Chapter 228 - Pathophysiology of Heart Failure Flashcards
Section XIV Cardiovascular Disease
Describe blood flow through the heart.
- Oxygenated blood from the lungs via the pulmonary vein into the left atrium > left ventricle > Aorta > to the body
- Deoxygenated blood from the body via the caudal and cranial vena cava into the right atrium > right ventricle > pulmonary artery.
What are the two main mechanical functions of the heart?
- Eject blood into the aorta and pulmonary arteries with sufficient force to meet perfusion requirements
- Receive blood from the pulmonary and systemic veins
Define after load.
Refers to the pressure the heart must work against to eject blood during systole.
Define pre-load.
Amount of blood left in the ventricle at the end of diastole.
Define stroke volume.
The volume of blood pumped out of the heart’s left ventricle during each systolic cardiac contraction.
What are the four broad functional mechanisms of heart failure?
- Heart failure resulting from impeded cardiac filling
- Heart failure resulting from increase resistance ejection of blood (Afterload)
- Heart failure resulting from impaired ejection or volume overload
- Heart failure resulting from arrhythmias and conduction disorders
List the conditions that can cause heart failure from impeded cardiac filling.
- Pericardial diseases with restricted filling e.g. cardiac tamponade or constrictive pericarditis
- Valvular inflow obstruction e.g. Atrioventricular valve stenosis or other anatomic obstructions such as cor triatriatum, neoplasia or granulomas
- Intrinsic myocardial disease with impaired diastolic function e.g. hypertrophic cardiomyopathy or restrictive cardiomyopathy
List the conditions that can cause heart failure resulting from increase resistance ejection of blood (Afterload).
1.Pulmonic and aortic stenosis
2. Hypertrophic obstructive cardiomyopathy
3. Thromboembolism of the great vessels
4. Pulmonary hypertension
List the conditions that can cause heart failure resulting from impaired ejection or volume overload.
- Primary and secondary myocardial disease with impaired systolic function e.g. DCM, ischaemic, infectious, nutritional and toxic myocardial disorders
- Misdirected blood flow resulting in volume overload e.g. valvular insufficiency, left to right shunts and arteriovenous fistula
- Chronic high-output states e.g. thyrotoxicosis and chronic anaemia
List the conditions that can cause heart failure from arrhythmia and conduction disorders.
- Sustained tachyarrhythmias e.g. supraventricular tachycardias (Atrial fibrillation, focal atrial tachycardia, macrore-entrant atrial tachycardia/atrial flutter) or ventricular tachyarrhythmias.
- Chronic bradycardia e.g. complete heart block
What are the primary determinants of stroke volume and cardiac output?
- Heart rate
- Pre-load
- Myocardial contractility
- Ventricular synchrony
What neuroendocrine responses occur in response to heart failure?
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
Describe the process of activation of the sympathetic nervous system and how it works.
Activation of the SNS is an early compensatory mechanism in heart failure which ultimately results in an increase in heart rate and contractility. In this early stage resting cardiac output can be restored.
Heart is increased by:
- Beta adrenergic stimulation increases the sino-atrial node firing rate by increasing the slow inward calcium current
- Norepinephrine also increases cAMP levels which causes the pacemaker current activation curve shifts to more positive voltages so it becomes active at voltages closer to zero leading toe faster rate of slow diastolic depolarisation.
Adrenergic stimulation also increased myocardial contractility:
- Through the action of stimulatory Gs protin, beta adrenergic stimulation leads to activation of adenylyl cyclase and the formation cAMP (cyclic adenosine monophosphate). cAMP then activates protein kinase A (PKA). Activated PKA phosphorylates key calcium handling proteins that facilitates calcium handling across the sarcoplasmic reticulum and increases calcium reuptake by the SR. PKA also affect contractile proteins including troponin 1, 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 preload. This causes diastolic stretch or myocardial, this combined with the increase sensitivity of contractile elements to cytosolic calcium results in a more forceful contraction.
Describe the consequences of chronic sympathetic activation.
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.
Where is Renin released from?
From juxtaglomerular cells of the kidney.
What stimulates the release of renin?
- Decrease renal tubular perfusion
- Reduced sodium reabsorption by renal tubules
- Beta-adrenegic stimulation
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.
Renin is released by juxtaglomeular cells of the kidney in response to decrease renal tubular perfusion, reduced sodium reabsorption by renal tubules and beta-adrenergic stimulation.
Renin accelerates the conversion of angiotensinogen, which is produced by the liver and stored in plasma, to angiotensin I (AT1) which is converted into angiotensin II (AT2) by angiotensin converting enzyme (ACE). ACE also inactivates a potent vasodilator - bradykinin). AT2 inhibits renin formation, causes vasoconstriction and promotes sodium and water retention via the direct effects of the renal tubules. Aldosterone is also produced by the adrenal glands in response to AT2, elevated potassium and adrenocorticotropic hormone. 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. 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.
Decreased renal perfusion and vasoconstriction results in decreased renal blood flow and increased sodium and water retention. The continued sodium and water retention ultimately leads to elevated venous pressures and the development of oedema and effusion.
Where are natriuretic peptides located?
Vascular endothelium or atria
What are the types of natriuretic peptides?
Atrial natriuretic peptides (ANP)
Brain (B-type) natriuretic peptides (BNP)
C-type natriuretic peptides (CNP)
Describe the role of natriuretic peptides in heart failure.
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.
What is the main use of ProBNP measurement in cats?
Can allow us to help differentiate between cardiac causes of dyspnoea and primary respiratory.
What is them main reason we don’t use point of care pro-BNP in dogs?
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.
Name the applications and limitation of the snap Pro-BNP tests in cats.
- 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.
Where is the anti-diuretic hormone release from?
Released from the neurohypophysis aka posterior pituitary gland
Describe the role of ADH in heart failure.
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.
Describe the neurohormonal alterations of the peripheral vasculature in heart failure.
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.
Describe the role of the endothelin system in heart failure.
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
Describe the nitric oxide pathway in heart failure.
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
What are the two types of cardiac remodelling?
Physiologic remodelling
Pathologic remodelling
What causes physiologic cardiac remodelling? What is the outcome?
Occurs in response to:
- Prolonged bed rest or weightlessness
- Extreme exercise
Effects are reversible once the physiologic challenge is resolved
Describe pathogenic cardiac remodelling and phase of the hypertrophic response.
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.
What are the two main types of pathogenic remodelling?
- Concentric hypertrophy (thickening of the heart wall without chamber dilation)
- Eccentric hypertrophy (thickening with chamber dilation).
Describe concentric hypertrophy.
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.
Describe eccentric hypertrophy.
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.
Which conditions can be associated with a mixed remodelling type?
- Aortic valve insufficiency and patent ductus arteriosus
- Ischaemic myocardiac disease
- DCM
Describe the cardiac remodelling that occurs in Aortic valve insufficiency and patent ductus arteriosus.
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.
Describe the cardiac remodelling that occurs in ischaemic cardiomyopathy.
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.
Describe the cardiac remodelling that occurs in DCM.
Shows a mixed remodelling pattern as well, but the eccentric hypertrophy phenotype predominates.
