Acute coronary syndrome (ACS) during sleep occurs at a relatively low frequency and the pathogenic background remains uncertain. The aim of the present study was to determine the significance of sleep-disordered breathing (SDB) and excess visceral fat with nocturnal dysregulation of adipocytokines in night-time onset of ACS. SDB, visceral fat area (VFA), and changes in circulating adipocytokine levels were assessed in 109 consecutive patients with ACS. SDB and VFA were assessed by cardiorespiratory monitoring and computed tomographic scan, respectively. Visceral fat accumulation was more common in patients with (12 to 7 a . m .) than without (7 to 12 a . m .) night-time onset of ACS (p <0.05). In patients with night-time onset of ACS, those with excess visceral fat were significantly more likely to have SDB and nocturnal dysregulation of adiponectin than those without such accumulation (p <0.05), but there was no difference between those with and without excess visceral fat (VFA cutoff 100 cm 2 ) in patients with non–night-time onset of ACS. In conclusion, night-time onset of ACS is associated with excess visceral fat and SDB (referred as to “syndrome Z”). SDB and excess visceral fat are treatable risk factors. Decrease of excess visceral fat and treatment of SDB could be beneficial in in preventing nocturnal cardiac events.
Acute coronary syndrome (ACS) generally occurs with a diurnal periodicity that peaks during morning to daytime activity. Fewer patients have onset of ACS during sleep and factors that influence the likelihood of ACS occurring during sleep are unknown but are potentially affected by several factors that differ between patients including the presence of sleep apnea. Many but not all patients with visceral obesity have sleep-disordered breathing (SDB), especially obstructive sleep apnea (OSA). Patients with OSA have a high frequency of sudden cardiac death from night to early morning. The cluster of visceral obesity, multiple risk factors, and OSA is referred to as “syndrome Z.” Recently we found dysregulation of adipocytokines during sleep in patients with obesity and OSA. A combination of SDB and excess visceral fat with dysregulation of adipocytokines may participate in increasing ACS risk during sleep. The aim of the present study was to clarify this point.
Methods
Of patients with clear-onset ACS who were admitted and underwent revascularization within the first 24 hours after admission to Kokura Memorial Hospital from April through September 2009, 109 consecutive Japanese patients who underwent overnight cardiorespiratory monitoring (Somté, Compumedics, Melbourne, Australia) before discharge from the hospital (about 1 week after onset of ACS) to assess the presence of SDB with informed consent were included in this study. Table 1 presents characteristics of study participants. Shift workers and patients with coronary spasm and nonsignificant organic stenosis were excluded from the study. All patients with ACS underwent coronary angiography and successful revascularization with percutaneous coronary intervention procedures within the first 24 hours after admission. ACS included ST-segment elevation acute myocardial infarction (n = 66, average peak creatinine kinase 3,137 ± 2144 IU/L mean ± SD), non–ST-segment elevation acute myocardial infarction (n = 27, average peak creatinine kinase 691 ± 192 IU/L), and high-risk unstable angina (n = 16, average peak creatinine kinase 182 ± 16 IU/L). ST-segment elevation acute myocardial infarction was diagnosed when new or presumed new ST-segment elevation 1 mm was seen in any location or new left bundle branch block was found on the index or qualifying electrocardiogram with 1 positive cardiac biochemical marker of necrosis. Non–ST-segment elevation acute myocardial infarction was diagnosed in the presence of 1 positive cardiac biochemical marker of necrosis without new ST-segment elevation seen on the index or qualifying electrocardiogram. High-risk unstable angina was the absence of ST-segment elevation on electrocardiogram and serum biochemical markers indicative of myocardial necrosis within each hospital laboratory’s normal range. With a discharge diagnosis of ACS the affected coronary artery was the left anterior descending coronary artery in 59 patients, left circumflex coronary artery in 11 patients, and right coronary artery in 39 patients. Date and time of onset of ACS (i.e., angina or chest pain) were determined through an interview and retrospective analysis of clinical charts. This strategy for assessing the onset time of ACS has been validated previously. Onset of ACS was defined as the time when chest pain occurred and was divided into 2 periods (night-time 12 to 7 a . m ., non–night-time 7 to 12 a . m .) according to the time of venous sample collection in the morning as reported previously. Numbers of patients with a history of myocardial infarction or angina and a family history of coronary artery disease were 16 (15%) or 11 (10%) and 11 (10%), respectively. The medical ethics committees of Osaka University and Kokura Memorial Hospital approved this study. All participants were Japanese and each gave a written informed consent. This study (Osaka University Visceral Fat [O-VF] Study) is registered under number UMIN 000002997.
