Metabolomics and metabolic therapy in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, with a prevalence estimated between 1:500 and 1:200 [1]. In most cases, HCM is an autosomal dominant genetic disorder caused by pathogenic variants of genes that code for proteins of the cardiac sarcomere. HCM is defined by left ventricular hypertrophy (LVH), with the diagnostic criterion being a maximal wall thickness (MWT) of ≥15mm, or ≥13mm in first degree family members of genotype-positive HCM patients, in the absence of abnormal loading conditions such as hypertension or congenital heart defects [2]. The penetrance of HCM is diverse: of family members with the exact same pathogenic variant, some experience a benign course and have a normal life expectancy, while others develop severe HCM early in life. Additionally, there is currently no method of predicting which individual with a pathogenic variant will develop HCM. Disease onset generally occurs between 20-50 years of age, and may develop into progressive cardiac disease as a result of dynamic left ventricle outflow tract (LVOT) obstruction or in the absence of obstruction, embolic stroke associated with atrial fibrillation (AF), or sudden cardiac death (SCD). Approximately 10% of all patients develop severe heart failure. Treatment strategies for manifested HCM have been effective at reducing mortality rates, although a preventive treatment is not yet available as the exact pathophysiology of HCM is still unknown [3]. Chapter 2 of this thesis is an outline of the clinical course of HCM, published in the Dutch journal of medicine (Nederlands Tijdschrift voor Geneeskunde). Chapter 3 is a review of sex-differences in HCM and formulates our hypothesis that female HCM patients are at risk for underdiagnosis and delayed treatment due to the lack of sex-specific diagnostic criteria for HCM. With Chapter 4 we informed the Dutch society of cardiology of our upcoming randomised clinical trial with a study design paper of the ENERGY trial, which described our plans to treat 40 G+/Ph- individuals with trimetazidine (TMZ) in a double-blind, placebo-controlled randomized clinical trial (RCT) to study the effect of metabolic therapy on myocardial external efficiency (MEE). Chapter 5 describes the results of the ENERGY trial, the first-ever RCT in the G+/Ph- group for HCM. 40 G+/Ph- individuals with a MYBPC3 or MYH7 pathogenic/likely pathogenic (P/LP) gene variant were included into a treatment group with TMZ (n=20) or placebo (n=20) stratified for sex. 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). Chapter 6 describes how patient cohorts and biobanks are crucial for cardiomyopathy research such as our metabolomics research of Chapter 7 and 8. In Chapter 7 we analysed the serum metabolome of three groups: G+/Ph- individuals (n=31), HCM patients (n=14), and healthy controls (n=9). Serum metabolites were identified using direct-infusion high-resolution mass spectrometry, after which we used multivariate modelling to generate a 30 metabolite biomarker panel which strongly distinguished the three groups, with equal performance to advanced cardiac imaging modalities in identifying G+/Ph- individuals and HCM patients. Chapter 8 describes a similar metabolomics approach as Chapter 7 in aortic stenosis (AS) which, like HCM, leads to LVH but by an entirely different pathomechanism. It can therefore be used as a genotype-negative comparison to a similar phenotype of LVH. We analysed the serum metabolome of AS patients (n=10) before and after surgical aortic valve replacement (AVR) and healthy controls (n=9). We identified a 30 metabolite biomarker panel which strongly distinguished AS patients from healthy controls. Chapter 9 summarizes the findings in this PhD thesis and provides future perspectives.