Pharmacological Management of Hypertrophic Cardiomyopathy: From Bench to Bedside

Abstract

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is still orphan of a specific drug treatment. The erroneous consideration of HCM as a rare disease has hampered the design and conduct of large, randomized trials in the last 50 years, and most of the indications in the current guidelines are derived from small non-randomized studies, case series, or simply from the consensus of experts. Guideline-directed therapy of HCM includes non-selective drugs such as disopyramide, non-dihydropyridine calcium channel blockers, or β-adrenergic receptor blockers, mainly used in patients with symptomatic obstruction of the outflow tract. Following promising preclinical studies, several drugs acting on potential HCM-specific targets were tested in patients. Despite the huge efforts, none of these studies was able to change clinical practice for HCM patients, because tested drugs were proven to be scarcely effective or hardly tolerated in patients. However, novel compounds have been developed in recent years specifically for HCM, addressing myocardial hypercontractility and altered energetics in a direct manner, through allosteric inhibition of myosin. In this paper, we will critically review the use of different classes of drugs in HCM patients, starting from “old” established agents up to novel selective drugs that have been recently trialed in patients.

Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy

“…Previous computational studies of HCM have investigated disease pathomechanisms from the molecular dynamics to the cellular and organ levels 9 . These studies have unravelled important insights linking mutations in sarcomere genes to changes in contractility and arrhythmogenesis 10 – 13 , providing predictions of key mechanisms that underlie arrhythmia in HCM whilst explaining the efficacy of pharmacological targets 14 .…”

Remodelling of potassium currents underlies arrhythmic action potential prolongation under beta-adrenergic stimulation in hypertrophic cardiomyopathy

“…From a clinical standpoint, this can be associated to the enhanced arrhythmogenicity and sudden cardiac death of HCM patients during exercise, especially in competitive athletes [11]. It is also reflected in the routine β-blocker therapy in these patients, as well as in current clinical guidelines, recommending reduced exercise intensity or its complete interruption in the most severe cases [2,12]. However, the main mechanisms underlying the aberrant β-ARS response in HCM remain unknown [5].…”

A pathogenic nonsense mutation (c.1522C>T) of the MYBPC3 gene is implicated with hypertrophic cardiomyopathy

“…Beta‐blockers are frequently considered first‐line medications in the treatment of both obstructive and non‐obstructive HCM patients. Beta‐blockers are able to generate multiple cardioprotective effects, such as slowing the heart rate, decreasing frequency and force of cardiac contraction, decreasing myocardial oxygen consumption, and decreasing blood pressure 23 . However, beta‐blockers scarcely resolve LV dysfunction and cardiac hypertrophy, due to the powerless in addressing the pathophysiological mechanisms of HCM.…”