In a large sample representative of the general US population, the association between QT-interval duration and all-cause, CVD, and CHD mortality was U-shaped, with increased risks at the lower and upper tails of the QT-interval distribution. Although the increase in risk was highest at the extremes of the distribution, the risk of mortality progressively increased with longer and shorter QT-interval duration compared with the population average with no clear threshold for risk change.
Population-based studies reporting associations between prolonged QT-interval duration and mortality rate have been inconsistent. Some studies7-17
have shown progressive associations of QT-interval duration with mortality rate, but other studies have shown U-shaped associations6,25
or nonsignificant associations.18-20
The categories used for evaluating the association of QT-interval duration with mortality rate in previous studies generally were wide and inconsistent across studies, making it difficult to evaluate dose-response relationships and to compare findings. Our results suggest that analyses of QT-interval duration and mortality rate need to carefully select the cut points and the reference category to avoid masking nonlinear dose-response relationships.
In experimental models, prolongation of the QT interval is associated with the occurrence of early after-depolarizations.26
Early after-depolarizations of sufficient amplitude can generate premature action potentials that lead to cardiac arrhythmias that may progress to ventricular fibrillation and sudden cardiac death.27,28
In general, longer QT intervals reflect longer ventricular action potentials, a reduction in repolarizing reserve29
that is associated with exaggerated spatial and temporal heterogeneity of electrical recovery of the ventricle. This would allow for the development of functional reentry, in which still-activated regions of ventricular myocardium reenter and reactivate regions with shorter action potentials, producing polymorphic ventricular tachycardias. The progressive association of QT-interval duration with mortality at the high end of the distribution then would reflect an increased likelihood of ventricular arrhythmias associated with increasing heterogeneity in ventricular action potential duration.
Although the literature regarding prolonged QT intervals is substantial, less is known regarding shortened QT intervals, especially at the population level. Short QT syndrome is a rare disease associated with hastened ventricular repolarization (QT intervals typically ≤320 milliseconds) and an increased risk of sudden cardiac death,3,4,18,30-32
although more recent studies33,34
have shown that genetically confirmed cases of short QT syndromemay have QT-interval durations of 320 to 360 milliseconds. Data from population-based studies regarding the risk associated with a QT interval at the low end of the distribution are limited. A small study in the Netherlands6
found no association for sudden cardiac death when comparing participants with a QTb of less than 400 vs 400 to 440 milliseconds. Similarly, a Finnish study of 10 822 participants found no association of all-cause mortality comparing participants with a QTb of less than 340 vs 360 to 449 milliseconds,18
and a study of 3596 participants in England reported no association for all-cause or cardiovascular mortality comparing participants with a QTb of less than 397 vs 410 to 422 milliseconds.25
None of these studies presented a more detailed dose-response analysis. Our findings indicate that the results of these analyses could depend on the cutoff points used to define the lower tail of the QT-interval distribution and on the QT-interval values used to define the reference category.
Similar to QT prolongation, shortening of the QT interval is not uniform in time and space in the ventricle. Thus, shortening of the QT interval is associated with exaggerated heterogeneity of repolarization in time and space. The exaggerated heterogeneity of action potential duration creates a substrate for functional reentry similar to that of long QT syndrome but with hastened recovery and reduced refractoriness in the ventricle, and arrhythmias are likely to be even more malignant in short compared with long QT syndromes.35
Traditionally, reference ranges for QT-interval duration in the general population were expressed in terms of QTb.18,30,31,36,37
The Bazett correction, however, has a strong residual correlation with heart rate and results in wider distributions compared with other adjustment methods with better control for heart rate.38
Indeed, the 2009 recommendations for the standardization and interpretation of the QT interval from the American Heart Association Electrocardiography and Arrhythmias Committee Council on Clinical Cardiology, the American College of Cardiology Foundation, and the Heart Rhythm Society recommended that linear regression functions rather than the Bazett formula be used for QT correction.39
The report further recommended that, in addition to rate, sex and age should be incorporated into QT adjustment because women and elderly individuals tend to have longer QT intervals. The report proposed a reference range for linear function–adjusted QT-interval duration from 390 to 450 milliseconds in men or 460 milliseconds in women. In the NHANES III, these values correspond to the 17th and 98th percentiles of the QTrras distribution in men and the 18th and 99th percentiles of that distribution in women. Our analysis thus indicates that QT-interval duration is associated with variations in mortality rate even within reference ranges calculated using the most recent normative standards. Moreover, our study showed that the observed associations were stronger when using the QTrras compared with the QTb, which might be explained partly by the imperfection of the Bazett correction formula.
Several limitations of this study need to be considered. The QT-interval duration was measured at a single baseline time, which may result in nondifferential measurement error because there is substantial within-individual variability. Repeated measurements of QT-interval duration are needed to reduce measurement error and to better characterize the association between QT interval and mortality rate in future studies. Causes of death were ascertained based on death certificates, and we did not have detailed adjudications of arrhythmic sudden cardiac deaths, an end point that more specifically may reflect the effect of QT-interval duration on mortality rate. Although potential misclassifications may occur by using death certificate data and by the limited adjudication of arrhythmic deaths, these inaccuracies were likely to be unrelated to baseline QT-interval data and therefore would tend to result in an underestimation of the association between QT-interval duration and specific causes of death in our study.
In conclusion, data from the NHANES III, a large sample representative of the general US population, showed a U-shaped relationship between QT interval and mortality end points. Shortened and prolonged QT-interval durations, even within reference ranges, were associated with increased risks of total, CVD, CHD, and non-CVD death. Detailed analyses of the dose-relationship between QT-interval duration and mortality in other populations should be conducted to confirm these findings, especially the mortality implications of a shortened QT interval, and to elucidate the mechanisms underlying these associations.