D.BASEM ELSAID ENANYLECTURER OF CARDIOLOGY

AINSHAMS UNIVERSITY

Pathophysiology of HF

NORMAL LEFT VENTRICULAR PRESSURE-VOLUME RELATIONSHIP

--The three major determinants of the left ventricular forward stroke volume/performance are the preload, myocardial contractility (the force generated at any given end–diastolic volume) and the afterload.--At end–diastole, the fibers have a particular stretch or length, which is determined by the resting force, myocardial compliance, and the degree of filling from the left atrium. This distending force is the preload of the muscle.--During ejection, the myocardium must also sustain a particular force, which is a function of the resistance and capacitance of the circulatory vasculature and is called the afterload (aortic impedance and wall stress)..

--The fall in cardiac output leads to increased sympathetic activity increasing both contractility and heart rate. --Also promotes renal salt and water retention leading to expansion of the blood volume, thereby raising end–diastolic pressure and volume which, via the Frank-Starling relationship, enhances ventricular performance and tends to restore the stroke volume. --Left ventricular hypertrophy is also part of the adaptive response to systolic dysfunction, since it unloads individual muscle fibers and thereby decreases wall stress and afterload.

Definition

--Abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of themetabolizing tissues, despite normal filling pressures.--35–50% therefore represent a ‘grey area’ and most probably have primarily mild systolic dysfunction.--Patients with HF-PEF are older and more often female and obese than those with HF-REF. They are less likely to have coronary heart disease and more likely to havehypertension and atrial fibrillation (AF). Patients with HF-PEF have a better prognosis than those with HF-REF

Progression of HF

--Two mechanisms are thought to account for this progression. The first is occurrence of further events leading to additional myocyte death (e.g. recurrent myocardial infarction).The other is the systemic responses induced by the decline in systolic function, particularly neurohumoral activation.--Two key neurohumoral systems activated in HF are the renin–angiotensin– aldosterone system and sympathetic nervous system {Maintenance of systemic pressure by vasoconstriction, resulting in redistribution of blood flow to vital organs* Restoration of cardiac output by increasing myocardial contractility and heart rate and by expansion of the extracellular fluid volume}these adaptations tend to overwhelm the vasodilatory and natriuretic effects of natriuretic peptides, nitric oxide, prostaglandins, and bradykinin. Volume expansion is often effective because the heart can respond to an increase in venous return with an elevation in end–diastolic volume that results in a rise in stroke volume (via the Frank-Starling mechanism)**Interruption of these two key processes is the basis of much of the effective treatment of HF

--Maladaptive consequences of neurohumoral activation:

*The elevation in diastolic pressures is transmitted to the atria and to the pulmonary and systemic venous circulations; the ensuing elevation in capillary pressures promotes the development of pulmonary congestion and peripheral edema*The increase in left ventricular afterload induced by the rise in peripheral resistance can both directly depress cardiac function and enhance the rate of deterioration of myocardial function.*Catecholamine-stimulated contractility and increased heart rate can worsen coronary ischemia*Catecholamines and angiotensin II may promote the loss of myocytes by apoptosis, the induction of maladaptive fetal isoforms of proteins involved in contraction, and hypertrophy

Sympathetic nervous system

--Early responseincreased release and decreased uptake of norepinephrine (NE) at adrenergic nerve endings {Downregulation of peripheral alpha-2 receptor function, which normally inhibits NE release}--Early in heart failure, catecholamine-induced augmentation of ventricular contractility and heart rate help maintain cardiac output {an increase in heart rate also enhances ventricular contractility due to the normal force-frequency relationship} With progressive worsening of ventricular function, these mechanisms are no longer sufficient.--Systemic and pulmonary vasoconstriction and enhanced venous tone increasing ventricular preload.--Renal vasoconstriction (mediated by both NE and angiotensin II) occurs primarily at the efferent arteriole, producing an increase in filtration fraction that allows glomerular filtration to be relatively well maintained despite a fall in renal blood flow. --Both NE and angiotensin II also stimulate proximal tubular sodium reabsorption, which contributes to the sodium retention characteristic of HF

--Increase in the plasma NE concentration, which correlates directly with the severity of the cardiac dysfunction and inversely with survival.--The degree of sympathetic activation can be reduced by effective treatment of HF, as with administration of an ACE inhibitor.-- Increase in cardiac efferent sympathetic activity in patients with heart failure increased cardiac NE spillover (ie, elevated NE levels in cardiac veins). {reduction in ventricular filling pressures reduces cardiac NE spillover}--Chronic increase in sympathetic activity also leads to downregulation and reduction in density of the cardiac beta-adrenergic receptors--Chronically increased stimulation of beta-adrenergic receptors may cause molecular and cellular abnormalities, which contribute to progression of myocardial dysfunction by the reexpression of fetal protein isoforms and the loss of cardiomyocytes due to apoptosis or necrosis

B2 receptors

-- Support the myocardial contractile response to sympathetic stimulation--Exert an anti-apoptotic effect that opposes the pro-apoptotic action of beta-1 receptor stimulation.

