Female Alms1-deficient mice develop echocardiographic features of adult but not infantile Alström Syndrome cardiomyopathy

Abstract

AbstractBackgroundAlström Syndrome (AS), a multisystem disorder caused by biallelicALMS1mutations, features major cardiac complications often causing early mortality. These are biphasic, including infantile dilated cardiomyopathy, and distinct adult-onset cardiomyopathy. Cardiomyocyte maturation defects, cardiac fibrosis and early atherosclerosis have all been invoked as contributors to heart failure in AS, but their relative importance and inter-relationships are unknown.MethodsCardiac function of globalAlms1knockout mice was assessed by echocardiography at postnatal day 15 (P15) and at 8 and 23 weeks of age. Echocardiography was also undertaken in female mice withPdgfrα-Cre-drivenAlms1deletion in cardiac fibroblasts and a small proportion of cardiomyocytes. Histological and transcriptional analysis of myocardium at P15 and 24 weeks of age was also performed.ResultsCardiac function was unaltered in knockout mice of both sexes at P15 and 8 weeks of age. At 23 weeks of age female but not male knockout mice showed increased left atrial area, decreased isovolumic relaxation time, and reduced ejection fraction, consistent with early restrictive cardiomyopathy. No histological or transcriptional changes could be identified in myocardium of 23-week old femaleAlms1KO mice, however.Pdgfrα-Cre-drivenAlms1KO in females did not recapitulate the phenotype of global KO at 23 weeks.ConclusionsAdult female, but not male,Alms1-deficient mice show echocardiographic evidence of cardiac dysfunction, consistent with the restrictive cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear, but may involve metabolic or endocrine differences between sexes. No infantile cardiomyopathy was found in this study.