnormal state cannot produce a new impulse on their own, they need an impulse acting as a trigger.
  • Drugs that prolong action potential duration (APD), e.g. class III antiarrhythmic, can cause triggered activity.
  • This triggered activity is called afterdepolarization (AD). It is of two types.
    • Early Atrial Depolarization (AED). Caused by slow activation and prolonged action potential.
    • Delayed afterdepolarization (DAD). Caused by the Ca++ overload.

1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823581/

https://www.uptodate.com/contents/enhanced-cardiac-automaticity

Paroxysmal Atrial Tachycardia (PAT) Characteristics

A type of Supraventricular Tachycardia

• Regular rhythm.
• Rate from 100 to 200 beats per minute (bpm).
• Usually, lasts for seconds or minutes. It can terminate and restart spontaneously. (It can become paroxysmal sustained tachycardia.)
• Incessant atrial tachycardia (incessant AT) is a term used when a patient has atrial tachycardia during the 90% of the monitoring time.
• The arrhythmia occurs due to the following abnormal impulses:
  • Enhanced automaticity of an ectopic atrial focus.
  • A reentrant circuit within atria.
  • Enhanced automaticity type may have a warm up and cool down period.
  • Reentrant form starts and stops abruptly as an atrial premature beat/contraction (PAC.) This is also called atypical atrial flutter.
• Normal healthy individuals of all ages can experience PAT.
• Digitalis toxicity can also cause PAT.

Causes of PAT/Focal AT

• Atrial stretch in patients with heart diseases. (Hypertension and cardiomyopathies.)
• Acute:
  • Myocardial infarction.
  • Pulmonary decompensation.
  • Infections.
  • Excessive alcohol ingestion.
  • Hypokalemia.
  • Hypoxia.
  • Stimulants.
  • Cocaine.
  • Theophylline.
• More commonly it occurs in healthy individuals and is benign.
• AT incidence is higher in patients that have undergone catheter ablation for atrial fibrillation.
• Digitalis toxicity causes AT as well due to increased central sympathetic outflow.

Site of Abnormal Focus

• The right atrium is involved in 63% of the cases and 37% involve the left atrium.
• Right atrium:
  • 35% tricuspid annulus.
  • 34% crista terminalis.
  • 17% coronary sinus ostium.
  • 9% perinodal tissue.
  • 4% RA appendage/auricle.
• Left atrium:
  • 67% pulmonary veins.
  • 17% mitral annulus.
  • 6% coronary sinus body.
  • 6% left intraatrial septum.
  • 4% LA appendage/auricle.

Clinical Presentation

• Palpitations during the episodes/runs.
• Rapid fluttering sensation in the chest or neck usually is associated with focal AT/PAT.
• Patients can, rarely, present with syncope. This usually occurs when the ventricular rate is 200 beats per minute or above.
• Symptoms of other cardiac comorbidities e.g. heart failure, angina may become exacerbated. (Dyspnea, chest pain, etc.)

PAT’s Diagnostic Criteria

• Heart rate greater 100 beats per minute.
• Driver/focus other than the SA node. (P wave morphology is different.)
• Sudden in onset and offset.
• An isoelectric interval between p waves.

EKG Presentation

• Heart rate greater 100 beats per minute.
• Driver/focus other than the SA node. (P wave morphology is different.)
• As the arrhythmia is focal (from a single point of origin) and sustained. EKG displays p waves that can have morphology from normal to abnormal. P wave morphology, however, will be consistent.
• The cycle length of tachycardia is variable.
• Warm up and cool down phases are short (a few beats.) Sinus tachycardia takes 30 seconds to minutes to warm up or cool down.
• Intermittent AV blocks may occur. These blocks, however, do not affect the PAT’s runs.
• The Same focal driver can erratically fire between runs, adding atrial ectopic p waves. These p waves will have the same morphology to the p waves during the PAT’s runs.

Mapping the origin of the focus

• An elaborate algorithm that predicted the arrhythmogenic focus in 93% of the patients has been devised.
• V1 is important:
  • Generally, a positive p wave or biphasic p wave with positive first is an indicator of the focus in the right atrium ( the majority of the cases.)
  • A negative p wave or biphasic p wave with the negative phase first is an indicator of the focus in the left atrium.
• Careful inspection of the p waves in the other leads can help locate the origin in possibly one of the following locations:
  • Coronary sinus, crista terminalis, right atrial appendage.
  • Interatrial septum.
  • Pulmonary veins, left atrial appendage.
• Locating the focus is important for the surgical ablation.

EKG Image

Photo credit: <a href="http://classconnection.s3.amazonaws.com/669/flashcards/3543669/jpg/proxymal_atrial_(supraventricular)_tachycardia-143E45A5E157FA1E468.jpg">Amazonaws.com</a>

PAT and PSVT

• Usually one cannot tell the difference between the focal atrial tachycardia (paroxysmal atrial tachycardia) and paroxysmal supraventricular tachycardia.
• Warm up and cool down rhythms are unique to PAT if present.
• Carotid massage does not affect PAT.
• PSVT can slow down or terminate with carotid massage.

Treatment of PAT

Consistent with 2015 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS)

• Acute

  • Rate, symptoms and hemodynamic status guides the acute treatment.
  • Treat the precipitating causes:
  • Administer potassium to hypokalemic patients.
  • If digitalis toxicity is suspected then discontinue digitalis and administer anti-digitalis antibodies if the hemodynamic status or other arrhythmias are life-threatening.
  • The vagal maneuver can be performed by the patient, or administer intravenous adenosine. (Both of these are usually less effective.)
  • IV beta blockers or nondihydropyridine Ca++ channel blockers (verapamil, diltiazem) can be given to hemodynamically stable patients.
  • IV Amiodarone can be better than the beta blockers, and verapamil and diltiazem.
  • Amiodarone can control acute tachycardia, terminate arrhythmia, and cause less hypotension.
  • Cardioversion may be tried but it is usually less effective for the following reasons:
  • Underlying pathology causing the arrhythmia may continue to trigger arrhythmias.
  • Enhanced automaticity of non-nodal tissue usually does not respond to cardioversion.
  • Hemodynamically unstable patients who fail to respond to above therapies may respond to chemical cardioversion with Amiodarone.

• Chronic suppressive or prophylactic

  • Patients with few or no symptoms and rare/brief spells of arrhythmia may not need chronic treatment.
  • Patients that do not respond to medical therapy or have been on drugs for a long time may need catheter ablation.
  • Patients that do not want catheter ablation may need amiodarone, or class Ic (flecainide, propafenone), or class III (sotalol) antiarrhythmic. Which drug to use should be consulted with a cardiologist experienced with arrhythmia management.
  • If catheter ablation also fails then cardiac pacemaker with AV nodal ablation may be considered.

• Treatment of incessant AT

  • Aggressive management to restore normal sinus rhythm should be made.
  • Beta blockers
  • Class Ic drugs (flecainide).
  • Usually, patients with incessant AT and LV systolic dysfunction that are not responding to medical therapy will need to undergo catheter ablation.

Drbeen Corp Disclaimer

• All information contained in and produced by the drbeen corp., is provided for educational purposes only. This information should not be used for the diagnosis or treatment of any health problem or disease.
• THIS INFORMATION IS NOT INTENDED TO REPLACE CLINICAL JUDGMENT OR GUIDE INDIVIDUAL PATIENT CARE IN ANY MANNER.

Let us continue with the EKG interpretation series. 

This lecture discusses the premature ventricular contractions (PVCs.) PVCs can be benign or malignant. 

History and lifestyle are essential considerations while working up PVCs. The patient usually contacts their provider because of the palpitations. They also may have issues sleeping correctly or sleeping on one side of their body etc.

In this lecture, we will go over the signs, symptoms, pathophysiology, EKG changes, diagnostic criteria, and clinical and surgical management of the PVCs.

In this lecture we will discuss Ventricular Tachycardia, also known as V-Tach.
V-Tach is defined as rapid and repetitive firing of 3 or more PVCs in a row, with a rate of 100-250 beats per minute, originating in the ventricles of the heart. 

Ventricular Fibrillation is a terminal event for a dying heart. This talk discusses the:

• Primary pathophysiology
• Signs and symptoms
• EKG changes
• Management approach
• Potential outcomes

In this lecture, we will discuss accelerated Idioventricular Rhythm. Accelerated Idioventricular Rhythm is also known as “Slow Ventricular Tachycardia”. AIVR is an increased ventricular rhythm that has at least 3 consecutive ventricular beats with a rate between 50 and 100 beats per minute.

Keep in mind that the AIVR differs from the following rhythm abnormalities. 

• Ventricular escape rhythm is a self-generated electrical discharge originating in the ventricles and causing their contraction. This is a protective response that occurs in the absence of impulses (e.g. during a third degree heart block when both the SA node and AV node are firing at a rate lower than that of the ventricle.) This occurs almost 2-3 seconds after an electrical impulse has failed to reach the ventricles. The heart rate is less than 40 beats per minute. Since it is a phenomena that prevents cardiac arrest from occurring, its management involves correcting the rhythm, not getting rid of it.

• Ventricular tachycardia, which is a heart rate greater than 120 beats per minute.

• Remember that both the ventricular escape and ventricular tachycardia are not AIVR 

AIVR affects only the ventricles, and is considered an ectopic arrhythmia.

It is usually regarded as a benign, self-limiting arrhythmia, therefore, it does not require treatment.

Watch the video to continue learning more ...

Dr. Syed discusses the EKG leads and normal waveform. {article:https://articles.drbeen.com/2016/05/22/electrocardiogram-clinical-review/}

General principles of the CVS Organization Heart as two pumps Series and parallel circuits Chemical composition of the venous and arterial blood Blood flow direction Various pressures in the CVS.

STUDY NOTES:

GENERAL PRINCIPLES OF CARDIOVASCULAR PHYSIOLOGY

ORGANIZATION OF THE CVS

HEART AS 2 PUMPS: The human heart has 4 chambers which are the two atria and the two ventricles. These 4 chambers are divided into 2 functional units referred to as the left heart and the right heart. These atria and ventricle in a single functional unit are separated by the atrioventricular valves. These AV valves are one way valves and allow blood flow in the forward direction only.

Right heart is formed by the right atrium and the right ventricle, and it forms one functional unit. The right atrium receives the venous deoxygenated blood from three sources, namely:

1) Superior vena cava: brings deoxygenated blood from the head, neck and upper limb region

2) Inferior vena cava: brings deoxygenated blood from the lower extremities, the abdominal region and the rest of the body except the heart itself.

3) Coronary sinus: brings deoxygenated blood from the veins of the heart itself.

During diastole when the atria contract, this deoxygenated blood is pumped into the right ventricle. During systole, the right ventricle pumps this deoxygenated blood out of the heart and into the pulmonary circuit via the pulmonary artery*. The right heart plus the pulmonary arteries, capillaries and veins together form the pulmonary circulation. The right side of the heart deals with deoxygenated blood only and it functions to send this deoxygenated blood to the pulmonary circulation to get oxygenated.

Left heart forms another functional unit and consists of the left atrium and left ventricle. The left atrium receives oxygenated blood from the pulmonary circuit via the 4 pulmonary veins*(two from each lung). When the atria contract, the left atrium pumps this oxygenated blood into the left ventricle. During systole, this oxygenated blood is pumped out of the heart via aorta, when the left ventricle contracts. The aorta then carries this oxygenated blood intothe systemic circulation. The left heart plus the systemic arteries (starting at the aorta), capillaries and veins together form the systemic circulation. For simplicity, it can be assumed that the left heart deals with the oxygenated blood and sends it to the systemic circulation via the aorta. 

NOTE: Arteries conduct blood away from the heart towards the tissues. Arteries normally carry oxygenated blood away from the heart, but an exception to this rule are the pulmonary arteries and the umbilical arteries(during fetal life only) which carry deoxygenated blood away from the heart and toward the lungs & placenta respectively. Veins normally carry deoxygenated blood, except the pulmonary veins in adults and the umbilical vein (during fetal life only) which bring back oxygenated blood to the heart from the lungs and the placenta respectively.

SYSTEMIC TISSUES:

As part of the systemic perfusion, the oxygenated blood in the aorta is eventually transported to the following 6 major systemic tissues. These systemic tissues receive blood via a parallel system of arteries which originate at various levels from the aorta itself.

1) Cerebral: The CNS plus the head & neck region. 15% of the cardiac output enters the cerebral arteries.

2) Coronary: The myocardium itself which receives oxygenated blood during diastole in contrast to the rest of the body which receives oxygenated blood as part of systole. 5% of the total cardiac output is designated for the myocardial perfusion via the kidneys.

3) Splanchnic: The gastrointestinal system and its accessory organs such as the liver, spleen, pancreas and the biliary system. 25% of the total cardiac output reaches the GIT system via the splanchnic arteries.

4) Renal: The kidneys and the genitourinary system. Kidneys, as part of the renal system, receive 25% of the total cardiac output.

5) Skeletal: Roughly 25% of the total cardiac output is reaches the skeletal system. Exercise increases the percentage of cardiac output which is made available for the skeletal system. Bones and the musculature of the body form part of this system.

6) Cutaneous: The skin and its associated structures (sebaceous glands, hair follicles). Around 5% of the total cardiac output reaches the cutaneous circulation. 

BLOOD FLOW DIRECTION & THE CHEMICAL COMPOSITION OF THE VENOUS & ARTERIAL BLOOD:

There are 4 pulmonary veins which bring back oxygenated blood from the lungs to left atrium. This blood is rich in oxygen (PaO2=100 mm Hg) and low in carbon dioxide(PaCO2=40 mm Hg). The mitral valve which forms the left atrioventricular valve, allows passage of blood from the left atrium into the left ventricle during the diastole phase. When the left ventricle begins to contract and its pressure rises more than the left atrial pressure, the mitral valve closes to prevent backflow of the blood. This ensures anterograde flow of blood in to the aorta i.e., the forward direction of blood flow. Backflow from the aorta back into the left atrium is prevented by the semilunar aortic valve. It's important to remember that all the valves of the heart are tricuspid i.e., having three cusps, except the mitral valve which is bicuspid i.e., having two cusps. However, only the right atrioventricular valve is referred to as the tricuspid valve. 

From the aorta, the blood is transported to the systemic tissues which are mentioned above. The aorta divides into large and medium sized arteries, which eventually give arise the arterioles. The arterioles continue to form capillaries, and these capillaries merge together to form venules at their venous ends. The venules eventually end up forming the veins. The veins are low pressure vessels which return the deoxygenated blood back to the right heart via the three above mentioned sources of venous return to the heart. This deoxygenated blood is low in oxygen (40 mm Hg) and rich in carbon dioxide (47 mm Hg). The right atrioventricular valve, which is also referred to as the tricuspid valve, allows this deoxygenated blood to flow from the right atrium into the right ventricle. During ventricular systole when the leftventricle contracts, this deoxygenated blood is pumped out ofthe right side of the heart via the pulmonary artery. The backflow of this deoxygenated blood into the right side of the heart during ventricular diastole is prevented by the semilunar pulmonary valve. This deoxygenated blood reaches the lungs and enters the pulmonary circuit to get oxygenated At this point the blood completes its route both around the pulmonary and systemic circuits.  

SERIES & PARALLEL CIRCUITS

The right and left sides of the heart are connected in a series circuit to both the pulmonary and systemic tissues respectively. By series circuit, what's meant here is that quantitatively, the blood flow through the lungs is equal to the blood flow through the rest of the body. For simplicity in understanding, it should be considered that the lungs are connected to the rest of the body in a series circuit. During a single cardiac cycle, the right and left ventricular outputs are the same. 

However, the blood supply of the systemic tissues is connected in a parallel circuit. This means that each organ system is supplied by an artery which originates as a branch of the aorta. This ensures that the blood which reaches a particular organ system is perfused at the same partial pressure of oxygen, as that of the site at which the branch originated from the aorta. If the organ systems were connected and perfused via a series circuit, by the time the blood reached the last organ system, it would have been completely depleted of oxygen and nutrients. The sum of blood flow to these individual systems adds up to the total left ventricular output (the cardiac output). 

VARIOUS PRESSURES IN THE CVS

• SYSTOLIC BLOOD PRESSURE (SBP): Systole is time interval when the ventricles are contracting. Systolic BP therefore is the pressure in the systemic arteries when the left ventricle is contracting. Therefore, SBP is the highest blood pressure in the systemic arteries during a cardiac cycle.

Average SBP in healthy adults is 120 mm of Hg.

• DIASTOLIC BLOOD PRESSURE (DBP): Diastole is the time interval when the ventricles are relaxing and therefore receiving blood from the atria. Diastolic BP is the pressure in the systemic arteries when the left ventricle is relaxing. DBP therefore is the lowest pressure in systemic arteries during a cardiac cycle. Average DBP in healthy adults is 80 mm of Hg.

• PULSE PRESSURE (PP): This is the difference between the systolic blood pressure and the diastolic blood pressure in the systemic arteries at any given time. Pulse pressure can therefore be calculated as following:

➢ Pulse pressure, PP = Difference between the systolic & diastolic blood pressures.

              PP= SBP- DBP

              PP = 120-80= 40 mm of Hg

Variations in pulse pressure can be in anaemia, fever, blood loss etc. Narrow pulse pressure can be seen when there is blood loss, aortic regurgitation. Pulse pressure widens during exercise.

• MEAN ARTERIAL PRESSURE: MAP is the average arterial pressure of the systemic arteries. However, quantitatively it's not an arithmetic mean of the SBP & DBP. Since the ventricular muscle spends 2/3 of the time of a cardiac cycle in diastole, the MAP is closer to the DBP, than it's to the SBP. 

MAP signifies the perfusion pressure of the tissues. If the MAP of the patient decreases below 60 mm of Hg, then it should be a cause of concern for the doctor. What this signifies is that a perfusion pressure below 60 mm of Hg would not be able to meet the nutritional needs of the systemic tissues. So, the MAP, which is easier to calculate quantitatively, can be used in lieu of systemic perfusion pressure.

➢ MAP = (CO x SVR) + CVP {CVP is negligible, so it can be ignored}

So, MAP = (CO X SVR) 

SVR is the sum of resistance of all the vessels in the systemic circuit. However, the major component of systemic vascular resistance is the arteriolar resistance.

Also, MAP can be calculated by using the following formula if the SBP and DBP are known:

➢ MAP = DBP + 1/3 (SBP - DBP) 

{For a normal healthy adult, DBP = 120 & SBP = 80}

So, MAP = 80 + 1/3 (120 - 80)

      MAP = 80 + 1/3 (40)

      MAP = 80 + 13.33

      MAP = 93 mm of Hg (After rounding off)

Alternatively MAP can also be calculated by the following formula:

➢ MAP= 2/3 DBP + 1/3 SBP

MAP= (2/3 x 80) + (1/3 x 120)

MAP= 53.33 + 40 = 93 mm of Hg

• PERFUSION PRESSURE: The pressure necessary to bring blood supply to the systemic tissues to ensure their nutritional needs.

Abbreviations:

• SBP= systolic blood pressure

• DBP=diastolic blood pressure

• MAP=mean arterial pressure

• PP= pulse pressure

• CO=cardiac output

• SVR=systemic vascular resistance

• CVP= central venous pressure

Heart as two pumps Series and parallel circuits Chemical composition of the venous and arterial blood Blood flow direction Various pressures in the CVS.

STUDY NOTES:

GENERAL PRINCIPLES OF CARDIOVASCULAR PHYSIOLOGY

ORGANIZATION OF THE CVS

HEART AS 2 PUMPS: The human heart has 4 chambers which are the two atria and the two ventricles. These 4 chambers are divided into 2 functional units referred to as the left heart and the right heart. These atria and ventricle in a single functional unit are separated by the atrioventricular valves. These AV valves are one way valves and allow blood flow in the forward direction only.

Right heart is formed by the right atrium and the right ventricle, and it forms one functional unit. The right atrium receives the venous deoxygenated blood from three sources, namely:

1) Superior vena cava: brings deoxygenated blood from the head, neck and upper limb region

2) Inferior vena cava: brings deoxygenated blood from the lower extremities, the abdominal region and the rest of the body except the heart itself.

3) Coronary sinus: brings deoxygenated blood from the veins of the heart itself.

During diastole when the atria contract, this deoxygenated blood is pumped into the right ventricle. During systole, the right ventricle pumps this deoxygenated blood out of the heart and into the pulmonary circuit via the pulmonary artery*. The right heart plus the pulmonary arteries, capillaries and veins together form the pulmonary circulation. The right side of the heart deals with deoxygenated blood only and it functions to send this deoxygenated blood to the pulmonary circulation to get oxygenated.

Left heart forms another functional unit and consists of the left atrium and left ventricle. The left atrium receives oxygenated blood from the pulmonary circuit via the 4 pulmonary veins*(two from each lung). When the atria contract, the left atrium pumps this oxygenated blood into the left ventricle. During systole, this oxygenated blood is pumped out of the heart via aorta, when the left ventricle contracts. The aorta then carries this oxygenated blood intothe systemic circulation. The left heart plus the systemic arteries (starting at the aorta), capillaries and veins together form the systemic circulation. For simplicity, it can be assumed that the left heart deals with the oxygenated blood and sends it to the systemic circulation via the aorta. 

NOTE: Arteries conduct blood away from the heart towards the tissues. Arteries normally carry oxygenated blood away from the heart, but an exception to this rule are the pulmonary arteries and the umbilical arteries(during fetal life only) which carry deoxygenated blood away from the heart and toward the lungs & placenta respectively. Veins normally carry deoxygenated blood, except the pulmonary veins in adults and the umbilical vein (during fetal life only) which bring back oxygenated blood to the heart from the lungs and the placenta respectively.

SYSTEMIC TISSUES:

As part of the systemic perfusion, the oxygenated blood in the aorta is eventually transported to the following 6 major systemic tissues. These systemic tissues receive blood via a parallel system of arteries which originate at various levels from the aorta itself.

1) Cerebral: The CNS plus the head & neck region. 15% of the cardiac output enters the cerebral arteries.

2) Coronary: The myocardium itself which receives oxygenated blood during diastole in contrast to the rest of the body which receives oxygenated blood as part of systole. 5% of the total cardiac output is designated for the myocardial perfusion via the kidneys.

3) Splanchnic: The gastrointestinal system and its accessory organs such as the liver, spleen, pancreas and the biliary system. 25% of the total cardiac output reaches the GIT system via the splanchnic arteries.

4) Renal: The kidneys and the genitourinary system. Kidneys, as part of the renal system, receive 25% of the total cardiac output.

5) Skeletal: Roughly 25% of the total cardiac output is reaches the skeletal system. Exercise increases the percentage of cardiac output which is made available for the skeletal system. Bones and the musculature of the body form part of this system.

6) Cutaneous: The skin and its associated structures (sebaceous glands, hair follicles). Around 5% of the total cardiac output reaches the cutaneous circulation. 

