MUSIC study population
Clinical characteristics of MUSIC study participants have been previously described16
. We analyzed high resolution ECGs of 924 MUSIC study participants. Patients with ECGs not eligible for QT variability analysis (due to atrial fibrillation/flutter, frequent premature beats, [n=346], or noise; [n=45]) were excluded from this study, and data of remaining 533 patients were further analyzed. Mean age was 62.8±12.0 years. The majority of patients were males (N=377; 70.7%), in NYHA HF class II (N=428; 80.3%), with LVEF > 35% in about half (N=254; 47.7%), and history of myocardial infarction (MI) in 238 (44.7%) patients. There were 125 deaths overall during median 44-months follow-up, including 105 cardiac deaths, 20 non-cardiac death, 53 non-sudden cardiac deaths and 52 cases of SCD. Amongst 254 HF patients with LVEF>35%, 39 died during follow-up, cardiovascular cause of death was established in 32 patients, and SCD- in 15 patients.
IDEAL study population
We analyzed data of 181 healthy subjects in the IDEAL database (mean age 38.7±15.7; range of age 18-82; males 51%; 93.8% whites), predominantly non-smokers (71.4%) with a mean body mass index of 24.1±4.5.
Beat-to-beat QT variability
QTVI was significantly higher in MUSIC HF patients than in healthy IDEAL participants (-1.56 [95%CI from-2.61 to-0.42] vs. -2.23 [95%CI from-3.39 to-1.05]; P<0.00001) (). To determine threshold of abnormally amplified QTVI, which would separate healthy individuals from HF patients at risk, we compared percentiles of QTVI in HF patients and healthy subjects. Threshold of the highest QTVI quartile in HF patients (above -1.19; 95 %CI from -1.27 to – 1.13) corresponded to the threshold of QTVI above the 97.5th percentile of healthy individuals’ values (above -0.97; 95%CI from -1.32 to -0.42).
Histograms showing QTVI distribution. Histograms showing the distribution of the QTVI in healthy IDEAL subjects (empty bars) and heart failure participants of MUSIC study patients (full bars).
Interestingly, HF patients with QTVI in the highest quartile had smaller LV mass and narrower QRS (). As expected, the highest QTVI quartile was characterized by significantly increased QTVN, faster heart rate, decreased QTm, diminished LogHRV, and reduced coherence (). Even though the heart rate at rest was slower in patients with LVEF >35%, there were no significant differences in QT variability parameters between HF patients with LVEF ≤35% and those with LVEF >35% ().
Clinical characteristics of MUSIC heart failure patients with QTVI, dichotomized at the 75th percentile
ECG parameters of MUSIC heart failure patients with QTVI dichotomized at the 75th percentile, and LVEF, dichotomized at 35%
Predictive value of QT variability: competing risk analyses
Overall mortality was almost twice as high in patients with QTVI in the highest quartile [42 deaths (31.6%, mean survival time 40.4 [95% CI 38.0-42.8] months) vs. 74 deaths (18.5%, mean survival time 44.8 [95% CI 43.6-46.0] months); P=0.002]. In competing risk analysis, neither QT variability nor HRV predicted non-cardiac death (). However, QTVI was a strong, independent predictor of cardiovascular mortality ( and ). In competing risk analysis QT and heart rate variability strongly predicted non-sudden cardiac death ( and ). However, no association between SCD and QTVI was found (, ). There was no significant interaction found between the highest QTVI quartile and LVEF above or below 35% (P=0.162 for non-sudden cardiac mortality, and P=0.426 for cardiovascular mortality), which confirmed that QTVI predicts cardiac death across the continuum of left ventricular dysfunction equally well.
Additional analysis was performed to assess whether combination of the predictors (QTVI and LVEF) would further improve risk stratification. As expected, patients with the highest QTVI quartile and LVEF ≤35% had the highest risk ( and ), whereas patients with QTVI in 3 lower quartiles and LVEF >35% had the lowest risk.
In order to separately examine the predictive value of the numerator and denominator in the QTVI formula one-by-one, we evaluated the predictive values of QTVI, QTVN, LogHRV, and coherence in univariate and multivariate competing risk analyses. Surprisingly, even in univariate analysis the highest quartile of QTVN did not predict any end-point (), whereas the lowest quartile of LogHRV was significantly associated with cardiovascular mortality and specifically, non-sudden cardiac death. Therefore, in this study, the predictive value of QTVI was due to the denominator in the QTVI formula, due to decreased heart rate variability. Importantly, we have found a similar risk for HF patients with the highest QTVI quartile and for patients with QTVI above the 97.5th percentile of healthy individuals’ values ().
Excluded from QT variability analysis ECG recordings
In univariate survival analysis risk of all-cause death was higher in patients, excluded from QTVI analysis due to arrhythmia at baseline (). However, in multivariate Cox regression after adjustment for age, gender, history of MI, NYHA HF class status of “analyzable” ECG did not carry independent predictive value [HR 0.79 (95%CI 0.60-1.03); P=0.085]. Cardiovascular mortality () and SCD () outcomes did not differ in included and excluded from QT variability analysis subjects.
Figure 4 Kaplan-Meier curves for the probabilities of all-cause death (A), cardiovascular death (B), and sudden cardiac death (C) in patients with available QT variability results (Included), and those who were excluded from QT variability analysis as non-analyzable. (more ...)