Williams syndrome (WS) affects 1 in 8,000 live births and has a high risk of sudden death. No previous studies have evaluated corrected QT (QTc) prolongation in WS. Retrospective review of all patients with WS evaluated at our institution from January 1, 1980 to December 31, 2007 was performed. WS was diagnosed by a medical geneticist and/or by fluorescence in situ hybridization. Patients with ≥1 electrocardiogram (ECG) with sinus rhythm and measurable intervals were included. Normal control ECGs were identified from a large clinical database. Corrected JT (JTc) interval was calculated when QRS and QTc intervals were prolonged. QTc interval ≥460 ms and JTc interval >340 ms were defined as prolonged. Prevalence comparisons were made using Fisher’s exact test. Statistical probability of <0.05 was considered significant. Of 270 patients identified, 188 had ECGs for review. Complete data were present in 499 of 517 ECGs (patients’ mean age 10.3 ± 9.9 years); 1,522 normal ECGs of age-similar patients composed the control group. QTc prolongation prevalences were 2.0% in controls and 13.6% in WS (p <0.0001); in those, JTc prolongation prevalences were 1.8% in controls and 11.7% in WS (p <0.0001). Four patients died during follow-up; 2 had QTc prolongation and 1 died during noncardiac surgery. Another patient with QTc prolongation sustained cardiac arrest during a procedure. In conclusion, cardiac repolarization is prolonged in WS. Presence of prolonged cardiac repolarization may contribute to the high incidence of periprocedural mortality in these patients. All patients with WS should be screened for cardiac repolarization abnormalities, especially before surgery.
Williams syndrome (WS) is a congenital multisystem developmental disorder resulting from the deletion of approximately 28 genes on chromosome 7q11.23. It affects 1 in 8,000 live births. Structural cardiovascular abnormalities occur most commonly and are present in approximately 80% of patients with WS. There is also an increased risk of sudden cardiac death in this population. In normal populations electrocardiographic abnormalities can sometimes account for susceptibility to sudden cardiac death. In particular, prolongation of the corrected QT (QTc) interval on electrocardiogram (ECG) is associated with an increased risk of ventricular tachyarrhythmias and subsequent sudden cardiac death in groups with congenital and acquired long QT syndrome (LQTS), myocardial infarction, dilated cardiomyopathy, and diabetes mellitus. Electrocardiographic abnormalities have not been characterized in WS. The aims of the present study were to (1) characterize electrocardiographic cardiac repolarization abnormalities in patients with WS and (2) determine what impact, if any, prolongation of the QTc interval in the setting of WS has on the risk of cardiovascular compromise and mortality.
Methods
We retrospectively reviewed available charts of all patients with WS evaluated at the Children’s Hospital of Philadelphia (Philadelphia, Pennsylvania) from January 1, 1980 through December 31, 2007. Records were reviewed from all patients seen in the Multidisciplinary Williams Syndrome Clinic and those evaluated in the division of cardiology. Diagnosis of WS was confirmed by the clinical phenotype assessed by an experienced medical geneticist and/or by demonstrating elastin hemizygosity by fluorescence in situ hybridization.
The MUSE Cardiology Information System (GE Healthcare Clinical Systems, Milwaukee, Wisconsin) was used to identify normal ECGs from among >230,000 patient recordings in the database. All ECGs had been previously read as normal by an attending cardiologist and included manually measured and calculated QT and QTc intervals. ECGs with nonsinus rhythm (i.e., low right atrial rhythm) or unmeasurable intervals were excluded. Patients with WS were identified from a database of all patients with WS evaluated at the Children’s Hospital of Philadelphia. In patients with WS and multiple ECGs, up to the 5 most recent ECGs were reviewed. All WS ECGs were reviewed independently by 2 blinded readers (R.T.C., P.F.A.). Electrocardiographic intervals were measured using standard techniques. QTc interval was determined using the Bazett formula. The corrected JT (JTc) interval was calculated for all ECGs using previously published methods. The JTc measurement was used to control for abnormalities in ventricular depolarization. A QTc interval ≥460 ms and a JTc interval >340 ms were defined as prolonged. Mean values of QTc and JTc intervals for the 2 readers were used for analysis.
All available cardiovascular data on identified patients were reviewed including histories, physical characteristics, and ancillary testing. Surgical records were analyzed to determine interventions performed. In those subjects who died, clinical charts and postmortem reports were reviewed, where applicable, to determine possible causes of death. The study was approved by the hospital’s institutional review board.
