Extra energy for hearts with a genetic defect: ENERGY trial

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy with an estimated prevalence of 1:500 to 1:200 [1‐4]. It is a cause of acute cardiac arrest at a young age and cardiac transplantation in end-stage heart failure patients [1, 2]. As familial HCM is an autosomal dominant genetic disorder, most patients are heterozygous for the mutation and carry one mutant and one normal allele. Even though the gene mutation is present at birth, disease onset generally occurs between 20 and 50 years of age, thus affecting patients in the prime of their life. The sarcomeric gene mutation causing HCM was first identified more than 25 years ago. Currently >1,400 HCM mutations have been found, of which ~90% reside in the genes encoding thick and thin filament proteins of the sarcomere [4]. The 3 most frequently affected genes (MYH7, MYBPC3 and TNNT2) encode the sarcomeric proteins myosin heavy chain (MyHC), myosin-binding protein C (cMyBP-C) and troponin T (cTnT) [2, 4]. With the advance in genetic screening, more genotype-positive phenotype-negative (G+/Ph-) individuals are currently being identified, which increases the number of people that are insecure of their fate as treatment to prevent disease is lacking [5].

Using metabolic therapy we aim to reverse deficits in cardiac energetics, which are observed at the very early disease stage in seemingly healthy (asymptomatic) mutation carriers (Fig. 1). A reduced ratio between phosphocreatine and adenosine triphosphate (PCr/ATP), a measure of energetic status of the heart, was observed in mutation carriers without hypertrophy [6]. In addition, myocardial external efficiency was significantly reduced in asymptomatic individuals with mutations in genes encoding thick filament proteins [7]. Imaging studies in HCM patients with advanced disease showed that myocardial efficiency did not further decline compared to asymptomatic mutation carriers, indicating that energy deficiency is an early change in the heart before the development of hypertrophy [8]. Research data has suggested that at cardiac muscle cell level, two mutation-mediated changes in myofilament function underlie reduced cardiac efficiency in HCM. Firstly, the mutation-induced increase in ATP utilisation of sarcomeres, which was reported in transgenic HCM mice [9]. In line with these findings, our studies in cardiac tissue from HCM patients showed an increased cost of muscle contraction, illustrated by a ~ 2-fold higher tension cost (ratio between ATP utilisation and generated force) compared with controls [7, 10]. Secondly, a mutation-related increase in myofilament calcium sensitivity was found in HCM mouse models [11], which increases both force development and ATP consumption. In accordance with HCM mouse models, studies in human cardiac tissue revealed higher calcium sensitivity in HCM human cardiac tissue compared with controls [12, 13]. Overall, these studies show that inefficient cardiac pump function and altered energetic status occur at an early disease stage even before development of cardiac hypertrophy, and may thus represent a target for preventive therapy.

Metabolic agents, which are already used in clinical practice such as anti-anginal agents, may be used to improve cardiac energetics and function [14‐19]. In the healthy heart energy demand is met by oxidation of fatty acids and carbohydrates. Although fatty acids represent the predominant fuel for the heart, they provide less ATP per O₂ molecule in comparison to carbohydrates [14]. Thus, agents which shift metabolism away from the preferred fatty acids towards carbohydrates would increase ATP supply and may prevent cardiac hypertrophy and failure. Abozguia et al. showed that metabolic therapy with perhexiline had a beneficial effect in advanced HCM [20]. We recently demonstrated that myocardial efficiency is already reduced in healthy human mutation carriers [7, 10]. Therefore, optimising the energetic status of the heart may benefit mutation carriers at a very early disease stage before hypertrophy is evident. The ENERGY trial will be a proof of concept study which builds on these previous preclinical and clinical studies. We aim to determine whether metabolic therapy has the potential to restore the reduced cardiac efficiency in HCM mutation carriers.

Trimetazidine is an anti-anginal drug, indicated as add-on therapy for the symptomatic treatment of stable angina pectoris in adults who are inadequately controlled by first-line therapies. Trimetazidine inhibits β‑oxidation of fatty acids by blocking the mitochondrial long-chain 3‑ketoacyl coenzyme A thiolase enzyme in the mitochondria [21]. Consequently, glucose oxidation is stimulated which yields more ATP per molecule O2, resulting in a more oxygen-efficient metabolism. The improved energy efficiency obtained with trimetazidine has the potential to correct the energy deficiency observed in HCM. As both ex vivo and in vivo studies showed a more severe energy deficiency in MYH7 compared with MYBPC3 mutations, we will include asymptomatic MYH7 mutation carriers in the ENERGY trial. This clinical trial will be a proof of concept study to determine whether trimetazidine can improve the myocardial energy efficiency of asymptomatic MYH7 mutation carriers, as measured by [¹¹C]-acetate positron emission tomography/computed tomography (PET/CT) and cardiac magnetic resonance (CMR) scans.