Clinical and Genetic Determinants of Disease Progression and Response to Lifestyle and Pharmacological Interventions in Patients With Hypertrophic Cardiomyopathy

Background and Rationale for the Study:

Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiac disease, affecting one in 500 individuals. The predominant cause is mutation of genes that encode protein components of the cardiac sarcomere. The mechanisms that lead from a sarcomere gene mutation to phenotypic expression of HCM are poorly understood, which impedes the search for a treatment that can disrupt the pathophysiological process.

The clinical diagnosis of HCM is based on hypertrophy of the left ventricle that cannot be explained by extrinsic factors such as increased afterload. The course of the disease is highly variable, ranging from an asymptomatic, benign course with a normal life expectancy to a progressive disease characterised by angina, heart failure, atrial fibrillation, stroke, malignant arrhythmia, syncope, or sudden cardiac death. Disease progression can relate to increasing left ventricular hypertrophy and fibrosis leading to worsening of diastolic (and occasionally systolic) function, increased left ventricular end-diastolic pressure, and left atrial enlargement. No medical treatment has been reliably shown to halt or reverse disease progression. Clinical trials demonstrated limited or no effect of angiotensin receptor blockers or late sodium current inhibitor on disease progression, cardiac structure and function, exercise tolerance and quality of life in patients with HCM. Accordingly, treatment recommendations are focused on the alleviation of symptoms, prevention of thromboembolic events, and implantation of prophylactic implantable cardioverter defibrillators in patients at high risk of sudden cardiac death.

Lifestyle interventions including physical activity and dietary nitrate supplementation are safe and can improve symptoms and signs in patients with heart failure. Exercise training is associated with a significant increase in exercise tolerance, but appear to have limited effect on measures of cardiac morphology or function in patients with HCM. Dietary supplementation with inorganic nitrate (i.e. concentrated nitrate-rich beetroot juice) improves exercise capacity, vasodilatation and cardiac output reserves while reduces arterial wave reflections, which are linked to a left ventricular diastolic dysfunction and remodelling.

Angiotensin receptor neprilysin inhibitor (ARNI) is a novel treatment shown to reduce mortality and hospitalisation in heart failure with reduced ejection fraction, while there is an ongoing trial to evaluate its effect on heart failure with preserved ejection fraction. Recent preliminary data suggest that ARNI improves left ventricular wall motion and exercise tolerance, while reduces markers of left ventricular wall stress. The impact of ARNI on parameters of cardiac function and remodeling has not been previously described in heart failure. Several trials are ongoing aiming provide mechanistic insight on the effect of ARNI in heart failure. The effect of ARNI has not been evaluated in patients with HCM.