Data were analyzed using SAS 9 (SAS Institute, Cary, North Carolina). The folded F test was used for comparison of distributions of categorical variables between the control and study groups. Independent-sample t test was used to compare means of continuous variables. Chi-square test was used to evaluate differences in gender distributions. Fisher’s exact test was used to compare the prevalence of prolonged QTc and prolonged JTc intervals on ECGs with prolonged QTc interval (JTc/QTc) and the prevalence of left ventricular hypertrophy within WS groups with and without prolonged QTc interval. Interobserver variabilities for measurements of QT, QTc, JT, and JTc intervals were tested using Cronbach alpha coefficient. Pearson coefficient was used to evaluate the correlation of QRS interval with QTc and JTc intervals. A step size of 10 ms was used to generate QTc distribution curves that were smoothed using the cubic spline method. Prevalences of QTc and JTc prolongation were determined using the bootstrapping method in >1,000 random sample sets. Statistical probability <0.05 was considered significant.
Results
Baseline demographic and electrocardiographic data for the 1,399 patients in the control group are listed in Table 1 . Range of QTc interval for the control group was 356 to 536 ms. Distributions of QTc interval in the control and WS groups are shown in Figure 1 . Distribution of QTc interval by quartiles for age in the control group is shown in Figure 2 .
| Variable | Controls | WS | p Value |
|---|---|---|---|
| (n = 1,522 ECGs) | (n = 499 ECGs) | ||
| Boys | 822 (54%) | 249 (50%) | 0.1110 |
| Age (years) | 9.7 ± 5.8 | 10.3 ± 9.9 | 0.1728 |
| Heart rate (beats/min) | 90 ± 23 | 104 ± 25 | <0.0001 |
| PR interval (ms) | 131 ± 22 | 124 ± 23 | <0.0001 |
| QRS interval (ms) | 81 ± 11 | 81 ± 17 | 0.4880 |
| QT interval (ms) | 348 ± 38 | 339 ± 44 | <0.0001 |
| Corrected QT interval (ms) | 418 ± 17 | 436 ± 27 | <0.0001 |
| JT interval (ms) | 267 ± 32 | 258 ± 34 | <0.0001 |
| Corrected JT interval (ms) | 321 ± 17 | 332 ± 27 | <0.0001 |
| JTc/QTc (ms) | 373 ± 20 ⁎ | 369 ± 32 † | 0.7632 |
Baseline demographic and electrocardiographic data for the 188 WS patients with ECGs available for review are presented in Table 1 . There were 517 ECGs available. Sinus rhythm was present in 503 of 517 (97.2%) ECGs. Complete data were present in 499 of the 503 available ECGs with sinus rhythm. Mean number of ECGs per patient was 2.7. The QTc range for the study group was 357 to 641 ms. Distribution of QTc interval by quartiles for age in the WS group is shown in Figure 3 . Interobserver correlations for single and averaged measurements of repolarization intervals were similar to previous studies and are presented in Table 2 .
| Interval | Single Measurement | Averaged Measurements |
|---|---|---|
| r (95% CI) | r (95% CI) | |
| QT | 0.937 (0.925–0.947) | 0.967 (0.961–0.973) |
| Corrected QT | 0.730 (0.686–0.768) | 0.844 (0.814–0.869) |
| JT | 0.890 (0.870–0.907) | 0.942 (0.931–0.951) |
| Corrected JT | 0.728 (0.684–0.767) | 0.842 (0.812–0.868) |
Prevalences of QTc and JTc/QTc prolongation in the WS and control groups are shown in Figure 4 . Range of JTc interval in controls was 263 to 419 ms. JTc/QTc prolongation was present in 26 of 30 (86.7%) control ECGs with QTc prolongation. Mean QTc interval for control ECGs with QTc prolongation was 473 ± 16 ms (461 to 536). Of those in the control group with JTc/QTc prolongation, 15 of 29 (51.7%) were male. Range of JTc interval in the WS group was 257 to 537 ms. JTc/QTc prolongation was present in 62 of 78 (79.4%) WS ECGs with QTc prolongation. Mean QTc interval for ECGs in the WS group with QTc prolongation was 476 ± 28 ms (460 to 641). Of those patients in the WS group with JTc/QTc prolongation, 29 of 43 (67.4%) were female.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