BLOOD FLOW DIRECTION & THE CHEMICAL COMPOSITION OF THE VENOUS & ARTERIAL BLOOD:

There are 4 pulmonary veins which bring back oxygenated blood from the lungs to left atrium. This blood is rich in oxygen (PaO2=100 mm Hg) and low in carbon dioxide(PaCO2=40 mm Hg). The mitral valve which forms the left atrioventricular valve, allows passage of blood from the left atrium into the left ventricle during the diastole phase. When the left ventricle begins to contract and its pressure rises more than the left atrial pressure, the mitral valve closes to prevent backflow of the blood. This ensures anterograde flow of blood in to the aorta i.e., the forward direction of blood flow. Backflow from the aorta back into the left atrium is prevented by the semilunar aortic valve. It's important to remember that all the valves of the heart are tricuspid i.e., having three cusps, except the mitral valve which is bicuspid i.e., having two cusps. However, only the right atrioventricular valve is referred to as the tricuspid valve. 

From the aorta, the blood is transported to the systemic tissues which are mentioned above. The aorta divides into large and medium sized arteries, which eventually give arise the arterioles. The arterioles continue to form capillaries, and these capillaries merge together to form venules at their venous ends. The venules eventually end up forming the veins. The veins are low pressure vessels which return the deoxygenated blood back to the right heart via the three above mentioned sources of venous return to the heart. This deoxygenated blood is low in oxygen (40 mm Hg) and rich in carbon dioxide (47 mm Hg). The right atrioventricular valve, which is also referred to as the tricuspid valve, allows this deoxygenated blood to flow from the right atrium into the right ventricle. During ventricular systole when the leftventricle contracts, this deoxygenated blood is pumped out ofthe right side of the heart via the pulmonary artery. The backflow of this deoxygenated blood into the right side of the heart during ventricular diastole is prevented by the semilunar pulmonary valve. This deoxygenated blood reaches the lungs and enters the pulmonary circuit to get oxygenated At this point the blood completes its route both around the pulmonary and systemic circuits.  

SERIES & PARALLEL CIRCUITS

The right and left sides of the heart are connected in a series circuit to both the pulmonary and systemic tissues respectively. By series circuit, what's meant here is that quantitatively, the blood flow through the lungs is equal to the blood flow through the rest of the body. For simplicity in understanding, it should be considered that the lungs are connected to the rest of the body in a series circuit. During a single cardiac cycle, the right and left ventricular outputs are the same. 

However, the blood supply of the systemic tissues is connected in a parallel circuit. This means that each organ system is supplied by an artery which originates as a branch of the aorta. This ensures that the blood which reaches a particular organ system is perfused at the same partial pressure of oxygen, as that of the site at which the branch originated from the aorta. If the organ systems were connected and perfused via a series circuit, by the time the blood reached the last organ system, it would have been completely depleted of oxygen and nutrients. The sum of blood flow to these individual systems adds up to the total left ventricular output (the cardiac output). 

VARIOUS PRESSURES IN THE CVS

• SYSTOLIC BLOOD PRESSURE (SBP): Systole is time interval when the ventricles are contracting. Systolic BP therefore is the pressure in the systemic arteries when the left ventricle is contracting. Therefore, SBP is the highest blood pressure in the systemic arteries during a cardiac cycle.

Average SBP in healthy adults is 120 mm of Hg.

• DIASTOLIC BLOOD PRESSURE (DBP): Diastole is the time interval when the ventricles are relaxing and therefore receiving blood from the atria. Diastolic BP is the pressure in the systemic arteries when the left ventricle is relaxing. DBP therefore is the lowest pressure in systemic arteries during a cardiac cycle. Average DBP in healthy adults is 80 mm of Hg.

• PULSE PRESSURE (PP): This is the difference between the systolic blood pressure and the diastolic blood pressure in the systemic arteries at any given time. Pulse pressure can therefore be calculated as following:

➢ Pulse pressure, PP = Difference between the systolic & diastolic blood pressures.

              PP= SBP- DBP

              PP = 120-80= 40 mm of Hg

Variations in pulse pressure can be in anaemia, fever, blood loss etc. Narrow pulse pressure can be seen when there is blood loss, aortic regurgitation. Pulse pressure widens during exercise.

• MEAN ARTERIAL PRESSURE: MAP is the average arterial pressure of the systemic arteries. However, quantitatively it's not an arithmetic mean of the SBP & DBP. Since the ventricular muscle spends 2/3 of the time of a cardiac cycle in diastole, the MAP is closer to the DBP, than it's to the SBP. 

MAP signifies the perfusion pressure of the tissues. If the MAP of the patient decreases below 60 mm of Hg, then it should be a cause of concern for the doctor. What this signifies is that a perfusion pressure below 60 mm of Hg would not be able to meet the nutritional needs of the systemic tissues. So, the MAP, which is easier to calculate quantitatively, can be used in lieu of systemic perfusion pressure.

➢ MAP = (CO x SVR) + CVP {CVP is negligible, so it can be ignored}

So, MAP = (CO X SVR) 

SVR is the sum of resistance of all the vessels in the systemic circuit. However, the major component of systemic vascular resistance is the arteriolar resistance.

Also, MAP can be calculated by using the following formula if the SBP and DBP are known:

➢ MAP = DBP + 1/3 (SBP - DBP) 

{For a normal healthy adult, DBP = 120 & SBP = 80}

So, MAP = 80 + 1/3 (120 - 80)

      MAP = 80 + 1/3 (40)

      MAP = 80 + 13.33

      MAP = 93 mm of Hg (After rounding off)

Alternatively MAP can also be calculated by the following formula:

➢ MAP= 2/3 DBP + 1/3 SBP

MAP= (2/3 x 80) + (1/3 x 120)

MAP= 53.33 + 40 = 93 mm of Hg

• PERFUSION PRESSURE: The pressure necessary to bring blood supply to the systemic tissues to ensure their nutritional needs.

Abbreviations:

• SBP= systolic blood pressure

• DBP=diastolic blood pressure

• MAP=mean arterial pressure

• PP= pulse pressure

• CO=cardiac output

• SVR=systemic vascular resistance

• CVP= central venous pressure

This video will present: Properties of the pulmonary vasculature. Division and the filtration function of the pulmonary vasculature. Metabolic functions of the pulmonary vasculature. Comparison of the pulmonary and systemic vasulatures. Change in the pressures with breathing and valsalva's manuver. Clinical points of the pulmonary vasculature.

STUDY NOTES:

PROPERTIES OF PULMONARY VASCULATURE

The heart pumps a volume of blood into the lungs which after getting oxygenated is transported back to heart. This oxygenated blood is then pumped out of the heart and into the aorta and subsequently into the systemic circulation. As a consequence, at any given time the lungs (pulmonary vasculature) contain around 500ml of blood, thereby allowing them to function as a reservoir of the blood. This reservoir volume is increased by another 500 ml when the person is in the supine or lying down position. This is because in supine position there's an increased venous return (due to the effect of gravity) to the right heart from the peripheries and therefore more blood accumulates in the central parts of body. Upon standing up, this extra 500ml of blood gets redistributed under the effect of gravity, to the now more dependent parts of the body which includes the peripheral tissues and the lower extremities.

The division of vasculature in the pulmonary circuit is somewhat different from that in the systemic circulation. The arteries in the pulmonary circuit divide in a binary fashion, thereby following the pattern of division of the airways. The veins too exhibit a pattern similar to the arterioles and the bronchioles, thereby finally converging into forming one large pulmonary vein. These pulmonary veins transport the oxygenated blood back to the heart.

Apart from the primary function of lungs to deliver oxygenated blood to the heart, it has several secondary functions as well:

1) Filtration: Pulmonary vascular bed acts as a filter for the blood received by the right side of the heart andbefore this blood leaves the left side of the heart to enter the systemic circulation. Blood arriving from the right side of the heart to the lungs may contain an embolus or a thrombus or any foreign particle that may result in obstruction of the vessels. The pulmonary artery divides into numerous small capillaries with diameters too small to allow passage of any dislodged particles into the pulmonary artery and subsequently in to the left side of the heart. Therefore, the pulmonary vascular bed acts as a filtration barrier that prevents introduction of any particles into the systemic circulation.

2) Metabolic Functions: The pulmonary vasculature also has some metabolic functions:

a) The endothelium of the pulmonary vessels is lined by fibrinolytic enzymes that cause lysis of the fibrin clots which get stuck in the pulmonary vasculature.

b) The pulmonary capillary endothelium is lined by another enzyme as well. This enzyme is called the Angiotensin Converting Enzyme (ACE). ACE functions to convert Angiotensin I to Angiotensin II. ACE is also present in the endothelium of other vascular beds and the plasma, however, the amount present in the pulmonary vascular bed is the highest.  ACE within the pulmonary vascular bed is responsible for more than 70% of the total conversion of Angiotensin I to Angiotensin II in the body.

This video will present: Velocity of the blood flow in aorta and smaller arteries. We will also look at the graphs that you might see in the USMLE tests. Formula to calculate the velocity.

PHYSIOLGY LECTURE # 3 STUDY NOTES

HEMODYNAMICS - BLOOD FLOW VELOCITY

The assumptions made in this lecture to understand the velocity of blood flow are as follows:

• 1 meter = 39.37 inches

• 1 millilitre = 1 cubic centimetre

• A cubic centimetre is diagrammed as a small cube which has all its lengths equal to 1 centimetre. Cardiac Output at rest: 5000mL

Let’s assume that the blood vessels are like cylinders and their cross section appear to be circular. Hence, the cross sectional area of a blood vessel is equal to the area of the circle. This can be calculated by the formula A=πr^2. Unit is cm2.

Velocity vs. Flow

Velocity is defined as the speed of blood in unit time. 

Flow is the amount of blood moving per unit time.

Velocity and Flow can be integrated in the same equation as per the following formula: 

​ 

Where:  V = velocity

              Q = Flow

              A = Cross sectional area of the vessel.

This shows that the velocity is inversely proportional to the cross sectional area and directly proportional to the flow of blood in the vessel. This principle is analogous to water pouring out of a water hose. Squeezing the outlet of the hose and making it narrower (decreasing the cross-sectional area) will cause the water to eject with higher than normal speed. 

The cross sectional area, of any part of the vasculature is taken as the sum of all the vessels at that level and not of a single vessel individually. Hence, the aorta which is a singlevessel, has the smallest cross sectional area of 2.5cm^2. On the other hand, the sum of cross-sectional areas of all the capillaries is calculated to be 3000cm^2.

The calibre of the blood vessels changes as the aorta divides into arteries, arterioles and capillaries during the process of transporting blood to the tissues. The change in vessel calibre is met with a subsequent change in the blood velocity. The aorta, with a cross sectional area of 2.5cm^2, has blood travelling at a velocity of 20m/min. By the time the blood reaches the capillaries, the velocity of blood drops to 1.6cm/min. This is because the cross sectional area of all the capillaries when summated becomes equal to 3000cm^2, a value which is 1000 folds greater than the cross sectional area of aorta. Following calculations can be used to calculate velocity of blood flowing through the aorta and the capillaries respectively: 

Velocity of the blood flow through Aorta:

➢ ​ 

= {ml and cm^3 can be substituted interchangeably}

=

= 2000 cm/min

= 20 m/min

= 33 cm/s

Velocity of the blood flow through the Capillaries:

➢ ​ 

=  {ml and cm^3 can be substituted interchangeably}

= 

= 1.6 cm/min

= 0.016 m/min

= 0.027 cm/s

To summarize, the aorta acts as a conducting vessel as it conducts blood at high velocity to the rest of the body. The capillaries on the other hand, need to contain the blood with minimal velocity which allows for efficient exchange of gases and transport of nutrients and waste products.

This video will present: Velocity of the blood flow in aorta and smaller arteries. We will also look at the graphs that you might see in the USMLE tests. Formula to calculate the velocity.

PHYSIOLGY LECTURE # 3 STUDY NOTES:

HEMODYNAMICS - BLOOD FLOW VELOCITY

The assumptions made in this lecture to understand the velocity of blood flow are as follows:

• 1 meter = 39.37 inches

• 1 millilitre = 1 cubic centimetre

• A cubic centimetre is diagrammed as a small cube which has all its lengths equal to 1 centimetre. Cardiac Output at rest: 5000mL

Let’s assume that the blood vessels are like cylinders and their cross section appear to be circular. Hence, the cross sectional area of a blood vessel is equal to the area of the circle. This can be calculated by the formula A=πr^2. Unit is cm2.

Velocity vs. Flow

Velocity is defined as the speed of blood in unit time. 

Flow is the amount of blood moving per unit time.

Velocity and Flow can be integrated in the same equation as per the following formula: 

​ 

Where:  V = velocity

              Q = Flow

              A = Cross sectional area of the vessel.

This shows that the velocity is inversely proportional to the cross sectional area and directly proportional to the flow of blood in the vessel. This principle is analogous to water pouring out of a water hose. Squeezing the outlet of the hose and making it narrower (decreasing the cross-sectional area) will cause the water to eject with higher than normal speed. 

The cross sectional area, of any part of the vasculature is taken as the sum of all the vessels at that level and not of a single vessel individually. Hence, the aorta which is a singlevessel, has the smallest cross sectional area of 2.5cm^2. On the other hand, the sum of cross-sectional areas of all the capillaries is calculated to be 3000cm^2.

The calibre of the blood vessels changes as the aorta divides into arteries, arterioles and capillaries during the process of transporting blood to the tissues. The change in vessel calibre is met with a subsequent change in the blood velocity. The aorta, with a cross sectional area of 2.5cm^2, has blood travelling at a velocity of 20m/min. By the time the blood reaches the capillaries, the velocity of blood drops to 1.6cm/min. This is because the cross sectional area of all the capillaries when summated becomes equal to 3000cm^2, a value which is 1000 folds greater than the cross sectional area of aorta. Following calculations can be used to calculate velocity of blood flowing through the aorta and the capillaries respectively: 

Velocity of the blood flow through Aorta:

➢ ​ 

= {ml and cm^3 can be substituted interchangeably}

=

= 2000 cm/min

= 20 m/min

= 33 cm/s

Velocity of the blood flow through the Capillaries:

➢ ​ 

=  {ml and cm^3 can be substituted interchangeably}

= 

= 1.6 cm/min

= 0.016 m/min

= 0.027 cm/s

To summarize, the aorta acts as a conducting vessel as it conducts blood at high velocity to the rest of the body. The capillaries on the other hand, need to contain the blood with minimal velocity which allows for efficient exchange of gases and transport of nutrients and waste products.

This video presents: Blood flow in the cardiovascular system. Factors affecting the blood flow. Method to calculate the blood flow.

PHYSIOLGY LECTURE # 4 STUDY NOTES:

HEMODYNAMICS - BLOOD FLOW

Basic Metric system:

1m = 39.37 inches 

1ml = 1 cubic centimetre (cm^3)

A cubic centimetre is diagrammed as a small cube which has all its lengths equal to 1 centimetre.

Cross-Sectional Area

The cardiovascular system is seen as a network of cylindrical tubes. If a cylinder is cut at normal (right angle) and the cross section viewed, it will appear as a circle. The area of a circle is calculated by the formula, (). The radius of the circle is determined by measuring the length from the centre of circle to any point along its circumference. The unit for the cross sectional area is cm^2.

Velocity vs. Flow

Velocity is defined as the distance covered in unit time (cm/s). For simplicity, velocity is defined as the speed of movement of a particle. Velocity of a particle in a fluid is independent of the total volume of the fluid itself. The velocity of the blood is equal to the distance it covers in unit time, irrespective of the volume moved. 

Flow however is dependant of the fluid volume. Flow refers to the volume of fluid that passes through a cross sectional area in unit time. With respect to hemodynamics, flow is measured as the volume of blood that passes through a particular area in unit time (ml/min). 

Formulae: 

➢ Velocity (cm/s) = Flow/Cross Sectional Area 

             = Q/A (Unit: [ml/m]/cm^2)

Assumptions: For the purpose of this lecture, the flow of blood in an average, healthy adult is assumed as 5L/min, which is also the cardiac output.

After being pumped from the heart, the blood first flows into the aorta and then into the major arteries. From there, the blood enters arterioles of the respective functional organ systems. The arterioles divide into small capillaries which anastomose with capillaries of the venules within the organ system. The venules empty into veins and the veins after collecting blood from all parts of the body, empty into the Superior and Inferior Vena Cava which deliver the blood back to the heart, completing the circuit. Together these components of the systemic vasculature form a closed circuit.

Therefore, the cross sectional area of the vessels changes as the blood flows through the body with subsequent changes in the velocity as well. According to the formula devised earlier, the velocity of blood is inversely proportional to the diameter of the blood vessel, given that the flow rate remains constant. For example, the aorta has the smallest diameter and a cross sectional area of 2.5cm^2. In a healthy individual, the velocity of blood in the aorta can be calculated by dividing the flow rate (approximated earlier as 5000ml) by the cross sectional area (2.5cm^2) of the vessel. This would give a value for the velocity of blood flowing through the aorta as 20 meters/min. The calculation for the velocity of blood flowing through the aorta is summarized below:

➢ Cross-sectional area of Aorta = 2.5cm^2

                     = 2.5cm^2

                  Diameter of Aorta = 1.78cm

➢ Velocity of the blood flow through Aorta:

​ 

=  {ml and cm^3 can be substituted interchangeably}

= 

= 2000 cm/min

= 20 m/min

= 33 cm/s

Before moving on, it should be noted that the diameter, and hence the cross sectional area, of the branching arteries is taken as the sum of all the arteries at that level and not of a single artery individually.  The capillaries, as a result, have a collective cross sectional area of 3000cm^2, a value which is 1000 folds greater than the cross sectional area of the aorta. Hence, the velocity of the blood drops considerably (1.6cm/min) as it reaches the capillaries. The calculation for the velocity of blood flowing through the capillaries is summarized below:

➢ Total Cross-sectional area of Capillaries = 3000cm^2

➢ Velocity of the blood flow through the Capillaries: 

​ 

=  {ml and cm^3 can be substituted interchangeably}

= 

= 1.6 cm/min

= 0.016 m/min

= 0.027 cm/s

The significance of these large differences in velocities is immense. The aorta is functionally a conducting vessel; therefore it contains blood travelling at a relatively high velocity so that the blood can reach the desired target organs efficiently. In contrast, the velocity of the blood drops significantly (1.6cm/min) as it reaches the capillaries. Therefore, the capillaries contain the blood with minimal velocity which allows for efficient exchange of gases and transport of nutrients and waste products across them.

This video will present: Poiseuille's Equation Factors contributing to the Poiseuille's equation Use of the Poiseuille's equation in the flow equation.

STUDY NOTES: 

HEMODYNAMICS – POISEUILLES EQUATION

The Poisuilles Equation takes into account factors such as blood viscosity, length and cross sectional area of a blood vessel and uses it to determine the resistance to the flow of blood.

(Assuming that the flow is laminar and the volume is constant) 

➢ Where: n: Viscosity of the blood

              L: Length of the blood vessel which is constant for blood vessels in our body

              r: Radius of the blood vessel

FACTORS CONTRIBUTING TO THE POISUILLES EQUATION

Blood viscosity has a direct relation with resistance, according to the Poisuilles equation. This means that increasing the viscosity of blood will result in an increase in resistance. Blood viscosity undergoes changes with alterations in the hematocrit. Hematocrit is the percentage of total number of particulate matter (RBCs, WBCs, proteins etc) in a given volume of blood. Under normal conditions, the value of hematocrit is 45%. Changes in the hematocrit can occur with both, physiological and pathological conditions. Dehydration causes decrease in the volume of blood which results in a relative physiological increase in hematocrit. Similarly, secondary polycythemia also causes physiological increase in the value of hematocrit as a result of increased production of red blood cells by the bone marrow. Pathological increase in the hematocrit is primarily seen in malignancy of the bone marrow in which large numbers of undifferentiated cells areproduced leading to an increase in the cell number. Multiple Myeloma is the neoplastic proliferation of plasma cells which produce excess immunoglobulins. This results in an increased protein content of the blood and a resultant increase in hematocrit.

On the other hand, anemia will cause a decrease in hematocrit and hence, a decrease in viscosity of blood. As mentioned earlier, a decrease in blood viscosity will result in a decrease in resistance to the flow of blood. Flow rate increases when there’s a decrease in resistance offered to blood flow. Increase in the flow rate can be problematic because it generates Eddy currents within the blood vessels. These Eddy currents cause pressure damage to the blood vessel and cause the blood flow to become turbulent. Turbulent blood flow within the heart results in murmurs. Turbulent blood flow within the blood vessels results in bruit. Most common sites of bruit are carotid artery and the aorta. Both murmur and bruit can be appreciated upon auscultation at the relevant sites.

The resistance to blood flow within the blood vessel is inversely proportional to the radius of the blood vessel raised to the fourth power. If the cross sectional area of thecylindrical blood vessel is decreased, there’s a resultant increase in resistance to blood flow in that vessel. So that basically means, if we take the radius and simply divide it by two (decreasing the radius of the vessel to half), the resistancewould increase by a factor of 16. This would result in a considerable decrease in the flow rate of the blood. Application of this concept is seen in pathological cases, such as the narrowing of blood vessels in atherosclerosis and arteriosclerosis, resulting in increased resistance and reduced blood flow. The diameter of blood vessels in our body is physiologically controlled by our body's autonomic nervous system (ANS). Arterioles are the vessels in which the autonomic effects are seen most prominently. For this reason they are also known as the resistance vessels or the functional sphincters of the cardiovascular system. The smooth muscles surrounding the arterioles contract or relax under the effect of the autonomic nervous system. When stimulated by the sympathetic nervous system (SANS), the alpha 1 receptors on the arteriolar smooth muscle get activated. These receptors are coupled intracellularly with Gq proteins which get activated and increase intracellular levels of second messengers, namely IP3 and DAG. The second messengers cause movement of calcium ions into the sarcoplasmic reticulum resulting in contraction of the smooth muscles. The same sympathetic innervation when stimulates the Beta 2 adrenergic receptors on the arteriolar smooth muscle of arterioles perfusing skeletal muscles, a Gi coupled response is initiated. This will cause a decrease in cAMP levels in smooth muscle cells of the arterioles. As a consequence, the smooth muscle will relax and the arteriole will dilate allowing more blood to perfuse the skeletal muscles. The distribution of extracellular receptors (beta 2, alpha 1, etc) on vascular smooth muscles depends on the demand for blood by different organs according to the situation. For example, during a fight and flight response, the blood vessels of the skeletal smooth muscles (innervated by beta 2 receptors) will dilate to provide more blood to the muscles. At the same time, the vascular smooth muscles of arterioles perfusing the visceras (GIT, Kidneys, etc) will contract, and the lumen will constrict in order for the blood to redirect to parts where it is needed more.

USE OF POISUILLES EQUATION IN THE FLOW EQUATION

The value of the resistance, calculated using the POISUILLES EQUATION, can be plugged into the flow equation (given below) to determine the flow rate:

➢ Flow = ΔP/R,

ΔP = MAP - Right Atrial Pressure

Therefore,

Flow = (MAP - RAP) /Resistance

ΔP: change in Pressure

R: Resistance

MAP: Mean Arterial Pressure

So, according to the equation, increase in resistance will cause a decrease in the flow of blood through a vessel. The resistance of a blood vessel is increased in conditions such as atherosclerosis and vasospasm due to increased sympathetic activity. Similarly, if the resistance is decreased, the flow of blood through a vessel will increase.

