What is the role of neurohormonal activation in the pathophysiology of dilated cardiomyopathy?

Updated: Mar 02, 2021
  • Author: Vinh Q Nguyen, MD, FACC; Chief Editor: Gyanendra K Sharma, MD, FACC, FASE  more...
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Decreased cardiac output with resultant reductions in organ perfusion results in neurohormonal activation, including stimulation of the adrenergic nervous system and the renin-angiotensin-aldosterone system (RAAS). Additional factors important to compensatory neurohormonal activation include the release of arginine vasopressin and the secretion of natriuretic peptides. Although these responses are initially compensatory, they ultimately lead to further disease progression.

Alterations in the adrenergic nervous system induce significant increases in circulating levels of dopamine and, especially, norepinephrine. By increasing sympathetic tone and decreasing parasympathetic activity, an increase in cardiac performance (beta-adrenergic receptors) and peripheral tone (alpha-adrenergic receptors) is attempted.

Unfortunately, long-term exposure to high levels of catecholamines leads to down-regulation of receptors in the myocardium and blunting of this response. The response to exercise in reference to circulating catecholamines is also blunted. Theoretically, the increased catecholamine levels observed in cardiomyopathies due to compensation may in themselves be cardiotoxic and lead to further dysfunction. In addition, stimulation of the alpha-adrenergic receptors, which leads to increased peripheral vascular tone, increases the myocardial workload, which can further decrease cardiac output. Circulating norepinephrine levels have been inversely correlated with survival.

Activation of the RAAS is a critical aspect of neurohormonal alterations in persons with CHF. Angiotensin II potentiates the effects of norepinephrine by increasing systemic vascular resistance. It also increases the secretion of aldosterone, which facilitates sodium and water retention and may contribute to myocardial fibrosis.

The release of arginine vasopressin from the hypothalamus is controlled by both osmotic (hyponatremia) and nonosmotic stimuli (eg, diuresis, hypotension, angiotensin II). Arginine vasopressin may potentiate the peripheral vascular constriction because of the aforementioned mechanisms. Its actions in the kidneys reduce free-water clearance.

Natriuretic peptide levels are elevated in individuals with dilated cardiomyopathy. Natriuretic peptides in the human body include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide. ANP is primarily released by the atria (mostly the right atrium). Right atrial stretch is an important stimulus for its release. The effects of ANP include vasodilation, possible attenuation of cell growth, diuresis, and inhibition of aldosterone. Although BNP was initially identified in brain tissue (hence its name), it is secreted from cardiac ventricles in response to volume or pressure overload. As a result, BNP levels are elevated in patients with CHF. BNP causes vasodilation and natriuresis.

Counterregulatory responses to neurohormonal activation involve increased release of prostaglandins and bradykinins. These do not significantly counteract the previously described compensatory mechanisms.

The body's compensatory mechanisms for a failing heart are eventually overwhelmed. Compensation for decreased cardiac output cannot be sustained without inducing further decompensation. The rationale for the most successful medical treatment modalities for cardiomyopathies is therefore based on altering these neurohormonal responses.

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