Background

Cardiovascular complications are the leading extrarenal cause for increased morbidity and mortality in patients with polycystic kidney disease (PKD). PKD is caused by dominant mutations in PKD1/2 (ADPKD) or recessive mutations in PKHD1 (ARPKD). PKD is known to results in endothelial dysfunction and increase reactive oxygen species. This, in turn, leads to renal failure, hypertension, and cardiac arrhythmias. Previous cohort studies have indicated an association between PKD and an increased incidence of atrial fibrillation. However, the underlying electrophysiological mechanisms that contribute to atrial arrhythmogenesis in PKD remain unclear to date.

Purpose

To elucidate the mechanism of arrhythmogenesis in PKD by performing a detailed phenotyping of the electrophysiological properties of atrial cardiomyocytes isolated from a rat model of ADPKD.

Methods

Patch-clamp measurements were conducted on single atrial cardiomyocytes that were isolated from female and male PCK rats (SD-1 background) carrying a recessive mutation in the PKHD1 gene. These experiments were complemented by blood tests and invasive blood pressure measurements.

Results

The PCK rats exhibited fulminant renal dysfunction as evidenced by significantly elevated serum urea levels compared to the corresponding wild type group (wt). This effect was particularly pronounced in male subjects. Invasive blood pressure measurements revealed severe arterial hypertension (systolic blood pressure 200±8 mmHg in male rats vs. 140±3 mmHg in wt rats). These findings confirm the phenotype of polycystic kidney syndrome, which appears to be pronounced in male animals. Patch-clamp measurements conducted on isolated atrial cardiomyocytes revealed a significantly increased cell size of 38±8 % in the male group compared to controls, confirming cardiac hypertrophy at the cellular level. Male animals further exhibited a significant shortening of the action potential duration at 50 % of repolarization (APD_50%) by 56±26 % and APD_90% by 47±17 % compared with the corresponding wt group. In female PCK rats, no significant changes in cell size or APD_50% were observed, although APD_90% was significantly shortened by 29±7 %.

Conclusion

The electrical alterations in atrial cardiomyocytes were notably more pronounced in male rats with PKD, as were renal dysfunction and arterial hypertension. The significant shortening of atrial action potentials suggests a molecular correlate of an atrial arrhythmopathy, which is most likely responsible for the increased incidence of atrial fibrillation in patients with PKD.