This video presents: Concept of compliance or capacitance or distensibility A comparison is also made to the elastance (opposite mechaism)

STUDY NOTES:

HEMODYNAMICS – VASCULAR COMPLIANCE

Capacitance is defined as the distensibilty of a blood vessel. In other words, capacitance is the ability of an object to get stretched. In contrast, elasticity is defined as the object's ability to recoil or return to its previous shape after beingstretched. Elastance is produced by elastin fibers present in the vascular wall. Take for example the aorta; it has the most layers (around 50 layers) of elastin fibers in its tunica media which makes it the most elastic blood vessel in the body. If the aorta is compressed or stretched, it will recoil back to its normal shape.

Compliance of a vessel is the opposite of its elastance. The veins are said to be compliant because if you keep increasing the volume of blood in the veins, their walls will distend allowing for more blood to be accommodated.

Arteries and veins possess relative percentage of both, elasticity and compliance. However, arteries are said to berelatively more elastic and less compliant owing to the fact that they have more elastic fibers. This explains why the aorta resists distension when blood at high pressure is pumped into it by the heart. The increase in pressure causes a small stretch in the wall (due to compliance) of aorta which is immediately diffused as the aorta recoils back (due to elasticity) to its original shape. Greater the amount of elastic tissue in a vessel wall, the higher is the elastance, and the lower is the compliance of the blood vessel. As the person’s age increases, the arteries become stiffer and further lose their compliance. Pathological conditions such as atherosclerosis also further decreases the arterial compliance. 

The opposite is true for the veins. The walls of the veins, being very compliant, will keep on stretching as more blood is added to the veins. There will be a small degree of recoil as well but the resultant force is not as strong as that in the arteries.Formulae:

➢ Compliance = Volume (ml)/ Pressure (mm Hg)

As seen in the formula, compliance can be written as a ratio of volume and pressure. This shows that more compliant vessels will allow more volume of blood to be added without causing any changes in pressure. On the other hand, the arteries try to resist changes in volume by generating more pressure as they are less compliant. This is the reason why the volume of blood in arteries is called stressed volume whereas the volume in veins is called unstressed volume. . Systemic veins are 20 times more compliant relative to systemic arteries. Due to this, the veins easily distend in response to high volumes of blood. Because of their ability to capacitate, the veins accommodate roughly 70% of the systemic blood volume. For this reason the systemic veins are a major blood reservoir of the body.

The table below contrasts the different properties of arteries and veins and the effect they have on hemodynamics. The result are further explained below:

• Compliance: Arteries are less compliant and veins are more compliant.

• Elastance: The arteries are more elastic. This property makes up the basis for “ windkessel effect” in the aorta. The aorta distends in response to the high pressure blood pumped by the heart and recoils back thereby maintaining the pressure between 120/80 mm Hg. The elastance of veins is low.

• Stress: The arteries face stress as the blood running in them is at high pressure. The stress on the walls of the veins is negligible.

• Volume: The arteries are not capable of housing large volumes of blood. The veins have more capacity as they are more distensible and compliant in the face of volume changes.

• Pressure: The pressure in the arteries is greater than that in the veins. Arterial wall recoils due to presence of elastic fibers, and this recoil is responsible for the arterial pressure. Veins on the other hand don’t have that much of an elastic component and therefore lack recoil ability and consequently the blood pressure is relatively low in the veins. 

• Flow: The flow is equal in both, the arteries and the veins, as the blood is flowing in a closed circuit. As the blood moves in a closed circuit, the flow is equal at all points. 

COMPLIANCE GRAPHS FOR VOLUME VS PRESSURE

X-axis = Volume (mL)

Y-axis = Pressure (mm Hg)

The graphs in the lecture compare the compliance of aorta with that of systemic veins. For understanding purpose, compliance can be referred to as the pressure change in the blood vessel when unit volume of blood is added to the vessel (aorta or the veins). The compliance of each vessel can be calculated as the gradient of the graph at any point.

Compliance = ΔV/ΔP

For Aorta, when unit volume of blood is added to it, there’s a significant rise in its pressure. The gradient of the volume vs. pressure curve is relatively less steep. This suggests that the aorta has a low compliance. Increase in pressure can also be explained by the greater recoil (elastance) of the aorta.

For veins, when blood is added to them, there’s no significant change in pressure. The gradient of the volume vs. pressure is very steep, which suggests that their compliance is very high. The veins can hold greater volume of blood without any increase in their pressure because they are very distensible.However, as we continue to add blood, there comes a point when the curve starts to flatten out and the vein cannot accommodate any more blood. The compliance at this point is zero. 

This video presents: Formula for the Renyold's number Effect of the laminar and turbulant blood flow on the Reynold's number.

STUDY NOTES:

HEMODYNAMICS – REYNOLDS NUMBER

Definition: Reynolds Number is used to predict the type of blood flow in a blood vessel. There are two types of blood flow:

• Laminar Flow: The laminar flow is described as the flow of fluid which is travelling in a calm, layered fashion. The layer of fluid flowing in the center most region of the blood vessel is said to have the highest velocity. Moving peripherally, the velocity of the layers decrease and the outer most layer, which is running along the vessel wall, is said to be travelling with the lowest velocity. This is due to friction which results in a backward drag produced by the wall on the layer adjacent to it. It is important for a blood vessel to exhibit laminar flow in order to maintain its physical integrity and carry out various cardiovascular functions. Laminar flow allows margination to occur efficiently among other functions. Margination is the process of adherence of blood cells to the vessel wall and their subsequent exit through the wall of the blood vessel to areas of need. This process gets largely disrupted if blood flow is not laminar.

• Turbulent Flow: Blood flowing viciously and in ahaphazard fashion produces turbulence within a blood vessel. The aorta normally contains blood with turbulent flow. This type of blood flow results in the production of Eddy currents within a blood vessel. These currents cause the blood to hit against the vessel wall with considerable amount of force. Repeated impaction of high pressure, turbulent blood on the vessel wall damages the elastic fibers within the tunica media. As a consequence, the elastic fibers break into smaller fragments, rendering the fibers non functional.

A small Reynolds number signifies that the blood is flowing in a smooth and laminar fashion. If the Reynolds number is high, the blood flowing through the blood vessel would be turbulent.

Murmurs and bruits point to the presence of turbulence in blood flow. These can be appreciated upon auscultation at the relevant areas. Murmurs are sounds of blood splattering on the rest of the blood due to turbulence. These disturbances result in vibrations that resonate through the walls of blood vessels or the heart itself. These are picked up as distinct sounds upon auscultation.

➢ 

The formula says that the value of Reynolds number is directly proportional to density of the blood, the blood's velocity and the diameter of the blood vessel. Increasing the magnitude of any of these parameters will result in an increase in Reynolds number, and add turbulence to the blood flow. Therefore, the aorta having the largest diameter compared to the rest of blood vessels, and the highest rate of blood flow, will give a large Reynolds number. Hence, the flow is turbulent.

The viscosity of blood has an inverse relationship with theReynolds number. Increased viscosity of a fluid results in its flow becoming more laminar. Increased viscosity will also decrease the velocity of the blood flow. Similarly, decreasing the viscosity of the fluid will result in more vicious and turbulent flow. In terms of hemodynamics of the blood flow, changing the hematocrit value results in a change in the viscosity of blood. Anemia causes a decrease in the viscosity of blood and hence is attributable to generation of Eddy currents due to high turbulent blood flow.

General principles of the CVS Organization Heart as two pumps Series and parallel circuits Chemical composition of the venous and arterial blood Blood flow direction Various pressures in the CVS

This video presents: Regulation of the Blood Flow. Long Term Flow is not covered in this chapter. Acute blood flow types i.e. Extrinsic and Intrinsic. Metabolic and myogenic theory of the intrinsic blood flow. Role of the blood vessels in the blood flow including ERDF and Endothelin.

CVS PHYSIOLOGY LECTURE # 9 STUDY NOTES:

AUTOREGULATION OF BLOOD FLOW

When we talk about autoregulation, it's not the blood pressure we are talking about but it's rather the blood flow over a changing pressure which is being regulated. In terms of hemodynamics, the flow across a blood vessel is determined by the pressure gradient across its two ends, assuming that the vessel diameter (resistance) remains unchanged. 

The equation for blood flow across a vessel is as following:

➢ Flow = ΔP/ R

Flow = [P1 - P2]/ R

Where,

ΔP = Pressure gradient

R       = Resistance to blood flow across the vessel

Blood flow change can occur if any of the following factors change:

• Blood volume

• Vessel diameter i.e., the resistance to blood flow changes

It's important to understand that any pressure changes of the blood result in flow changes across capillaries supplying blood to the tissues. If the flow changes, there can be derangements in the perfusion of the tissues. One of the major functions of cardiovascular system is to provide optimal perfusion to the tissues. Perfusion ensures optimal delivery of nutrients and oxygen and removal of metabolic waste products from the tissues. So for this reason, if there are any pressure changes then the body will try to regulate the blood flow accordingly in order to maintain optimal perfusion of the systemic tissues. So it's safe to assume that it is the blood flow which is regulated as part of hemodynamics, not the vascular resistance (arteriolar diameter). In fact, vascular resistance is altered in order to regulate blood flow.

Autoregulating tissues are those which exhibit local blood flow regulation, thereby maintaining a constant blood flow even if the perfusion pressure changes (MAP). The blood pressure range over which an autoregulating tissue can maintain a constant blood flow is called the autoregulatory range. The autoregulatory range in our body is from a MAP of 70 mm of Hg to 175 mm of Hg. Outside the autoregulatory range (MAP < 70 and MAP > 175), the flow doesn't remain constant. There is a proportional decrease or increase in flow if the MAP falls below 70 mm Hg or increases above 175 mm Hg, respectively. 

Following is a brief summary of what's happening to the flow at points A, B & C on the autoregulation graph in drawn in the lecture:

• Point A: This point falls outside the lower limit of autoregulatory range (MAP < 70). Up till point A, as the MAP increases from 0 to 70 mm Hg, the blood vessel is maximally dilated. The blood vessel is as relaxed as possible and as the blood flow through it increases, there's a proportional increase in the blood pressure of the vessel.

• Point B: This point falls within the autoregulatory range. The increased blood pressure resulting from an increased flow results in smooth muscle contraction of the vessel. This reduces the diameter of the blood vessel and the flow is kept constant. The blood vessel continues to constrict until the upper limit of the autoregulatory range is reached 

(MAP = 175). 

• Point C: This point falls outside the upper limit of autoregulatory range (MAP > 175). Outside this range, the vasculature can't constrict any further so the blood flow can't be kept constant anymore. Hence, any further increase in the blood pressure will always be accompanied by an increase in blood flow.

NOTE: The blood flow is primarily governed by dilating or constricting the smooth muscle within the walls of the arterioles, provided that other factors such as viscosity of blood, blood volume and other physiological factors are kept constant. 

There are several types of blood flow regulations:

1) Long term regulation: This is done by achieved by increasing the size and diameter plus increasing the number of blood vessels. It can take from months to years to achieve such kind of a change. This long term blood flow regulation will later be discussed in a separate lecture. 

2) Acute regulation: This responds to the local needs of a metabolically active tissue. Only those tissues which require greater blood flow owing to their metabolic activity receive a greater blood flow. This ensures that the blood flow to whole of the body is not increased if a particular tissue needs more perfusion. Overall, this makes sure that the workload on the heart doesn't increase too much. Acute regulation of blood flow is further divided into the following types:

• Extrinsic regulation involves SANS and PANS input to regulate vascular diameter. Extrinsic regulation will be discussed later in a separate lecture.

• Intrinsic regulation involves mediators released from the tissue itself which ensure that adequate perfusion to the tissue is maintained. Autoregulating tissues fall under this category of tissues which have their perfusion regulated by the tissue itself, and examples of these are as following:

▪ Cerebral circulation

▪ Coronary circulation

▪ Skeletal muscle vasculature (during exercise)

▪ Renal Circulation

There are two major mechanisms which are used toexplain intrinsic regulation (autoregulation). These include the metabolic and myogenic mechanisms. Both these mechanisms cause vasodilation of the blood vessel which leads to an increase in the perfusion of the tissues supplied. Metabolic mechanism is the primary theory which regulates the local vascular diameter of the vessel. The myogenic theory is the subordinate theory to the metabolic theory. 

3) Vascular system control on the blood flow: It is also involved in the regulation of blood flow to tissues. It falls both under both the intrinsic and the extrinsic categories, so it's discussed separately here. Certain substances suchas EDRF (endothelium derived relaxing factor) and Endothelin are released which act on the endothelium itself and subsequently regulate the blood flow to the tissues. EDRF acts to cause vasodilation whereas Endothelin causes vasoconstriction. 

VASCULAR SMOOTH MUSCLE CONTRACTION OR RELAXATION AND THE RESULTANT CHANGE IN BLOOD FLOW

The blood supply to a tissue brings oxygen and nutrients and removes the carbon dioxide and other waste products away as part of the perfusion. The blood vessel is surrounded by smooth muscle within its wall. Relaxation of vascular smooth muscle causes vasodilation, allowing more blood flow through the blood vessel. On the other hand, the contraction ofvascular smooth muscle results in vasoconstriction of the blood vessel which decreases the diameter of the vessel and reduces forward flow. The cascade of events which occur during the vascular smooth muscle contraction are explained below:

1) On the smooth muscle surface membrane there are T-tubules along which the action potential travels.

2) Sarcoplasmic reticulum is the site for intracellular calcium, which is released when depolarization of the smooth muscle cell occurs. 

3) Calcium is released from the sarcoplasmic reticulum. This increases the intracellular Calcium levels. In a smooth muscle the interaction of actin and myosin is controlled by a protein called calmodulin (Tropnin-C molecule is not present is smooth muscle). Calcium-calmodulin complex forms when a single molecule of calmodulin binds to 4 calcium ions. 

4) Myosin molecule has a myosin head and a myosin light chain. Myosin light chain has an enzyme called myosin light chain kinase (MLCK). The calcium-calmodulin complex activates the enzyme myosin light chain kinase (MLCK). Calcium-Calmodulin complex is responsible for regulating the cross-bridge cycling in a smooth muscle.

5) MLCK is activated by increased intracellular calciumlevels. Upon activation MLCK phosphorylates the myosin light chain utilizing an ATP molecule. When a phosphate binds to myosin light chain, it activates the myosin head which brings about a conformational change of the myosin head. The myosin head now binds to the exposed myosin binding site on the actin molecule.

6) The myosin binding sites on Actin are covered by troponin and tropomyosin. After binding to its binding site on actin, the myosin head initiates a power stroke which results in movement of the actin filament. In a smooth muscle this cross-bridging of actin and myosin plus subsequent power stroke together result in an increased tension in the smooth muscle. Increased tension of the vascular smooth muscle results in vasoconstriction of the blood vessel.

7) There's another enzyme called myosin light chain phosphatase (MLCP), which has function opposite to that of MLCK. Post the power stroke, MLCP functions to remove the ADP from the myosin molecule. Once the ADP molecule is detached from the myosin head, the myosin head returns to its normal relaxed state. This decreases the tension inside the vascular smooth muscle and there’s vasodilation of the blood vessel.

NOTE: Activation of MLCK results in the contraction of vascular smooth muscle, and the resultant diameter of the vessel is reduced. In contrast, MLCP activation results in relaxation of the vascular smooth muscle and this subsequently results in vasodilation of the blood vessel.

[The steps involved in the vascular smooth muscle contraction aren’t correctly explained in the lecture.  The steps explained in the lecture are the ones involved in the skeletal muscle contraction. However, a blood vessel has a smooth muscle component so the steps involved should be those of a smooth muscle excitation-contraction coupling. 

In the lecture it’s mentioned that Troponin-C is and tropomyosin molecules are covering the binding site of the myosin heads on the actin molecule. However, Troponin C is absent in smooth muscle. Instead, calmodulin molecule is present in the vascular smooth muscle. With smooth muscle depolarization there’s an influx of calcium ions. The calmodulin molecule (like Troponin molecule in skeletal muscle) binds to four calcium ions. This calcium-calmodulin complex is what’s responsible for activating the MLCK enzyme. The subsequent cross-bridging sequence is similar in both smooth and skeletal muscle.

Also the enzymes MLCK & MLCP are only present in the smooth muscle and not in the skeletal muscle.]

METABOLIC THEORY OF AUTOREGULATION

The metabolic theory proposes that the oxygen delivery to a metabolically active tissue is determined by two factors:

• Presence or absence of oxygen in the tissue.

• Presence or absence of metabolites in the tissue.

Oxygen & Metabolic theory: Putting oxygen into the metabolic theory equation suggests that oxygen delivery can be matched to the oxygen consumption of that tissue by varying the diameter of the arterioles, which in turn alters the blood flow. As a tissue performs active metabolism, it utilizes the oxygen delivered to it via the arterioles. As a result the oxygen levels of the local arteriolar blood tend to drop. This means that less oxygen is available for the arteriolar endothelium and smooth muscle. Within the arteriolar smooth muscle, less oxygen is available for the phosphorylating activity of the MLCK. As a result the actin-myosin cross bridging is disrupted and the arteriolar smooth muscle tends to relax. End result of this cascade is that the arterioles undergo vasodilation and there is a relatively reduced resistance to the flow. Consequently tissue perfusion increases secondary to arteriolar vasodilation and increased flow.

Metabolic Vasodilators & Metabolic theory: Actively metabolizing tissues produce certain vasodilatory metabolites which can regulate the blood flow to the tissue itself. The concentration of these metabolites is directly proportional to the level of metabolic activity performed by that particular tissue. Increased concentration of metabolites results in vasodilatation of the arterioles, which results in decreased resistance to the blood flow. This increased blood flow is in coherence with the increased oxygen demands of the tissue. In contrast, the arterioles constrict if the concentration of these metabolites decrease. Several key vasodilator metabolites are mentioned below:

• Adenosine: ↑Adenosine → + G-stimulatory protein →increased cAMP (cyclic AMP) → - inhibition of MLCK. 

As the kinase function of the MLCK is inhibited, the vascular smooth muscle relaxes and vasodilation follows.

• Carbon Dioxide

• H+ ions

• K+ ions

• Lactate

• Prostaglandins: Also uses the G-stimulatory coupled cAMP pathway.

• Prostacyclins

These vasodilator metabolites can be produced both due to oxygen demand or oxygen supply mismatch situations.

• Oxygen demand mismatch: Active metabolism by the tissue cells utilizes the oxygen available to them. There’s a resultant increase in oxygen demand by the tissues, while the supply remains unchanged. This is what happens in a rapidly exercising muscle cell. In order to match the oxygen demand, the flow to the muscle needs to be increased.

• Oxygen supply mismatch: Alternatively there can be an oxygen supply mismatch. In this case the tissue need remains unchanged but the perfusion to the tissue decreases due to some reason. Following are the situations which can lead to a supply mismatch situation:

▪ High Altitude (decreased atmospheric pressure)

▪ Carbon Monoxide poisoning (CO has greater affinity for Hemoglobin than Oxygen)

▪ Cyanide poisoning (Cyanide inhibits cytochrome c oxidase and renders the electron transport chain non-functional)

▪ Mechanical block to blood vessels perfusing the tissue

▪ Pneumonia (can cause ventilation perfusion mismatch in the lungs, which decreases the flow available to tissues)

In another scenario let’s assume that there is a spontaneous increase the perfusion to a tissue. This increase in perfusion can be secondary to an increase in blood volume (transfusion) or stroke volume (inotropic drugs). In the beginning, there will be an increase in blood flow that will deliver more oxygen for metabolic activity and simultaneously “wash out” the vasodilator metabolites. Consequently, there will be a local dilution of vasodilator metabolites around the tissue. Decreased vasodilator metabolites result in arteriolar vasoconstriction and a compensatory decrease in blood flow back to the normal level.

Role of calcium: when the nerve impulse stimulates NMJ the calcium is released from the sarcoplasmic reticulum causes activation of MLCK and causes vasoconstriction by its action on Gq receptor, alpha 1 receptor and increases the concentration of ITP i.e. inosine triphosphate.

Metabolic theory also explains the phenomena of active hyperaemia and reactive hyperaemia:

• Active Hyperaemia explains that blood flow to a metabolically active tissue is directly proportional to its metabolic needs. For example, as a result of strenuous exercise the metabolic demands of the skeletal muscle are greatly increased. As compensation, the blood flow (perfusion) to the skeletal muscles is readily increased in order to meet the metabolic demands of the tissue. Active hyperaemia can be explained by both the metabolic and the myogenic theories of autoregulation.

• Reactive Hyperaemia refers to an increase in blood flow to a tissue which received a decreased perfusion due to some reason. The reason for decreased perfusion can be arteriolar occlusion of the arterioles supplying the tissue. Over time, due to decreased blood flow the tissue switches to anaerobic means of respiration which creates an oxygen debt situation within the tissue.  Also due to occluded blood supply, there’s a build up vasodilator metabolites within the tissue which aren’t washed up due to decreased perfusion.  These vasodilator metabolites with time increase in concentration and result in vasodilatation of the arterioles which perfuse the tissue. As the blood supply resolves, the tissue receives a greater than normal perfusion until the oxygen debt situation is resolved. Reactive hyperaemia is governed by the law of compensation of blood flow.  Reactive hyperaemia can only be explained by the metabolic theory of autoregulation; the myogenic theory cannot be used to explain it.

MYOGENIC THEORY OF AUTOREGULATION

Myogenic theory of autoregulation suggests that the vascular smooth muscle itself is also responsible for its own control of contraction and relaxation. An inherent property of the smooth muscle is that that it contracts in response to stretch. Thus, if arterial pressure is suddenly increased, the arterioles are stretched and the vascular smooth muscle in their walls contracts in response to this stretch. The decreased arteriolar resistance ensures that the flow doesn't increase significantly. If there's a sudden drop in flow, there's a reduced stress placed on the arterial walls and therefore the vascular smooth muscle relaxes. The compensatory vasodilation ensures that blood flow to the tissue doesn't drop significantly. 

There are sodium channels within the vascular smooth muscle cells. These sodium channels are normally closed and are connected to the cytoskeleton of the smooth muscle cell. As the blood flow within the vessel increases, it stretches the blood vessel plus the smooth muscle surrounding the bloodvessel. This stretch will also cause the microtubules within the cytoskeleton to stretch. The stretch on microtubules will create a mechanical pull upon the closed sodium channels and cause them to open. Sodium channels will cause an influx of sodium ions into the smooth muscle cells and bring about depolarization. Result of this cascade is that the vascular smooth muscle contracts and decreases the lumen of the vessel. Decreased lumen will decrease the flow back to the normal. 

The concept of reactive hyperaemia is explained above. It's important to remember that reactive hyperaemia cannot be explained in terms of myogenic theory. 

THE ROLE OF EDRF, NITRIC OXIDE & ENDOTHELIN IN REGULATING LOCAL BLOOD FLOW

EDRF and Endothelin are chemical substances released by the endothelium which act on the vascular smooth muscle to alter the diameter of vessel. Nitric oxide is one of the most important very important EDRF. Blood travelling at high velocity causes a shearing effect on the wall of the blood vessels as the endothelial cells endure a drag force produced due to friction. This results in a mechanical trigger which stimulates release of nitric oxide.

