Unveiling the complexity of nonobstructive hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic heart disorder defined by the presence of a maximal wall thickness of at least 15 mm with two main forms: obstructive (oHCM) and nonobstructive (nHCM). While oHCM is characterized by left ventricular (LV) outflow tract obstruction (LVOTO), nHCM lacks this feature and shows significant variability in its hemodynamic and anatomical traits. In nHCM, LV hypertrophy (LVH) presents diverse morphologies, including apical hypertrophy and reverse septal curvature, the latter potentially causing mid-ventricular obstruction and near-complete LV emptying. Apical hypertrophy is associated with the risk of LV aneurysms, potentially leading to arrhythmias and thromboembolism. These findings challenge the belief that nHCM is a more benign phenotype than oHCM and highlight the necessity for improved diagnostic and therapeutic strategies. Symptoms in nHCM, such as fatigue and dyspnea, are often attributed to diastolic dysfunction, whereas symptoms like angina are attributed to microvascular dysfunction. However, current treatment options remain limited, as traditional heart failure therapies frequently fail to provide substantial benefits. Given its heterogeneity, a more personalized treatment approach is warranted, including optimizing comorbidities, assessing coronary microvascular dysfunction, and considering alternative pharmacologic strategies. Emerging therapies, such as myosin inhibitors mavacamten and aficamten, target sarcomeric hypercontractility and show promise in early trials, but their clinical impact on nHCM is still under investigation. Gene therapies also hold potential, though their applicability to nHCM is limited by the high rate of mutation-negative cases and the potential irreversibility of advanced disease states. This review critically analyzes the pathophysiological mechanisms of nHCM, evaluates current and emerging therapeutic strategies, and provides guidance on contemporary management approaches for this complex and often underrecognized condition.