Apart from perturbed contractility, cardiac performance may be impaired by altered energetics of the myocardium. The energy homeostasis may be affected by the HCM mutation through the following mechanism: both impaired and increased contractility (at physiological Ca
2+ concentrations) may lead to increased ATP utilisation of the sarcomeres and a relative depletion of energy storage. A mismatch between energy supply and demand is thought to initiate a self-perpetuating cycle in which other ATP consuming mechanisms in cardiomyocytes, such as re-uptake of Ca
2+ by the sarcoplasmic reticulum Ca
2+ ATPase pump, will prolong cytosolic Ca
2+ transients and stimulate Ca
2+ dependent hypertrophic signalling pathways [
12], rendering the myocardium less efficient in patients with HCM mutations. Indeed, several studies in transgenic mice harbouring mutations in genes encoding myosin heavy chain [
13] and the thin filament protein troponin T [
14,
15] suggested increased ATP utilisation by the sarcomeres. In humans, indirect evidence of increased ATP consumption has been obtained using cardiac imaging studies. With magnetic resonance spectroscopy, it has been shown that cardiac phosphocreatine (PCr) to ATP ratio, an indirect measure of energy status, is reduced by 30 % in HCM patients compared with controls, irrespective of the extent of hypertrophy [
16,
17]. This suggests that energy deficiency is a primary event rather than a secondary consequence of left ventricular remodelling. This is supported by results from a pharmacological intervention study in HCM patients using perhexiline, a modulator of substrate metabolism, shifting metabolism from free fatty acids to the more efficient glucose. After 4.6 ± 1.8 months of perhexiline treatment, improved diastolic function and increased exercise capacity were observed in HCM patients treated with perhexiline [
18]. However, the positive effects of perhexiline may also be explained by improvement of myocardial perfusion. Moreover, direct evidence of increased ATP utilisation for sarcomere contraction in human HCM is lacking. Therefore, the assumption that increased ATP consumption of affected sarcomeres plays an important role in the development of HCM is still debatable. By using a translational approach, within the ENGINE study (
ENer
Get
Ics in hypertrophic cardiomyopathy: tra
Nslation between MRI, P
ET and cardiac myofilament function), we aim to determine to what extent disturbances of myocardial energy metabolism underlie disease progression in HCM.