Chapter 228 - Pathophysiology of Heart Failure

Question 1

Describe blood flow through the heart.

Answer 1

1. Oxygenated blood from the lungs via the pulmonary vein into the left atrium > through the mitral valve > left ventricle > aortic valve > Aorta > to the body
2. Deoxygenated blood from the body via the caudal and cranial vena cava into the right atrium > the the tricuspid valve > right ventricle > pulmonic valve > pulmonary artery.

Question 2

What are the two main mechanical functions of the heart?

Answer 2

1. Eject blood into the aorta and pulmonary arteries with sufficient force to meet perfusion requirements
2. Receive blood from the pulmonary and systemic veins

Question 3

Define after load.

Answer 3

Refers to the pressure the heart must work against to eject blood during systole.

Question 4

Define pre-load.

Answer 4

Amount of blood left in the ventricle at the end of diastole.

Question 5

Define stroke volume.

Answer 5

The volume of blood pumped out of the heart’s left ventricle during each systolic cardiac contraction.

Question 6

What are the four broad functional mechanisms of heart failure?

Answer 6

1. Heart failure resulting from impeded cardiac filling
2. Heart failure resulting from increase resistance ejection of blood (Afterload)
3. Heart failure resulting from impaired ejection or volume overload
4. Heart failure resulting from arrhythmias and conduction disorders

Question 7

List the conditions that can cause heart failure from impeded cardiac filling.

Answer 7

1. Pericardial diseases with restricted filling e.g. cardiac tamponade or constrictive pericarditis
2. Valvular inflow obstruction e.g. Atrioventricular valve stenosis or other anatomic obstructions such as cor triatriatum, neoplasia or granulomas
3. Intrinsic myocardial disease with impaired diastolic function e.g. hypertrophic cardiomyopathy or restrictive cardiomyopathy

Question 8

List the conditions that can cause heart failure resulting from increase resistance ejection of blood (Afterload).

Answer 8

1.Pulmonic and aortic stenosis
2. Hypertrophic obstructive cardiomyopathy
3. Thromboembolism of the great vessels
4. Pulmonary hypertension

Question 9

List the conditions that can cause heart failure resulting from impaired ejection or volume overload.

Answer 9

1. Primary and secondary myocardial disease with impaired systolic function e.g. DCM, ischaemic, infectious, nutritional and toxic myocardial disorders
2. Misdirected blood flow resulting in volume overload e.g. valvular insufficiency, left to right shunts and arteriovenous fistula
3. Chronic high-output states e.g. thyrotoxicosis and chronic anaemia

Question 10

List the conditions that can cause heart failure from arrhythmia and conduction disorders.

Answer 10

1. Sustained tachyarrhythmias e.g. supraventricular tachycardias (Atrial fibrillation, focal atrial tachycardia, macrore-entrant atrial tachycardia/atrial flutter) or ventricular tachyarrhythmias.
2. Chronic bradycardia e.g. complete heart block

Question 11

What are the primary determinants of stroke volume and cardiac output?

Answer 11

1. Heart rate
2. Pre-load
3. Myocardial contractility
4. Ventricular synchrony

Question 12

What neuroendocrine responses occur in response to heart failure?

Answer 12

Increase in activity of the:
1. Sympathetic nervous system
2. RAAS system
3. Overexpression of ANP and BNP
4. Increased release of endothelin and antidiuretic hormone
5. Amplified expression of pro-inflammatory cytokines such as tumour-necrosis factor-alpha, interleukin 1 and interleukin 6

And reduced activity of the Nitric oxide pathway

Question 13

Describe the process of activation of the sympathetic nervous system and how it works during heart failure.

Answer 13

Increased heart rate and contractility via sympathetic activation are the primary early adaptations of heart failure.

SNS increased heart rate by:
1. Beta-adrenergic stimulation increases SA node firing rate by increasing the slow inward calcium current.
2. SNS activation shifts the activation curve of the inward pacemaker current, If, to more positive voltages via Gs-dependent stimulation of adenylyl cyclase, which means that the current which is normally activated at more negative voltages, becomes active at voltages closer to zero or even slightly positive. Leading to a faster rate of slow diastolic depolarization. This, in turn, can lead to an increased heart rate.

