The genetic and phenotypic spectrum of hypertrophic cardiomyopathy

This thesis aims to expand the genetic and phenotypic spectrum of hypertrophic cardiomyopathy (HCM) by leveraging genetic information and novel imaging and monitoring methods. In Part 1 we used extensive genetic and cellular data, from which we first concluded that the specific affected location of a genetic variant can explain cellular differences between subjects with the same variant. Furthermore, we constructed a polygenic risk score which explains, in part, the large disease variability seen in HCM patient cohorts. We investigated the utility of novel imaging markers on transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging. We discovered that subtle alterations in left atrial function were found in HCM variant carriers compared to healthy controls, although this was not useful in the prediction of development of HCM in the future. We discovered that CMR has excellent performance in distinguishing genotype-positive subjects compared to healthy controls by measuring and detecting specific phenotypic expressions implicated in HCM, including anterobasal hooks, the presence of myocardial crypts, and several morphological and volumetric differences.

In Part 2 we investigated the application of imaging and monitoring methods in various clinical scenarios, in an attempt to better recognize expression and progression of disease. We established the usefulness of a simple echocardiographic marker explaining symptomatic status in subjects with obstructive HCM. Using computed tomography angiography, we found that myocardial bridging occurs often in HCM, but that it had no impact on the usefulness of risk prediction scores for coronary artery disease, nor on prognosis. We explored the use of implantable loop records (ILR) in the assessment of HCM patients with low or intermediate risk for sudden cardiac death. Use of ILR impacted clinical management in a large number of subjects compared to conventional follow-up, but it did not significantly impact decision making in regard to implantable cardioverter-defibrillator implantation. We investigated how Doppler flow abnormalities can suggest the presence of apical aneurysms (AA) in apical or mid-ventricular HCM, when image quality is suboptimal and outline the temporal pattern leading up to AA formation. Lastly, we investigated the implementation of CMR imaging on top of electrocardiography (ECG) and TTE in the context of cardiac screening of HCM family members, showing that nearly a quarter of those without HCM on TTE are diagnosed with HCM following CMR testing.

In Part 3 we focused on sex differences, first by reviewing existing literature. Afterwards, we showed that prognosis after undergoing septal myectomy is the same for men and women, even though there are signs of more progressive disease in women at time of surgery. The impact of body size differences in regard to HCM diagnoses was assessed as well. We revealed that the establishment of body size- and sex-specific normal values impacts overall diagnoses of HCM in gene variant carriers, particularly by reclassifying larger men previously diagnosed with HCM. Lastly, in Part 4 we look towards the future and show several ongoing collaborative efforts that will be integral to the advancement of knowledge of HCM in the future.