Neurohormonal Model

Development and progression of HF involves activation of neurohormonal pathways including the SNS and the RAAS. This model begins with an initial precipitating event or myocardial injury resulting in a decline in CO, followed by the compensatory mechanisms previously discussed. This includes activation of neurohormonal path ways with pathologic consequences including the RAAS, SNS, endothelin and vasopressin, and those with counterregulatory properties such as the natriuretic peptides and nitric oxide. This model currently guides our therapy for chronic HF in terms of preventing disease progression and mortality.

Angiotensin II

AT2 is a key neurohormone in the pathophysiology of HF. The vasoconstrictive effects of AT2 lead to an increase in systemic vascular resistance (SVR) and blood pressure (BP). The resulting increase in afterload contributes to an increase in myocardial oxygen demand and opposes the desired increase in SV. In the kidneys, AT2 enhances renal function acutely by raising intraglomerular pressure through constriction of the efferent arterioles.6 However, the increase in glomerular filtration pressure may be offset by a reduction in renal perfusion secondary to AT2's influence over the release of other vasoactive neurohormones such as vasopressin and endothelin-1 (ET-1). AT2 also potentiates the release of aldosterone from the adrenal glands and norepinephrine from adrenergic nerve terminals. Additionally, AT2 induces vascular hypertrophy and remodeling in both cardiac and renal cells. Clinical studies show that blocking the effects of the RAAS in HF is associated with improved cardiac function and prolonged survival. Thus, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the cornerstone of HF treatment.


Aldosterone's contribution to HF pathophysiology is also multifaceted. Renally, al-dosterone causes sodium and water retention in an attempt to enhance intravascular volume and CO. This adaptive mechanism has deleterious consequences because excessive sodium and water retention worsen the already-elevated ventricular filling pressures. Aldosterone also contributes to electrolyte abnormalities seen in HF patients. Hypokalemia and hypomagnesemia contribute to the increased risk of arrhythmias. In addition, evidence supports the role of aldosterone as an etiologic factor for myocardial fibrosis and cardiac remodeling by causing increased extracellular matrix collagen deposition and cardiac fibrosis.6 Aldosterone potentially contributes to disease progression via sympathetic potentiation and ventricular remodeling. In addition, the combination of these multiple effects is likely responsible for the increased risk of sudden cardiac death attributed to aldosterone. As elevated aldosterone concentrations have been associated with a poorer prognosis in HF, its blockade has become an important therapeutic target for improvement of long-term prognosis.


Norepinephrine is a classic marker for SNS activation. It plays an adaptive role in the failing heart by stimulating HR and myocardial contractility to augment CO and by producing vasoconstriction to maintain organ perfusion. However, excess levels are directly cardiotoxic. In addition, sympathetic activation increases the risk for arrhythmias, ischemia, and myocyte cell death through increased myocardial workload and accelerated apoptosis (i.e., programmed cell death). Ventricular hypertrophy and remodeling are also influenced by norepinephrine.8

Plasma norepinephrine concentrations are elevated proportionally to HF severity, with the highest levels correlating to the poorest prognosis. Several mechanisms relate to diminished responsiveness to catecholamines (e.g., norepinephrine) as cardiac function declines.6 Adrenergic receptor desensitization and downregulation (decreased postreceptor responses and signaling and decreased receptor number) occur under sustained sympathetic stimulation. The desensitization contributes to further release of norepinephrine.5 P-Adrenergic blocking agents, although intrinsically negatively inotropic, have become an essential therapy for chronic HF. P-Adrenergic blockers negate deleterious effects of norepinephrine, and therefore decrease HF disease progression.


ET-1, one of the most potent physiologic vasoconstrictors, is an important contributor to HF pathophysiology.9 ET-1 binds to two G-protein-coupled receptors, endothelin-A (ET-A) and endothelin-B (ET-B). ET-A receptors mediate vasoconstriction and are prevalent in vascular smooth muscle and cardiac cells. ET-B receptors are expressed on the endothelium and in vascular smooth muscle, and receptor stimulation mediates vasodilation. Levels of ET-1 correlate with HF functional class and mortality.

Arginine Vasopressin

Higher vasopressin concentrations are linked to dilutional hyponatremia and a poor prognosis in HF. Vasopressin exerts its effects through vasopressin type 1a (Via) and

vasopressin type 2 (V2) receptors. ' Via stimulation leads to vasoconstriction, while actions on the V2 receptor cause free water retention through aquaporin channels in the collecting duct. Vasopressin increases preload, afterload, and myocardial oxygen demand in the failing heart.

Counterregulatory Hormones (Natriuretic Peptides, Bradykinin, and Nitric Oxide)

Atrial natriuretic peptide (ANP) and B-type (formerly brain) natriuretic peptide (BNP) are endogenous neurohormones that regulate sodium and water balance. Natriuretic peptides decrease sodium reabsorption in the collecting duct of the kidney.10 Natriuretic peptides also cause vasodilation through the cyclic guanosine monophosphate (cGMP) pathway. ANP is synthesized and stored in the atria, while BNP is produced mainly in the ventricles. Release of ANP and BNP is stimulated by increased cardiac chamber wall stretch, usually indicative of volume load. Higher concentrations of natriuretic peptides correlate with a more severe HF functional class and prognosis. BNP is sensitive to volume status; thus, the plasma concentration can be used as a diagnostic marker in HF.10

Bradykinin is part of the kallikrein-kinin system, which shares a link to the RAAS through ACE. Bradykinin is a vasodilatory peptide that is released in response to a variety of stimuli, including neurohormonal and inflammatory mediators known to be activated in HF.9 As a consequence, bradykinin levels are elevated in HF patients and thought to partially antagonize the vasoconstrictive peptides.

Nitric oxide, a vasodilatory hormone released by the endothelium, is found in higher concentrations in HF patients and provides two main benefits in HF: vasodilation and neurohormonal antagonism of ET.9 Nitric oxide production is affected by the enzyme inducible nitric oxide synthetase (iNOS), which is upregulated in the setting of HF, likely due to increased levels of AT2, norepinephrine, and multiple cytokines. In HF, the physiologic response to nitric oxide appears to be blunted, which contributes to the imbalance between vasoconstriction and vasodilation.

Cardiorenal Model

There is growing evidence of a link between renal disease and HF.8 Renal insufficiency is present in one-third of HF patients and is associated with a worse prognosis. In hospitalized HF patients, the presence of renal insufficiency is associated with longer lengths of stay, increased in-hospital morbidity and mortality, and detrimental neurohormonal alterations. Conversely, renal dysfunction is a common complication of HF or results from its treatment. Renal failure is also a common cause for HF decompensation.

Proinflammatory Cytokines

Inflammatory cytokines have been implicated in the pathophysiology of HF.9 Several proinflammatory (e.g., tumor necrosis factor-a [TNF-a], interleukin-1, interleukin-6, and interferon-y) and anti-inflammatory cytokines (e.g., interleukin-10) are overex-pressed in the failing heart. The most is known about TNF-a, a pleiotrophic cytokine that acts as a negative inotrope, stimulates cardiac cell apoptosis, uncouples P-adren-ergic receptors from adenylyl cyclase, and is related to cardiac cachexia. The exact role of cytokines and inflammation in HF pathophysiology continues to be studied.

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