Contractility Enhancement
- Through the action of stimulatory Gs Protein, beta-adrenergic stimulation leads to the activation of adenylyl cyclase, and the formation of cyclic adenosine monophosphate (cAMP), which then activates protein kinase A (PKA). Activated PKA phosphorylates key calcium-handling proteins that facilitate calcium transport across the sarcolemma, augments calcium-induced calcium release by the sarcoplasmic reticulum and increase calcium reuptake by the SR.
- PKA also affects contractile proteins (troponin I, myosin-binding protein C) to augment the rate and force of contractions.

Adrenergic venous constriction in patients with heart failure results in an immediate increase in venous return (preload):

Increased preload induces a more forceful cardiac contraction and a corresponding increase in stroke volume as described by the Frank-Starling law of the heart
Increased diastolic stretch of myocardial fibers increases the sensitivity of the contractile elements to cytosolic calcium, a process that is sometimes referred to as length-dependent activation

Question 14

Describe the consequences of chronic sympathetic activation.

Answer 14

Myocardial performance in patients with diminished contractile reserves may be negatively impacted by the resulting mismatch of afterload to contractility. This occurs by

• Beta1-receptor downregulation (by reduced mRNA transcription) in chronic heart failure which further diminishes the contractile response.
• Beta-receptor uncoupling from G proteins (via beta-receptor kinase and beta arrestin) thereby reducing the subsequent production of cyclic AMP
• Depletion of myocardial norepinephrine stores which augments mismatching as it renders the heart overly reliant on circulating levels of catecholamines
• There is also reduced responsiveness to adrenergic stimulation over time

The result of all these perturbations is a diminished increase in heart rate and myocardial contractility in response to adrenergic stimulation.

Further more, if the heart rate become too high, the shortened diastolic interval reduces the stroke volume leading to reduced cardiac output.

Question 15

Where is Renin released from?

Answer 15

From juxtaglomerular cells of the kidney.

Question 16

What stimulates the release of renin?

Answer 16

1. Decrease renal tubular perfusion
2. Reduced sodium reabsorption by renal tubules
3. Beta-adrenegic stimulation

Question 17

Describe the RAAS system and its role in heart failure and how it can lead to elevated venous pressure and the development of oedema and effusion.

Answer 17

Renin is released by juxtaglomerular cells of the kidney in response to decreased renal tubular perfusion, reduced sodium reabsorption by renal tubules and SNS activation via beta-adrenergic stimulation.

Angiotensinogen is a precursor protein produced in the liver and cleaved by renin to form angiotensin I. AT1 is converted into angiotensin II (AT2) by angiotensin converting enzyme (ACE).

Action of
- AT2 stimulate the release of aldosterone from the adrenal gland.
- Causes vasoconstriction in arterioles
- Stimulate Na+ reabsorption
- Increases the release of norepinephrine
- Increase thirst sensation and stimulate ADH release

Additional action of ACE
- Inactivates a potent vasodilator - bradykinin

Action of aldosterone
- Aldosterone acts on the distal collecting ducts of to increase absorption of sodium ions and excretion of potassium
- it also contributes to baroreceptor dysfunction, enhancing activity of the SNS and diminishing the actions of the parasympathetic nervous system and causes vasoconstriction.
- It is also involved in pathogenic remodelling in the vasculature, kidney and heart via an inflammatory process.
In heart failure, several mechanisms can result in renal retention of sodium and water.

The continued sodium and water retention ultimately leads to elevated venous pressures and the development of oedema and effusion. Despite intravascular volume expansion, inadequate cardiac output results in a decreased effective arterial blood volume. This is sensed by arterial baroreceptors and results in sustained activation of the SNS and RAAS.

Question 18

Where are natriuretic peptides located?

Answer 18

Vascular endothelium or atria

Question 19

What are the types of natriuretic peptides?

Answer 19

Atrial natriuretic peptides (ANP)
Brain (B-type) natriuretic peptides (BNP)
C-type natriuretic peptides (CNP)

Question 20

Describe the role of natriuretic peptides in heart failure.