Nitric oxide, after its release from the endothelium, diffuses into the vascular smooth muscle. Inside the vascular smooth muscle, the NO triggers the guanylate cyclase to convert cGTP to cGMP. The increased levels of cGMP cause activation of the enzyme Myosin Light Chain Phosphatase (MLCP). The activated MLCP enzyme in turn dephosphorylates myosin light chains, which results in relaxation of the contractile apparatus of the blood vessel. As a result, the vessels become dilated.

Angiotensin II receptors are present on both the vessel endothelium and also the smooth muscle surrounding the blood vessel. When Angiotensin II acts directly on the its endothelial receptor, it results in release of NO. This NO causes vasodilation by the mechanism explained above. If the Angiotensin II acts directly on its receptor on the vascular smooth muscle, then it'll cause vasoconstriction of the blood vessel. Angiotensin II receptor on the vascular smooth muscle is Gq coupled, and when bound to this receptor, Angiotensin II can act as a powerful vasoconstrictor. 

Sildenafil is a drug that is used to treat erectile dysfunction. It is a Phosphodiesterase (PDE-5) inhibitor.  Normally, PDE-5 is an enzyme that binds to and cleaves cGMP. As a result, the half-life of cGMP is reduced as its levels fall. Sildenafil acts by binding to PDE-5 and antagonizes its function (decreasing cGMP levels). With PDE-5 inhibited, the cGMP levels remain high for a longer period of time. The effect of parasympathetic NS and acetylcholine results in release of NO. This Nitric Oxide diffuses inside the vascular smooth muscle of the arteries which are responsible for penile erectile tissue perfusion. Within the vascular smooth muscle, the NO results in formation of large quantities of cGMP. Inhibited PDE-5 can no longer cleave the cGMP which stays for a longer time. cGMP activates enzyme MLCP which promotes relaxation of the vascular smooth muscle. Therefore, the penile vasculature remains dilated and engorged with blood and the erection is maintained for a longer period.

Endothelin is released from damaged endothelium. After its release, Endothelin binds to its receptor on the vascular smooth muscle. Endothelin receptor is a Gq coupled receptor, which upon activation inhibits the MLCP enzyme. The inhibition of MLCP enzyme promotes contraction of the vascular smooth muscle and the vessel undergoes vasoconstriction. Hence the vascular diameter is decrease to reduce the blood flow through the damaged vessel. This is important in order to prevent blood loss at the site of damaged endothelium. 

Another important function of EDRF is that these not only increase the local blood flow. EDRF also causes vasodilation of upstream blood vessels for the tissues that need greater perfusion. This makes sure that overall blood flow is directed to those tissues which are in need of greater perfusion due to their metabolic demands. 

This video presents the mechanism of action of the NO and the factors that trigger its release.

STUDY NOTES:

AUTOREGULATION - NITRIC OXIDE

Nitric Oxide is called an endothelium derived relaxing factor(EDRF) as it is released by the endothelium of the blood vessel. EDRF cause relaxation of the vascular smooth muscle, and as a result cause vasodilation of the blood vessel. The following factors contribute to the release of nitric oxide from the endothelium:

1) Blood travelling at high velocity causes a shearing effect on the wall of the blood vessels. As the endothelial cells endure a drag force produced due to friction. This results in a mechanical trigger which stimulates release of nitric oxide.

2) Vasoactive Amines are chemical mediators that mediate the release of nitric oxide.

3) The endothelium possesses Histamine H1 receptors that also take part in nitric oxide release.

4) Prostacyclins are also said to be responsible for the release of nitric oxide.

Mechanism of Action of Nitric Oxide 

Nitric oxide, when released, triggers the soluble guanylate cyclase or Guanyl cyclase to convert cGTP to cGMP. Theincreased levels of cGMP cause activation of cGMP dependent kinases which activate the enzyme Myosin Light Chain Phosphatase (MLCP). The activated MLCP enzyme in turn dephosphorylates myosin light chains which results in relaxation of the contractile apparatus. As a result, the vessels become dilated.

Atherosclerosis is the formation of fibromuscular plaques on the endothelium lining of the blood vessel. These atherosclerotic plaques render the endothelium non functional. The endothelium is therefore unable to produce sufficient amounts of nitric oxide. Consequently, the levels of cGMP reduce as less cGTP is converted to cGMP. This reduction in cGMP levels in turn leads to increased levels of Myosin Light Chain Kinases (MLCK) which are enzymes with activity opposite to that of MLCP. The contractile apparatus is activated as MLCK causes cross bridging of actins and myosin heads. The tension produced within the vascular smooth muscle as a result of the vascular smooth muscle contraction in turn causes vasoconstriction of the blood vessel.

Angiotensin II receptors are present on both the vessel endothelium and also the smooth muscle surrounding the blood vessel. Depending on the receptor activated, Angiotensin II can have vasodilating or vasoconstricting effects. At times these opposing effects are balanced out and one effect compensates for the other.   

• The vasoconstricting activity of Angiotensin II is mediated via two pathways. If Angiotensin II binds to the Gq-coupled receptors on the vascular smooth muscle, it will cause direct deactivation of MLCP enzyme. It also causes the production of IP3 which enables the release of calcium ions from the sarcoplasmic reticulum. The calcium ions activate MLCK. The activation of MLCK and inactivation of MLCP results in contraction of the smooth muscles surrounding the blood vessel. This is the vasoconstricting effect.

• The vasodilating effect of Angiotensin II occurs simultaneously to mitigate the vasoconstricting effects to some extent. This effect is mediated by binding of the Angiotensin II to its receptor on the vascular endothelium. This activation of endothelial Angiotensin II receptor cause active release of nitric oxide from the endothelium. This NO diffuses into the vascular smooth muscle and stimulates the activity of guanylate cyclase enzyme which converts cGTP to cGMP. The increases cGMP levels cause activation of the MLCP enzyme. The activated MLCP enzyme in turn dephosphorylates myosin light chains, which results in relaxation of the contractile apparatus of the blood vessel. As a result, the vessels become dilated.

Sildenafil (Viagra) is a drug that is used to treat erectile dysfunction. It is a Phosphodiesterase-5 (PDE-5) inhibitor. PDE-5 is an enzyme that binds to and cleaves cGMP. As a result, the half life of cGMP is reduced as its levels fall. Sildenafil acts by binding to PDE-5 and antagonizes its function. As a result, the cGMP levels remain high for a longer period of time. Therefore, the penile vasculature remains dilated and engorged with blood and, hence, erection is maintained.

This video is part of the blood flow regulation series. We present the blood flow in a muscle during the resting and active state. Extrinisc vs. intrisic blood flow and the triggering factors are disucssed.

STUDY NOTES:

AUTOREGULATION – MUSCLE BLOOD FLOW

The metabolic requirements of a muscle change duringexercise compared to when it is at rest.  The blood flow also changes accordingly with the metabolic demands of the muscle. Therefore, the purpose of this lecture is to establish a better understanding of the regulation of blood flow to a muscle, both during rest and exercise. Both of these regulations will be discussed separately:

BLOOD FLOW TO A RESTING MUSCLE

The blood flow to a muscle at rest is controlled globally along with the rest of the body through extrinsic regulation. Blood flow is extrinsically regulated through the following auto-regulatory mechanisms:

• Sympathetic Nervous System [SANS]

• Para sympathetic Nervous System [PANS]

• Hormonal Control

The vascular smooth muscles possess both, alpha-1 (α-1) and beta-2 (β-2) receptors on their surface membrane that are innervated by the SANS. It is worth noting that during sympathetic outflow, the β-2 response is dominant over the α-1 response. This explains why sympathetic stimulation, which occurs in situations of flight and fight, causes the vessels supplying the skeletal muscles to dilate while causing the vessels supplying the visceras i.e. splanchnic, renal and skin to constrict. This allows shunting of maximum amounts of blood towards the skeletal muscles. 

The α-1 receptors are G-q coupled receptors that cause contraction of the vascular smooth muscle upon stimulation. The β-2 receptors are innervated by sympathetic supply as well, but their effect is inhibitory. This is because the β-2 receptors are G stimulatory transmembrane proteins that decrease the intracellular levels of cAMP, thereby causing relaxation of the vascular smooth muscle and vasodilation follows. As mentioned above, the β-2 response is predominant over the α-1 response. However, the response can be shifted towards α-1 if sympathetic overflow occurs. With SANS response, there’s an overflow of epinephrine. At low concentration, epinephrine occupies β-2 receptors and encourages vasodilation of vessels perfusing the skeletal muscle. However, at high concentration, epinephrine occupies α-1 receptors and encourages vasoconstriction of vessels perfusing the skeletal muscle. 

So, at rest the blood flow to skeletal muscles is predominantly regulated by SANS.  This SANS control is predominantly mediated via the β-2 receptors. Since these receptors are Gstimulatory, the response generated encourages vasodilation.

[Note: In the lecture it’s mentioned that β-2 receptor is G-s coupled. However this is not the case. In fact, β-2 receptors are G-i coupled, and there response is inhibitory. Please correct this.]

BLOOD FLOW TO AN EXERCISING MUSCLE(ACTIVE STATE)

During exercise, the control of vascular smooth muscles becomes totally dependent on intrinsic regulatory factors. The extrinsic control becomes unresponsive and is overwhelmed by the intrinsic control. This is justified by the fact that during exercise, the demand for oxygen and the need to remove metabolic waste increases multiple folds. Therefore, the vascular caliber increases in order to increase blood flow and provide for the increase demand. The factors responsible for intrinsic control are actually waste metabolites that also have vasodilatory properties. 

These vasodilator metabolites include the following:

• H+ ions 

• Lactic acid

• Carbon dioxide

• Adenosine

• Potassium ions.

These above mentioned metabolites also diminish norepinephrine's ability to vasoconstrict the arterioles. Moreover, the increased endothelial shear-stress of increased blood flow liberates nitric oxide from the endothelium itself. This NO diffuses into the vascular smooth muscle and activates the cGMP pathway via the myosin light chain phosphatase enzyme activation as discussed previously (CVS Physiology Lecture#11: Nitric Oxide). This eventually causesvasodilation.

The skeletal muscles are also responsive to Angiotensin II. Angiotensin II predominantly causes vasoconstriction but it can also cause vasodilation to some extent. The vasodilatingeffect is carried out to balance out the more potent vasoconstricting effect of Angiotensin II. The vasodilating effect of Angiotensin II involves its binding to the ATII receptors on the endothelium which subsequently releases NO.  This NO then diffuses into the vascular smooth muscle and causes vasodilation to occur. The Angiotensin II induced vasoconstriction is due to its binding to receptors on vascular smooth muscles.

Also, during exercise the muscle activity increases. This enables the muscles to act as muscular pumps that increase the blood flow and allows for rapid removal of metabolic waste.

SUMMARY

At rest, the blood flow is controlled mainly by the beta 2 activity which leads to vasodilatation

During exercise, the blood flow is taken in control by intrinsic factors that are metabolites with vasodilating properties. The rapidly contracting and relaxing muscles during exercise act as pumps that help increase blood flow.

Finally the endothelium in the local working tissues will create metabolites which will cause vasodilatation.

This video is part of the blood flow regulation series. We will discuss the blood flow control for the skin. We will discuss the unique blood flow control of the skin with temperature changes.

STUDY NOTES: AUTOREGULATION – CUTANEOUS BLOOD FLOW

The cutaneous blood flow is primarily regulated by extrinsic factors, i.e. the sympathetic and parasympathetic nervous system. Another extrinsic factor, exclusive to cutaneous blood flow, is the regulation of blood flow due to thermal changes. Therefore, skin is the only organ whose blood supply is regulated with alterations in temperature.

REGULATION OF BLOOD FLOOD FLOW VIA THE AUTONOMIC NERVOUS SYSTEM (ANS)

The blood vessels of skin are innervated by both PANS and SANS. The receptors present are predominantly α-1 adrenergic receptors which are G-q coupled. α-1 adrenergic receptors, when stimulated, cause vasoconstriction of the blood vessels perfusing the skin. This results in reduced blood flow and hence, reduced blood volume supplied to the cutaneous regions. This vasoconstriction is also accompanied with pressure changes within the cutaneous blood flow. Vasoconstriction in arterioles causes a decrease in downstream pressure and an increase in the upstream pressurewith respect to the area of constriction. The significance of these changes lies in the fact that lesser amount of blood is now exposed to a large surface area through which heat exchange is carried out.

REGULATION OF BLOOD FLOW DUE TO CHANGES IN TEMPERATURE

The anterior neurons of hypothalamus are modified to detect changes in temperature. This enables the hypothalamus to work as a thermostat of the body. If the temperature of the body undergoes changes, as happens during fever, the hypothalamus makes some adjustments in the body in order to bring the temperature back to normal (homeostasis). During a fever, the default thermostat of the hypothalamus which is normally set at 37'C, is disturbed and is raised to a higher value. Inflammatory mediators, such as Interleukin-1 and PGE2, play a major role in disturbing this set temperature point. The temperature of the body is raised in order to equalize the newly set temperature by the hypothalamus. The following events occur in the body in order to raise the body's temperature:

• Shivering: This is caused by rapid contraction and relaxation of the muscles. A large amount of heat is generated during the process. This heat is utilized to raise the temperature of the body.

• Cutaneous Vasoconstriction: The arterioles and the venules supplying the superficial parts of the body begin to constrict. This is mediated by increase in SANS outflow to the superficial vessels. As a result, thefractional volume of blood exposed for heat conduction reduces and minimal amount of heat is dissipated via the superficial vessels. This cutaneous vasoconstriction causes a decrease in cutaneous blood pressure, blood flow and blood volume; however, the velocity of the blood in these cutaneous vessels increases. All these changes ensure that less heat is dissipated to allow for conservation of heat within the core of the body.

• Decreased Sweating: Decreased cholinergic sympathetic activity causes the sweat glands to suppress sweat production. Heat is, therefore, prevented from losing through evaporation of sweat.

• Hair Erection: The contraction of pilorector muscle causes the hair on skin to stand on their ends. These hair trap air which acts as an insulator (air is a poor conductor of heat). Hence, heat loss is minimized.

The opposite of the aforementioned sequence happens when fever is broken and the pyretic (fever causing) agents are neutralized. The hypothalamic set point is normalized and the body's temperature is brought back to 37'C through the reversal of events described earlier:

• Cutaneous Vasodilation: SANS outflow to cutaneous vessels is reduced. This increases the cutaneous blood flow allowing for more heat dissipation from the superficial vessels. . This cutaneous vasodilation causes an increase in cutaneous blood pressure, blood flow and blood volume; however, the velocity of the blood in these cutaneous vessels decreases. All these changes ensure that more heat is dissipated to allow for less conservation of heat within the core of the body.

• Increased Sweating: Increased cholinergic sympathetic outflow to sweat glands increases perspiration. This sweat, upon evaporation, has a cooling effect on the body.

• Hair erection: The pilorector muscles relax and the cutaneous hair are relaxed. The insulating effect of trapped air is reduced. More heat is lost from the body.

This video is part of the blood flow regulation series. In this video we will present: Role of the blood brain barrier. Brain's predeominant use of the autoregulation for its control. Role of changing pH for the blood flow. Role of the oxygen vs. carbon dioxide for the brain's blood flow. Various nuclei that take part in controlling the blood flow and pressure in the body to optimize the flow to the brain.

CVS PHYSIOLOGY LECTURE # 14 STUDY NOTES:

AUTOREGULATION – CEREBRAL BLOOD FLOW

The vessels supplying the brain tissue are separated from the CSF by a blood-brain barrier. Blood flow in these vessels is autoregulated through intrinsic mechanisms(autoregulation). The brain does have sympathetic nerves innervating its blood vessels but these nerves do not play any role in regulating the blood flow. Intrinsic mechanisms that are involved in autoregulation of cerebral blood flow are theorized as follows:

1) Myogenic theory: This theory states that increase in blood flow in cerebral vasculature is counteracted by contraction of smooth muscles surrounding the blood vessels. This action helps to nullify the increase in blood flow and pressure.

2) Metabolic theory: According to the metabolic theory, the brain has the ability to autoregulate blood flow in response to changes in pH of the blood. The pH of blood circulating in the cerebral vasculature is different from that in the CSF. In other words, it is not necessary that the CSF will undergo changes in its pH if the blood being delivered to the brain has a different pH. This is explained by the fact that H+ ions, being positively charged, cannot travel across the blood-brain barrier. The pH of blood changes regularly with changes in the body. Hypoventilation causes respiratory acidosis which causes the pH to decrease. Similarly, ingesting drugs like aspirin, sulfonamides etc also cause marked changes in pH of blood. Therefore, if the H+ ions were allowed to pass uninterruptedly across the blood-brain barrier, the consequent changes in pH would have caused devastating effects on the brain tissue. On the other hand, gases such as carbon dioxide and oxygen can cross the blood-brain barrier as they don’t carry a charge. The relation of blood flow with carbon dioxide is linear, i.e. increase in carbon dioxide concentration will directly cause increase in blood flow. The effects of oxygen on the cerebral blood flow are negligible; however, pathologically increasing oxygen concentration will show a prominent decrease in blood flow.

Hypoventilation causes carbon dioxide levels to increase in the blood. After crossing the blood brain barrier, carbon dioxide enters the CSF where it reacts with water and carbonic acid . The carbonic acid formed disassociates into hydrogen ion and bicarbonate ion. The H+ ions act on the ventrolateral part of medulla which is the central chemoreceptor of the body. The chemoreceptor zone detects changes in the chemical content of the body. The role of central chemoreceptors is different from that of the peripheral chemoreceptors in maintaining the homeostasis in the body. When triggered, it sends impulses to the nuclei present on the lower 1/3rd of Pons and upper parts of Medulla. These areas of brain are involved in cardiovascular and respiratory changes that are carried out through sympathetic and parasympathetic nerves. As a result, the vessels in the body as well as in the brain vasodilate and the blood flow increases. Moreover, intrinsic metaboliteswhich are released by the cerebral tissues cross the blood-brain barrier and act on the vascular smooth muscles. This causes further vasodilation of the cerebral vessels. These vasodilator metabolites include the following:

• K+ ions

• H+ ions

• Bradykinin

• Nitric Oxide

The Monro-Kellie Doctrine: The principle says that the combined volume of Brain, blood and CSF in the cranial vault is maintained at a constant value in all circumstances. If a change in volume occurs in either of the constituents, the volume of the other fluid is shifted out or into the cranium in order to compensate for the change.

This video is part of the blood flow regulation series. In this video we will present one of the most important topic in the CVS physiology i.e. Coronary Blood Flow Regulation. We will present the properties of the coronary circulation. We will discuss the coronary filling during the diastole instead of the systole. We will discuss the impact of the coronary arteries supplying from the surface instead of being embedded in the tissue.

STUDY NOTES:

AUTOREGULATION – CORONARY BLOOD FLOW

The coronary vasculature supplies blood to the muscles of the heart (myocardium). These coronary arteries are the first branches (right & left coronary arteries) that arise from the aorta, and they run on the surface of the heart's muscle. Branches from the arteries penetrate the muscle in order to supply blood to deeper myocardial tissues. When the heart contracts during systole, the small arteries that are embedded deeply within the heart musculature are also squeezed along with the heart. This mechanical compression of coronary arteries causes a brief period of occlusion of coronary blood flow during systole. Therefore, it should be established that the whole body receives oxygenated blood during systole except for the heart itself. The heart will be supplied with the oxygenated blood when the atria and ventricles are in a relaxed state which happens during diastole. At that time, the coronary vasculature is not compressed and the perfusion is at a maximum. The right heart muscles contract with lesser force compared to the left heart. Hence, a relatively small amount of perfusion is maintained in the right heart even during systole.

Even under normal resting conditions, the heart tissue extracts 80% of the total oxygen content from the blood that is supplied to it. This high extraction of oxygen is necessary to meet the demands of highly active muscles of the heart. The demand for oxygen is increased substantially when there is an increase in the heart rate, as happens during exercise. Compared to the cardiac muscle, the skeletal muscle extracts only 20% of oxygen from the blood at normal resting conditions. In other tissues, when oxygen demand increases, vasodilatory metabolites such as H+ ions and carbon dioxide cause a rightward shift of the oxygen dissociation curve. This allows greater dissociation of oxygen from the hemoglobin.However, this rightward shift of the hemoglobin oxygen dissociation curve is not valid for the blood in the coronary circulation. This is because the extraction of oxygen by heart tissue is already at maximum level even under normal resting conditions. Therefore, the increased demand for oxygen during exercise can only be compensated by increasing the blood flow rate of the coronary circulation.

The flow of coronary vasculature is under the influence of both intrinsic and extrinsic mechanisms. The extrinsic mechanisms include the sympathetic and parasympathetic nervous systems. 

• The PANS input is relayed by the right and left vagus nerves. Right vagus nerve innervates the Sinoatrial node i.e SA Node, while the left vagus nerve innervates the AV Node. The PANS regulates the blood flow indirectly by controlling the heart rate (chronotropy) and the force of contraction (inotropy). 

• The SANS innervates the SA Node &AV Node, the myocardium and also the vascular smooth muscle of coronary vessels. SANS receptors are alpha-1, beta-2 predominantly the alpha-1 type. Hence, SANS regulates the heart rate, force of contraction of ventricular myocardium and the flow into the coronary vasculature. However, the extrinsic mechanisms involved in vascular diameter changes are ineffective during physiologicalconditions. Although there is sympathetic stimulation on the vascular smooth muscles, the effects are negated by the constant release of nitric oxide from the endothelium. If this nitric oxide release is blocked by an atherosclerotic plaque, the unchecked sympathetic stimulation causes vasoconstriction leading to the pain of angina. Atherosclerosis decreases coronary perfusion by reducing the coronary artery lumen and also by blocking the release of NO from the coronary artery endothelium.  

Under physiological conditions, the metabolism induced changes in vascular caliber are more prominent. The metabolites produced by the heart tissue responsible for vasodilation are:

• H+ ions

• K+ ions

• Adenosine

• Bradykinin and Prostaglandins

Volume - Work Relationship

There is a direct relationship between the volume of blood entering the heart (preload) and the work done by the heart to pump it out. The pressure remains the same as there is no change in myocardial contractility or afterload. This can be observed when a person is exercising during which the volume of blood returning to the heart increases.

Pressure - Work Relationship

There is a direct relationship between the pressure developed in the peripheral vasculature and the work done by the heart against it. The demand for oxygen in pressure overload situations is higher than in volume overload. Patients with atherosclerosis show this kind of pressure - work relationship in their cardiovascular system.

This video will present: Properties of the pulmonary vasculature. Division and the filtration function of the pulmonary vasculature. Metabolic functions of the pulmonary vasculature. Comparison of the pulmonary and systemic vasulatures. Change in the pressures with breathing and valsalva's manuver. Clinical points of the pulmonary vasculature.

This video will present: Properties of the pulmonary vasculature. Division and the filtration function of the pulmonary vasculature. Metabolic functions of the pulmonary vasculature. Comparison of the pulmonary and systemic vasulatures. Change in the pressures with breathing and valsalva's manuver. Clinical points of the pulmonary vasculature.