| Age (years) | 66 ± 12 (40–91) |
| Men/women | 93/16 |
| Body mass index (kg/m 2 ) | 23.8 ± 3.4 (17.8–37.4) |
| Waist circumference (cm) | 87 ± 10 (64–112) |
| Hip circumference (cm) | 92 ± 6 (80–112) |
| Total fat area (cm 2 ) | 239 ± 95 (69–523) |
| Visceral fat area (cm 2 ) | 127 ± 63 (22–361) |
| Subcutaneous fat area (cm 2 ) | 112 ± 55 (18–284) |
| Polysomnographic findings | |
| Apnea–hypopnea index (events/hour) | 11 ± 12 (0–61) |
| Baseline arterial oxygen saturation (%) | 95 ± 2 (91–98) |
| Lowest arterial oxygen saturation (%) | 83 ± 4 (72–94) |
| 4% oxygen desaturation index (events/hour) | 14 ± 12 (1–69) |
| Percent time at arterial oxygen saturation <90% | 2 ± 4 (0–25) |
| Apnea–hypopnea index | |
| <5 | 46 (42%) |
| ≥5–<15 | 37 (34%) |
| ≥15–<30 | 19 (18%) |
| ≥30 | 7 (6%) |
| Obstructive sleep apnea index/central sleep apnea index/mixed apnea index/hypopnea index | 3.5 ± 5.7/1.5 ± 3.1/1.8 ± 3.7/4.3 ± 4.2 |
| Serum adiponectin (μg/ml) | 9.2 ± 6.6 (2.3–38.3) |
| Plasma total plasminogen activator inhibitor-1 (ng/ml) | 24.5 ± 11.6 (5.0–61.0) |
| Serum soluble CD40 ligands (pg/ml) | 2.4 ± 1.9 (0–8.3) |
For overnight cardiorespiratory monitoring, the recorded signals (airflow, arterial oxygen saturation, thoracic and abdominal wall movements) were analyzed for number of apneas and hypopneas during sleep. The oxygen desaturation index, lowest arterial oxygen saturation, baseline arterial oxygen saturation, and time at desaturation <90% in minutes of total bedtime were measured for the entire night. Apnea was defined as cessation of airflow >10 seconds. Hypopnea was defined as a decrease in airflow signal to <70% of the preceding level associated with >4% desaturation. Sleep apnea was categorized as OSA, central sleep apnea, and mixed apnea as reported previously. Apnea–hypopnea index was defined as the total number of apneas/hypopneas per hour of recording time according to the guideline. An apnea–hypopnea index ≥5 established the diagnosis of SDB. All recordings were scored manually by an experienced polysomnographer and duration of sleep was estimated using self-reported sleep time and recorded data as reported previously.
Height and weight were measured in a standing position. Body mass index was calculated as weight (kilograms) divided by height (meters) squared. Waist circumference (centimeters) at the umbilical level was measured with a nonstretchable tape in late expiration while standing. Hip circumference was measured horizontally at the level of the greater trochanter of the femur with the patient standing. Waist-to-hip ratio was defined as waist circumference divided by hip circumference. Visceral fat area (VFA) and subcutaneous fat area were computed or measured manually on computed tomographic scan at the umbilical level. Visceral fat accumulation was measured by computed tomographic scan and defined as VFA ≥100 cm 2 .
Blood pressure was measured with a standard mercury sphygmomanometer on the right arm after the patient had rested in a supine position for ≥10 minutes. Venous blood samples were collected for laboratory measurements after the subject awoke and was in a supine position. In each sleep study that included adiponectin monitoring, venous blood samples were obtained before sleep onset (∼10:00 p . m .) and after waking (∼7:00 a.m .) while the subject was in a supine position. For the present study serum samples that were obtained at baseline from each participant and stored at −20°C were thawed and assayed for circulating adiponectin (Otsuka Pharmaceutical, Co., Tokushima, Japan), total plasminogen activator inhibitor-1 (PAI-1; (LPIA•tPAI test; Mitsubishi Kagaku Iatron, Tokyo, Japan), and soluble CD40 ligand levels (Quantikine Human Soluble CD40 Ligand Immunoassay, R&D Systems, Inc., Minneapolis, Minnesota).
Hypertension (n = 62, 57%) was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg or current treatment for hypertension (calcium channel antagonists in 21, angiotensin-converting enzyme inhibitors in 53, angiotensin receptor blockers in 46, β blockers in 71, diuretics in 9). Diabetes mellitus (n = 62, 57%) was defined according to World Health Organization criteria or as nonfasting plasma glucose concentration ≥6.1 mmol/L, and/or current treatment for diabetes mellitus (sulfonyl ureas in 9, biguanides in 1, α-glucosidase inhibitors in 18, insulin in 2). Dyslipidemia (n = 65, 60%) was defined as low-density lipoprotein cholesterol concentration >3.6 mmol/L, triglyceride concentration ≥1.69 mmol/L, high-density lipoprotein cholesterol concentration <1.04 mmol/L, and/or treatment for dyslipidemia (statins in 82, fibrates in 2). We included subjects receiving medications with antiplatelet drugs (aspirin in 107, ticlopidine in 41, clopidogrel in 61). With regard to smoking status 49% (n = 53) of subjects were current smokers, 15% (n = 17) were former smokers, and 36% (n = 39) were nonsmokers.
