This document summarizes the pathophysiology of heart failure (HF). It discusses how HF results from abnormalities in cardiac structure/function that limit oxygen delivery to tissues, despite normal filling pressures. The progression of HF is driven by neurohumoral activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, which initially help compensate but eventually exacerbate cardiac remodeling and dysfunction. The document outlines the effects of various neurohormones involved in HF, including their normal and maladaptive roles in the progression of disease. Management of HF focuses on interrupting the harmful effects of long-term neurohumoral activation.

1. D . B A S E M E L S A I D E N A N Y
L E C T U R E R O F C A R D I O L O G Y
A I N S H A M S U N I V E R S I T Y
Pathophysiology of HF

2. 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).
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3. --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.

4. Definition
--Abnormality of cardiac structure or function leading to
failure of the heart to deliver oxygen at a rate
commensurate with the requirements of the
metabolizing 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 have
hypertension and atrial fibrillation (AF). Patients with HF-
PEF have a better prognosis than those with HF-REF

7. 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

8. --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

11. Sympathetic nervous system
--Early responseincreased 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

12. --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

13. 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

14. 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

15. 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.

16. 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.

17. 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.

18. 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

19. 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.

20. 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.

21. Thank you