This video is part of the blood pressure regulation series. We discuss the baroreceptors and their contribution for maintaining the blood pressure. We will discuss the various type of mechanisms that help control the blood pressure. {article:https://articles.drbeen.com/2016/10/19/blood-pressure-control-by-baroreceptors/}

CVS PHYSIOLOGY LECTURE # 16 STUDY NOTES:

BLOOD PRESSURE CONTROL BY BARORECEPTORS

The MAP i.e. mean arterial pressure, also considered as the perfusion pressure, is taken as the pressure difference between the arteries and the veins. The regulation of blood pressure is done in order to maintain the MAP. The MAP hence dictates the amount of oxygen and nutrients that is supplied by the blood vessels and the waste that is carried away from the tissues.

The body has the ability to counteract long term as well as short term changes in blood pressure. The long term pressure changes cause the body to respond through the activation of renin-angiotensin system. 

Rapid/short term changes in blood pressure compel the body to activate the following receptors:

• Baroreceptor present on the arch of aorta and carotid sinus

• Chemoreceptors present all over the body, aorta and carotid sinuses

• Atrial receptors present on the wall of right atrium

These receptors are modified nerve endings that are sensitive to rapid offsets in blood pressure. Rapid offsets in pressure can occur, for example, in a previously standing person who suddenly sits down. During the process, a large volume of blood is shifted from the peripheral to the central regions of the body. Consequently, a large volume of blood enters the heart and this volume overload (increased preload) causes the heart to increase its cardiac output. A simultaneous increase in blood pressure will also be observed with increase in cardiac output. The increase in blood pressure is registered by the baroreceptors which are densely situated on the walls of the arch of aorta and the carotid sinus which is present on internal carotid artery.

Similarly, a drop in blood pressure is registered by the baroreceptors when the person stands up suddenly from a sitting position. These pressure sensing bodies are modified nerves with stretch receptors on their ends. These stretch receptors are attached to the cytoskeleton present within the nerve endings. These nerve endings are called spray type nerves. High blood pressure in the blood vessels causes stretch of these receptors which results in movement of sodium ions into the nerve endings, thereby, initiating an action potential. 

These baroreceptors have a baseline firing pattern. That means they have an intrinsic potential to generate action potentials at a particular frequency at all times. This frequency is increased when the baroreceptors receive a stretch stimulus secondary to increase in blood pressure. The carotid sinuses increase their rate of impulse generation when the pressure in them builds up to values greater than 50 mm Hg. Below thisthreshold pressure, the carotid baroreceptors fail to initiate an action potential. On the other hand, the arch of aorta can record drops in blood pressure up to 30 mm Hg. The upper limit for blood pressure, after which the frequency of action potential stops increasing, is 175 mm Hg. The normal MAP is calculated to be 93 mm Hg. At this pressure, the baroreceptors are believed to be the most sensitive and even slight changes in pressure will result in rapid firing of action potentials. At blood pressures lower than 30 mm Hg, the chemoreceptors come into play. The chemoreceptors function by sensing the arterial concentration of carbon dioxide, oxygen, Ph and other metabolites rather than detecting changes in blood pressure.

STRUCTURE OF THE CAROTID SINUS

The carotid sinus is present on the base of internal carotid artery at the level of bifurcation of the common carotid artery. The sinus area is slightly dilated as the tunica media which is normally comprised of muscles, is relatively thin. The tunica adventitia, on the other hand, is thicker than usual. This is the layer of the blood vessels where the nerve receptors are situated. Same is true for the location of baroreceptors on the arch of aorta.

THE BARORECEPTOR REFLEX

The baroreceptor reflex, like other reflex arcs, is comprised of three units: 

1) Afferent nerve carrying impulses from the receptors, 

2) Central processing unit 

3) An efferent nerve that innervates the effector

Afferent impulses from the carotid sinus are carried by the Herring nerve, a branch of Glossopharyngeal nerve (CN-9). In the case of baroreceptors present on the arch of aorta, the Vagus nerve (CN-10) is the afferent nerve that carries impulses to the spinal cord. Both, the Vagus nerve and the Glossopharyngeal nerve, feed impulses from the baroreceptors into the nucleus of tractus solitarius. These nuclei are situated in the medulla of the spinal cord and their job is to process the incoming afferent impulses. Also within the Medulla and lower 1/3rd of the Pons, there arevasoconstricting center, the vasodilatory center and the cardio-inhibitory center. These centers receive processed impulses from the nucleus of tractus solitarius and from here efferent impulses in the form of sympathetic and parasympathetic nerves arise. Impulses are carried to the heart via the parasympathetic Vagus nerve. Sympathetic impulses travel down the intermedio-lateral segment of the spinal cord and give rise to efferent motor spinal nerves which enter the sympathetic ganglion running parallel to the spinal cord. Postganglionic sympathetic nerves ultimately supply the heart and the peripheral vasculature. Another preganglionic sympathetic nerve also supplies the adrenal medulla which results in the release of epinephrine and norepinephrine, which further contribute in enhancing the sympathetic activity. The end result is either an increase or decrease in the blood pressure, thereby correcting the disturbance in hemodynamics of the body. This phenomenon is also referredto as the buffering effect, since the change in pressure is buffered back to normal. The Vagus and Glossopharyngeal nerves, because of the same reason, are therefore known as the buffering nerves.

The factors responsible for change in mean arterial pressure are formulated as follows:

➢ MAP = Heart Rate x Cardiac Output (CO)

Whereas, CO = SV (stroke volume) x TPR (total peripheral resistance)

Therefore, MAP = HR x SV x TPR

The stroke volume is altered by altering the force of contractility of the heart muscles. The sympathetic nerves supplying the heart muscles affect the stroke volume. The parasympathetic nerves supplying the SA and AV node are responsible for producing changes in heart rate. The TPR can be increased or decreased by changing the diameter of peripheral vasculature which is under the control of the sympathetic nervous system.

EFFECTS OF BARORECEPTORS DURING VARIOUS CONDITIONS

1) DUE TO CHANGES IN BLOOD PRESSURE

a. Reduced Blood Pressure: Reduction in blood pressure will result in a decrease in the number of afferent impulses from the baroreceptors. The sympathetic activity will increase and as a result, the TPR, HR and the stroke volume will allincrease. At the same time, the parasympathetic input will taper down. All these changes will result in increasing the blood pressure back to normal

b. Increased Blood Pressure: This happens in situations like exercise or stress. Increased blood pressure will result in stretching of the stretch receptors. This increases the frequency of afferent impulses. Sympathetic supply will decrease and the parasympathetic system will take over. Finally, the blood pressure is decreased back to normal.

2) DUE TO CHANGES IN CARDIAC OUTPUT

a. Decreased Cardiac Output: Occurs in situations of vomiting, diarrhea, hemorrhage etc. As a result of these, both the volume, and therefore pressure of the blood decreases. Afferent impulse firing of the baroreceptors decreases. As a consequence, there’s a sympathetic overflow which causes an increase in HR, TPR and SV. Due to an increase in these parameters, the blood pressure is raised back to normal.

b. Increased Cardiac Output: There’s an increased impulse generation from the baroreceptors due stretch caused by increased volume of blood. This increased afferent input from the baroreceptors results in activation of the PANS. Once activated, the parasympathetic nervous system decreases the blood pressure back to normal.

3) MASSAGING THE CAROTID SINUS

Massaging the carotid sinuses physically increases the pressure on the baroreceptors present there. The carotid baroreceptors respond by increasing the rate of afferent impulse firing. The sympathetic system will be shut down and the parasympathetic system is activated. This results in events leading to decrease in blood pressure of the body. Patients who have atrial arrhythmias are asked to massage carotid sinus to decrease heart rate.

4) STENOSIS OF CAROTIDS

Stenosis of carotids proximal to the sinus or obstruction of the carotids due to atherosclerosis will cause the baroreceptors to register a decrease in pressure. Therefore, sympathetic system activation follows. Increased sympathetic activity causes a resultant increase in blood pressure. This increase in blood pressure may cause hypertension in an otherwise normal person.

The above factors and their affect on the baroreceptor response are summarized in the table below:

It’s important to understand that baroreceptor control of BP is a short term regulation of blood pressure. Any short term derangements are dealt via the baroreceptor response, whereas long term control of the BP is controlled via the RAAS (Renin Angiotensin Aldosterone System). The baroreceptors alsohave the ability to adapt to chronic changes in blood pressure. If the mean pressure is changed over time to a new value, the baroreceptors will start using that MAP as the baseline. Any subsequent blood pressure changes will then be rectified keeping in view the new baseline value of MAP.

CVS PHYSIOLOGY LECTURE # 17 STUDY NOTES:

ELECTROPHYSIOLOGY OF HEART

STRUCTURE OF THE CONDUCTING SYSTEM

The atria are separated from the ventricles by a ring of fibrous tissue. This fibrous demarcation acts as an insulator, thereby barricading the entrance of electrical activity from the atria into the ventricles. The functional structure of the heart requires it to fill the atria with blood before the ventricles. Therefore, it is important for the atrial musculature to contract first and force blood into the ventricles before the ventricles undergo contraction. After a time lapse of milliseconds, electrical activity in both the ventricles causes them to contract and pump blood to the pulmonary circuit and to the rest of the body.

Electrical activity in the cardiac muscle is initiated by the sinoatrial node (SAN), located near to the opening of superior vena cava. The SA node is comprised of a collection of modified cardiac cells that have the potential to generate electrical signals. Multiple pathways, originating from the SAN, carry electrical signals to the atrial muscles. Similarly, one of the pathways stimulates the atrioventricular node (AVN) present at the base of right atrium and limited by the coronary sinus, the atrial septum and the tricuspid valve (Coch’s triangle). Bundles of fibers arise from the AV node, pierce the atrioventricular fibrous ring and enter the ventricles. In the ventricles, the fibers recollect and divide into two bundles that run down the interventricular septum. These bundles are known as the bundle of His. Upon reaching the apex of the heart, the bundles of His give rise to Purkinje fibers that ascend along the ventricular walls in a fashion which allows for spread of electrical activity in an ascending fashion (from the apex to upwards). As the conduction fiberspass from atria to ventricles their diameter increases.

TYPES OF CELLS PRESENT IN THE CARDIAC SYSTEM

The cells of the cardiac system are primarily classified as follows:

• Functional Cells

• Electrical Cells

1) Functional cells of the heart are further divided into contractile cells and conducting cells. Contractile cells are basically muscular cells that are joined together at their ends forming intercalated discs. Gap junctions between cells within the intercalated discs allow movement of ions, thereby causing the heart to work as a syncytium (single unit). Hence, the contractile cells show properties of conduction as well. Conducting cells, on the other hand, are modified to allow passage of electrical current only and do not exhibit any contractile properties.In the embryonic stage they were contractile muscle cells which later became conducting cells.

2) Electrical cells are sub-classified into fast and slow fibers depending upon the conduction velocity and speed of depolarization which they exhibit. The rate at which an action potential travels through a conducting fiber depends on its diameter and the presence of various channels on its cell membrane. Purkinje fibers have the largest diameter relative to the rest of the fibers in the conducting system. Hence, Purkinje fibers have the highest conduction velocity. The diameter of His Purkinje fibers is 150 times larger than AV fibers and 6 times larger than Ventricular muscle fibers. In general, the conducting fibers in the heart also possess fast sodium channels on their cell membranes. The number of these fast sodium channels helps determine the rate of depolarization and hence, the conduction velocity.Velocity of conduction of His Purkinje fibers is 4m/sec while that of AV fibers is 2m/sec.

The two nodes (SAN & AVN), on the other hand, have slow calcium channels present on their cell membranes. They do not have sodium channels. Movement of ions through these channels results in a gradual increase in the membrane potential leading to slow depolarization of the nodes. They have slow depolarizing fibers.

Another determinant affecting conduction velocity is the presence of gap junctions between cardiac cells. Gap junctions facilitate movement of ions from one cell to another. Higher the number of these gap junctions, higher would be the conduction velocity as more cells get depolarized at a time. The AV node and its emergentfibers have the least number of gap junctions and hence, the conduction velocity is slowest. 

BEATS PER MINUTE:

The size of the cardiac cycle is determined by the formula

60 seconds

Number of beats per minute = 60/72=0.8 seconds.

DIRECTION OF IMPULSE TRAVEL

Before moving on, it should be noted that the two nodes (SAN & AVN) and all the conducting fibers in the heart muscle have an intrinsic ability to undergo depolarization. This explains why even if the heart is isolated from the rest of the body, it will resume its pacemaker activity and continue to beat on its own. An isolated SA node has the highest frequency of impulse generation, i.e. 100 beats/min. This intrinsic rhythm of the SAN is regulated down to 72 beats/min under the influence of the autonomic nervous system. Similarly, the AV node has the ability to depolarize at a rate of 60 beats/min. SA node, having a considerably higher frequency of depolarization, overrides the pace maker activity of the AV node. This causes the AV node to generate action potentials at a rate similar to SA node. Upon cessation of high frequency impulses from SA node, as happens during bundle blocks, due to ischemia or experimental destruction of SA Node the AV node is shown to beat at its own inherent frequency. There is a respective decrease in the frequency of depolarization as we move along the bundle of His and the Purkinje fibers. This relative difference in the intrinsic rhythm of different parts of the cardiac conduction system allows a uni-directional flow of impulses across the entire conducting system. 

It’s important to remember that, AV bundle is the only pathway which allows electrical transmission of impulses from atria to the ventricles. Moreover, the impulses are prevented from propagating in retrograde direction (back into the atria from the ventricles) by the fibrous atrioventricular ring or annulus (insulating layer). If the impulses were allowed to travel back into the atria through accessory pathways, the heart would lose its rhythmical beating and arrhythmias may ensue.

DURATION OF IMPULSES

Duration of impulses is important as it dictates periodic filling of the atria and ventricles and ejection of blood effectively. The duration of an impulse travelling along the conducting system can be briefly described as follows:

• It takes 0.03 seconds for an impulse to travel from SA node to the AV node. 

• The speed is substantially reduced as impulses reach AV node because of its smaller diameter (1*3*5mm) and fewer gap junctions. As a consequence, a time lapse of 0.09 seconds occurs within the AV node. Since, impulse transmission is the slowest within the AVN; it’s a site for various drugs that affect the heart rate.

• Travelling further, it takes 0.04 seconds for the impulse to move along the AV bundle and the bundle of His. 

• It takes another 0.06 seconds for the impulse to spread throughout the ventricular muscles as the fast Purkinje fibers allow rapid and instantaneous conduction of nerve impulses. This is made possible due to the large diameter of Purkinje fibers and presence of numerous gap junctions. The latter allows the ventricles to work as a syncytium, resulting in simultaneous contraction of the entire ventricular musculature. If simultaneous contraction of ventricles does not occur then arrhythmiasare induced and the person dies due to low cardiac output.

ACTION POTENTIAL:

The action potentials from SA node, Atria, AV node, Bundle of His, Ventricles are different from each other.  Nodal action potential from SA node does not have phase I, II but has phase 0, III, IV. If we superimpose all the Action potentials on the ECG the Ventricular muscle depolarization coincides with the QRS complex while that of Atrial muscle with P wave. Repolarization of atria is buried in the QRS complex while that of ventricle is T wave.

This video presents nodal action potentials. These action potentials occur in the cardiac tissues that exhibit automaticity. A comparison of the myocardial action potential with the nodal action potential is also made to make sure that you are not confused during the Steps.

STUDY NOTES:

NODAL ACTION POTENTIAL

NODAL ACTION POTENTIAL VS. VENTRICULAR ACTION POTENTIAL

The nodal tissues and the Purkinje fibers exhibit automaticity in their properties as they are able to undergo spontaneous depolarizations. In other words, these tissues do not require the need of an external stimulus or a trigger to undergo depolarization. This is in contrast to ventricular fibers that do not show automaticity. The reason behind this phenomenon can be explained as follow:

• The resting membrane potential (RMP) of nodal tissues is less negative than the RMP of ventricular fibers. This allows the nodal tissue channels to operate in a semi-activated state even during the resting phase of the action potential. The comparatively more negative ventricular fibers do not show this property and hence, are not easily activated by low voltage impulses.

• Secondly, the presence of fast sodium channels and slow calcium channels, in ventricular fibers and nodal tissue respectively, play an important role in the automaticity of a cell. The slow calcium channels in the nodal tissues are responsible for the peak voltage occurring during a nodal action potential. Whereas, in the ventricular muscle fibers, the fast sodium channels are responsible for the same voltage spike and the calcium channels are involved only during the plateau phase.

PHASES DURING AN ACTION POTENTIAL

SLOPE OF DEPOLARIZATION DURING NODAL ACTION POTENTIAL

There is a gradual increase in the RMP of nodal tissues from -55mV to -40mV. This is known as the slope of depolarization, after which occurs the Phase 0 of action potential. This slope is important as multiple factors, such as the ANS and certain drugs, act to alter this phase and bring about changes in the rate and rhythm of cardiac activity. An increase in the slope of depolarization will cause the SA Nodeto generate action potentials at a higher rate. Flattening of the slope will result in fewer numbers of action potentials in a given time which greatly decreases the rate at which the heart beats.

CONTROL OF HEART RATE & CONDUCTION VELOCITY

An isolated SA node has the highest intrinsic rhythm of impulse generation, i.e. 100 beats/min. This intrinsic rhythm of SA Node is regulated down to 72 beats/min under the influence of the autonomic nervous system. Similarly, the AV node has the ability to depolarize at a rate of 55 beats/min. SANode, having a considerably higher frequency of depolarization, overrides the pace maker activity of the AVNode. This causes the AV node to generate action potentials at a rate similar to SA node. Upon cessation of high frequency impulses from SA node, as happens during bundle blocks, the AV node is shown to beat at its own inherent frequency. Impulse generation of purkinje fibers is at a rate of 15-30 beats/min. There is a respective decrease in the frequency of depolarization as we move along the bundle of His and the Purkinje fibers. This relative difference in the intrinsic rhythm of different parts of the cardiac conduction system allows a uni-directional flow of impulses across the entire conducting system. 

As described above, the SA node has the highest rate of depolarization and therefore, it dictates the rate of cardiac activity. Altering with the mechanics of SA node will cause alterations in the rate of heart beat as a whole. Similarly, the velocity of conduction is controlled by the AV node(dimensions are 1*3*5 mm) and AV bundles as the speed of impulse travelling through them is the slowest. Time duration for conduction through these is 0.12 seconds. Velocity of impulse at AV node and AV bundle is 2 meters per second and 4 meters per second in purkinje fibers. Dromotropes act on these areas of the conducting system and cause changes in the velocity of impulse conduction.

DIFFERENT ION CHANNELS AND THEIR AFFECT ON THE ACTION POTENTIAL

1) VENTRICULAR ACTION POTENTIAL​​

• The Phase 0 of ventricular action potential is brought about by fast voltage gated sodium channels. This phase is referred to as the upstroke of action potential and corresponds to the QRS complex of the ECG.

• At the end of depolarization, there is a brief fall in the voltage of action potential as a result of opening of transient chloride and potassium channels. This isPhase 1 of the depolarization. Fast sodium channels transition to their inactivated state.

• L-type Calcium channels open in the Phase 2 of action potential. The inward calcium current balances the outward potassium current and there’s little change in membrane potential, which explains the plateau. During this plateau phase no change in the voltage is registered. Phase 2 or the plateau phase of the ventricular action potential corresponds to ST segment of the ECG.

• Phase 3 corresponds to repolarization during which Potassium channels open in response to voltage and ion concentration difference. By this time L-type Calcium channels, which were open during the plateau phase, have also closed. Repolarization corresponds to the T-wave on the ECG. Inward Potassium current enters via the:

▪ IK1 channels: Inward rectifying K channel 

▪ IKR channels: Slow and rapid delayed rectifying K channel 

• The action potential is brought back to the resting membrane potential (RMP) or Phase 4. The sodium-potassium ATP-ase is responsible for the maintenance of RMP until the arrival of the next action potential. Fast Na+, L-type Ca2+, and rectifying K+ channels (IKR) close, but IK1 channels remain open.

2) NODAL ACTION POTENTIAL

It’s important to understand that the nodal tissue (SA and AV) lacks fast Na+ channels. Thus, the upstroke of the action potential is mediated by inward calcium current rather than the sodium current. In addition, note that phases 1 and 2 are absent in the nodal tissue.

• The RMP (Phase 4) in nodal tissue is kept at -55mV by the Na-K ATPase pump. The less negative RMP of nodal tissue, compared to -70mV of ventricular tissues, allows it to exhibit automaticity. At -55mV, the fast sodium channels (also known as 'funny' channels) are in a semi-open state which causes leakage of positive ions into the nodal cells. Leakage of ions causes an increase in the membrane potential in a positive direction. The membrane potential gradually increases to -40mV. Upon reaching this threshold potential, the sodium channels close and remain closed for the rest of the action potential as they enter a state of refractoriness. 

• At this point the slow-gated T-type calcium channels open which creates the spike of depolarization (Phase 0). These differ from the L-type calcium channels (in the ventricular tissue) in that they open at a more negative membrane potential (-70 mV).The calcium ions that enter the cells during this phase are also involved in excitation-contraction coupling of the myosin light chains with actin filaments. 

• Repolarization (Phase 3) in nodal tissue is similar to that of ventricular muscle fibers. Inward Potassium current enters via the IK1 & IKR (rectifying K currents) channels. The fall in membrane potential will result in activation of the sodium-potassium ATPase and the cycle is repeated.

CVS PHYSIOLOGY LECTURE # 19 STUDY NOTES:

AUTONOMIC CONTROL OF NODAL ACTION POTENTIAL

INNERVATION OF THE HEART

1) PARASYMPATHETIC NERVOUS SYSTEM (PANS)

The right and left Vagus nerve (CN10) supply the SA node and the AV node respectively. Apart from the two nodes, the Vagus nerve also innervates the atrial muscles and the AV bundle. Parasympathetic supply to the ventricular muscles is very sparse as only a few vagal branches innervate the ventricles. Therefore, it is safe to say that the Vagus supply is limited to the two nodes and the atrial muscles only. PANS causes a marked decrease in heart rate (negative chronotropic effect) and a slight decrease in heart muscle contractility (negative inotropic effect).

2) SYMPATHETIC NERVOUS SYSTEM (SANS)

On the other hand, the sympathetic supply to the heart is global as it supplies the two nodes as well as the atrial and ventricular muscles. SANS increases the heart rate and the contractility of the myocardium i.e. positive chronotropic and inotropic effect.

RATE OF DISCHARGE OF NODAL TISSUE

There is a gradual increase in the RMP i.e. resting membrane potential of nodal tissues from -55mV to -40mV and this is referred to as the slope of depolarization. Phase 4 is followed by the Phase 0 of action potential. At -55mV, the fast sodium channels (also known as 'funny' channels) are in a semi-open state which allows leakage of positive ions into the nodal cells. Leakage of sodium ions causes an increase in the membrane potential in the positive direction (towards 0). The membrane potential gradually increases to -40mV. Upon reaching this threshold potential, the sodium channels close and remain closed for the rest of the action potential as they enter a state of refractoriness. 

An increase in the slope of depolarization will cause the SA node to generate action potentials at a higher rate. Flattening of the slope will result in decreased number of action potentials in a given time which greatly reduces the rate at which the heart beats.

