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 KATP (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/m2 in CS, n=30; 26.6 [24.1–32.8] g/m2 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.

Original languageEnglish
Article numbere027363
JournalJournal of the American Heart Association
Issue number24
StatePublished - Dec 2022


  • ABCC9
  • cardiomegaly
  • echocardiography
  • heart failure
  • high-output state


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