Defining the role of the immune response in hypertrophic cardiomyopathy

The primary biophysical consequences of the myofilament mutations that cause hypertrophic cardiomyopathy (HCM) are increasingly understood, as are the final common pathways of cardiomyocyte dysfunction. This has led to ongoing trials of novel treatments. However, major secondary changes, most notably fibrosis, occur in the non-myocyte compartment that will limit treatment efficacy in established disease. We have shown that there is metabolic crosstalk between stressed cardiomyocytes and neighbouring cells, and our preliminary data indicate that this, and other aspects of remodelling, are mediated, at least in part, by cells of the immune system that accumulate in HCM myocardium. We have shown that ablation of the adaptive immune system markedly worsens remodelling in a well-validated HCM mouse model. We hypothesise that local cardiac immune activity, both acquired and innate, plays an essential and dynamic role in HCM with, as is typical in immunity, a balance of deleterious and protective effects. We will test this by identifying the role of specific immune components in the progression of HCM using reductionist experiments in HCM mouse models, studies in affected human myocardium and large-scale human genetic interrogation. Identification of the immune activity involved will inform novel disease-modifying therapy for established disease.