The action of the ANS on the Phase 0 of the action potential brings about changes in heart rate. SANS acts to increase the slope of depolarization so that the threshold potential (-40mV) is reached earlier than normal. This results in an increase in the heart rate. The PANS, via the vagal stimulation, causes a decrease in the slope of depolarization which causes a delay in reaching the threshold potential for spontaneous depolarization. This subsequently results in an increase in the duration of action potential, thereby decreasing the heart rate(negative chronotropic effect).

Additionally, changes in ionic conduction across the cell membrane also cause changes in the heart rate. However, the part of action potential that undergoes changes relies on the type of ions involved:

• Changes in sodium ion conduction cause a change in the slope of depolarization. This is similar to the effects of the autonomic nervous system. 

• Calcium channel conduction affects the rapid upstroke or Phase 0 of depolarization.  

• The repolarization phase is dependent upon the conductance of potassium ions. Hence, any changes in potassium ion conductance will affect the time taken for the nodal tissue to repolarize.

Faster the conduction of the above mentioned ions across the cell membrane, higher would be the frequency of depolarizations and vice versa. Dromotropy is a property of the cardiac conducting system which determines the conduction velocity of impulses across the cardiac conduction system. Impulse velocity is determined by the conductance of above mentioned ions. SANS causes positive dromotropic effect, thereby increasing the conduction velocity across the conduction system of the heart. On the other hand, PANS results in a negative dromotropic effect. Negative dromotropic effect will result in decreased conduction velocity across the cardiac conduction system. 

Rate changes in the SA node occur mainly via the action of autonomic nervous system. Whereas, the AV node and rest of the conduction system exhibit changes in their rate of depolarizations secondary to the movement of ions across their cell membranes.

TERMS USED TO DESCRIBE HEART RATE & CONTRACTILITY

1) Chronotropy: It refers to the rate of cardiac activity i.eheart rate. For example, the parasympathetic nervous system causes negative chronotropy and the sympathetic nervous system causes positive chronotropy.

2) Dromotropy: This term is used to describe the velocity of conduction within the conducting fibers. Negative dromotropic agents decrease the velocity of conduction. Positive dromotropy occurs when there is an increase in the velocity of conduction.

3) Inotropy: This is a term used to describe the contractility of the cardiac musculature (ventricular muscle mainly). SANS has a positive inotropic effect whereas PANS stimulation has a mildly negative chronotropic effect which isn’t that pronounced. 

MECHANISM OF ACTION OF AUTONOMIC NERVOUS SYSTEM AT MOLECULAR LEVEL

Primary neurotransmitters (Acetylcholine in PANS stimulation and adrenaline or noradrenalin in SANS stimulation) activate the G-coupled proteins present on the cell membrane of the conducting tissues. This results in the detachment of intracellularly bonded alpha subunit of the G proteins which acts on the sodium and calcium channels. The channels get activated or deactivated depending on the type of stimulation that occurs initially.

This video presents: Excitation contraction coupling in the heart tissue. Properties of the cardiac muscle compared to smooth and skeletal muscles Role of the extra cellular fluid calcium Beta agonists Action of actylcholine Cardiac glycocides (digitalis)

This video presents heart contractility and the factors influecing it namely: Heart rate Bowditch/trepp Post extrasystole Stretch Sympathetic system Parasympethetic system Cardiac glycosides (digitalis)

This video presents the concepts of preload and afterload. Both of these concepts are important to understand to assess the performance of the heart. Sarcomere structure function and its relationship to preload and afterload is also discussed. We will also discuss the difference between the passive tension and active tension. Notice that cardiac performance is assessed by: Heart rate Conduction velocity Preload Afterload Contractility

This video presents the physiology of the cardiac cycle. 
We will discuss: 

• Definition 
• Duration 
• Electrical activity of the heart during a cardiac cycle 
• Mechanical changes 
• Pressure changes in the atria ventricles and aorta 
• Volume changes in heart chambers 
• Heart sounds
• Venous pulse graph

This video presents the cardiac pressure volume graph and how to approach it when you see it in the Steps. There are high chances that you will get this loop in your steps exams.

This video presents the cardiac pressure volume graph and how to approach it when you see it in the Steps. There are high chances that you will get this loop in your steps exams.

This video presents the measurement of the cardiac output using Fick's method. We will also touch upon the doppler and thermodilution.

This video presents: Vascular function curve/graph Cardiac function curve/graph We will combine the two graphs and understand how to approach it in the exams. We will also see the effects of: Inotropy changes Venous return changes Total peripheral resistance changes We will also explain the difference between: Mean systemic pressure Mean circulatory pressure

Review This video presents: Vascular function curve/graph Cardiac function curve/graph We will combine the two graphs and understand how to approach it in the exams. We will also see the effects of: Inotropy changes Venous return changes Total peripheral resistance changes We will also explain the difference between: Mean systemic pressure Mean circulatory pressure

This video presents normal and abnormal heart sounds. Heart sound posts for auscultation Mechanism of the sound generation Abnormalities that can generate additional heart sounds or change the sounds

This video presents the mechanics of the murmur generation and the types of murmurs. Pathologies that give rise to murmurs are handled in the Pathology module.

Difference between intra-embryonic mesoderm and coelom Vasculogenesis angiogenesis Heart forming regions and the development of the heart tube Heart tube dilatations and their derivatives Septum transversum mesocordial septum transverse sinus Retinoic acid Levo Dyenin VE GF Kartagener's syndrome/primary cilliary disease Situs inversus.

STUDY NOTES:

HEART TUBES

INTRODUCTION: Cardiovascular system is the first organ system to start developing and reach a functional state; which is even before its own development is complete. Cardiovascular development occurs during the 3rd to 5th week of intraembryonic life. Up until the second week, diffusion is enough for embryo to receive the oxygen, nutrition and to get rid of the waste products. The lacunae of maternal blood filled spaces and embryonic villi of the syncytio-trophoblast are involved in an intimate relationship, which allows gaseous exchange via diffusion in between the developing embryo and the maternal blood. However, into the third week, diffusion alone is not sufficient to match the needs of the growing embryo and it needs a circulatory system, hence heart has to develop.

GASTRULA STAGE: Gastrula is a stage of development of embryo, when it is in the form of tri-laminar germ disc including ectoderm, mesoderm and endoderm. Endoderm is associated with umbilical vesicle; ectoderm is associated with Amniotic cavity. Cytotrophoblast around the gastrula develops multiple cavities. The cavities merge to form one big cavity called extraembryonic coelom. The cytotrophoblast is connected to embryo through the connecting stalk. The cellular layer from cytotrophoblast which covers the gastrula is called extraembryonic mesoderm. The Gastrula is a slipper shaped structure. From the dorsal view it has a neural plate with a primitive node a primitive pit and a primitive groove. Cranial side has a Buccopharyngeal membrane which would later develop into mouth. Caudal end has a cloacal membrane which would develop into anus.

HEART FORMING REGIONS: Around 15th day of intraembryonic life, multiple cavitations start appearing in the lateral plate mesoderm which later merge together to form a Horseshoe-shaped Intraembryonic Coelom. The Horseshoe shaped Coelom divides lateral plate mesoderm into two layers which are called Splanchnopleure (connected to underlying Endoderm) and Somatopleure (connected to overlying Ectoderm). It’s the splanchnic layer of mesoderm which mainly forms the cardiogenic area in the latter half of the 3rd week. In addition to this, Neural crest cells also contribute to heart formation especially the Aorticopulmonary septum and the Endocardial Cushion regions.

Around 17the day of intraembryonic life, the Endoderm layer of the Gastrula secretes VEGF, which causes Ectodermal cells to migrate into the cranial end of the underlying mesoderm and form Blood islands. A horseshoe shaped area forms on either side of the neural plate. The blood islands formed above the Prechordial plate (Cranial side) are called PrimaryCardiogenic or Heart-forming regions. 

CRANIAL & LATERAL BODY FOLDINGS: By the 17-18 days brain starts developing at a faster pace and overtakes the body’s growth so that the heart descends downwards to the chest region. Cephalic-caudal Body folding ensures that the cardiogenic area and septum Transversum (future diaphragm) come to lie under and below the prechordal plate and in frontof the foregut. The heart hangs from the foregut by a connection called prechordium.Lateral body folding approximates the intraembryonic coelom in the midline, folds of which give rise to adult pericardial sacs which envelope the cardiogenic area in the midline. 

DEVELOPMENT OF PRIMITIVE HEART TUBES: The ectodermal cells migrate into the mesoderm as cardiogeniccells which condense to form a pair of primordial Heart tubes. The pharyngeal area mesoderm contributes further cells which form a secondary heart forming region around the primordial heart tubes. Further cells are contributed the Splanchnic Mesoderm which form the myocardium around the primordial heart tubes. This newly formed Myocardium will start secreting Hyaluronic acid and other connective tissue components which are termed together and called as Cardiac Jelly. Cardiac jelly in future becomes the connective tissue of the heart. These newly formed primordial heart tubes are surrounded by pericardial cavity which provides the outer Parietal layer of the Pericardium which is adherent to the Fibrous pericardium in the adult heart. The Caudal or Inflow part of the Heart tube that is Sinus Venosus provides the cells which form the visceral or inner layer of pericardium, also called EPICARDIUM. By the 21st day the two primordial heart tubes fuse by apoptosis into a single endocardial or Heart tube. On 22nd day the embryonic heart starts beating.

DILATATIONS & DERIVATIVES OF THE HEART TUBE: The Primordial heart tube now orients itself into a cephalic INFLOW (Venous region) and a cranial OUTFLOW (Arterial Region) ends. At this point the primitive heart tube has five dilatations which are as following:

1. Truncus Arteriosus (Arterial Outflow region): Forms Adult Aorta, Pulmonary trunk and their respective semilunar valves.
2. Bulbus Cordis: Forms Smooth parts of Adult right ventricle (conus arteriosus) and left ventricle (aortic vestibule).
3. Primitive Ventricle: Forms trabeculated/rough parts of right and left ventricles.
4. Primitive Atrium: Forms trabeculated/rough parts of right and left atriums i.e., the pectinate muscles.
5. Sinus Venosus: On the right side it forms Sinus Venarum (smooth part of right Atrium), Superior vena cava and the inferior vena cava. On the left side it forms Coronary sinus and oblique vein of left atrium.

Note: (a) The vascular parts when incorporated into the adult heart form the smooth regions of the heart whereas the primitive chambers form the rough or trabeculated parts of the respective adult heart chambers.

(b) Incorporation of parts of the Pulmonary veins forms the smooth-walled part of the left Atrium. On the right side, incorporation of right sinus venosus forms the smooth-walled part of right atrium.

DEXTRAL LOOPING: The heart tube at this point undergoes Right sided bending or rotation which referred to as Dextral looping. The Truncus Arteriosus or the ventricularend of the heart tube grows more rapidly and tends to fold downwards, forwards and to the right side. Subsequently, the lower parts of the tube i.e., the primitive atria and sinus venosus tend to fold upwards, backwards and to the left side. This dextral looping tends to place the chambers of heart in their adult anatomic positions where the right ventricle forms most of the right border plus the anterior surface of the heart and the left atrium is the posterior most chamber of the heart. Also, the ventricles are rather more anteriorly placed relative to atria in an adult heart.

THE ROLE OF LEVO-DYNEIN, DEXTROCARDIA, SITUS INVERSUS & KARTEGENER SYNDROME: Levo-Dynein is a protein which involved in the formation of Cilia. However, Levo-Dynein also functions to create symmetry within the human body. An abnormality of Levo-dynein can lead to symmetry problems such as, Situs Inversus whereas the visceras tend to be present on the opposite sides of their normal anatomical location. It can also lead to Dextrocardia, which is a rare clinical condition in which the Apex of the heart is located on the right side of the body. The above two abnormalities often present as part of Kartagener Syndrome (Primary Ciliary Dyskinesia). Kartagener Syndrome results due to a defect in the dynein arm of the cilia which renders cilia immotile. It is a cause of infertility in both males and females due to immotile sperm and dysfunctional fallopian tube cilia respectively. In females there's an additional risk of ectopic pregnancies. Besides Dextrocardia on CXR and infertility in both sexes, Kartagener Syndrome can also lead to Bronchiectasis and recurrent sinusitis due to ineffectiveness of mucociliary escalator.

MESOCORDIUM & TRANSVERSE SINUS: Post the cranial-caudal body folding, the embryonic heart tubes come to lie in front of the foregut. This is before the fusion of the primordial heart tubes into a single Heart tube. At this point the primordial heart tubes are connected to the foregut via the Mesocordium. The Mesocordium itself is a derivative of peritoneum. Subsequently, a gap appears within the Mesocordium which is called transverse sinus and this eventually results in degeneration of Mesocordium, following which the Pericardial cavity is thus separated from the Foregut.

TERATOGENS EXPOSURE: Teratogens are substances (normally drugs) which can either cause birth defects or they can accelerate other embryonic deformities that are present. Developing embryo is most susceptible to teratogens exposure during its embryonic period which is from 3rd to 8th week (first 2 months).This is because the embryonic period is the time when most organ systems are developing; hence teratogen exposure at this point can be disastrous. Teratogens frequently tested by the USMLE are given below:

1. ACE Inhibitors: Cause Renal damage
2. Aminoglycosides: Cranial nerve 8, Vestibulocochlear Nerve Abnormalities.
3. Carbamazepine: Facial dysmorphism, developmental delay and neural tube defects.
4. Lithium (used to treat the manic phase of Bipolar disorder): Ebstein Anomaly in which the tricuspid valve leaflets are displaced inferiorly into the right ventricle. It presents with widely split S2 and Tricuspid Regurgitation.
5. Phenytoin: Can cause fetal Hydantoin syndrome i.e., cleft palate, cardiac defects and phalanx or fingernail hypoplasia.
6. Tetracyclines: Discoloration of teeth.
7. Thalidomide: Limb defects.

ROLE OF RETIONOIC ACID: Increased retinoic acid concentration in an area of blood vessel formation leads to formation of a venous channel. However, a decrease in retinoic acid concentration favours the formation of an arterial channel.

DIFFERENCE BETWEEN VASCULOGENESIS & ANGIOGENESIS:  Vasculogenesis is defined as formation of a new blood vessel literally from nothing or scratch. Angiogenesis on the other hand is defined as, formation of a new blood vessel from an existing vascular channel by branching. Regions of an existing blood vessel bud of as part of angiogenesis to create a new branch.

Review Difference between intra-embryonic mesoderm and coelom Vasculogenesis angiogenesis Heart forming regions and the development of the heart tube Heart tube dilatations and their derivatives Septum transversum mesocordial septum transverse sinus Retinoic acid Levo Dyenin VE GF Kartagener's syndrome/primary cilliary disease Situs inversus

This video presents: 1. Cells taking part in the development of the conduction system of the hear. 2. Origin and development of the annulus fibrous (fibrous insulating ring). 3. Formation of the conduction pathway. 4. Difference of the His purkenje from the rest of the conduction system.

STUDY NOTES:

CONDUCTION SYSTEM OF THE HEART

SAN which is present near the opening of the superior vena cava. SA nodal cells have the highest intrinsic rhythm of spontaneous depolarization (roughly 60- 100/min) which makes them the automatic choice for the pacemaker of the heart.

The AVN is present behind the endocardial cushions and in front of the coronary sinus. It's important to remember that the coronary sinus is actually the attritioned left horn of the sinus venosus. AV nodal cells have the second highest intrinsic rhythm (40-60/min). This automatically makes AVN the as the pacemaker of heart in case there's a damage to the SA nodal cells.

Bundle of HIS originates from the AV node and subsequently branches into two within interventricular septum. These two branches are the right and left bundle branches which ends up forming the HIS Purkinje system that supplies the papillary muscles and the rest of the ventricular myocardium. Papillary muscles are part of the trabeculated region of the ventricles which are derived from the primordial ventricle. Although, Purkinje cells are specialized for conduction only, they still possess an intrinsic rhythm of 35/min which gives them the property of automaticity. Hence, Purkinje system is third in line to take over as the pacemaker of the heart if anything goes wrong with both the SA and AV nodal cells.

The SA and the AV node develop from the sinus venosus. Before the sinus venosus gets incorporated into the right atrium and forms the conducting system of the heart, the primitive atrium serves as the function of the pacemaker.Atrial myocytes around the sinus venosus develop a faster intrinsic rhythm thereby naturally taking over as the pacemaker cells. These myocytes are derived from mesoderm.This means that as the myocardial cells are developing to form atria, they develop this ability to depolarize spontaneously. This allows the primitive heart to start beating by the 22nd day and that too without a true pacemaker, hence the primitive atria starts depolarizing even before the pacemaker is formed. Since sinus venosus is at the caudal end of the heart tube and serves as the inflow region. The initial pulsations are in coherence with the direction of the blood flow i.e., from caudal to the cranial side of the developing heart tube.  Eventually as the sinus venosus is incorporated into the right atrium, the SA node develops from the sinus venosus near the entry of the superior vena cava. 

The AV node also develops from the sinus venosus near the opening of the coronary sinus. As the AV node develops, bundle of HIS also develops along with it from the sinus venosus. The bundle of HIS develops within the interventricular septum and divides into right and left bundle branches. The cells around the AV node which become consolidated into forming the Bundle of HIS exhibit the MSX-2 homeobox gene. Purkinje fibers are actually modified contractile myocytes which start to function as conducting fibers when they become connected with Bundle of HIS cells.

Another important structure is the fibrous septum which insulates the ventricles from the depolarization of the atria and vice versa. This fibrous skeleton of the heart develops from the epicardium which is the visceral pericardium of the heart. The cells of the epicardium are derived from the local mesodermal cells around the sinus venosus as well.

Interatrial septal development. Right atrium and sinus venosus Right atrium and pulmonary veins Fate of sinus venosus Development of the left atrium Smooth vs pectinate parts of the atria.

STUDY NOTES:

ATRIAL DEVELOPMENT & CONGENITAL DEFECTS

Development of Interatrial Septum:

. Common congenital cardiac anomalies mostly occur due to defects in the formation of these septae. In this lecture and its subsequent review, we discuss the high yield topic of atrial septation and development plus relevant congenital defect which can occur during this process.

FUNCTION OF INTERATRIAL SPETUM:

1) It divides the primitive atria into a right and left atria.

2) During fetal life provides it provides a patent right to left shunt and ensures the shunt is not in the opposite direction of left to right shunt. During fetal life right to left shunts are essential for the survival of the fetus. A hallmark of the fetal circulation, which differentiates itfrom the adult circulation, is that the right atriumreceives the oxygenated blood from the placenta via the inferior vena cava. In an adult heart, the right side deals with the deoxygenated blood!

3) After birth, when there's no need a right to left shunt since the lungs have become functional, foramen ovaletends to close. At this point interatrial septum divides adult left and right atria into separate non-communicating chambers.

ATRIAL SPETATION:

Initially the right and the left atria are actually one single chamber which is referred to Primitive Atrium. Sinus Venosus provides the Inflow in this primitive atrium. The primitiveatrium is divided into two separate left and right atria following the process of atrial septation. Atrial Septation is actually a series of events which involves 2 septae (Septum Primum & Septum Secundum) and 2 foraminae (Foramen Primum & Foramen Secundum) forming within the primitive atria, thereby dividing it into a right and left atrium.

STEPS INVOLVED IN ATRIAL SEPTATION:

From the roof of the primitive atrium a flexible and crescenteric shaped Septum Primum grows inferiorly towards the endocardial cushions. The initial defect in between the down growing septum primum and the endocardial cushions is referred to as foramen primum. Foramen Primum functions to allow shunting of blood from the right atrium to the left atrium

1) Foramen Primum is eventually obliterated when the inferior edge of the septum primum fuses with the endocardial cushions. Just before the foramen primum closes, multiple small secondary defects form within the upper wall of septum primum as result of apoptosis. These multiple small defects in the upper wall of septum primum coalesce into forming a single defect called the foramen secundum. Foramen secundum is formed before the foramen primum is closed, and it serves to maintain the very important function of reinforcing a right to left shunt of the oxygenated blood entering the right atrium via the inferior vena cava.

2) While the septum primum is undergoing these changes, from the roof of the atrium and just to the right of septum primum, a second crescentic shaped septum secundum starts developing.  As the septum secundumgrows downwards, it extends and obliterates most of the foramen secundum. The remaining part of foramensecundum which isn't obliterated by the septum secundum is referred to as Foramen Ovale. The function of foramen ovale is the same as that of the foraminae primum and secundum, which was to maintain a right to left shunt.

3) It's important to remember that septum primum is a rather flexible structure compared to septum secundum which is a relatively rigid structure. This rather flexible property of the septum primum allows its inferior flap (which isn't covered by the septum secundum) to function as valve for foramen ovale. This valve allows the flow of blood from the right to left side thereby reinforcing the shunt, but it tends to disallow the backflow of the blood from the left atria to the right atria.

4) Septum Primum and Septum Secundum eventually fuse to form the interatrial septum. Most of the interatrial septum is formed from two septae (primum and secundum). However, the inferior part of the interatrial septum forms from a single septum (septum primum only), and hence this part is rather thinner compared to the rest of the atrial septae. This thinner part of the interatrial septum in the adult heart is referred to as Fossa Ovalis and is a major anatomical landmark of the adult right atrium. Fossa ovalis presents as a marked crescentic ridge on the medial wall of the right atrium.

5) Immediately after birth Foramen Ovale tends to close. After birth there's an increase in left atrial pressure. The above mentioned decreased right atrial and increased left atrial pressure changes result in closure of the foramen ovale after birth. 

CLINICAL & PATHOLOGICAL CONSIDERATIONS:

PROBE PATENCY OF FORAMEN OVALE: A probe is passed from the right atrium into the left atrium to check whether the foramen ovale has closed or not. In cases where the probe can pass through into the left atrium, it means that septum secundum & septum primum have not fused completely together and hence the foramen ovale is still patent

FORAMEN SECUNDUM DEFECT/ SECUNDUM TYPE ASD: This is the most common type of ASD. It occurs due to excessive resorption of the septum primum and septum secundum. It usually presents with delayed clinical symptoms after the age of 30, before the age of 30 it's usually asymptomatic. Identified after thirty years of age due to Right ventricular hypertrophy

primum type atrial septal defects result due to a failure of the septum primum to fuse inferiorly with the endocardial cushions

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1) COR TRICLOCULARE BI VENTRICULARE: It's basically a three chambered heart with one common atrium and two ventricles, thereby highlighting the situation where interatrial septum fails to develop. 

2) PREMATURE CLOSURE OF THE FORAMEN OVALE: As mentioned earlier that foramen ovale is supposed to remain patent until after birth. If however,foramen ovale closes early due to premature fusion of septae primum & secundum before birth, this can result in a hypertrophied right side of heart plus an underdeveloped left sided chambers.

DEVELOPMENT OF RIGHT ATRIUM & THE FATE OF SINUS VENOSUS: 

Heart tube with its dilatations undergoes an S-shaped bending which results in an orientation where the outflow tract (truncus arteriosus) lies most anteriorly. Behind the truncus arteriosus is the primitive ventricle and still behind is the primitive atrium. On the posterior surface of the primitive atrium opens the sinus venosus along with its branches. Branches of sinus venosus are anterior cardinal vein, posterior cardinal vein and the common cardinal vein. Two vitelline and umbilical veins also drain into sinus venosus. Initially the sinus venosus drains into the middle of the posterior wall of primordial atrium, however due to flow and hemodynamic changes, sinus venosus starts growing towards the right side. Ultimately sinus venosus ends up opening at the posterior right end of the right atrium. Hemodynamic changes responsible for this right side shifting of sinus venosus are as following:

1) An anastomosis forms between the anterior cardinal veins of either side, and the blood starts flowing from the left to the right side.