Answer 20

ANP and BNP are stored mainly in the atria as ProANP and ProBNP and sudden rises occur following atrial stretch. As heart disease progresses BNP > ANP as the major site of BNP production switches to the ventricles. ANP and BNP act via the A-type naturetic peptide receptor to induces natriuresis and diuresis by inhibiting tubular sodium transport in the collecting duct of the kidney. The same receptor type mediates vasorelaxion of systemic and pulmonary arteries to reduce vascular resistance.

A second receptor type B (NPR-B) responds to ANP and BNP but preferentially response to CNP to result in vasodilation via relaxation of vascular smooth muscle and inhibits vascular remodelling.

A third receptor type C (NPR-C) acts to clear mature ANP and BNP from the system.

Question 21

What is the main use of ProBNP measurement in cats?

Answer 21

Can allow us to help differentiate between cardiac causes of dyspnoea and primary respiratory.

Question 22

What is them main reason we don’t use point of care pro-BNP in dogs?

Answer 22

We dont use point of care NT-ProBNP in dogs because the magnitude of change in dogs compared to cats and humans in less dramatic.

Question 23

Name the applications and limitation of the snap Pro-BNP tests in cats.

Answer 23

• Has good diagnostic accurate for discriminating cats with cardiac and non-cardiac causes of respiratory distress
• Snap pro-BNP provides rapid results with reasonable diagnostic accuracy, but is not as accurate an external laboratory pro-BNP, but is not reasonable for assisting with decision making relating to a cat with respiratory distress because of the delay in receiving results
• Can be used on plasma of pleural fluid
• Can be useful for assess cats with suspect subclinical cardiomyopathy where echocardiography is not available.

Question 24

Where is the anti-diuretic hormone release from?

Answer 24

Released from the neurohypophysis aka posterior pituitary gland

Question 25

Describe the role of ADH in heart failure.

Answer 25

ADH is released from the neurohypophysis in response to: - Increased plasma osmolality - Hypovolaemia - Sympathetic stimulation - ATII When plasma volume is reduced stretch receptors in the atria and large veins decrease their firing rate. stimulating the release of ADH. ADH reacts with V1A receptors in the vasculature and heart to result in vasoconstriction. ADH also reacts with V2 receptors in the kidney to stimulate water reabsorption. Baroreceptors also respond to ADH to lower the heart rate to reduce blood pressure.

Question 26

Describe the neurohormonal alterations of the peripheral vasculature in heart failure.

Answer 26

When cardiac output falls, systemic blood flow in preferentially redirected to vital organs. This done via multiple mechanisms: 1. Adrenergic system is the main system involved in increasing peripheral vascular resistance 2. Down regulation of parasympathetic tone 3. Upregulation of the RAAS 4. Increased expression and release of ADH and endothelin. 5. Changes in local blood flow autoregulation These vasoconstrictors (norepinephrine, angiotensin II, endothelin, ADH) work through G protein receptors that activate the inositol triphosphate (IP3) signaling system, regulating calcium release in smooth muscle cells. Chronic activation leads to vascular remodeling through protein kinase C pathways, causing smooth muscle hypertrophy and extracellular matrix changes. Reduced parasympathetic activity contributes to vasoconstriction by removing its normal vasodilatory effects. While these adaptations temporarily maintain blood pressure and cardiac filling, the increased afterload ultimately worsens cardiac remodeling and dysfunction.

Question 27

Describe the role of the endothelin system in heart failure.

Answer 27

Vascular tone is regulated by a balance between endothelium-derived vasodilators (nitric oxide, prostacyclin) and vasoconstrictors (primarily endothelins) The endothelin family consists of three related peptides: ET-1, endothelin-2, and endothelin-3 ET-1 production is stimulated by multiple factors: Hypoxemia and mechanical factors (stretch and low shear stress) Vasoactive substances (angiotensin II, vasopressin, norepinephrine, bradykinin) Growth factors and cytokines (transforming growth factor beta, TNF-alpha, IL-1) ET-1 acts through two receptor subtypes with opposing effects: - ETA receptors: Mediate vasoconstriction, increase myocardial contractility, stimulate aldosterone secretion, and promote vascular smooth muscle and cardiac hypertrophy with chronic stimulation - ETB receptors: Promote vasodilation through aldosterone secretion, mediated by increased nitric oxide production, creating a complex balance mechanism of vascular tone. ET-1 interacts with the renin-angiotensin-aldosterone system (RAAS) to suppress renin production while stimulating aldosterone secretion

Question 28

Describe the nitric oxide pathway in heart failure.

