ABSTRACT
Background
Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular complications. OSA and coronary artery disease (CAD) share the same risk factors and coexist in many patients. In previous studies, repeated nocturnal cardiac ischemic events in OSA patients with CAD have been reported.
Hypothesis
We hypothesized that OSA may precipitate myocardial ischemia, evidenced by ST‐segment depression and elevated N‐terminal brain natriuretic peptide (NT‐proBNP) and high‐sensitivity troponin T (hs‐TropT) levels in patients with severe OSA and concomitant CAD. We also aimed to evaluate if the effects could be reversed by continuous positive airway pressure (CPAP) therapy.
Methods
Twenty‐one patients with severe OSA (apnea‐hypopnea index >15/h, nadir oxygen desaturation ≤80%), and coexisting CAD underwent in‐hospital polysomnography at baseline and under CPAP. Blood samples for hs‐TropT and NT‐proBNP measurements were drawn prior and immediately after sleep. ST‐segment depression was measured at the time of maximum oxygen desaturation during sleep.
Results
CPAP significantly decreased elevated NT‐proBNP levels from 475 ± 654 pg/mL before sleep to 353 ± 573 pg/mL after sleep and attenuated ST‐segment depression during sleep. hs‐TropT was not elevated and did not differ after nocturnal oxygen desaturation at baseline and after CPAP.
Conclusions
CPAP significantly reduced NT‐proBNP in patients suffering from severe OSA and coexisting CAD. Repeated nocturnal myocardial ischemia did not cause myocyte necrosis evidenced by elevated hs‐TropT or ST‐segment depression.
Introduction
Obstructive sleep apnea (OSA) is linked up with an increased risk of morbidity and mortality, with a predominance of cardiovascular deaths.1, 2 OSA is characterized by intermittent hypoxia during sleep and is associated with elevated sympathetic activity, cardiovascular variability, and intrathoracic pressure fluctuations.3 OSA results in hemodynamic changes with an increase in preload and afterload.4 Atrial fibrillation, coronary artery disease, congestive heart failure, and arterial hypertension are clinical manifestations and more common in patients with OSA.5, 6 Stress imposed on the myocardium by repeated severe hypoxemia during sleep and an increased oxygen demand by sympathetic overstimulation in OSA may result in subclinical myocardial injury.7 Cardiac troponin T is an important biomarker in myocardial injury and predictor of clinical outcome.8, 9 Cardiac myocytes also constitute the major source of cardiac neurohormone brain natriuretic peptide (NT‐proBNP). It is secreted by ventricular myocytes after myocardial hypoxemia and in response to volume expansion and pressure load.10, 11 NT‐proBNP production is strongly upregulated in cardiac failure and locally in the area surrounding a myocardial infarction.12 The standard treatment for moderate and severe OSA is nasal continuous positive airway pressure (CPAP).13
It was hypothesized that OSA may precipitate myocardial ischemia, evidenced by ST‐segment depression and elevated NT‐proBNP and high‐sensitivity troponin T (hs‐TropT) levels in patients with severe OSA and concomitant coronary artery disease (CAD). We also aimed to evaluate if the effects could be reversed by CPAP therapy.
Methods
The prospective study was conducted between February 2012 and September 2013. The study was approved by the ethics committee of the State Medical Council of Hessen, Germany (approval number FF 6/2912). Informed consent was obtained from each patient.
Study Population
Eighty patients were screened for the presence of severe OSA with an apnea‐hypopnea index (AHI) >15/h and oxygen desaturation ≤80% during apnea. Although there are no generally accepted classifications for severity of oxygen desaturation, reductions to <80% usually are considered severe. After complete polysomnography, 59 patients did not satisfy the inclusion criteria. Finally, this study enrolled 21 patients with severe OSA and coexisting CAD (Figure 1).
Figure 1.
Study flow diagram. Abbreviations: AHI, apnea‐hypopnea index; CAD, coronary artery disease; CPAP, continuous positive airway pressure; hs‐TropT, high‐sensitivity troponin T; NT‐proBNP, N‐terminal brain natriuretic peptide; OSA, obstructive sleep apnea.
Inclusion criteria were as follows: age >18 years, severe OSA with AHI >15/h, oxygen desaturation ≤80%, and proven history of CAD. Exclusion criteria were moderate and severe heart failure (left ventricular ejection fraction [LVEF] <40% measured by echocardiography), renal insufficiency (glomerular filtration rate <50 mL/min estimated by the Cockcroft‐Gault formula).