2) Umbilical and vitelline veins on the left side start degenerating. This results in an increased blood flow into the right side as blood from the caudal part of the fetus is also shunted to the right side of the right atrium.

3) Eventually the right umbilical vein also degenerates, and the right vitelline vein starts increasing in calibre. Endresult of these hemodynamic changes is that sinus venosus shifts and starts growing on the right side. 

On the left side the remaining degenerating pieces of the sinus venosus become the coronary sinus. Right vitelline vein in future becomes the inferior vena cava. The common cardinal vein becomes the future superior vena cava.  All these changes contribute to an increase in the size of right atrium since sinus venosus= has also shifted there as part of its development. Anterior view of the right atrium shows that it's divided by the crista terminalis into a smooth and rough or trabeculated part. The trabeculated parts of right atrium and the right auricle are derived from the primitive atria. The smooth parts are derived from the primitive inflow tract which was sinus venosus. Crista terminalis is the landmark where parts of sinus venosus were absorbed into right atrium as parts of right atrial development. The lower part of the sinus venosus marks the valve of the inferior vena cava. Also there is an opening of coronary sinus which actually is the degenerated left sinus venosus draining into the right atrium.

DEVELOPMENT OF THE LEFT ATRIUM: Left atrial development is relatively not as complicated. Trabeculated part and the left auricle form a very small component of left atrium and they're derived from the primitive atrium. Majority of the left atrium is its smooth part which is derived from the primordial pulmonary trunk which gets absorbed as part of left atrial development. Primordial pulmonary trunk is actually a budding off of the left atrium. The primordial pulmonary turn initially grows and forms four branches. However, so much of the primordial pulmonary trunk is absorbed into the making of left atrium that its four branches end up opening directly into the left atrium.

Atrial & Ventricular septum formation process begins at the same time by the start of the 4th week and wraps up by the 8th week. Though occurring simultaneously, however, atrial septation is a little ahead of ventricular septation. Common congenital cardiac anomalies mostly occur due to defects in the formation of these septae. In this lecture and its subsequent review, we discuss the high yield topic of atrial septation and development plus relevant congenital defect which can occur during this process.

FUNCTION OF INTERATRIAL SPETUM:

1. It divides the primitive atria into a right and left atria.

2. During fetal life provides it provides a patent right to left shunt and ensures the shunt is not in the opposite direction of left to right shunt. During fetal life right to left shunts are essential for the survival of the fetus. A hallmark of the fetal circulation, which differentiates it from the adult circulation, is that the right atrium receives the oxygenated blood from the placenta via the inferior vena cava. In an adult heart, the right side deals with the deoxygenated blood!

3. After birth, when there's no need a right to left shunt since the lungs have become functional, foramen ovale tends to close. At this point interatrial septum divides adult left and right atria into separate non-communicating chambers.

ATRIAL SEPTATION:

Embryonic timeline of Atrial Septation:  Late 4th week to the middle of the 6th week.

Initially the right and the left atria are actually one single chamber which is referred to Primitive Atrium. Sinus Venosus provides the Inflow in this primitive atrium. The primitive atrium is divided into two separate left and right atria following the process of atrial septation. Atrial Septation is actually a series of events which involves 2 septae (Septum Primum & Septum Secundum) and 2 foraminae (Foramen Primum & Foramen Secundum) forming within the primitive atria, thereby dividing it into a right and left atrium.

STEPS INVOLVED IN ATRIAL SEPTATION:

1. From the roof of the primitive atrium a flexible and crescenteric shaped Septum Primum grows inferiorly towards the endocardial cushions. The initial defect in between the down growing septum primum and the endocardial cushions is referred to as foramen primum. Foramen Primum functions to allow shunting of blood from the right atrium to the left atrium. Endocardial cushion itself is a derivative of neural crest cells and gives rise to the following structures in a adult heart:

   1. Atrioventricular Valves

   2. Membranous part of Interventricular septum

   3. Aorticopulmonary septum

   4. Left & Right Atrioventricular canals

2. Foramen Primum is eventually obliterated when the inferior edge of the septum primum fuses with the endocardial cushions. Just before the foramen primum closes, multiple small secondary defects form within the upper wall of septum primum as result of apoptosis. These multiple small defects in the upper wall of septum primum coalesce into forming a single defect called the foramen secundum. Foramen secundum is formed before the foramen primum is closed, and it serves to maintain the very important function of reinforcing a right to left shunt of the oxygenated blood entering the right atrium via the inferior vena cava.

3. While the septum primum is undergoing these changes, from the roof of the atrium and just to the right of septum primum, a second crescentic shaped septum secundum starts developing.  As the septum secundum grows downwards, it extends and obliterates most of the foramen secundum. The remaining part of foramen secundum which isn't obliterated by the septum secundum is referred to as Foramen Ovale. The function of foramen ovale is the same as that of the foraminae primum and secundum, which was to maintain a right to left shunt.

4. It's important to remember that septum primum is a rather flexible structure compared to septum secundum which is a relatively rigid structure. This rather flexible property of the septum primum allows its inferior flap (which isn't covered by the septum secundum) to function as valve for foramen ovale. This valve allows the flow of blood from the right to left side thereby reinforcing the shunt, but it tends to disallow the backflow of the blood from the left atria to the right atria.

5. Septum Primum and Septum Secundum eventually fuse to form the interatrial septum. Most of the interatrial septum is formed from two septae (primum and secundum). However, the inferior part of the interatrial septum forms from a single septum (septum primum only), and hence this part is rather thinner compared to the rest of the atrial septae. This thinner part of the interatrial septum in the adult heart is referred to as Fossa Ovalis and is a major anatomical landmark of the adult right atrium. Fossa ovalis presents as a marked crescentic ridge on the medial wall of the right atrium.

6. Immediately after birth Foramen Ovale tends to close. After birth there's an increase in left atrial pressure due to decreased pulmonary vascular resistance which enhances pulmonary blood flow and subsequent return of blood to the left side of the heart. Also, closure of the umbilical veins tends to decrease the right atrial pressure with respect to left atrial pressure. The above mentioned decreased right atrial and increased left atrial pressure changes result in closure of the foramen ovale after birth.

CLINICAL & PATHOLOGICAL CONSIDERATIONS:

1. PROBE PATENCY OF FORAMEN OVALE: A probe is passed from the right atrium into the left atrium to check whether the foramen ovale has closed or not. In cases where the probe can pass through into the left atrium, it means that septum secundum & septum primum have not fused completely together and hence the foramen ovale is still patent. Patent foramen ovale is present in 25% of normal adults without any symptoms. Even if it's patent, the foramen ovale remains functionally closed due to post birth increased left atrial pressure. However, transient increase in right atrial pressure above the left atrial pressure (such as during Valsalva manoeuvre) can lead to a right to left shunt via the patent foramen ovale. This can lead to paradoxical emboli, where venous thromboemboli cross into the systemic arterial circulation and can cause various clinical complications.

2. FORAMEN SECUNDUM DEFECT/ SECUNDUM TYPE ASD: This is the most common type of ASD, which usually presents with delayed clinical symptoms after the age of 30, before the age of 30 it's usually asymptomatic. Secundum type ASD presents with variable sized defects in between the right and left atria. These defects are present in the central part of the interatrial septum, just above the limbus. Secundum type defects may occur due to one of the  following, or both:

   1. Excessive resorption of the Septum Primum can result in a very large Foramen Secundum being formed which couldn't be effectively closed by the Septum Secundum.
   2. Alternatively Secundum type defects can occur when there's an underdeveloped septum secundum which has a relatively smaller size and hence cannot efficiently obliterate the foramen ovale.

Besides Secundum type defects, although much less common but there are also Primum type atrial septal defects. These primum type atrial septal defects result due to a failure of the septum primum to fuse inferiorly with the endocardial cushions. These Primum type defects can be located in the lower aspect of interatrial septum. Fossa ovalis tends to normal in primum type defects.

Clinical signs of atrial septal defects include:

1. Wide, fixed splitting of S2.
2. Systolic ejection murmur best audible in the 2nd intercostals space along the left sternal border.
3. Atrial septal defects can also lead to paradoxical emboli similar to those in case of patent foramen ovale.

1. COR TRICLOCULARE BI VENTRICULARE: It's basically a three chambered heart with one common atrium and two ventricles, thereby highlighting the situation where interatrial septum fails to develop.

2. PREMATURE CLOSURE OF THE FORAMEN OVALE: As mentioned earlier that foramen ovale is supposed to remain patent until after birth. If however, foramen ovale closes early due to premature fusion of septae primum & secundum before birth, this can result in a hypertrophied right and left ventricles plus an underdeveloped left sided chambers.

DEVELOPMENT OF RIGHT ATRIUM & THE FATE OF SINUS VENOSUS:

Heart tube with its dilatations undergoes an S-shaped bending which results in an orientation where the outflow tract (truncus arteriosus) lies most anteriorly. Behind the truncus arteriosus is the primitive ventricle and still behind is the primitive atrium. On the posterior surface of the primitive atrium opens the sinus venosus along with its branches. Branches of sinus venosus are anterior cardinal vein, posterior cardinal vein and the common cardinal vein. Two vitelline and umbilical veins also drain into sinus venosus. Initially the sinus venosus drains into the middle of the posterior wall of right atrium, however due to flow and hemodynamic changes, sinus venosus starts growing towards the right side. Ultimately sinus venosus ends up opening at the posterior right end of the right atrium. Hemodynamic changes responsible for this right side shifting of sinus venosus are as following:

1. An anastomosis forms between the anterior cardinal veins of either side, and the blood starts flowing from the left to the right side.

2. Umbilical and vitelline veins on the left side start degenerating. This results in an increased blood flow into the right side as blood from the caudal part of the fetus is also shunted to the right side of the right atrium.

3. Eventually the right umbilical vein also degenerates, and the right vitelline vein starts increasing in calibre. End result of these hemodynamic changes is that sinus venosus shifts and starts growing on the right side.

On the left side the remaining degenerating pieces of the sinus venosus become the coronary sinus. Right vitelline vein in future becomes the inferior vena cava. The common cardinal vein becomes the future superior vena cava.  All these changes contribute to an increase in the size of right atrium since sinus venosus has also shifted there as part of its development. Anterior view of the right atrium shows that it's divided by the crista terminalis into a smooth and rough or trabeculated part. The trabeculated parts of right atrium and the right auricle are derived from the primitive atria. The smooth parts are derived from the primitive inflow tract which was sinus venosus. Crista terminalis is the landmark where parts of sinus venosus were absorbed into right atrium as parts of right atrial development. The lower part of the sinus venosus marks the valve of the inferior vena cava. Also there is an opening of coronary sinus which actually is the degenerated left sinus venosus draining into the right atrium.

DEVELOPMENT OF THE LEFT ATRIUM: Left atrial development is relatively not as complicated. Trabeculated part and the left auricle form a very small component of left atrium and they're derived from the primitive atrium. Majority of the left atrium is its smooth part which is derived from the primordial pulmonary trunk which gets absorbed as part of left atrial development. Primordial pulmonary trunk is actually a budding off of the left atrium. The primordial pulmonary turn initially grows and forms four branches. However, so much of the primordial pulmonary trunk is absorbed into the making of left atrium that its four branches end up opening directly into the left atrium.

Embryology and fate of the pharyngeal arch artries.

STUDY NOTES:

PHARYNGEAL ARCH ARTERIES

The aorta arises from the left ventricle as its outflow tract. Aorta forms an arch before descending downwards as the thoracic/descending aorta. This arch of aorta gives rise to three arteries; from right to left these arteries are the, left common carotid and the left subclavian artery. On the right side the brachiocephalic trunk gives rise to right subclavian artery and then continues as the right common carotid artery which eventually divides into internal and external carotid arteries of the right side. The left common carotid artery is a direct branch of arch of aorta and it ends up dividing into external carotid and internal carotid arteries of the left side. Finally the left subclavian artery arises from the arch of aorta prior to the ductus arteriosus, after which the arch curves downwards and continues as descending or thoracic aorta.

As the embryo is developing, two dorsal aortae develop on either side and give off branches to oxygenate ventral and dorsal parts of the embryo. Simultaneously the pharyngeal arches develop along with their pharyngeal arteries. There are six pharyngeal arteries that develop. The first two pairs of pharyngeal arteries develops by the 3rd and 4th week and the sixth pair develops by the 6th or 7th week. By the time the last pair (6th pair) of the pharyngeal arteries develops, the first and second pair of pharyngeal arteries has degenerated. It's important to remember that all six pairs of pharyngeal arch arteries aren't present at the same time. The 1st and 2nd pharyngeal arch arteries give rise to part of Maxillary artery and Stapedial artery respectively. Other than that the first two pharyngeal arch arteries degenerate. The 3rd pharyngeal arch artery is of importance, as it combines with the adjacent part of dorsal aorta to form common carotid and proximal part of the internal carotid arteries. The 4th pharyngeal arch artery on the right side gives rise to Brachiocephalic trunk part before the origin of common carotid artery while the left side it gives rise to the aortic arch. The 5th pharyngeal arch artery normally doesn’t develop in humans. However, in cases where it does develop, it tends to be rudimentary and degenerates soon.5th pharyngeal arch artery regresses and degenerates. The 6th pharyngeal arch artery gives rise to ductus arteriosus on the left side and it regresses on the right side. 

On the right side, the 1st, 2nd, 5th and 6th pharyngeal arch arteries tend to regress (completely or partially) whereas, the 3rd and 4th are of importance in terms of giving rise to adult structures. On the left side 1st, 2nd and 5th pharyngeal arch arteries tend to regress (completely or partially), whereas the 3rd, 4th and 6th give rise to arterial structures. This above information is summarized in the table overleaf:

So what happens is, that the first two pharyngeal arch arteries degenerate and the third one ,as mentioned earlier, is directly connected to the dorsal aortae on either side. The parts of dorsal aortae connected to the 4th, 5th and 6th pharyngeal arches tend to degenerate as well. As a result the 3rd pharyngeal arch arteries on either side get directly connectedin the middle to the aortic sac. Inferiorly, the aortic sac is connected to the truncus arteriosus which at this point is undergoing septation to form aorta and the pulmonary trunk.  So, the initial part of the pulmonary trunk is formed by the truncus arteriosus whereas the point where the pulmonary trunk bifurcates into two pulmonary arteries (proximal parts of pulmonary arteries) is formed by the 6th pharyngeal arch artery.  

Eventually, the 3rd pharyngeal arch (which is directly connected to the aortic sac) starts dividing along with the aortic sac. This division eventually results in the brachiocephalic trunk developing on the right side. On the left side, part of the 3rd pharyngeal arch forms the aortic arch. Common carotid and part of internal carotid arteries on both sides are formed by the 3rd pharyngeal arch artery as well. However, distal part of internal carotid is formed by the dorsal aorta. 

The fate of dorsal aorta is different on either side. On the right side, the dorsal aorta ends up forming the right subclavian artery. On the left side however, the dorsal aorta forms a part of the descending aorta and the arch of aorta. Aorta primarily forms from the aortic sac. Although, part of aorta that is proximal to the commencement of the common carotid artery on the left side, is formed by the artery of the 4th pharyngeal arch. On the right side as well, the part just before the commencement of the common carotid artery from the brachiocephalic trunk is formed by the 4th pharyngeal arch artery. Right Subclavian artery forms from the dorsal aorta, whereas the left subclavian artery forms from existing vasculature as part of angiogenesis.

On the right side, the right vagus nerve gives rise to right recurrent laryngeal nerve which passes under the right subclavian artery to ascend towards the larynx region. On the left side, the left vagus nerve gives rise to left recurrent laryngeal nerve which hooks around the ligamentum arteriosum and further curves under the aortic arch to ascend and reach the larynx. On the right side, part of the 6th pharyngeal artery tends to degenerate hence the right recurrent laryngeal nerve has to pass behind the right subclavian artery on, as it courses upward. 

An important clinical correlate to remember is that, as the left recurrent laryngeal nerve curves under the arch of aorta, it can get damaged by aortic arch aneurysm or a malignancy. Left recurrent laryngeal nerve damage can result in paralysis of the left vocal cords. On the right side, since right recurrent laryngeal is unaffected by any aortic arch pathologies because it arises from the right vagus nerve in the root of the neck and subsequently passes under the subclavian artery (and not under the arch of aorta).

Ligamentum arteriosum is the embryologic remnant of the ductus arteriosus. Ductus arteriosus itself arises from the left 6th pharyngeal arch artery. Ductus arteriosus opens into underside of the arch of aorta (distal to origin of the left subclavian artery) and it functions to form a shunt which allows the flow of deoxygenated blood from the pulmonary trunk to the aorta (right to left shunt). This right to left shunting allows the deoxygenated blood to complete bypass the pulmonary circuit.

COARCTATION OF AORTA

Coarctation of aorta is a constriction of the aorta just after it has given rise to subclavian artery. Post the coarctation site, the aorta becomes significantly narrowed and the blood supply to the lower limb and the abdomen is diminished which results in weak pulses of the lower limb. As compensation, over time collaterals develop around the chest wall and the abdomen to supply the lower body. Coarctation of aorta also affects the heart, which now has to pump against greater peripheral resistance and hence at a higher pressure in order to maintain peripheral circulation, thus it may lead to cardiac failure in severe cases. 

It's important to understand the underlying cause for this coarctation of aorta. During development, the ductus arteriosus is composed of a specialized smooth muscular contractile tissue. This specialized contractile tissue at times makes its way into the arch of aorta. Hence, after birth when this migrated contractile tissue contracts and tends to narrow the aortic lumen (similar to obliteration of ductus arteriosus in response to increased oxygen and decreased PGE levels), there's a resultant coarctation of the aorta. Alternatively,developmental alteration can also result in the coarctation of aorta.

Clinically, coarctation of aorta manifests with the following:

1. Brachial-femoral pulse delay.
2. Blood pressure discrepancies between upper and lower extremities. These discrepancies normally present as hypertension in the upper extremities but feeble and delayed pulses in the lower limb.
3. Associated with bicuspid aortic valve.

Coarctation of aorta is divided into two types based on the location of the narrowing of aorta with respect to the position of ductus arteriosus:

• PREDUCTAL COARCTATION is also referred to as the infantile type, and it occurs prior to the site of ductus arteriosus. In this case the ductus arteriosus tends to remain patent. As part of compensation, the patent ductus arteriosus provides blood to the descending aorta and hence the lower parts of the body. Prostaglandin E analogues tend to keep the ductus arteriosus patent and they are administered to newborns in cases where DA patency is required. An important high yield point to remember is that preductal coarctation has a strong association with Turner's syndrome. 
• POSTDUCTAL COARCTATION is the more common type and tends to occur in the adults. The narrowing of aorta in this case is distal to the origin of ductus arteriosus and hence DA tends to obliterate according to its normal timeline (immediately after birth). The compensatory collateral circulation in utero in this case is provided by the by the collaterals which develop between the left subclavian, internal thoracic and intercostals to supply blood to lower part of body. Over time, the collateral intercostal arteries enlarge resulting in erosion of the lower border of ribs which presents as notched appearance of ribs on the chest x-ray. This notched appearance of ribs on CXR is referred to as costal notching.
• In Patent Ductus Arteriosus antiprostaglandins i.e.NSAIDS like Indomethacin and Ibuprofen are given.

This video presents

1. Development of the interventricular septum
2. Development of the aorticopulmonary septum
3. Clinical points related to these topics
   1. Patent truncus arteriosus
   2. Transformation of the great artries
   3. Tetralogy of fallot.

STUDY NOTES:

VENTRICLES & AORTICOPULMONARY SEPTUM

DEVELOPMENT OF INTERVENTRICULAR SEPTUM & PARTITION OF PRIMITIVE VENTRICLES

Embryonic time line of IV SEPTUM DEVELOPMENT: begins in the late 4th week and beginning of 5 th week. By the end of 4th week, the primitive ventricle is one single chamber which receives blood from the atria via the divided atrioventricular canal. Then there's also a single aorticopulmonary trunk opening into primitive ventricles which forms the outflow tract. At this point aorticopulmonary trunk is formed of bulbus cordis and truncus arteriosus and it provides the outflow tract for the primitive ventricles. During later parts of the development the bulbus cordis gets incorporated into the right and left ventricles. Upon incorporation, on the right side the bulbus cordis forms the infundibulum of the right ventricle, and on the left side it forms the vestibule of the left ventricle. Hence, bulbus cordis forms the smooth outflow tracts of the ventricles on either side. Truncus arteriosus on the other hand develops into forming aorta and the pulmonary trunk on the left and the right sides respectively.

Adult IV septum consists of two parts, a muscular part (derived from the myocardial cells) which forms the majority of the septum, and a relatively thin membranous part which forms the superior aspect of the IV septum which is part of the outflow tract.

By the early 5th week, the muscular IV septum develops as an IV septal ridge from the floor of the primitive ventricle near the apex of the heart. This interventricular septal ridge ascends towards the atrioventricular canal, and thereby partially divides the primitive ventricle into left and right ventricles. The IV septal ridge extends towards the atrioventricular canal but it does not reach it, hence giving rise to a gap or defect which is referred to as interventricular foramen (IV Foramen). Thus the IV foramen is formed by the concave upper edge of the IV septum which gives rise to a gap through which shunting of blood between the right and left ventricles occurs.

The membranous IV septum descends downward from the AV canal and fuses with the muscular IV septum thereby completely obliterating the IV foramen. The membranous part of IV septum is contributed by the following:

• Endocardial cushions (Neural crest cells derivative)
• Aorticopulmonary trunk septum (neural crest cell derivative)
• Muscular IV septum (Myocardial cells derivative)

CLINICAL DISORDERS ASSOCIATED WITH INTERVENTRICULAR SEPTUM DEVELOPMENT

• COR TRILOCULARE BIATRIUM: It's a three chambered heart with a single/common primitive ventricle and two atria. It occurs due to failure of development of the interventricular septum.
• MUSCULAR IV SEPTAL DEFECTS: During its development the muscular IV septum can present with defects or holes allowing left to right shunts. Severity of these defects depends upon the size of these gaps. The resultant shunting caused by these defects can lead to right ventricular hypertrophy.
• MEMBRANOUS IV SEPTAL DEFECTS: This is the most common of the IV septal defects. Part of the membranous IV septum is derived from the endocardial cushions which themselves are neural crest cells derivatives. Neural crest cells are also involved in the craniofacial development, therefore, abnormal migration of neural crest cells will result in concurrent facial and cardiac defects (mostly septal defects & atrioventricular valve problems). As mentioned earlier that it's the membranous IV septum which is responsible for filling the gap formed by the IV foramen. If there is any defect in the formation of the membranous part of IV septum, the IV foramen will remain patent and left to right shunting of blood will occur. The severity of the left to right shunting due to IV septal defects depends upon the size of the defect.  Clinically IV septal defects manifest themselves as following:
  • Excessive fatigability upon exertion.
  • A harsh holosystolic murmur, best audible at the left lower sternal border.
• EISENMENGER COMPLEX: Initially the left to right shunting of the blood via the VSD is noncyanotic because it’s the oxygenated left ventricular blood mixing with the deoxygenated right ventricular blood. However, if this left to right shunt is left uncorrected, the increased blood flow into the right side of the heart can lead to pulmonary hypertension due to increased blood flow to the lungs. With time, this pulmonary hypertension can cause pathologic remodeling of pulmonary vasculature. This remodeling involves marked proliferation of tunica intima & media of the muscular pulmonary arteries and arterioles. Ultimately, pulmonary vascular resistance and the compensatory right ventricular hypertrophy together reverse the initial direction of the shunt from "left to right" to "right to left". After birth, a right to left shunt is cyanotic, because the blood via the shunt is bypassing pulmonary gaseous exchange process and hence remains deoxygenated. Eisenmenger complex presents with late cyanosis, clubbing and polycythemia.

