We investigated breathing patterns and the occurrence of arrhythmias and ST-segment changes during sleep in patients with Brugada syndrome. Patients with Brugada syndrome are more likely to die from ventricular arrhythmias during sleep. ST-segment changes have been correlated with risk of sudden cardiac death. Whether sleep disturbances may contribute to arrhythmogenesis is unknown. Patients with Brugada syndrome underwent overnight polysomnography with simultaneous 12-lead electrocardiographic recording. A control group matched by age, gender, and body mass index (BMI) also underwent polysomnography. Twenty patients were included (50 ± 15 years old, 75% men). Despite their normal BMI (24.7 ± 2.7 kg/m 2 ), 45% had sleep-disordered breathing (SDB), with a mean apnea-hypopnea index of 17.2 ± 14 events/hour. In patients with a high risk of arrhythmias, 5 (63%) had SDB. In the control group, 27% had SDB. Atrial or ventricular arrhythmias were not observed. Spontaneous ST-segment changes occurred in 2 patients over 45 different time points. Most ST-segment changes were observed during rapid eye movement sleep (31%) or within 1 minute of arousals (44%). Regarding respiratory events, 25 (56%) of ST-segment changes were related to occurrence of apnea or hypopnea. In conclusion, patients with Brugada syndrome have a high prevalence of SDB even in the setting of normal BMI. The higher incidence of nocturnal death in patients with Brugada syndrome may be conceivably related to co-morbid SDB. Moreover, autonomic instability encountered in rapid eye movement sleep and arousals could potentiate the risk of arrhythmias.
Brugada syndrome was described in 1992 in patients presenting with recurrent aborted sudden cardiac death (SCD) and typical electrocardiographic sign of ST-segment elevation in leads V 1 to V 3 . It was later shown that patients die from ventricular tachycardia or fibrillation often during sleep. The arrhythmogenic role of sleep is being increasingly recognized. Nocturnal occurrence of apnea and hypopneas has been related to SCD and atrial fibrillation. Apneic events elicit significant autonomic responses, which have been linked to ST-segment elevation in patients with Brugada syndrome. In addition to respiratory events, changes from nonrapid eye movement (non-REM) sleep to REM sleep are associated with autonomic instability, which can play a role in arrhythmogenesis. Therefore, this study evaluated breathing patterns during sleep in patients with Brugada syndrome and investigated the occurrence of arrhythmias and ST-segment changes during different sleep stages.
Methods
Consecutive patients being evaluated at the Hospital Clinic, University of Barcelona, were invited to participate in the present study. Patients were recruited from sudden death and implantable cardioverter–defibrillator outpatient clinics, and about 10% of those invited declined participation. Inclusion criteria were age >21 years and a definite diagnosis of Brugada syndrome based on spontaneous or drug-induced type 1 Brugada electrocardiogram (ECG). Patients underwent overnight polysomnography with simultaneous recording of 12-lead ECG throughout the night. The control group (recruited in Rochester, Minnesota) consisted of healthy subjects of similar age, gender, and body mass index (BMI) as patients. This study was approved by the institutional review boards of the University of Barcelona and the Mayo Clinic (Rochester, Minnesota) and all patients signed an informed consent. Patients were classified as high risk for fatal arrhythmias according to the following criteria: (1) previous aborted SCD associated with type 1 ECG (spontaneous or induced) or (2) unexplained syncope with spontaneous type 1 ECG.
