Diabetes mellitus can affect ventricular repolarization, and we investigated the impact of diabetes on the risk for cardiac events in older patients with long QT syndrome (LQTS). The study population consisted of 1,152 patients with QTc interval ≥450 ms who were enrolled in the United States portion of the International Long QT Syndrome Registry and survived >40 years of age. Patients were categorized as having diabetes if they received oral diabetic medication or insulin. End points after 40 years of age included first cardiac event (syncope, aborted cardiac arrest, sudden cardiac death, whichever occurred first) and all-cause mortality. Follow-up extended from 41 to 75 years of age. Risk factors for end points were evaluated by the Cox model. During follow-up, 193 patients had a first cardiac event, and 99 patients died. Of patients with LQTS, development of diabetes in adult patients with LQTS was not associated with an increased risk of first cardiac events dominated by syncope. Risk factors for mortality were syncope before 41 years of age, QTc interval ≥500 ms, heart rate >80 beats/min, and diabetes; there was no mortality interaction involving diabetes and QTc interval ≥500 ms. In conclusion, diabetes and prolonged QTc interval contributed independent mortality risks in adult patients with LQTS, with no interaction between these 2 risk factors.
Although many previous studies on long QT syndrome (LQTS) have focused on pediatric and young adult patients with this disorder, a few recent studies have highlighted the association of LQTS with common co-morbidities in adults >40 years of age. No study, however, has focused on the risk conferred by diabetes mellitus (DM) in patients with LQTS, although QTc prolongation occurs in diabetic patients and contributes to increased risk in patients with DM. The present study examined whether development of DM is associated with an increased risk for cardiac events in older adults with LQTS.
Methods
We studied patients >40 years of age who were enrolled in the United States portion of the International Long QT Syndrome Registry. Baseline clinical data were obtained on all enrolled family members <41 years of age, and this included electrocardiograms and history of LQTS-related syncope as previously reported. Patient selection criteria for this study required survival >40 years of age in LQTS Registry subjects who had an electrocardiogram with QTc interval ≥450 ms and answered a prospective follow-up questionnaire regarding the age of non-LQTS–related co-morbidities related to coronary artery disease (CAD), hypertension, and DM during follow-up extending to 75 years of age. We did not collect information on hyperglycemia or degree of diabetic control. Patients were considered to have DM if they were taking oral diabetic medication or were receiving insulin during follow-up. End points for patients >40 years of age were first cardiac events (syncope, aborted cardiac arrest, or sudden cardiac death using a 1-hour definition for the terminal event, whichever occurred first) and all-cause mortality.
Patients were identified as having CAD if they indicated on the medical questionnaire the date when they had been hospitalized for a myocardial infarction, coronary angioplasty, coronary artery bypass graft surgery, or were prescribed medication for the treatment of angina pectoris.
Clinical characteristics were compared using chi-square or Fisher’s exact test for categorical variables and Student’s t test for continuous variables. Graphic display of the time to event before and after time-dependent diabetes was identified used the method of Byar and Mantel. Contributions of relevant clinical variables including QTc interval, time-dependent DM, time-dependent β-blocker therapy, and prespecified interactions to the risk of a first cardiac event and separately for mortality were determined using Cox proportional hazards regression models.
Statistical significance was determined by a p value ≤0.05, and all tests were 2-sided. SAS 9.1.3 (SAS Institute, Cary, North Carolina) was used to perform statistical analyses.
Results
The study population involved 1,152 patients with LQTS who were followed past the age of 40 years. DM was identified in 71 patients at some time during follow-up. Clinical characteristics of the study population are presented in Table 1 . Overall, diabetic patients had faster heart rates and there was a trend toward an increased frequency of coronary disease compared to those unaffected by diabetes. During follow-up, 193 patients had a first cardiac event, and 99 patients died.
| Variable | QTc Interval ≥450 ms (n = 1152) | p Value | |
|---|---|---|---|
| DM | |||
| No (n = 1,081) | Yes (n = 71) | ||
| Women | 753 (70%) | 43 (61%) | 0.11 |
| Caucasian | 1047 (97%) | 67 (94%) | 0.28 |
| Age at electrocardiographic recording (years) | 48 ± 15 | 53 ± 13 | 0.001 |
| Electrocardiographic data | |||
| QTc interval baseline (ms) | 488 ± 42 | 484 ± 47 | 0.04 |
| RR interval baseline (ms) | 874 ± 186 | 791 ± 158 | <0.001 |
| β blockers | 517 (48%) | 31 (44%) | 0.50 |
| LQTS mutations (n = 318) | |||
| LQT1 | 149 (49%) | 4 (27%) | 0.09 |
| LQT2 | 124 (41%) | 10 (67%) | 0.04 |
| Other/multiple | 30 (10%) | 1 (7%) | 0.99 |
| Non-LQTS co-morbidities (n = 191) ⁎ | |||
| Coronary artery disease | 13 (54%) | 61 (37%) | 0.10 |
| Hypertension | 129 (77%) | 17 (71%) | 0.49 |
| Stroke | 17 (10) | 2 (8) | 0.99 |
| End points | |||
| First cardiac events † | 181 (17%) | 12 (20%) | 0.49 |
| Mortality | 89 (8%) | 10 (17%) | 0.02 |
⁎ Number of patients with available information.
† Syncope, aborted cardiac arrest, or sudden death, whichever occurred first.
Probabilities of developing a first cardiac event or all-cause mortality before and after development of DM in patients affected with LQTS are shown in Figure 1 . The probability of a first cardiac event was similar in diabetics and nondiabetics, but death was more frequent in diabetics than nondiabetics ( Figure 1 ).
As presented in Table 2 , risk factors for a first cardiac event (syncope or mortality, whichever occurred first) after 40 years of age included history of a cardiac event before 41 years of age, QTc interval ≥500 ms, and female gender. Beta-blocker therapy was associated with a lower probability of cardiac events, with a hazard ratio of 0.59. Time-dependent development of diabetes did not make a significant contribution to the cardiac event risk model.
| Factor | HR | 95% CI | p Value |
|---|---|---|---|
| Time-dependent diabetes | 0.77 | 0.28–2.08 | 0.60 |
| Cardiac event before age 41 years | 2.96 | 2.14–4.11 | <0.001 |
| QTc interval ≥500 ms | 1.79 | 1.34–2.40 | <0.001 |
| Female gender | 1.41 | 1.00–1.98 | 0.05 |
| Treatment with β blockers | 0.59 | 0.40–0.87 | <0.01 |
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