Abstract 4371412: Cardiac dysfunction in a preclinical model of Autosomal Dominant Polycystic Kidney Disease

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder caused by dominant mutations in either the PKD1 or PKD2 genes. Both mutations contribute to disease progression; however, mutations in PKD1 are linked to more severe clinical outcomes. While ADPKD is primarily characterized by the development of renal cysts and fibrosis leading to end-stage renal failure, it is increasingly recognized as a systemic disorder with significant cardiovascular involvement. Common cardiac manifestations of ADPKD include left ventricular hypertrophy, systolic and diastolic dysfunction, and valvular heart disease. Goal: Given the systemic nature and cardiovascular risks associated with ADPKD, we sought to investigate the progression of cardiac dysfunction in a mouse model carrying the Pkd1 R3277C (RC) mutation. This mouse model recapitulates human ADPKD disease progression with renal failure by 9 months of age. Methods: Echocardiographic assessment of the left ventricle was performed in anesthetized mice (9-14 months old) using long- and short-axis view recordings acquired with a Vevo 2100 system and MS400 transducer. M-mode and strain were analyzed using Vevo analysis software. Results: We performed histology and morphometry on kidneys and hearts from wild-type (WT), heterozygous (Het), and homozygous (RC) mice. As expected, extensive cyst formation and double kidney weight over tibia length were observed in RC mice (1 year old). Additionally, our data show no macroscopic changes in heart weight or chamber dimensions. Short-axis echocardiographic analysis revealed a preserved ejection fraction (EF) and normal left ventricle (LV) mass, despite a reduction in the estimated LV volume. A parasternal long-axis view obtained with B-mode echocardiography and analyzed with Vevo Strain software showed decreased cardiac output, stroke volume, and end-diastolic volume (EDV). Moreover, global longitudinal strain (GLS) was significantly reduced in RC mice compared to wild-type controls. Conclusions: Our findings suggest the presence of subclinical cardiac dysfunction in this Pkd1 mouse model. Further studies are warranted to comprehensively evaluate diastolic function and to elucidate the underlying mechanisms of cardiovascular involvement in ADPKD.