All subjects underwent full-night polysomnography using a Compumedics Siesta802 wireless amplifier/recorder (Compumedics, Abbotsford, Victoria, Australia). Airflow was monitored by an oronasal thermal airflow sensor and respiratory effort was monitored by calibrated respiratory impedance plethysmography. During all polysomnographic procedures, electroencephalogram, electro-oculogram, and submental electromyogram were recorded according to American Academy of Sleep Medicine standards. Oxyhemoglobin saturation was recorded by finger pulse oximetry. Polysomnograms were scored by an experienced polysomnographic technologist who was blind to subjects’ status and arrhythmic risk. Apneas were defined as a ≥90% decrease in peak sensor excursion from baseline for ≥10 seconds. Hypopneas were defined by a ≥50% decrease in sensor excursion for ≥10 seconds accompanied by an oxyhemoglobin desaturation of ≥4%. Disordered breathing events were quantified by the apnea–hypopnea index. An apnea–hypopnea index ≥5 events/hour established the diagnosis of sleep-disordered breathing (SDB). A 12-lead ECG was simultaneously recorded in LabVIEW (National Instruments Corporation, Austin, Texas) and processed using ScopeWin software (Institute for Scientific Instruments, Brno, Czech Republic). The ECG was analyzed by a cardiac electrophysiologist blinded to patients’ arrhythmic risk and to sleep stages. A spontaneous change in the ST segment was considered if there was modification in the type of Brugada ECG or a visible change in the T wave in the right precordial leads according to a previously published method. Time points where these changes began were correlated to sleep stages and respiratory events on polysomnographic tracings.
Data are summarized as frequencies for categorical variables and means ± SDs for continuous variables. Group differences were evaluated by Wilcoxon rank-sum test. Differences in proportions were tested by Fisher’s exact test. Analyses were performed with JMP 7 (SAS Institute, Cary, North Carolina). For all comparisons a p value <0.05 for a 2-tailed test was considered statistically significant.
Results
Twenty patients were included in the study. Mean age was 50 ± 15 years, BMI was 24.7 ± 2.7 kg/m 2 , and most patients were men (75%). Six patients (30%) had unexplained syncope and 3 (15%) had aborted SCD. A family history of SCD was reported by 7 patients (35%; Table 1 ). Twelve patients (60%) had an implantable cardioverter–defibrillator, 2 of whom were also on medication, 1 on quinidine and the other on a β blocker. The control group consisted of 11 subjects with mean age 43 ± 16 years and mean BMI 25 ± 3 kg/m 2 and 82% were men.
| Patient Number | Age (years)/Sex | BMI (kg/m 2 ) | Familial History of SCD | VF/SCD | Syncope | High Arrhythmic Risk | HTN | DM | Sleep Efficiency (%) | REM (%) | Lowest SpO 2 (%) | AHI (events/hour) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patients without sleep-disordered breathing | ||||||||||||
| 1 | 32/F | 24 | + | 0 | 0 | 0 | 0 | 0 | 93 | 19 | 97 | 0 |
| 2 | 66/F | 21 | 0 | 0 | + | 0 | + | 0 | 89 | 15 | 94 | 0 |
| 3 | 31/M | 26 | 0 | + | + | + | 0 | 0 | 90 | 16 | 86 | 0.1 |
| 4 | 31/M | 23 | + | 0 | 0 | 0 | 0 | 0 | 75 | 12 | 93 | 0.4 |
| 5 | 60/M | 27 | 0 | + | + | + | 0 | 0 | 78 | 28 | 90 | 0.5 |
| 6 | 29/M | 24 | 0 | 0 | 0 | 0 | 0 | 0 | 80 | 24 | 93 | 0.6 |
| 7 | 22/M | 25 | 0 | 0 | + | + | 0 | 0 | 87 | 19 | 94 | 0.8 |
| 8 | 50/M | 23 | 0 | 0 | 0 | 0 | 0 | 0 | 86 | 28 | 87 | 1.5 |
| 9 | 56/M | 28 | + | 0 | 0 | 0 | + | 0 | 69 | 9 | 89 | 1.5 |
| 10 | 39/M | 24 | 0 | 0 | 0 | 0 | 0 | 0 | 81 | 21 | 91 | 1.7 |