On the other hand:--Presynaptic beta-2 adrenergic receptors stimulate norepinephrine release increase the propensity for ventricular fibrillation

Renin–angiotensin system

--Decreased stretch of the glomerular afferent arteriole, reduced delivery of chloride to the macula densa, and increased beta-1 adrenergic activity increase renin.--Angiotensin II can be synthesized locally at a variety of tissue sites including the kidney, blood vessels, adrenal gland, and brain measurement of the plasma renin activity or angiotensin II concentration may underestimate tissue angiotensin II activity.--There is evidence of local cardiac angiotensin II and angiotensin converting enzyme production is in proportion to the severity of heart failure could explain why ACEI are more beneficial in patients with HF than other vasodilators

Angiotensin II

-- Increasing sodium reabsorption (an effect mediated in part by enhanced release of aldosterone).--Inducing systemic and renal vasoconstriction. --Act directly to promote pathologic remodeling via myocyte hypertrophy, reexpression of fetal protein isoforms, myocyte apoptosis, and alterations in the interstitial matrix.

Aldosterone

--Secondary hyperaldosteronism in heart failure has been thought to reflect angiotensin II-mediated stimulation of the adrenal glands. --However, there is also local production of aldosterone in the failing heart in proportion to the severity of heart failure, an effect that is mediated by the induction of aldosterone synthase (CYP11B2) by angiotensin II in the failing ventricle.

ACE gene polymorphism

--Plasma and tissue concentrations of ACE, and therefore of angiotensin II, are in part determined by the ACE gene three genotypes (DD, ID, and II).--Plasma and cardiac levels of ACE are 1.5 to 3-fold higher in patients with the DD compared to the II genotype; the values are intermediate in patients with ID genotype. --The DD genotype of the angiotensin converting enzyme gene has been associated with a number of adverse cardiovascular events, increased mortality and reduced transplant-free survival in patients with HF due to idiopathic dilated cardiomyopathy may be abolished with beta blocker therapy.

Antidiuretic hormone

--Activation of the carotid sinus and aortic arch baroreceptors by the low cardiac output in heart failure enhanced release of ADH and stimulation of thirst.Elevated levels of ADH may contribute to the increase in systemic vascular resistance in HF via stimulation of the V1A receptor, which is found on vascular smooth muscle cells, and also promote water retention via the V2 receptor by enhancing water reabsorption in the collecting tubules.--The combination of decreased water excretion and increased water intake via thirst often leads to a fall in the plasma sodium concentration. The severity of these defects tends to parallel the severity of the heart failure. As a result, the degree of hyponatremia is an important predictor of survival in these patients

Atrial and brain natriuretic peptides

--When the load on any chamber is increased (e.g.by AF, pulmonary embolism, and some non-cardiovascular conditions, including renal failure)--Atrial natriuretic peptide (ANP) is primarily released from the atria in response to volume expansion (atrial stretch) increased in heart failure. --Plasma ANP levels rise early in the course of the disease and have been used as a marker for the diagnosis of asymptomatic left ventricular dysfunction. --Chronic heart failure ventricular cells can also be recruited to secrete both ANP and brain natriuretic peptide (BNP), an analogous peptide, in response to the high ventricular filling pressures. --These relationships have allowed the plasma concentration of these peptides, particularly BNP, to be used to detect heart failure and to predict the outcome and perhaps guide therapy in patients with established disease--Optimal exclusion cut-off point is 300 pg/mL for NT-proBNP and 100 pg/mL for BNP--Mid-regional atrial natriuretic peptide (MR-proANP), at a cut-off point of 120pmol/L, was shown to be non-inferior to these thresholds for BNP and NT-proBNP in the acute setting.

Endothelin

--Produced by the vascular endothelium, may contribute to the regulation of myocardial function, vascular tone, and peripheral resistance in HF.-- Plasma endothelin concentrations are increased in patients with HF; (from cardiac myocytes and coronary vascular endothelium), and that angiotensin II may contribute to the high circulating levels in HF.--Over the long-term, high levels of endothelin (as with angiotensin II) may be deleterious to the heart due, for example, to pathologic remodeling evaluation of endothelin inhibition as a therapy for heart failure.

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