A Unique High‐Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance in Cantu Syndrome

BACKGROUND: Cardiomegaly caused by left ventricular hypertrophy is a risk factor for development of congestive heart failure, classically associated with decreased systolic and/or diastolic ventricular function. Less attention has been given to the phenotype of left ventricular hypertrophy with enhanced ventricular function and increased cardiac output, which is potentially associated with high‐output heart failure. Lack of recognition may pose diagnostic ambiguity and management complexities. METHODS AND RESULTS: We sought to systematically characterize high‐output cardiac hypertrophy in subjects with Cantu syndrome (CS), caused by gain‐of‐function variants in ABCC9, which encodes cardiovascular K(ATP) (ATP‐sensitive potassium) channel subunits. We studied the cardiovascular phenotype longitudinally in 31 subjects with CS with confirmed ABCC9 variants (median [interquartile range] age 8 years [3–32 years], body mass index 19.9 [16.5–22.9], 16 male subjects). Subjects with CS presented with significant left ventricular hypertrophy (left ventricular mass index 86.7 [57.7–103.0] g/m(2) in CS, n=30; 26.6 [24.1–32.8] g/m(2) in controls, n=17; P<0.0001) and low blood pressure (systolic 94.5 [90–103] mm Hg in CS, n=17; 109 [98–115] mm Hg in controls, n=17; P=0.0301; diastolic 60 [56–66] mm Hg in CS, n=17; 69 [65–72] mm Hg in control, n=17; P=0.0063). Most (21/31) subjects with CS exhibited eccentric hypertrophy with normal left ventricular wall thickness. Congestive heart failure symptoms were evident in 4 of the 5 subjects with CS aged >40 years on long‐term follow‐up. CONCLUSIONS: The data define the natural history of high‐output cardiac hypertrophy resulting from decreased systemic vascular resistance in subjects with CS, a defining population for long‐term consequences of high‐output hypertrophy caused by low systemic vascular resistance, and the potential for progression to high‐output heart failure.