The sequence and causality of the pathomechanisms that initiate and exacerbate HCM are unknown, and current treatment options are insufficient to prevent the disease. Longitudinal studies of
in vivo cardiac function and
in vitro studies (muscle preparations, HCM mouse models) are needed to elucidate the pathogenesis of HCM and identify novel drug targets (Fig.
1b). In the early stage of the disease (stage I), deficits are seen in energetic status of the heart, reflected by a reduced phosphocreatine/ATP ratio and reduced myocardial efficiency [
31‐
33]. Moreover, Ho and colleagues [
34] detected early pro-fibrotic signalling in patients with thick filament mutations before the onset of hypertrophy or detectable fibrosis on CMR. Thus, while mutation carriers (stage I) do not exhibit symptoms and do not show LV hypertrophy, the intrinsic properties of their heart muscle clearly differ from a healthy control population. Recent studies in human cardiac muscle revealed high sensitivity to calcium of the sarcomeres, which may underlie arrhythmias [
35,
36], reduced contractile performance of single cardiomyocytes [
37] and high energetic costs for muscle contraction [
33]. These cellular pathomechanisms should be further explored [
38,
39], and interventions aiming to correct these cellular deficits should be tested in an experimental setting (animal models). Such treatments include gene correction, and therapies targeting sarcomere function, ion channels or metabolism [
40]. Subsequently, clinical trials are needed to build proof for novel preventive treatment strategies. Based on positive effects of the L‑type Ca
2+ channel blocker diltiazem in mouse models of HCM, a clinical pilot study was performed in G+/Ph− individuals [
41]. This double-blind, randomised, placebo-controlled clinical trial proved that preclinical treatment with diltiazem is safe and feasible and revealed that the drug treatment has a positive effect. Diltiazem prevented the progressive reduction in LV cavity size characteristic of HCM development. The improvement was lost within a year after treatment was interrupted. This study illustrates the strength of a well-designed clinical trial in G+/Ph− individuals. In order to further unravel the pathomechanisms of HCM, basic scientists and clinical cardiologists should work together with their ultimate goal being the development of a curative treatment of this common disease.