Prolonged heart rate-corrected QT interval and cardiovascular risk in Asian populations

The QT interval is the electrocardiographic representation of total ventricular electrical activity, the summation of ventricular depolarization and repolarization. The prolongation of heart rate-corrected QT-interval (QTc) duration remains the most traditional and widely used parameter reflecting abnormal ventricular repolarization. Abnormal ventricular repolarization is an established mechanism of arrhythmogenesis.¹ It has been shown in several population-based studies to constitute a risk marker of cardiovascular morbidity and mortality,^{2, 3} although its reliability is not generally accepted,⁴ and it also has problems in measurement and interpretation.⁵ Indeed, there is a continuous debate on the clinical significance of prolonged QTc interval measured in resting standard 12-lead ECG. QTc-interval prolongation has been associated with several unfavorable conditions: autonomic system imbalance and autonomic neuropathy, mutation of genes affecting cardiac ion channels involved in cardiac repolarization, nonconducting scar tissue resulting from myocardial infarction or slowly conducting tissues because of myocardial ischemia, hypokalemia and other electrolyte abnormalities, obesity and ventricular hypertrophy. Moreover, QTc-interval prolongation has been associated with several cardiovascular risk factors, including hiperinsulinemia, hyperglycemia and the conjunction of the metabolic syndrome. The association between prolonged QTc and cardiovascular risk factors implicated in atherosclerosis, and also the association with carotid intima-media thickness suggests that QTc-interval prolongation may be a marker of subclinical atherosclerosis.⁶

A recent qualitative overview⁴ on the prognostic impact of prolonged QTc in population-based cohorts, encompassing seven prospective studies published until 2000, showed no consistent evidence for increased cardiovascular mortality risk and for sudden death, except maybe in patients with prior cardiovascular disease. Nevertheless, in more recent studies with occidental populations, including individuals of both genders, the prognostic influence of prolonged QTc interval beyond other established cardiovascular risk factors was reaffirmed. Dekker et al.² showed in black and white middle-aged men and women that QT-interval prolongation was a predictor for coronary heart disease events. Straus et al.⁷ reported its prognostic influence in an older population for sudden cardiac death. However, Kim et al.⁸ reported in Pima Indians that a prolonged QTc interval had no prognostic impact on cardiovascular mortality; the low proportion of baseline cardiovascular disease may have contributed, in part, to the lack of association in this study. Two other studies, one in postmenopausal women³ and another in older man⁹ showed the prognostic influence of QTc-interval length on coronary heart disease events and on cardiovascular morbidity and mortality, respectively.

Plausible explanations for differences in the prognostic impact of prolonged QTc interval among the studies are the occurrence of chance, bias and uncontrolled confounding variables. Chance could have a role, as most of the studies have insufficient statistical power to detect differences between the subgroups, and also gender differences. Moreover, differences among the results of the studies may be partially explained by differences in the outcomes, in studied populations, in classification of QTc interval and gender-specific QTc interval cutoff values used. Furthermore, in most studies, QTc prolongation was based on a single baseline ECG measurement; given the marked individual variability of QTc interval over the 24-h period, repeated measures may be necessary to detect confident associations. And, also relevant, one single ECG was related to outcomes that usually occurred many years later. Exposure to etiological factors during follow-up that may have lengthened QTc –interval, or interventions that could lead to shortening of QTc interval, were not accounted for. Differences in duration and completeness of follow-up may also account, at least in part, for the differences between the studies. Bias may also be present because of imprecise measurement of QTc interval and to differences in the prevalence of cardiovascular disease at baseline. Another aspect is the fact that most of the studies were not designed to investigate whether QTc prolongation was associated with cardiovascular morbidity and mortality and some variables not obtained or not adjusted for may have influenced the results.

However, studies in Asian populations are scarcer.^{10, 11} The first one reported in an elderly Japanese population without cardiovascular disease at baseline (3543 individuals, 64% women, mean age 65 years) that QTc-interval prolongation (>440 ms) was an independent risk marker for cardiovascular and coronary heart disease mortality, whereas no gender difference on the effects of QTc interval on mortality was observed. On the other hand, Maebuchi et al.,¹¹ in this issue of the Journal, showed also in a Japanese population (2439 individuals, 59% women, mean age 58 years) that prolonged QTc interval was associated with the future development of cardiovascular disease, coronary heart disease and stroke, independent of other traditional risk factors, only in males. The reasons for differences of prognostic impact of prolonged QTc interval between genders in the second study are not clearly apparent. Conflicting results may be explained, in part, by differences in the outcomes (only fatal events were evaluated in the first study¹⁰), and by differences in selected populations. Indeed, individuals in this study were younger and had a lower prevalence of prolonged QTc interval, particularly in women, than individuals enrolled in the first cohort. Nonetheless, the fact that the present study had a longer follow-up and a greater number of events than the earlier study indicates that it probably had enough power to have detected any significant effect of QTc-interval prolongation on cardiovascular outcomes in women, if it actually exists. However, even using higher QTc interval cutoff values for women (⩾450 and ⩾460 ms), no significant association was observed. Other possible explanations for the controversial finding of a lack of association between QTc-interval prolongation and cardiovascular events in women have been discussed by Mabeuchi et al.¹¹ Possibly, it may be easier to show the prognostic influence of prolonged QTc interval in older postmenopausal women than in younger females.

Most relevant, this prospective long-term follow-up study further supports the concept of a quantitative approach to electrocardiography and provides evidence that ventricular repolarization prolongation, assessed by a prolonged QTc-interval duration, represents an important risk marker for future cardiovascular morbidity and mortality also in Asian populations, above and beyond other traditional cardiovascular risk factors. Hence, QTc-interval measurement is an inexpensive, easily accessible and noninvasive tool that may contribute to improve cardiovascular risk stratification also in these populations.