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. Corrected QT interval was measured by surface 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 a high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure and hence were diagnosed with HFpEF. Programmed electric stimulation demonstrated increased susceptibility to VA in HFpEF rats (P<0.001 versus controls). The arrhythmogenicity index was increased (P<0.001) and the corrected QT 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 reentry circuits during induced VA. Single-cell recordings of cardiomyocytes isolated from HFpEF rats confirmed a delay of repolarization (P=0.001) and revealed downregulation of transient outward potassium current (I_to; P<0.05). The rapid components of the delayed rectifier potassium current (I_Kr) and the inward rectifier potassium current (I_K1) were also downregulated (P<0.05), but the current densities were much lower than for I_to. In accordance with the reduction of I_to, 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 QT prolongation, delayed repolarization from downregulation of potassium currents, and multiple reentry circuits during VA. Our findings are consistent with the hypothesis that potassium current downregulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death.

背景：保留射血分数（HFpEF）的心力衰竭约占心力衰竭的一半，并且其发生率持续增加。HFpEF的主要死亡原因是猝死，但对潜在机制了解甚少。

方法：从7周龄开始，对Dahl盐敏感的大鼠喂食高盐饮食（8％NaCl）以诱导HFpEF（n = 38）。喂食正常盐饮食（0.3％NaCl）的大鼠作为对照组（n = 13）。进行超声心动图检查以评估14周龄以后的收缩和舒张功能。经过HFpEF验证和控制的大鼠接受了程序性的电刺激。通过表面心电图测量校正后的QT间隔。通过光学作图，全细胞膜片钳测量动作电位持续时间和离子电流，以及定量聚合酶链反应和蛋白质印迹法研究离子通道表达的变化，探讨室性心律失常（VA）的机制。

结果：高盐饮食7周后，38只大鼠中有31只表现出舒张功能障碍和射血分数，并伴有心力衰竭的迹象，因此被确诊为HFpEF。程序性电刺激显示HFpEF大鼠对VA的敏感性增加（与对照组相比，P <0.001）。在HFpEF大鼠中，心律失常性指数增加（P <0.001），ECG的校正QT间隔延长（P <0.001）。HFpEF心脏的光学定位显示了诱发的VA期间动作电位延长（P <0.05）和多次折返。从HFpEF大鼠中分离出的心肌细胞单细胞记录证实了复极化的延迟（P= 0.001）并显示出瞬时向外钾电流的下调（I_至; P <0.05）。延迟整流器钾电流（I _Kr）和内向整流器钾电流（I _K1）的快速分量也被下调（P <0.05），但电流密度远低于I _to。随着I _to的降低，HFpEF大鼠心脏中的Kcnd3转录本和Kv4.3蛋白水平均降低。

结论： HFpEF大鼠对VA的易感性明显增加。潜在的异常包括QT延长，钾电流下调引起的延迟复极化以及VA期间的多次折返回路。我们的发现与以下假设相符：钾电流下调会导致HFpEF异常复极化，进而导致VA和心源性猝死。