Sleep Arousal-Related Ventricular Repolarization Lability Is Associated With Cardiovascular Mortality in Older Community-Dwelling Men

Abstract

Background: Sleep is fragmented by brief arousals, and excessive arousal burden has been linked to increased cardiovascular (CV) risk, but mechanisms are poorly understood.

Research question: Do arousals trigger cardiac ventricular repolarization lability that may predispose people to long-term cardiovascular mortality?

Study design and methods: This study analyzed 407,541 arousals in the overnight polysomnograms of 2,558 older men in the Osteoporotic Fractures in Men sleep study. QT and RR intervals were measured beat-to-beat starting 15 s prior to arousal onset until 15 s past onset. Ventricular repolarization lability was quantified by using the QT variability index (QTVi).

Results: During 10.1 ± 2.5 years of follow-up, 1,000 men died of any cause, including 348 CV deaths. During arousals, QT and RR variability increased on average by 5 and 55 ms, respectively, resulting in a paradoxical transient decrease in QTVi from 0.07 ± 1.68 to -1.00 ± 1.68. Multivariable Cox proportional hazards analysis adjusted for age, BMI, cardiovascular and respiratory risk factors, sleep-disordered breathing and arousal, diabetes, and Parkinson disease indicated that excessive QTVi during arousal was independently associated with all-cause and CV mortality (all-cause hazard ratio, 1.20 [95% CI, 1.04-1.38; P = .012]; CV hazard ratio, 1.29 [95% CI, 1.01 -1.65; P = .043]).

Interpretation: Arousals affect ventricular repolarization. A disproportionate increase in QT variability during arousal is associated with an increased all-cause and CV mortality and may reflect ventricular repolarization maladaptation to the arousal stimulus. Whether arousal-related QTVi can be used for more tailored risk stratification warrants further study, including evaluating whether arousal suppression attenuates ventricular repolarization lability and reduces subsequent mortality.

Clinical trial registration: ClinicalTrials.gov; No.: NCT00070681; URL: www.

Clinicaltrials: gov.

Keywords: QT variability index; all-cause mortality; cardiovascular mortality; sleep apnea; sleep arousal; ventricular repolarization.

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

A, Graphical example of ECG and EEG activation during an arousal episode. Heart period and repolarization variability prior to (B), during (C), and following (D) the onset of arousal from sleep. P value indicates the repeated measures analysis of variance results. SDQT and SDRR = QT and RR variance; QTVi = QT variability index.

Figure 2

QTVi and mortality. All-cause mortality across QTVi quartiles at baseline (A), arousal onset (C), and postarousal onset (E). Cumulative incident function curves comparing the competing risk of CV and non-CV mortality of dichotomized QTVi at baseline (B), arousal onset (D), and postarousal onset (F). QTVi values were dichotomized using the fourth quartile of the arousal onset QTVi distribution. P value shows log-rank test results. CV = cardiovascular; Q1-Q4 = quartiles of the QT variability index for Baseline QTVi, Arousal onset QTVi and Post Arousal onset QTVi; QTVi = QT variability index.

Figure 3

The exposure-response relationship of arousal-related QTVi and CV mortality adjusted for age, history of stroke, myocardial infarction/coronary artery disease, atrial fibrillation, congestive heart failure, diabetes, hypertension, COPD, asthma, mean heart rate, mean respiratory rate, Physical Activity Scale for Elderly, systolic and diastolic blood pressures, time of sleep spent below 90% oxygen saturation, BMI, apnea-hypopnea index, arousal index, average corrected QT, arousal burden, and drink and smoking habit. CV = cardiovascular; QTVi = QT variability index.

Figure 4

Cumulative incident function curves compare the competing risk of cardiovascular and noncardiovascular mortality in the men of the first quartile of baseline QTVi. Group 1 represents men whose QTVi values following arousal onset were still in Q1 (QTVi less than –0.96); Group 2 represents participants whose QTVi shifted to upper quartiles (Q2-Q4) following arousal onset. The P value indicates log-rank test results. HR = hazard ratio; QTVi = QT variability index.