Mechanistic insights into the potential reversal of Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopathy (HCM) is characterised by unexplained thickening of heart muscle, causing breathlessness, chest pain, blood flow obstruction and, rarely, sudden death. Often genetic from sarcomeric protein mutations, the links between gene and clinical manifestations are poorly understood. Key myocardial “substrate changes” are disarray, fibrosis, small vessel disease and electrical remodelling. In 2023, the first HCM treatments – cardiac myosin inhibitors (CMIs – one approved, one submitted) were developed. These improve symptoms in obstructive HCM, with gradient reductions, LVH reduction and blood troponin normalisation. In the last 5 years, we have developed, with BHF support, a suite of new techniques to probe HCM biology. The most promising of these are quantitative myocardial perfusion, AI hypertrophy measurement, a HCM proteomics blood test and advanced ECG imaging. For the first time will use these to study 60 HCM patients at 3 timepoints around CMI clinical initiation. We want to understand myocardial biology: the interaction between contraction and perfusion, electrical and structural remodelling and blood biomarker changes. We are on the edge of an era where HCM is treatable but we want to know when and why it may be reversible and when and why drug therapy may leave residual disease.