255PKD2 mutations lead to impaired calcium cycling in the heart and predispose to heart failure

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PurposeMutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2), cause autosomal dominant polycystic kidney disease (ADPKD). Although the leading cause of mortality in ADPKD is cardiovascular disease, the relationship between these conditions remains poorly understood. Interestingly, even young ADPKD patients with normal blood pressure and renal function exhibit ventricular dysfunction. PC2 is an intracellular calcium channel and is thus hypothesized to modulate intracellular calcium signaling, possibly affecting cardiac function. Our aim was to study cardiac function in a zebrafish model lacking PC2 (Pkd2 mutants). Next, we aimed to explore the relevance of this zebrafish model to human ADPKD by examining an ADPKD database for an association between ADPKD and idiopathic dilated cardiomyopathy (IDCM).MethodsFor zebrafish cardiac output measurements, heart rates were counted and images of blood flow in the dorsal aorta were captured at a high frame rate. Tracking of red blood cells during one cardiac cycle and measurement of aorta diameter allowed stroke volume to be calculated. For calcium imaging experiments, isolated hearts were loaded with fluo-4 AM, followed by de-esterification before imaging. The isolated hearts were paced electrically and stimulated with drugs. The entire coding and flanking intronic regions of PKD1 and PKD2 were screened for mutations by direct sequencing, and PKD mutations were confirmed in 374 patients.ResultsPkd2 mutant zebrafish showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling with slow transients, calcium alternans, and reduced intracellular calcium stores. Reactions to beta-agonists, caffeine, and pacing were blunted in the pkd2 mutant hearts. In human ADPKD patients, we found IDCM to coexist frequently with ADPKD when compared to the general population, where the prevalence of IDCM is approximately 1:2500. This association was strongest in patients with PKD2 mutations; approximately 9% of PKD2 patients also had IDCM.ConclusionsWe found a novel association between ADPKD and IDCM and suggest modulation of calcium signaling by PC2 as a potential mechanism. Our results from the zebrafish studies indicate heart failure in the pkd2 mutants. Further studies are warranted to study the relationship between ADPKD and IDCM in more detail, as well as the mechanisms of cardiomyopathy in ADPKD patients with PKD1 and PKD2 mutations. Meanwhile, we propose ADPKD to be considered a risk factor for development of IDCM in the clinical setting.

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