All values were expressed as mean ± SD (range, minimum to maximum) and p values <0.05 were considered statistically significant. Relations between 2 continuous variables were analyzed using scatter plots and Pearson correlation coefficients. Differences among groups were compared by 1- or 2-way analysis of variance with Fisher’s protected least significant difference test for multiple-group analysis or unpaired Student’s t test for experiments involving only 2 groups. Frequencies of each group were compared by chi-square test. All statistical analyses were performed with STATVIEW-J 5.0 (SAS Institute, Cary, North Carolina).
Results
Frequency of SDB diagnosed by overnight cardiorespiratory monitoring was 58% (n = 63) in patients with ACS, although mean body mass index was 23.8 kg/m 2 ( Table 1 ). In patients with ACS VFA correlated positively with circulating total PAI-1 levels and negatively with circulating adiponectin levels ( Table 2 ) as reported previously in the general population. Subcutaneous fat area correlated positively only with total PAI-1. The present study found a positive correlation between VFA and soluble CD40 ligand levels in patients with ACS as in a previous study.
| VFA | SFA | |||
|---|---|---|---|---|
| r | p Value | r | p Value | |
| Apnea–hypopnea index | 0.15 | 0.008 | 0.18 | 0.062 |
| Peak creatinine kinase | 0.17 | 0.077 | 0.11 | 0.264 |
| Adiponectin after waking | −0.41 | 0.0001 | −0.19 | 0.052 |
| Total plasminogen activator inhibitor-1 after waking | 0.28 | 0.004 | 0.25 | 0.008 |
| Soluble CD40 ligands after waking | 0.21 | 0.034 | 0.08 | 0.441 |
As presented in Table 3 patients with visceral fat accumulation (VFA ≥100 cm 2 ) had a higher body mass index, larger VFA and subcutaneous fat areas, higher total PAI-1, and lower adiponectin than patients with VFA <100 cm 2 . Prevalence of hypertension and dyslipidemia was higher in patients with VFA ≥100 cm 2 compared to patients with VFA <100 cm 2 . These results suggest that excess visceral fat in patients with ACS correlates with metabolic disorders and dysregulation of adipocytokines.
| VFA <100 cm 2 | VFA ≥100 cm 2 | p Value ⁎ | |
|---|---|---|---|
| Subjects (men/women) | 45 (36/9) | 64 (57/7) | 0.19 |
| Age (years) | 67 ± 11 | 65 ± 13 | 0.29 |
| Body mass index (kg/m 2 ) | 21.7 ± 2.2 | 25.2 ± 3.4 | <0.0001 |
| Visceral fat area (cm 2 ) | 63 ± 22 | 146 ± 43 | <0.0001 |
| Subcutaneous fat area (cm 2 ) | 101 ± 49 | 146 ± 65 | <0.001 |
| Culprit coronary lesion (left anterior descending coronary artery/left circumflex coronary artery/right coronary artery) | 27/4/14 | 32/7/25 | 0.74 |
| Peak creatinine kinase (IU/L) | 1,806 ± 2,277 | 2,269 ± 1,998 | 0.27 |
| Smoke (never/ex/current) | 20/5/20 | 19/12/33 | 0.27 |
| Diabetes mellitus | 26 (58%) | 36 (56%) | 0.87 |
| Hypertension | 18 (40%) | 44 (69%) | <0.01 |
| Dyslipidemia | 15 (33%) | 40 (62%) | <0.01 |
| Apnea–hypopnea index (events/hour) | 8 ± 8 | 12 ± 14 | <0.05 |
| Adiponectin after waking (μg/ml) | 12.9 ± 8.2 | 6.5 ± 3.1 | <0.0001 |
| Adiponectin before sleep onset (μg/ml) | 12.5 ± 8.1 | 6.6 ± 3.0 | <0.0001 |
| Total plasminogen activator inhibitor-1 after waking (ng/ml) | 22.5 ± 10.0 | 27.3 ± 11.4 | <0.05 |
| Total plasminogen activator inhibitor-1 before sleep onset (ng/ml) | 23.1 ± 13.2 | 19.5 ± 7.0 | 0.10 |
| Soluble CD40 ligand after waking (pg/ml) | 2.0 ± 2.0 | 2.7 ± 1.8 | 0.07 |
| Soluble CD40 ligand before sleep onset (pg/ml) | 1.5 ± 1.3 | 1.8 ± 1.7 | 0.44 |
To clarify the significance of visceral fat accumulation on night- and non–night-time onset of ACS, we divided patients into 4 groups according to time of onset of ACS and visceral fat accumulation ( Table 4 ). Prevalences of VFA ≥100 cm 2 was 68% (n = 17 or 25) in patients with night-time onset of ACS and 56% (n = 47 of 84) in those with non–night-time onset of ACS. Furthermore, prevalence of SDB and apnea–hypopnea index was significantly higher in those with VFA ≥100 cm 2 than in those with VFA <100 cm 2 in patients with night-time onset of ACS ( Figure 1 , Table 4 ). In contrast, prevalence of SDB and apnea–hypopnea index was not different between those without and those with excess visceral fat in patients with non–night-time onset of ACS. Of patients with night-time onset of ACS, those with VFA ≥100 cm 2 had significantly lower circulating adiponectin levels and higher circulating total PAI-1 levels and tended to have higher circulating soluble CD40 ligand levels (p = 0.051) than those with VFA <100 cm 2 ( Table 4 ). Further analysis of patients with night-time onset of ACS showed that change in adiponectin in those with VFA ≥100 cm 2 was −0.4 ± 6.4%, whereas the change in those with VFA <100 cm 2 was 5.6 ± 4.7%; the difference between the 2 groups was significant ( Table 4 ).
