The contribution of a short electrocardiographic diastolic interval to diastolic dysfunction and HFpEF

Background: Women are prone to develop heart failure with preserved ejection fraction (HFpEF) and have a longer QT interval compared to men at comparable heart rates, which results in shorter electrical and mechanical diastole. We hypothesize that a shorter electrical diastole increases HFpEF risk, independent of heart rate. Methods: In 85,145 women and men visiting the Cardiology Centers of the Netherlands between 2007 and 2018, we calculated electrical diastolic intervals (TQ and TP) by subtracting the QT interval, or the sum of the QT- and PQ intervals, respectively, from the RR interval using 12-lead ECG recordings. Electrical diastolic intervals were compared between patients with prevalent left ventricular diastolic dysfunction (LVDD), HFpEF and controls. We validated the TQ interval’s association with diastolic function using right atrial pacing and sotalol infusion in a pig model (n = 6). Results: TQ intervals were approximately 30 ms shorter in women than men. Patients with LVDD or HFpEF had shorter TQ intervals compared to controls (LVDD: 479 ± 128ms, HFpEF: 485 ± 138ms and controls: 523 ± 137ms). Shorter TQ intervals increased the risk of prevalent LVDD/HFpEF (per SD decrease in TQ: OR = 1.37, 95%CI: 1.28, 1.45 and 1.16, 95%CI: 1.01, 1.35, respectively) in fully adjusted models in both sexes. After a median follow-up of 8 [IQR = 6–10] years, shorter TQ intervals were associated with a significant higher risk of death (HR = 1.13, 95%CI:1.02, 1.25) in patients with LVDD and HFpEF. In the subgroup with “delayed relaxation”, beta-blocker use was associated with a significantly lower risk of death, which was not observed in those with “stiff” ventricles showing pseudonormalization or restrictive inflow patterns. Findings were independent of heart rate, and not exclusive to women. In pigs, paced at 100 bpm, sotalol infusion decreased the TQ interval, and TQ shortening was correlated to decreasing e’/a’ ratio (r = 0.371, p = 0.018) and E/A ratio (r = 0.337, p = 0.030). Conclusion: A short electrical diastole is associated with a higher risk of prevalent LVDD and HFpEF in both women and men at cardiovascular risk, independent of heart rate. Experimental shortening of the electrical diastole induced functional diastolic abnormalities in pigs. This overlooked mechanism of electrical diastolic shortening may contribute to the complex HFpEF syndrome, with beta-blockers potentially benefiting selected groups. Clinical trial number: Not applicable.