ArticlesEfficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial
Introduction
Hypertrophic cardiomyopathy is the most common hereditary cardiac disease, affecting one in 500 individuals.1 The predominant cause is mutation of genes that encode protein components of the cardiac sarcomere.2, 3, 4, 5 The mechanisms that lead from a sarcomere gene mutation to phenotypic expression of hypertrophic cardiomyopathy are poorly understood, which impedes the search for a treatment that can disrupt the pathophysiological process.6 No medical treatment has been reliably shown to halt or reverse disease progression.7 Accordingly, treatment recommendations are focused on the alleviation of symptoms, prevention of thromboembolic events, and implantation of prophylactic implantable cardioverter defibrillators (ICDs) in patients at high risk of sudden cardiac death.8
The clinical diagnosis of hypertrophic cardiomyopathy is based on hypertrophy of the left ventricle that cannot be explained by extrinsic factors such as increased afterload.8 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.9, 10, 11, 12
The angiotensin II receptor blocker (ARB) losartan reduces left ventricular hypertrophy caused by hypertension.13 Results from several animal studies and small clinical studies in patients with hypertrophic cardiomyopathy suggest that ARBs or angiotensin-converting-enzyme (ACE) inhibitors could affect hypertrophy, diastolic function, and collagen synthesis in hypertrophic cardiomyopathy, despite the fact that the disease is caused by intrinsic mechanisms and not by increased afterload.14, 15, 16, 17, 18, 19, 20, 21 Therefore, we aimed to assess the effect of losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy.
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Study design and patients
The INHERIT trial (INHibition of the renin angiotensin system in hypertrophic cardiomyopathy and the Effect on hypertrophy—a Randomised Intervention Trial with losartan) was a single-centre, randomised, double-blind, placebo-controlled study done at the Unit for Inherited Cardiac Diseases, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. We consecutively screened all adult patients (aged 18 years and older) with hypertrophic cardiomyopathy for possible inclusion.
Results
Of 318 patients screened between Dec 1, 2011, and May 1, 2013, 133 patients (mean age 52 years [SD 13], 35% women) from 118 families were enrolled in the study and randomly assigned, 69 to placebo and 64 to losartan (figure 1). CMR was done in 81 (61%) of 133 patients (40 in the placebo group and 41 in the losartan group) and CT in the remaining 52 (39%) patients (29 in the placebo and 23 in the losartan group) at baseline. Baseline demographic and clinical characteristics were well balanced
Discussion
Our results show that losartan does not have an effect on left ventricular mass compared with placebo in patients with hypertrophic cardiomyopathy. We also noted no effect on left ventricular maximum wall thickness, fibrotic mass, or left atrial volume. Treatment with losartan was well tolerated in patients with obstructive as well as non-obstructive hypertrophic cardiomyopathy (panel).
During the past decade several pilot studies have assessed the effect of ARBs on hypertrophy, fibrosis, and
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2022, International Journal of CardiologyCitation Excerpt :Furthermore, comparing our LGE data with those reported in adult population by Todiere et al., we observed that LGE prevalence is lower (45% vs 81% respectively), such as the LGE extent (1,85% in sarcomeric-HCM vs 4% of LV mass). These data of prevalence and LGE extent, measured with the 6-standard deviation method (6 SD), are consistent with the well-established concept that fibrosis is a progressive phenomenon, both in adults and children [19–23]. In our cohort 21 patients had hard cardiac events (18%), mostly in sarcomeric HCM (69%).