Early Cardiovascular Changes of Familial Hypertrophic Cardiomyopathy in the Young

University dissertation from Paediatrics (Lund)

Abstract: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, transmitted in an autosomal dominant fashion, i.e. 50% risk for transmission of the disease-causing mutation to each child of the affected family. Previous studies reveal a high risk for HCM related cardiac events including sudden cardiac death (SCD) during childhood, with a peak incidence of up to 10% during the first two decades of life. HCM remains the most common cause of sudden cardiac death in young people and athletes, probably due to fatal arrhythmias mainly caused by structural and functional changes in the myocardium leading to increased risk for major cardiac events. In young athletes, the distinction between physiological and pathological hypertrophy is often very challenging. The diagnosis of HCM in childhood is more difficult in its early phases, due to the progressive nature of the disease and the lack of HCM symptoms. The increasing population with HCM genotype with little or no detectable myocardial hypertrophy along with the increased risk for cardiac events even in these individuals are important aspects that emphasize the stringent need to improve early diagnosis of HCM in the young. In these studies, we sought to investigate indices of early cardiovascular changes in young individuals with or without myocardial hypertrophy on echocardiography. Study I showed altered diastolic function both in HCM and HCM-risk individuals vs. controls and young athletes. There were altered microvascular responses to acetylcholine, indicating an early endothelial dysfunction present in both the HCM-risk and HCM patients, measured by laser Doppler of peripheral circulation. These microvascular changes were associated with abnormalities in diastolic myocardial function measured by TDI. Study II demonstrated decreased myocardial perfusion (MP) during adenosine induced hyperemia in non-fibrotic myocardium even without diastolic dysfunction in young HCM patients, but not subjects at risk or controls, indicating that microvascular disease can be the cause of MP decrease. Study III showed decreased regional perfusion in hypertrophied compared to non-hypertrophied myocardium and even lower perfusion in areas of fibrotic, hypertrophied myocardium in young HCM patients. The adenosine stress-induced hypoperfused areas were found larger than regions with LGE (fibrosis), indicating that hypoperfusion may be a more sensitive marker of diseased myocardium. Study IV suggests adverse changes of circulating biomarkers reflecting myocardial matrix remodeling, microfibrosis and vascular endotheliopathy in the early stage of hypertrophic cardiomyopathy in the young. Study V showed the superiority of the 2-parameter 12-lead A-ECG score, which is significantly more sensitive and specific than pooled, age-specific conventional ECG criteria for detecting MYBPC3-HCM and in distinguishing such patients from healthy controls, including endurance-trained athletes.

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