Genotype positive hypertrophic cardiomyopathy is associated with myocardial perfusion abnormalities

Hypertrophic cardiomyopathy (HCM) is a highly heterogenous disease both genotypically and phenotypically. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) for fibrosis detection and adenosine stress perfusion are key techniques for HCM phenotyping. Recent advances in DNA sequencing, in particular high throughput next generation sequencing (NGS), have enabled more extensive genetic analysis of larger cohorts of patients. We sought to assess the link between genotype and the microvascular circulation in a cohort of patients with HCM.

We recruited 288 patients with HCM according to standard criteria, who were undergoing clinical CMR. All patients had assessment of LV volumes, mass and function and LGE, except 1 for volumes and 2 for LGE. Overall, 214 (74%) also underwent adenosine stress perfusion. Detailed demographic and outcome data were collected over a mean of 3 years follow up. 120 genes with a known or putative role in cardiomyopathy were sequenced in every patient using SureSelect target DNA capture and SOLiD next-generation sequencing, and variants were identified using GATK and LifeScope. Subjects were stratified according to the presence or absence of a likely causative genetic variant in the principal sarcomeric HCM genes.

The main finding of this study is that genotype positive patients are more likely to have abnormal myocardial perfusion. It is known that genotype positive HCM patients have a higher rate of sudden cardiac death (and a trend towards death was seen in this study), and this has been postulated to be related to ischemia. Our finding that sarcomeric variants were associated with lower LV mass was unexpected and is worthy of further study given the comparatively large size of this cohort. Previous studies have highlighted the association between maximum LV wall thickness and extent of LGE with the presence of a known HCM mutation, but this finding was not replicated in the present study. More comprehensive genetic analyses enabled by next generation technologies, coupled with cutting-edge phenotypic evaluation, may enable the dissection of genotype-phenotype relationships in HCM.

This work was supported by the National Institute of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital and Imperial College, London.