Prevalence and Significance of Rare Sarcomere Variants in Secondary Left Ventricular Hypertrophy due to Arterial Hypertension and Wild-Type Transthyretin-Related Cardiac Amyloidosis

The term left ventricular hypertrophy (LVH) describes an augmentation of LV mass (LVM) caused by increased cardiomyocyte size. LVH can be physiological or it can be a pathological condition, which is either primary (i.e., genetic) or secondary. The degree of LVH is very heterogeneous within each condition associated with it, and in both primary and secondary LVH, the phenotype is influenced by several genetic and environmental modifiers. Mutations in sarcomere (SARC) genes classically associated with the development of hypertrophic cardiomyopathy (HCM), a typical example of primary LVH. However, rare SARC varaints have been found outside of the HCM phenotype, with a prevalence in the general population of up to 1:200, and, independently from the cardiac morphology, SARC variants have been associated with adverse cardiovascular outcomes. Their role in secondary forms of LVH, however, has never been investigated. We investigated prevalence and clinical correlated of rare SARC variants in two cohorts of secondary LVH, a group of patients with LVH due to arterial hypertension and a group of patients with wild-type transthyretin-related cardiac amylodosis (ATTRwt). In the arterial hypertension cohort, the prevalence of rare SARC variants was 19% (3 out of 16 patients), while in the ATTRwt cohort it was 23% (5 out of 22 patients). Patients carriers of SARC variants from both cohorts did not show significant differences in terms of LV morphology as compared to non-carriers. In this pilot cross-sectional study, rare SARC variants were found in a non-negligible proportion of patients with secondary LVH, warranting further investigations. Definitive results regarding a possible role of rare SARC variants as predisposing factors for LVH development, outside the HCM phenotype, cannot be drawn to date. Larger cohorts, with control groups, are needed to ascertain their role and relevance within the different subsets of secondary LVH. Pathophysiological mechanisms at the basis of LVH due to arterial hypertension and ATTRwt remain largely undefined. Unravelling specific predisposing factors in the two conditions may prove beneficial to develop targeted treatments.