| 11 | 43/M | 24 | 0 | 0 | 0 | 0 | 0 | 0 | 75 | 18 | 86 | 4.4 |
| Patients with sleep-disordered breathing | ||||||||||||
| 12 | 65/F | 26 | 0 | + | + | + | + | 0 | 72 | 10 | 85 | 5.3 |
| 13 | 71/F | 22 | 0 | 0 | + | + | + | 0 | 57 | 7 | 87 | 6.5 |
| 14 | 56/M | 28 | + | 0 | 0 | 0 | 0 | 0 | 94 | 8 | 84 | 10.4 |
| 15 | 62/F | 21 | + | 0 | 0 | 0 | 0 | 0 | 91 | 14 | 79 | 10.7 |
| 16 | 64/M | 26 | 0 | 0 | + | + | 0 | 0 | 61 | 11 | 89 | 10.7 |
| 17 | 52/M | 22 | + | 0 | 0 | 0 | 0 | 0 | 79 | 11 | 78 | 14.5 |
| 18 | 51/M | 24 | 0 | 0 | + | + | 0 | 0 | 69 | 13 | 84 | 16.5 |
| 19 | 58/M | 23 | 0 | 0 | + | + | 0 | 0 | 62 | 4 | 78 | 32.4 |
| 20 | 61/M | 28 | + | 0 | 0 | 0 | + | + | 86 | 29 | 72 | 48.1 |
Nine patients (45%) had SDB on polysomnogram with a mean apnea–hypopnea index of 17.2 ± 14 events/hour. Six patients had a diagnosis of obstructive sleep apnea, 2 with central sleep apnea and 1 patient had mixed sleep apnea. In the control group, 3 (27%) had SDB and all were diagnosed as having obstructive sleep apnea. Regarding clinical characteristics, groups with or without SDB were very similar except that patients with SDB were older (mean age 60 ± 6 vs 42 ± 14 years, p = 0.008). There was no difference in mean BMI between the SDB and non-SDB groups (25 vs 24.4 kg/m 2 , p = 0.85). Clinically defined high-risk patients were more frequently observed in the SDB group (56%) than in the non-SDB group (27%). During sleep, patients with SDB spent less time in REM (12% vs 19%, p = 0.02), had a lower arterial oxygen saturation nadir (82% vs 91%, p <0.001) and a higher apnea–hypopnea index (17.2 vs 1.0 events/hour, p <0.001; Table 1 ). Eight patients (40%, 75% men, mean age 53 ± 17 years) were classified as having a high risk for fatal arrhythmias as described earlier. Despite their relatively normal BMI (25 ± 1.6 kg/m 2 ), 5 patients (63%) had sleep apnea in this subgroup with a mean apnea–hypopnea index of 14.3 ± 11 events/hour. There was no significant difference in mean age or BMI between patients with or without SDB (62 vs 38 years old, p = 0.10; 24.2 vs 25.9 kg/m 2 , p = 0.29, respectively).
Atrial or ventricular arrhythmias were not observed in this study population. Analysis of bradyarrhythmias was limited because 60% of patients had an implantable cardioverter–defibrillator with backup pace setting. In 2 patients without an implantable cardioverter–defibrillator, 6 episodes of significant bradycardia were observed: 5 sinus pauses of a maximal duration of 3.1 seconds and 1 episode of Mobitz I second-degree atrioventricular block (pause 2.5 seconds). None of them had SDB or high arrhythmic risk.
Spontaneous ST-segment changes were found in 2 patients (10%). These 2 patients were previously asymptomatic, had low arrhythmic risk, and were not on medications. However, these 2 patients were in their third decade of life and had a history of SCD in a first-degree relative. One had an apnea–hypopnea index of 14.5 events/hour and the other an index 1.5 events/hour. Changes observed in the first patient were spontaneous augmentation of ST-segment elevation in leads V 1 and V 2 and a shift in lead V 3 pattern from type 3 to type 2 or 1 ( Figure 1 ). In the second patient, there was a visible change in T-wave structure and amplitude in lead V 1 . ST-segment changes occurred over 45 different time points. Most ST-segment changes were observed during REM sleep (31%) or within 1 minute of arousals (44%). There were no changes in ST segments during sleep stage 3 or 4 ( Figure 2 ). With regard to respiratory events, 25 (56%) ST-segment changes occurred during or within 1 minute after an episode of apnea or hypopnea.
