Clinical significance and genetic basis of hypertrophic cardiomyopathy with apical phenotype: comparison of pure-apical form and distal-dominant form

Abstract Background Apical hypertrophic cardiomyopathy (apical HCM) is a variant of HCM first reported in Japan. The definition of apical HCM in the Japanese Circulation Society guideline is left ventricular hypertrophy limited to the level of the apex below the papillary muscle level. On the other hand, apical HCM in Western countries often includes hypertrophy that extends to the ventricular septum beyond the true LV apex. Although these variations may have different clinical characteristics and prognoses, they are often considered the same. Therefore, we previously proposed two phenotypes of apical HCM. Pure-apical form follows the definition of the JCS guideline. Distal-dominant form is defined as demonstrating apical hypertrophy extended to the ventricular septum without basal septal hypertrophy. However, the clinical significance and genetic basis of these phenotypes have not been reported. This study aimed to clarify clinical differences and yield of genetic testing in apical phenotype of HCM. Methods Regarding clinical presentation and prognosis, we retrospectively investigated 111 consecutive HCM patients with apical phenotype. HCM-related adverse events were defined as HCM-related death and nonfatal HCM-related events: heart failure admission, embolic stroke admission, and sustained ventricular tachycardia with hemodynamic instability or appropriate implantable cardioverter-defibrillator discharge. Furthermore, we performed a genetic analysis including 145 genes associated with cardiomyopathy in 69 unrelated patients within the cohort. Results In the cohort, 60 patients were pure-apical, and 51 were distal-dominant. The age at diagnosis was about 60 years, and the majority were male in both groups. The comorbidity rate of hypertension did not indicate a statistically significant difference. During the follow-up period of 10.3 ± 6.9 years, the occurrence of HCM-related adverse events was significantly higher in the distal-dominant group than in the pure-apical group (log-rank p=0.007). Detection rate of pathogenic or likely pathogenic variants in sarcomeric protein-encoding genes was significantly higher in the distal-dominant group than in the pure-apical group (21% vs. 3%; p=0.044). Conclusions Two phenotypes of apical HCM should be recognized and distinguished clinically because they have different prognoses and genetic features.