Delayed Repolarization Underlies Ventricular Arrhythmias in Rats with Heart Failure and Preserved Ejection Fraction
Background—Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms.
Methods—Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation (PES). QTc interval was measured by surface electrocardiography (ECG). The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and western blotting to investigate changes in ion channel expression.
Results—After 7 weeks of high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure, hence diagnosed with HFpEF. PES demonstrated increased susceptibility to VA in HFpEF rats (p<0.001 vs. controls). The arrhythmogenicity index was increased (p<0.001), and the QTc interval on ECG was prolonged (p<0.001) in HFpEF rats. Optical mapping of HFpEF hearts demonstrated prolonged action potentials (p<0.05) and multiple re-entry circuits during induced VA. Single-cell recordings of cardiomyocytes isolated from HFpEF rats confirmed a delay of repolarization (p=0.001) and revealed down-regulation of transient outward potassium current (Ito) (p<0.05). The rapid component of the delayed rectifier potassium current (IKr), and the inward rectifier potassium current (IK1), were also down-regulated (p<0.05), but the current densities were much lower than for Ito. In accordance with the reduction of Ito, both Kcnd3 transcript and Kv4.3 protein levels were decreased in HFpEF rat hearts.
Conclusions—Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QTc prolongation, delayed repolarization from down-regulation of potassium currents, and multiple re-entry circuits during VA. Our findings are consistent with the hypothesis that potassium current down-regulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death.
- Heart Failure with Preserved Ejection Fraction
- Sudden Cardiac Death
- Action Potential Prolongation
- heart failure
- electrical stimulation
- action potential
- Received March 3, 2017.
- Revision received August 21, 2017.
- Accepted September 7, 2017.