Sympathetic activation and the role of beta‐blockers in chronic heart failure

Chronic heart failure (CHF) is associated with activation of the sympathetic nervous system. This activation provides short term haemodynamic support to the failing myocardium, but may be deleterious over longer periods as chronic catecholamine excess appears to contribute to disease progression and increased mortality in this condition. Therefore, blockade of sympathetic activation represents a logical, if somewhat counter‐intuitive, approach to the management of the patient with systolic CHF. Pharmacological approaches to blockade of this system include inhibition of central sympathetic outflow (using central sympatholytics, e.g. rilmenidine, moxonidine), blockade of the catecholamine biosynthetic pathway (dopamine beta hydroxylase antagonists) and blockade of the cardiac effects of sympathetic activation (beta‐adrenoceptor blocking agents). Beta‐blockers have now been extensively studied in patients with symptomatic CHF of the New York Heart Association (NYHA) Class II and III severity. Provided beta‐blocker therapy is carefully up‐titrated from sub‐therapeutic doses and given for at least three to four months, these agents have been associated with favourable long term haemodynamic, functional and mortality outcomes. Furthermore, beta‐blockers delay disease progression in CHF by reversing the pathological myocardial remodelling process that accompanies the disease. Non‐selective beta‐adrenoceptor blocking drugs appear to be of particular benefit in CHF therapy. Myocardial β 2 receptors are down‐regulated to a lesser extent than β 1 receptors in CHF, therefore blockade of the β 2 receptor sub‐type may assume greater importance in inhibiting the deleterious effects of sympathetic activation on the myocardium in this disease. Newer agents that possess additional vasodilator properties (carvedilol, bucindolol, nebivolol) may be useful in overcoming the initial negative inotropy of the beta‐blocking component of the drug, however, it is unlikely that vasodilation contributes greatly to long term clinical benefits. Drugs such as carvedilol are also anti‐oxidant, anti‐protiferative and have anti‐endothelin: actions; the clinical significance of these properties is yet to be determined. Unanswered questions remain regarding the use of beta‐blockers in heart failure. Ongoing studies are further examining mechanisms underlying the clinical benefits of these agents as well as their therapeutic potential in NYHA Class IV patients, heart failure post‐myocardial infarction and patients with asymptomatic left ventricular dysfunction.