| Time of Onset of ACS | 12–7 a.m. | 7–12 a.m. | ||
|---|---|---|---|---|
| VFA <100 | VFA ≥100 | VFA <100 | VFA ≥100 | |
| Subjects (men/women) | 8 (6/2) | 17 (17/0) † | 37 (30/7) | 47 (40.7) |
| Age (years) | 64 ± 14 | 62 ± 12 | 68 ± 10 | 66 ± 13 |
| Body mass index (kg/m 2 ) | 21.0 ± 2.2 | 25.8 ± 3.8 † | 21.9 ± 2.3 | 24.9 ± 3.3 § |
| Waist–hip ratio | 0.9 ± 0.1 | 1.0 ± 0.1 † | 0.9 ± 0.0 | 1.0 ± 0.1 § |
| Visceral fat area (cm 2 ) | 56 ± 29 | 151 ± 50 † | 64 ± 21 | 145 ± 41 § |
| Subcutaneous fat area (cm 2 ) | 81 ± 34 | 147 ± 60 † | 105 ± 41 | 145 ± 68 § |
| Smoke (never/ex/current) | 4/0/4 | 2/1/14 | 16/16/5 | 22/7/18 |
| Diabetes mellitus | 4 (50%) | 7 (41%) | 22 (35%) | 29 (47%) |
| Hypertension | 5 (63%) | 13 (76%) | 12 (35%) | 31 (66%) § |
| Dyslipidemia | 5 (63%) | 7 (41%) | 20 (54%) | 33 (70%) |
| Apnea–hypopnea index (events/hour) | 3 ± 3 | 14 ± 15 ‡ | 9 ± 8 | 12 ± 14 |
| Adiponectin before sleep onset (μg/ml) | 16.9 ± 12.7 | 6.3 ± 2.1 ‡ | 11.6 ± 6.8 | 6.8 ± 3.2 § |
| Adiponectin after waking (μg/ml) | 18.0 ± 12.7 | 6.2 ± 2.0 † | 11.7 ± 6.7 | 6.7 ± 3.4 § |
| Change in adiponectin (%) ⁎ | 5.6 ± 4.7 | −0.4 ± 6.4 ‡ | 0.6 ± 12.1 | −2.3 ± 11.0 |
| Total plasminogen activator inhibitor-1 before sleep onset (ng/ml) | 16.0 ± 5.6 | 19.6 ± 6.7 | 24.1 ± 13.7 | 19.4 ± 7.2 |
| Total plasminogen activator inhibitor-1 after waking (ng/ml) | 17.6 ± 8.0 | 28.6 ± 13.2 ‡ | 21.7 ± 10.8 | 26.8 ± 10.8 ∥ |
| Change in total plasminogen activator inhibitor-1 (%) ⁎ | 37 ± 19 | 33 ± 34 | 12 ± 71 | 25 ± 28 |
| Soluble CD40 ligand before sleep onset (pg/ml) | 1.5 ± 1.2 | 1.4 ± 1.7 | 1.5 ± 1.3 | 1.9 ± 1.6 |
| Soluble CD40 ligand after waking (pg/ml) | 1.4 ± 1.5 | 2.3 ± 1.8 | 2.2 ± 2.0 | 2.8 ± 1.8 |
| Change in soluble CD40 ligand (%) ⁎ | −90 ± 227 | 117 ± 437 | −29 ± 256 | −15 ± 280 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
