👤 Amy Harms

Previous studies have shown that individuals with a hypertrophic cardiomyopathy (HCM) pathogenic variant (PV) or likely pathogenic variant (LPV) without a HCM phenotype (PV/LPV carrier) have decreased myocardial external efficiency (MEE), which is thought to be a key pathomechanism in the onset and progression of HCM. Metabolic treatments improved exercise capacity in HCM patients, but evidence that such drugs correct reduced MEE is lacking. The ENERGY trial is a double-blind, placebo-controlled randomized clinical trial to define if the metabolic drug trimetazidine (TMZ) corrects reduced MEE in PV/LPV carriers for HCM. 51 MYBPC3 or MYH7 PV/LPV carriers were screened after which 40 were included and randomized into a treatment group (n = 20) or placebo group (n = 20) stratified for sex. Participants were treated with TMZ 20 mg or placebo three times daily during 8 weeks. The main outcome of this study was MEE as measured by [11C]-acetate positron emission tomography/computed tomography (PET/CT) and cardiac magnetic resonance (CMR) scan. Secondary outcomes were exercise parameters as measured by cardio-pulmonary exercise testing (CPET). Drug safety was monitored by (serious) adverse event registration. Treatment groups were comparable in terms of age, sex, body mass index, P/LP gene variant, and echocardiographic parameters without significant differences. Baseline CMR parameters and MEE were not significantly different between treatment groups. Eight weeks of treatment with TMZ did not significantly alter MEE compared to placebo. The mean MEE changed from 30.3 ± 3.8 to 29.8 ± 4.3% in the placebo group and from 30.1 ± 4 to 29.1 ± 4% in the TMZ group. Compared to placebo, the TMZ group did not have a significantly different MEE (difference -0.44, 95% interaction CI, -2.863 to 1.986, P = 0.68). The mean V'O2max as a percentage of predicted V'O2max (V'O2max %pred) changed from 108 ± 17 to 111 ± 19 (95% CI, -6 to 10, P = 0.84) percent in the placebo group and from 105 ± 17 to 113 ± 14 (95% CI, 1 to 16, P = 0.03) percent in the TMZ group. After adjustment for baseline, the TMZ group had a significantly increased V'O2max %pred (difference 6.37, 95% interaction CI, -3 to 16, P = 0.04). The ENERGY trial is the first proof-of-concept randomized controlled trial to test the hypothesis that TMZ improves MEE in MYBPC3 or MYH7 PV/LPV carriers. We conclude that metabolic therapy with TMZ may not correct the P/LP gene variant-related decrease in MEE. Netherlands Trial Register NL7492 (URL https://onderzoekmetmensen.nl/nl/trial/25078). Show less

Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity. Show less

Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of human HCM disease. Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, and 6 sarcomere mutation-negative, HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating [Ca(2+)]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca(2+)]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers. We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers. Show less