Cardiac health, type I collagen, and aging in the oim/oim mouse model of osteogenesis imperfecta and a cohort of adults with OI.

Abstract

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder with marked skeletal fragility and increased recognition as a pleiotropic type I collagenopathy. The impact of OI-causing gene variants on cardiac health and lifespan is just beginning to be understood. To begin to investigate cardiac manifestations of OI-causing type I collagen variants, we utilized the osteogenesis imperfecta murine (oim/oim) model to examine survival with increased age, as well as cardiac function and collagen expression at 4 and 18 mo of age. We determined male oim/oim mice had 50% decreased survival by 18 mo of age compared with wild-type (WT) littermates. Cardiac magnetic resonance imaging and echocardiography revealed 18-mo-old male oim/oim mice had increased left ventricular end-diastolic and end-systolic volumes concomitant with decreased function, as well as the presence of aortic stenosis in a subset of 4- and 18-mo-old male oim/oim mice compared with WT littermates. Female oim/oim survival and cardiac function were equivalent to their WT counterparts. Cardiac evaluations of an adult patient cohort with OI corroborated increased incidences of valvular dysfunction in the patient population with OI, with much of the male cohort also presenting with altered left ventricular function. Little is known concerning the impact of OI-causing variants on patient cardiac health and the influence of sex and age. Using an OI mouse model, we determined that 18-mo-old male oim/oim mice have cardiac dysfunction with decreased lifespan, confirming the need for further investigations to understand pleiotropic extraskeletal manifestations and disease progression in osteogenesis imperfecta.NEW & NOTEWORTHY The heritable skeletal dysplasia, osteogenesis imperfecta (OI), recently recognized as a pleiotropic collagenopathy, shows growing evidence of cardiac involvement impacting lifespan. Evaluating cardiac function (magnetic resonance imaging and echocardiography) using an OI mouse model revealed increased left ventricular end-diastolic and end-systolic volumes concomitant with decreased function and reduced survival in 18-mo-old male OI mice. Additional cardiac evaluations of an adult patient cohort with OI corroborated increased incidences of valvular dysfunction in the patient population with OI.