Answer 28

NO is produced from L-arginine by endothelial nitric oxide synthase. NO promotes vasodilation through multiple mechanisms: - Increases cyclic GMP (cGMP) in vascular smooth muscle - Directly activates potassium channels, leading to cell hyperpolarization and vasodilation NO also inhibits ET-1 synthesis, creating a negative feedback mechanism In heart failure patients, impaired endothelial function reduces NO synthesis, contributing to excessive vasoconstriction

Question 29

What are the two types of cardiac remodelling?

Answer 29

Physiologic remodelling Pathologic remodelling

Question 30

What causes physiologic cardiac remodelling? What is the outcome?

Answer 30

Occurs in response to: - Prolonged bed rest or weightlessness - Extreme exercise Effects are reversible once the physiologic challenge is resolved

Question 31

Describe pathogenic cardiac remodelling and phase of the hypertrophic response.

Answer 31

Compensatory and adaptive remodelling process are transformed when the haemodynamic stresses are prolonged in duration or excessive or when physiologic patterns of neurohormonal activation are excessively modified (RAAS, NE, ET-1) and when vascular remodelling exerts its toll on myocardial perfusion. Which ultimately results in irreversible remodelling, reduced systolic or diastolic performance and eventual cardiac decompensation. There are three phases of the hypertrophic response: - An initial stage where hypertrophy develops in response to wall stress - A compensated stage where wall stress has been normalised by the hypertrophic response - An exhaustion phase characterised by death of cardiomyocytes, death of myocardial fibrosis, ventricular dilation and reduce cardiac output. The law of laplace emphasizes that any increase in chamber size should be accompanied by a proportional increase in wall thickness if normal wall stress is to be maintained.

Question 32

What are the two main types of pathogenic remodelling?

Answer 32

1. Concentric hypertrophy (thickening of the heart wall without chamber dilation) 2. Eccentric hypertrophy (thickening with chamber dilation).

Question 33

Describe concentric hypertrophy.

Answer 33

Concentric hypertrophy is caused primarily due to pressure overload, where the heart has to pump against increased resistance. This results in increase in width of myocytes leading to thicker walls and a smaller chamber volume. It is associated with condition such as pulmonic stenosis or aortic stenosis.

Question 34

Describe eccentric hypertrophy.

Answer 34

Caused primarily due to volume overload which increases diastolic wall stress to which cardiomyocytes respond by replicating new sarcomeres in series (end to end). The ventricle becomes more spherical and the diameter of the chamber becomes larger. Associated conditions: Mitral regurgitation: Where the additional volume load is ejected into a low-pressure reservoir, the left atrium.

Question 35

Which conditions can be associated with a mixed remodelling type?

Answer 35

1. Aortic valve insufficiency and patent ductus arteriosus 2. Ischaemic myocardiac disease 3. DCM

Question 36

Describe the cardiac remodelling that occurs in Aortic valve insufficiency and patent ductus arteriosus.

Answer 36

Aortic valve insufficiency and patent ductus arteriosus represent examples of combined volume and pressure overload wherein an additional volume of left ventricular blood is ejected into a high-pressure reservoir, the aorta.

Question 37

Describe the cardiac remodelling that occurs in ischaemic cardiomyopathy.

Answer 37

In the compensated phase of ischemic cardiomyopathy, the adaptive responses are more similar to those observed in pressure overload due to the chronic operation of potent neuroendocrine adaptive responses. However, in the decompensated phase, cardiomyocytes begin to elongate, the collagen matrix begins to disintegrate, and the chamber dilates, indicating a shift in intracellular signaling.

Question 38

Describe the cardiac remodelling that occurs in DCM.

Answer 38

Shows a mixed remodelling pattern as well, but the eccentric hypertrophy phenotype predominates.