Other than with ventricular septal defects, Eisenmenger complex can also present along with atrial septal defects and patent ductus arteriosus. It's important to remember that post birth, right to left shunts result in early cyanosis. Whereas, "left to right" shunts result in late cyanosis. Children suffering from late cyanosis are referred to as blue kids in contrast to the newborns which present with cyanosis at birth and are referred to as blue babies.

DEVELOPMENT OF AORTICOPULMONATY SEPTUM

Aorticopulmonary trunk arises from the primitive ventricles and serves as an outflow tract for the primitive ventricle. An aorticopulmonary septum forms within the aorticopulmonary trunk, thereby subsequently dividing it into the aorta & pulmonary trunk. Aorticopulmonary septum is formed by the migration of neural crest cells into the c conotruncal and bulbar ridges of the truncus arteriosus. These neural crest cells grow in a spiral fashion and fuse to form aorticopulmonary septum. As the aorticopulmonary septum descends as part of its growth, it spirals in such a fashion that aorta becomes the left ventricular outflow tract and the pulmonary trunk becomes the right ventricular outflow tract. As mentioned earlier, as part of its descent the aorticopulmonary septum contributes to the development of the membranous part of interventricular septum and therefore helps fill in the opening formed by the interventricular foramen.

DEFECTS IN THE DEVELOPMENT OF AORTICOPULMONARY SEPTUM result due to defects in migration of neural crest cells into the truncus arteriosus. At birth these aorticopulmonary septal defects always present with some cyanosis due to right to left shunting of the blood. Following are the congenital abnormalities associated with development of AP septum:

• PERSISTENT TRUNCUS ARTERIOSUS occurs when there's complete failure of the development of the AP septum due to abnormal migration of neural crest cells. As a result the separation of left ventricular and right ventricular outflow tracts never occurs. Therefore, the aorta and pulmonary trunk form a single outflow vessel (persistent truncus arteriosus) which receives blood from both the right and left ventricles. The common outflow tract allows mixing of oxygenated and deoxygenated blood, resulting in cyanosis of varying degree. Even though thetwo outflow tracts separate downstream, but by that time the mixing of oxygenated and deoxygenated blood has already occurred, hence it's a cyanotic defect. Persistent truncus arteriosus is always accompanied by a membranous VSD (AP septum contributes to the formation of membranous part of IV septum, only muscular IV septum forms)and therefore this further allows right to left shunting of the blood. 
• TRANSPOSITION OF GREAT ARTERIES occurs when there's a failure of the AP septum to develop in a spiral fashion secondary to a defective migration of the neural crest cells. This results in a transposition of the outflow tracts, as a result of which, the left ventricle is connected to the pulmonary trunk and the right ventricle is connected to the aorta. Consequently, two completely closed non-communicating circuits are formed which involve the systemic and pulmonary circulations. The systemic circuit forms a closed loop carrying completely deoxygenated blood involving the right side of the heart and the aorta. The pulmonary circuit forms another closed loop carrying oxygenated blood, and involves the left side of the heart and the pulmonary trunk. As expected, transposition and resultant complete separation of pulmonary and systemic circulations lead to a situation which is incompatible with life in the absence of an accompanying shunt or mixing defects. Therefore, infants born alive with this defect tend to have other defects as well, which allow shunting and therefore mixing of oxygenated and deoxygenated bloods in between two otherwise closed circuits. As a result, for these newborns, accompanying shunting disorders (ASD, VSD, PDA, PFO)* are rather protective. Absence of a mixing defect requires an atrial septoplasty surgery to create a shunt so that mixing of could occur and thereby sustain life. Transposition of outflow tracts is the most common cause of severe cyanosis, which occurs and persists immediately after birth. Without any surgical intervention or maintenance of PDA (Prostaglandin E analogue administration), most infants don't survive past the first few months. It's important to remember that upon imaging, in case of great vessels transposition, the echocardiogram shows an aorta which lies anteriorly and to the right of the pulmonary artery.
• TETRALOGY OF FALLOT (ToF) is the most common of cyanotic congenital heart defect. This is caused by a misalignment of the aorticopulmonary septum, where it fails to divide the aorticopulmonary trunk in the midline. In case of ToF the AP septum is displaced anteriorly and towards the right or pulmonary side. This results in forming two unequal sized outflow vessels, with a very stenosed pulmonary artery and larger than normal aorta. As the name suggests, Tetralogy of Fallot has 4 component defects which coexist simultaneously. These 4 defects which as following  (best remembered with mnemonic PROVe):
  • Pulmonary Stenosis: it's a direct manifestation of the defective rightward misalignment of the AP septum.
  • Overriding/Straddling Aorta: larger than normal calibre aorta which receives blood from both the left and right ventricles.
  • Ventricular Septal defect: failure of AP septum to form the membranous part of the IV septum and subsequently fuse with the muscular IV septum, hence the IV foramen isn't closed which gives rise to a VSD.
  • Right Ventricular Hypertrophy: develops secondary to pulmonary stenosis, because right ventricle has to pump against a greater resistance of a stenosed outflow tract thereby resulting in compensatory hypertrophy of the right ventricle.

Due to the presence of a ventricular septal defect, and a stenosed pulmonary outflow tract which presents with greater resistance to blood flow, there's a right to left shunting of the blood. This right to left shunting results in cyanosis because the blood leaving the heart via the aorta is mixed with deoxygenated blood from the right ventricle. A very important point to remember and which is highly tested as well is that, squatting tends to improve this cyanosis. This is because squatting tends to increase systemic vascular resistance or afterload, which tends to decrease right to left shunting of the blood via the VSD and thereby helps improve the cyanosis. 

Clinically, ToF presents with a harsh systolic ejection murmur which can be auscultated at middle to left sternal border. This murmur occurs due to presence of right ventricular outflow tract obstruction.

KEY:

ASD= Atrial septal defect

VSD= Ventricular septal defect

PDA= Patent ductus arteriosus

PFO= Persistent foramen ovale

AP= Aorticopulmonary 

IV= Interventricular

This video presents the review of: a) Development of the interventricular septum b) Development of the aorticopulmonary septum c) Clinical points related to these topics i) Patent truncus arteriosus ii) Transformation of the great artries iii) Tetralogy of fallot

Development of the inferior venca cava. We will look at the sinus venosus and cardinal veins with the regression of some of the systems that eventually lead to the formation of the IVC.

STUDY NOTES:

DEVELOPMENT OF INFERIOR VENA CAVA

Sinus venosus forms the inflow tract of the primitive heart tube. On each side of the sinus venosus, the common cardinal veins open into it. Anterior and posterior cardinal veins combine to form the common cardinal vein on each side of the sinus venosus. The common cardinal vein on the right side forms part of the superior vena cava. Besides the common cardinal veins, the umbilical and the vitelline veins also drain into the sinus venosus. On the left side, these veins undergo specific remodeling. This results in formation of specific anastomosis on the left side, giving rise to left to right shunts thereby causing most of the blood to be received by the right side of the sinus venosus. Consequently, the veins of the right side start maturing and increase in size relative to their left side counterparts. As the sinus venosus also grows and matures, it becomes incorporated into the right side of the primitive atrium. Eventually the vitelline, common cardinal and the umbilical veins of the left side degenerate. The blood received by the left side of sinus venosus is greatly reduced and as a result the left side of the sinus venosus shrinks.  Inferiorly the posterior cardinal veins anastomose together and form the iliac veins.

The formation of the inferior vena cava is contributed by three set of veins:

• Anterior & posterior cardinal veins
• Subcardinal veins
• Supracardinal veins (develop a little latter)

The anterior cardinal and the common cardinal veins on the left side give rise to brachiocephalic and the left subclavian vein which drain into the SVC.  It is important to remember that, the umbilical vein on both sides and the vitelline vein on the left side, all tend to degenerate.  The vitelline vein on the right side along with the common cardinal vein of the right side together form parts of the SVC. 

The subcardinal veins have an anastomosis in the middle which is referred to as subcardinal venous anastomosis. These subcardinal veins are also connected to the posterior cardinal vein and form another anastomosis which is referred to as the mesonephric shunt. Later on the inferior part of posterior cardinal vein on the left side starts degenerating, however, it's still connected to the subcardinal vein via the mesonephric shunt. Also, there are tiny buds arising from the subcardinal veins, these form parts of the future ovarian and spermatic veins. 

Subcardinal veins on the right side separate from the posterior cardinal veins and are joined in by the hepatic veins. This will later form the initial parts of the IVC. At this point it's important to understand that an anastomosis forms between the supracardinal and the subcardinal veins, which is referred to as the supra-subcardinal anastomosis. This anastomosis becomes part of the IVC and later gives rise to the renal vein and parts of the spermatic veins. Over time the posterior cardinal vein on the right side also degenerates.

As the IVC is formed, it is composed of the following parts:

• HEPATIC PART comes from the liver sinusoids and the hepatic vein. It also has a contribution from the sinusvenosus.
• PRERENAL PART of the IVC is contributed by the subcardinal veins. Primarily the right subcardinal vein has a greater contribution in forming this part. 
• RIGHT AND LEFT SUPRARENAL VEINS are also parts of the IVC. They also develop from the subcardinal veins. 
• RENAL SEGMENT OF THE IVC arises from the mesonephric shunt of the right side. The mesonephric shunt itself forms as a result of the anastomosis between the subcardinal and the posterior cardinal veins. Right renal vein also arises from this renal segment of the IVC. On the left side the mesonephric shunt becomes incorporated into the IVC and gives rise to the left renal vein. The spermatic/ovarian vein on the left side drains into the left renal vein which then opens into the IVC. However, on the right side, the right spermatic/ovarian vein opens directly into the IVC.
• POSTRENAL SEGMENT OF THE IVC is the region below the renal segment of IVC. Supracardinal veins contribute to the formation of the post renal segment of the IVC. 
• ILIAC VEINS form the most inferior parts of the IVC. The inferior anastomosis between the posterior cardinal veins is responsible for the formation of iliac veins. 

Fetal circulation Shunts Chemical substances alterting the flow Flow dynamics Oxygenation Changes at birth Remnants of the fetal circulation components.

STUDY NOTES:

FETAL CIRCULATION & SHUNTS

DIFFERENCE OF FETAL CIRCULATION FROM AN ADULT CIRUCLATION

• The fetus has a connection with the maternal blood supply at the site of placenta. This connection is formed by the two umbilical arteries and a single umbilical vein. The umbilical arteries carry deoxygenated blood from the whole body to the placenta which is the gaseous exchange site prenatally. On the other hand, the umbilical vein returns oxygenated blood from the placenta back to the fetus.

• The fetal heart has a right to left shunt in the form of a patent foramen ovale. This has extensively been discussed in the previous lectures. As part of interatrial septal development, the two septae (septum foramen and secundum) leave a defect in the interatrial septum which allows the shunting of the blood from the right to left atrium.

• The ductus arteriosus opens at the underside of the aorta and connects it with the pulmonary trunk. The role of ductus arteriosus and its situation just distal to the origin of the left subclavian artery will be discussed later into the notes. 

• Ductus venosus connects umbilical vein to the inferior vena cava, allowing the blood to bypass the hepatic route in doing so. 

FLOW BEFORE BIRTH

Before birth, two umbilical arteries carry deoxygenated blood from the fetus to the placenta. Placenta allows gaseous exchange via diffusion to take place between the maternal oxygenated blood and the fetal deoxygenated blood. It's important to remember that the fetal and maternal bloods don't come into direct contact. Prenatally the fetal lungs are collapsed; hence placenta is the site of gaseous exchange before birth. Although the placenta has maternal deoxygenated blood but still it's able to provide fetus with its oxygen requirements. This is made possible by the higher oxygen affinity of the fetal hemoglobin, HbF. HbF has 2 alpha and two gamma globin chains, which allows it to extract oxygen from a relatively deoxygenated maternal blood.

Ductus venosus connects umbilical vein (coming from the placenta) to the inferior vena cava, thereby forming a shunt that allows half of the placental blood to bypass the hepatic route. Hence 50% of the oxygenated blood from the placenta enters the hepatic sinusoids. This blood that enters the hepatic sinusoids is returned via the hepatic veins to the inferior vena cava. All of the oxygenated blood doesn't enter the liver and the hepatic sinusoids because the passage through the hepatic sinusoids can take a very long time for the blood to reach the heart. The oxygenated blood in the IVC (80% oxygen saturation) at this point mixes with the deoxygenated blood from the hepatic veins (26% oxygen saturation). Before entering into the right atrium, the blood in the IVC has an oxygen saturation of around 67%.  

A hallmark of fetal circulation is that, the superior vena cava returns deoxygenated blood from the head, neck and upper extremities region to the right atrium. This deoxygenated blood reaching the heart via the SVC is directed into the right ventricle and subsequently into the pulmonary trunk. The inferior vena cava on the other hand brings relatively oxygenated blood (67% Oxygen saturation) to the right atrium, which due to flow dynamics passes through the patent foramen ovale into the left atrium. As discussed in earlier lectures, foramen ovale forms a right to left shunt which allows the oxygenated blood coming from placenta to bypass the pulmonary circuit. After birth, foramen ovale becomes obliterated and forms the fossa ovalis. Once it's in the left atrium, this relatively oxygenated blood (coming from right atrium via foramen ovale) goes into the left ventricles and subsequently leaves the heart via the aorta. Most of this blood then leaves via the three large branches of aorta (brachiocephalic trunk, left common carotid and the left subclavian arteries) towards the head, neck and upper extremities region. There's no mixing of the blood coming from SVC and IVC, though they're both received by the right atrium. 

The deoxygenated blood (25% oxygen saturation) coming from the SVC entering the right atrium, is directed into the right ventricle and subsequently into the pulmonary trunk. The ductus arteriosus opens into the underside of the aorta, and connects the pulmonary trunk to the arch of aorta. Thus, ductus arteriosus forms a right to left shunt allowing the deoxygenated blood to bypass the pulmonary circuit. This shunting across the pulmonary circuit occurs because fetal pulmonary vascular resistance is very high resulting in just 10% of the right ventricular output goes to the lungs. The rest 90% of right ventricular output is shunted from the pulmonary trunk to the aorta. This deoxygenated blood from the SVC which is in the aorta, now mixes with the relatively more oxygenated blood which came from the placenta and passed through the foramen ovale.

As mentioned earlier, only 10% of the fetal right ventricular output is directed to the lungs. This blood is brought back to the left atrium by the pulmonary veins and it leaves the left side of the heart via the aorta. The blood in the aorta after the opening of ductus arteriosus is at an oxygen saturation of 60%. This blood via the descending aorta is now directed to the abdomen and lower parts of the fetus and finally reaches the internal iliac arteries. Most of the deoxygenated blood now enters the two umbilical arteries and is taken to the placenta. The umbilical arteries on their route to the placenta touch bladder as well. Later on, the proximal parts of the umbilical arteries later form the superior vesical arteries. 

Levels of oxygen saturation in different fetal vessels in decreasing order of oxygen saturation:

• Umbilical Vein

• Ductus Venosus 

• IVC          

• Right Atrium   

PRENATAL SHUNTS

Before birth there are 3 vascular shunts which allow bypass of the blood flow mainly around the lungs and the liver. These 3 shunts are right to left in direction and tend to close immediately after birth. These shunts are as following:

Earlier there was a brief mention of the high pulmonary vascular resistance and need for a shunt across the pulmonary circuit. Let’s touch that subject now in order to gain more clarity on this concept. Before birth the fetal lungs are collapsed. Since the fetus is inside the womb surrounded by amniotic fluid, the lungs are also filled with fluid and this keeps them collapsed. Since the lungs are collapsed as a result the pulmonary arterioles are also collapsed. This is because, the alveoli are filled with fluid at this point and the surrounding arterioles tend to exhibit vasoconstriction due to this resultant hypoxia (due to absence of oxygen in the alveoli). This hypoxic pulmonary arteriolar vasoconstriction results in a very high pulmonary vascular resistance and as a consequence the lungs remain in a collapsed state before birth. Since the right ventricle has to pump against a very high pulmonary vascular resistance, it results in the right ventricle being more hypertrophied than the left ventricle before birth. Fortunately only 10% of the right ventricular output flows to the lungs (other 90% is shunted across the pulmonary circulation by DA in the aorta) so the degree of hypertrophy isn't that pronounced at the time of birth. This situation is reversed within one month after the birth. 

FLOW AFTER BIRTH, REASON FOR FLOW CHANGES & THE CHEMICAL SUBSTANCES INVOLVED

After birth, the 3 above mentioned shunts tend to close because of changes in pressure gradients and in oxygen tension. Immediately after birth, as the newborn breathes the lungs become expanded. As the alveoli expand, the pulmonary vasculature also tends to expands due to decreased effects of hypoxic pulmonary vascular resistance. This results in an overall decrease in pulmonary vascular resistance and blood from the right ventricle is directed via the pulmonary trunk towards the pulmonary circulation. The increased pulmonary blood flow to the lungs also results in an increased pulmonary venous return to the left atrium. Consequently left ventricular output increases and the aorta receives more blood resulting in an increase in aortic blood pressure. Hence, the increased pressure in the aorta tends to reverse the shunt across the ductus arteriosus. Overall the pressure on the left side of the heart tends to increase more than the right side of the heart. As the lungs become functional, the following changes occur:

• Increased bradykinin levels 

• Increased oxygen tension (more than 50mm of Hg)

• Decreased PGE2 and prostacyclin levels

Overall, there's an increased oxygen tension due to expansion of lungs and an increased released of bradykinin from the lungs. Following this, there's an immediate drop in PGE2 and prostacyclin levels which were being produced as a result of hypoxia. Prostaglandin E actually is an inhibitor of contracting response of ductus arteriosus to an increased oxygen tension. An oxygen tension above 50 mm of Hg promotes the closure of the ductus arteriosus. Therefore, all the above mentioned changes result in the contraction of specialized smooth muscle in the walls of ductus venosus and ductus arteriosus. Consequently, DV and DA become obliterated over the next couple of hours after birth. Failure of the ductus arteriosus results in a patent ductus arteriosus after birth. The closure of ductus arteriosus is a slow event and it's summarized below: 

The umbilical vein also closes upon birth as the umbilicus is clipped and the connection between the placenta and the fetus is severed. Closure of umbilical vein reduces the amount of blood flowing via the inferior vena cava into the right atrium. Hence the right atrial pressure tends to further drop relative to left atrial pressure. The increased left atrial pressure results in fusion of the septum primum and secundum and the foramen ovale is subsequently closed. Closed foramen ovale is referred to as fossa ovalis. The floor of the fossa ovalis is formed by the septum primum and its margin called the limbus ovalis is derived from the septum secundum. Closure of the foramen ovale means that the right heart is connected to the pulmonary circulation and the left heart is connected to the systemic circulation. 

Once the umbilical connection to the placenta is severed after birth, the ductus venosus also begins to start closing. The closure of ductus vensosus is a slow process and it can take a month after birth to completely become obliterated. In cases where the newborn is anemic, the ductus venosus can be cannulated from the outside to initiate a blood replacement therapy. Adult remnant of the ductus venosus is referred to as the ligamentum venosum.

REMANANTS IN ADULTS FROM THE FETAL CIRCULATORY SYSTEM

Postnatal changes which occur after birth result in formation of some adult remnants from the fetal circulatory system. These remnants and the changes after birth which give rise to them are summarized in the table below:

PATENT DUCTUS ARTERIOUS, ITS SIGNIFICANCE IN FETAL LIFE AND CLOSURE AFTER BIRTH

The ductus arteriosus is formed from the 6th pharyngeal arch artery on the left side. It connects aorta to the pulmonary trunk just distal to the origin of the left subclavian artery and forms a right to left shunt. This right to left shunt enables most of the right ventricular output to bypass the pulmonary circuit because the lungs are collapsed at this time and as a result the pulmonary vascular resistance is quite high. The ductus arteriosus is composed of specialized smooth muscle which releases PGE2 and prostacyclins in response to low oxygen tension/ relevant hypoxia. The PGE2 and prostacyclins release tends to keep the ductus arteriosus open before birth. Normally, the ductus arteriosus closes within few hours after birth due to contraction of the smooth muscle in its wall and is referred to as ligamentum arteriosum. 

Congenital condition which can cause hypoxia after birth can prevent the ductus arteriosus from closing. One such condition is erythroblastosis fetalis. As mentioned earlier, the low oxygen tension due to hypoxia can cause a release of prostaglandins and prostacyclins which will prevent the ductus arteriosus from closing. Other than that, babies born with a preductal coarctation of aorta tend to have a patent ductus arteriosus which should be kept open. In case of preductal coarctation, the ductus arteriosus remains patent and provides blood flow into the descending aorta and thereby the abdomen and lower parts of the body. In situations where a left to right shunt is important for the survival of the newborn, the ductus arteriosus is necessary to be kept patent. Congenital heart defects such as transposition of great vessels requires such an intervention to keep the ductus arteriosus open. Prostaglandin E analogues such as dinoprostone, are administered in such cases which helps in keeping the ductus arteriosus patent.

In preterm babies, the lungs aren't fully developed, therefore after birth there is a decreased arterial oxygen tension and an increased prostaglandin E2 and prostacyclins synthesis in response to this relative hypoxia. Hence, the incidence of a patent ductus arteriosus is very high in preterm/premature infants. Patent ductus arteriosus results in a left to right shunt after birth, which is non-cyanotic and the newborn has a machine-like murmur audible upon auscultation. In such cases, prostaglandin E inhibitors such as indomethacin and ibuprofen are administered in order to promote the closure of ductus arteriosus. 

Foramen ovale: to keep the foramen ovale open in TGA atrial septoplasty is done.

The situation of ductus arteriosus just distal to the origin of left subclavian artery has great significance. Most of the oxygenated blood entering the right atrium is directed towards the head and neck region via the 3 branches large branches of the arch of aorta. Just distal to the origin of subclavian artery, the aorta is connected to the pulmonary trunk via the ductus arteriosus. At this point the deoxygenated blood (coming originally from the SVC) in the pulmonary trunk is shunted into the aorta (via DA) and is allowed to mix with the oxygenated blood which originally came from the placenta. Hence, most of the oxygenated blood from the placenta directed to the head and neck region which at that that point of development has greater oxygen demands. This remaining blood in the aorta, after it has mixed with the shunted deoxygenated blood from the pulmonary trunk, has an oxygen saturation of 50% and is now directed to the rest of the body (abdomen and lower limb).