Hypertrophic Cardiomyopathy (HCM) is a common inherited heart disease with poor risk prediction due to incomplete penetrance and a lack of clear genotype–phenotype correlations. Advanced imaging techniques have shown altered myocardial energetics already in preclinical gene variant carriers. To determine whether disturbed myocardial energetics with the potential to serve as biomarkers are also reflected in the serum metabolome, we analyzed the serum metabolome of asymptomatic carriers in comparison to healthy controls and obstructive HCM patients (HOCM). We performed non-quantitative direct-infusion high-resolution mass spectrometry-based untargeted metabolomics on serum from fasted asymptomatic gene variant carriers, symptomatic HOCM patients and healthy controls (n = 31, 14 and 9, respectively). Biomarker panels that discriminated the groups were identified by performing multivariate modeling with gradient-boosting classifiers. For all three group-wise comparisons we identified a panel of 30 serum metabolites that best discriminated the groups. These metabolite panels performed equally well as advanced cardiac imaging modalities in distinguishing the groups. Seven metabolites were found to be predictive in two different comparisons and may play an important role in defining the disease stage. This study reveals unique metabolic signatures in serum of preclinical carriers and HOCM patients that may potentially be used for HCM risk stratification and precision therapeutics.
Bibliographical noteFunding Information:
Funding: We acknowledge the support from the Netherlands Cardiovascular Research Initiative, an initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS); NWO (NWO-ZonMW; 91818602 VICI grant to Jolanda van der Velden); ZonMW and the Dutch Heart Foundation, translational research program 95105003. We acknowledge the support from the Dutch Cardiovascular Alliance, an initiative with the support of the Dutch Heart Foundation (2020B005, Double-Dose). MN is supported by a ZonMW VICI grant 2020 (09150182010020).
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