Sympathetic Activation in Heart Failure
Sympathetic activation of the heart causes an increase in heart rate and inotropy via the release of norepinephrine acting primarily upon β1-adrenoceptors. The increase in inotropy by sympathetic activation, however, may not be sufficient to restore normal inotropy in ventricles having systolic dysfunction. Inotropic responses are also blunted because of down regulation of β1-adrenoceptors.
Sympathetic activation has other important effects which can be deleterious, including ventricular hypertrophy, enhanced arrhythmogenesis, and molecular and biochemical changes that lead to further dysfunction over time.
Therefore, although sympathetic activation plays a compensatory role in the failing heart, there is considerable evidence that prolonged sympathetic activation exacerbates heart failure. For this reason, beta-blockers that block the effects of sympathetic stimulation on the heart are commonly used in the treatment of heart failure associated with systolic dysfunction.
Arterial and venous vessels are richly innervated by sympathetic nerves. Activation of these nerves causes release of norepinephrine that binds primarily to post-junctional α1-adrenoceptors causing smooth muscle activation and vasoconstriction. Arterial vasoconstriction increases systemic vascular resistance which raises arterial pressure. In heart failure, particularly when cardiac output is significantly reduced, arterial vasoconstriction helps to maintain arterial pressure. The increased systemic vascular resistance, however, contributes to an increase in afterload on the heart, which can further depress systolic function. Peripheral vasoconstriction, particularly in the smaller arterioles, limits muscle perfusion during exercise thereby contributing to a decrease in exercise capacity. Contraction of venous vessels enhance venous return and preload, which helps to maintain stroke volume through the Frank-Starling mechanism. The resulting increase in venous pressure, however, can lead to peripheral edema.
In summary, peripheral vasoconstriction caused by enhanced sympathetic activation can be both beneficial and deleterious in heart failure. The deleterious aspects of sympathetic activation in patients can be offset by using arterial and venous vasodilator drugs. This therapeutic approach is very important in the treatment of heart failure.
Enhanced sympathetic outflow to the kidneys causes an increase in renin release. This is mediated by β-adrenoceptors in the kidney. Plasma renin activity, therefore, is often elevated in heart failure patients, in part, because of increased sympathetic activity. Increased renin release causes increased formation of angiotensin II and subsequent formation of aldosterone. These circulating hormones cause sodium and water retention by the kidneys that increases blood volume. Angiotensin II also has direct vasoconstrictor actions on blood vessels, which contributes to the increase in systemic vascular resistance. These hormones also stimulate cardiac remodeling that occurs during chronic heart failure. Although the actions of these hormones serve as important compensatory responses to heart failure, overactivation can have deleterious long term actions. Therefore, patients with chronic heart failure are commonly treated with drugs that inhibit the formation or actions of these hormones.