In this meta-analysis, we found consistent associations between prolonged QT-interval length and increased risk of total, cardiovascular, coronary, and sudden cardiac death mortality. At the population level, these associations are substantial and comparable in magnitude to the effect of other traditional cardiovascular risk factors.29
While smaller studies were possibly affected by publication bias, the associations remained when the analyses were restricted to the largest studies in the meta-analysis, which are less prone to publication and other sources of selection bias.
The electrocardiographic QT interval corrected for heart rate (QTc) is approximately normally distributed in the general population.4,30–34
Normal values for QTc range from 350 to 450 ms for adult men, and 360 to 460 ms for adult women.4,30,32,35–36
but up to 10–20% of otherwise healthy persons may have QTc values outside of this range.35,37
Marked prolongations of the QT interval may be caused by genetic disorders (e.g., long QT syndrome), pharmacologic agents (e.g., antiarrhythmics, antipsychotics, antibiotics), electrolyte abnormalities (e.g., hypokalemia and hypomagnesemia), and their interactions.2
Other factors associated with QT interval length variability in the population include age, sex, hypertension, BMI, medication usage, low-calorie diets, serum potassium levels,38–39
and common genetic variants.32
Finally, within-person variability and measurement error are additional sources of variability in QT-interval length.
Several mechanisms may explain an increased risk of mortality with prolonged QTc. In animal models, prolongation of the QT interval is associated with the occurrence of early afterdepolarization, in which abnormal depolarization occurs during phases 2 or 3 of the action potential before repolarization is completed.40
These premature or triggered action potentials can generate cardiac arrhythmias such as torsade de pointes, which may progress to ventricular fibrillation and sudden cardiac death.41–42
In general, longer QT intervals driven by longer ventricular action potentials tend to be more spatially and temporally heterogeneous because of a reduction in repolarizing reserve.43
This allows 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 such as torsade de pointes.
QT-interval prolongation may also be associated with conditions affecting autonomic tone or left ventricular structure, including left ventricular hypertrophy or myocardial infarction.41
While it has been speculated that the QT interval may simply be a marker for the severity of underlying clinical or subclinical cardiac disease,44
most studies in our meta-analysis adjusted for blood pressure levels or for the presence of hypertension, and either excluded or adjusted for the presence of pre-existing coronary heart disease. Furthermore, the direct link established between genetic variations in QT-interval length and sudden cardiac death indicates that QT prolongation is a direct causal contributor to mortality risk. Indeed, common genetic polymorphisms that partly explain population variability in QTc, such as NOS1AP
, may also explain a significant fraction of the risk in sudden cardiac death.45
Our meta-analysis provides evidence of substantial heterogeneity in the methodology used to study QT- and-mortality relationships across studies. This heterogeneity has likely complicated the elucidation of the role of an increase in QT-interval length as a risk factor for mortality in the general population. Some factors contributing to this heterogeneity were the lack of uniform criteria for choosing the ECG leads to measure the QT interval, differences in the method for determining the end of the T wave, and differences in the method for correcting for heart rate.46
The 12-lead ECG was the most frequently used technique for measuring the QT interval. However, some studies averaged the intervals across all 12 leads, while others used the single longest QT across all leads. The longest QT interval may be related to QT dispersion, which may represent the heterogeneity of ventricular repolarization,41,47
and may carry different implications than mean QT in terms of arrhythmogenesis. The mean and the longest QT are not very well related to each other and may not be used interchangeably.41
24-hour Holter monitoring was also used in one study.3
Holter methodology is more often employed to detect infrequent extreme QT intervals and diurnal variations, and QT interval measured using the Holter monitoring may not correspond directly to those from standard 12-lead ECG.37,46
Bazett's formula was the most commonly used method for adjustment of heart rate, although it tends to underestimate the duration of repolarization when heart rate is particularly slow (or overestimate when heart rate is fast).37
Other methods, such as Hodge's or Rautaharju's linear equations,12,16,21
may provide a more uniform correction over a wide range of heart rates, but may report discordant results as compared with the Bazett's formula.4,12
Reassuringly, in resting conditions with heart rates 60–90 beats/min, different formulae tend to provide equivalent results for detecting QT prolongation, and so the impact of the method of correction may have been relatively minor in population studies.46
In addition, studies varied substantially in the cutoffs used to present the associations between QT-interval length and mortality. We selected the comparisons of the highest vs the lowest reported categories for our meta-analysis. This is likely to result in between-study heterogeneity, as the cut-points for the highest category ranged from 420 to 470 ms and those for the lowest category from 360 to 460 ms. However, even with this degree of heterogeneity, virtually all studies reported a positive association. More uniform reporting standards in this area would facilitate comparison across studies and should therefore be a priority in future studies.
Other limitations of our meta-analysis need to be considered. Most studies included in this meta-analysis measured QT interval at a single point in time. Given the large degree of within-person variability in QT-interval length,48
it is likely that the relative risks obtained in these studies underestimated the association between QT interval and mortality. Repeated measurements under uniform conditions would more reliably estimate the associations.2
Furthermore, subjects at the extremes of normal QT distribution may have been eliminated by previous ECGs showing an abnormal interval, or by selective mortality. Also, there was large variability in the prevalence of cardiovascular disease at baseline across studies. However, half of the studies adjusted for previous cardiovascular disease in their models, which may help reduce potential confounding due to preexisting disease. In addition, there was substantial variability in the measures of association and the adjustment factors used in each study, adding to the heterogeneity of the results. It is also possible that some individual studies failed to adjust for key risk factors or electrocardiographic parameters that may account for the observed association of QT interval duration and mortality endpoints.
Finally, not all mortality endpoints were reported consistently across all studies, and only 5 studies specifically reported sudden cardiac death. Lack of data on this outcome in most studies was likely caused by the substantial difficulty in assigning sudden cardiac death in population study settings due to the unpredictable nature of this event and the lack of standard definition.49
Indeed, estimates of the incidence of sudden cardiac death in the US vary from less than 200,000 to 450,000 per year, depending on the source.50
Epidemiologic studies of sudden cardiac death are plagued by difficulties in phenotyping and case definition. Conventional estimates, such as those from the National Center for Health Statistics, use death certificate adjudication, which overestimates sudden cardiac death rates. Prospective, multisource identification of sudden cardiac death, such as in the Seattle Emergency Rescue data and the Oregon Sudden Unexpected Death study, are more likely to provide accurate estimates.51
In spite of methodological heterogeneity across studies, our meta-analysis identified consistent increases in mortality associated with a prolonged QT interval. In combination with genetic findings relating to genetic variability in QT-interval length and mortality, our findings indicate that QT-interval length is a determinant of mortality in the general population. Our analysis calls for more standardized methods for measuring and reporting QT-interval measurements, population characteristics, and sudden cardiac death, in order to estimate more precisely the magnitude of the increase in risk associated with QT prolongation.