Polysomnography
The presence and severity of OSA was determined by overnight complete polysomnography using a computerized system (Alice 5; Philips Respironics, Herrsching, Germany). Standard techniques such as electroencephalography, electrooculography, electromyography, oximetry, electrocardiogram, thermistor measurements of air flow, thoracoabdominal motion, pulse oximetry of arterial oxyhemoglobin saturation (SPO2), and body position were used for monitoring of sleep‐disordered breathing. Bedtime was 11 pm to 6 am. Sleep stages were scored according to the standard criteria of the American Academy of Sleep Medicine.14 Apnea was defined as an absence of airflow for > 10 seconds. Hypopnea was defined as a more than 30% reduction in airflow accompanied by a decrease in SPO2 > 4%. AHI was calculated as the average number of apneas and hypopneas per hour of sleep. An AHI ≥15/h was defined as severe OSA.
Measurement of hs‐TropT and NT‐proBNP
Quantitative measurement of hs‐TropT was done with an immunoassay for the in vitro quantitative determination of cardiac troponin T in human serum and plasma (Cobas e 411 Roche Troponin T hs STAT; Roche Diagnostics, Indianapolis, IN), with a lower limit of normal <14 ng/L representing the 99th percentile in a normal reference population and a coefficient of variation <10%. Hs‐TropT values below the limit of blank are reported as <3 ng/L.
NT‐proBNP levels were measured with an immunoassay for the in vitro quantitative determination of NT‐proBNP in heparinized venous blood (Cobas Roche Cardiac proBNP+; Roche Diagnostics). The measuring range is 60 to 9000 pg/mL, with a mean of the variation coefficients below 15% in the range of 60 to 1200 pg/mL, and below 20% in the range of 1200 to 9000 pg/mL. The normal range of NT‐proBNP is subject to gender‐ and age‐specific variability. A clinical cutoff of 125 pg/mL allows sufficient diagnostic accuracy.
Venous blood samples (5 mL) were collected at different time points: before (9 pm) and after (7 am) polysomnography. The measurements were performed immediately after the blood samples were drawn.
ST‐Segment Analysis in the Electrocardiogram
A continuous electrogram (ECG) recording was performed simultaneously during sleep in all patients to screen for ST‐segment depression episodes. Lead II was used to analyze the ST segment for myocardial ischemia. Additional leads I, III, aVL, aVR, and aVF were used as backup for further evaluation of features suggestive of cardiac ischemia observed in the main ECG lead. An ischemic episode was defined as a horizontal or downsloping ST‐segment depression ≥1 mm (100 μV) from baseline, measured 80 ms after the J point. The time point of maximum oxygen desaturation during sleep was determined by continuous oximetry. Ten cardiac cycles after the time point of minimum oxygen saturation, the ST segment changes in 10 consecutive cardiac cycles were analyzed and averaged.
CPAP Treatment
Optimal CPAP pressure was titrated in the sleep laboratory on a second night after 1 diagnostic night at baseline. All patients were monitored under CPAP treatment conducted after pressure titration.
Statistics
Results were expressed as mean ± standard deviation (SD) for continuous variables. For the descriptive statistics, the arithmetic mean, SD, median, minimum and maximum, and first and third quartiles were calculated. For comparison of 2 groups, the Fisher exact test and the Wilcoxon‐Mann–Whitney U test were used. The Wilcoxon matched pairs test was applied for paired samples. Statistical analyses were performed using a statistical software package (BiAS für Windows, version 10.09, Epsilon‐Verlag, Darmstadt, Germany). P values < 0.05 were considered statistically significant.
Results
The study population consisted of 21 patients with OSA and CAD. In this group, previous coronary artery bypass graft operation had been performed in 5 patients, percutaneous coronary interventions in 16 patients, and CAD proven by angiogram was treated medically in 2 patients. Anthropometric characteristics, clinical data, and sleep parameters are given in the Table 1.
Table 1.
Clinical Characteristics and Sleep Parameters
| Patients, n = 21 | |
|---|---|
| Demographics | |
| Gender, female/male | 5/16 |
| Age, y | 61 ± 11 |
| Body mass index, kg/m2 | 35 ± 7 |
| Medical history | |
| Hypertension | 19 (90%) |
| Hypercholesterolemia | 17 (81%) |
| Diabetes mellitus | 10 (48%) |
| Arrhythmia | 6 (29%) |
| Stroke | 2 (10%) |
| Myocardial infarction | 12 (57%) |
| COPD | 4 (19%) |
| Medication | |
| Nitrates | 3 (14%) |
| β‐Blockers | 19 (90%) |
| Renin inhibitors | 0 (0%) |
| ACE inhibitors | 14 (67%) |
| Angiotensin receptor blockers | 3 (14%) |
| Diuretics | 11 (52%) |
| Calcium channel blockers | 9 (43%) |
| α‐Blockers | 1 (5%) |
| Cardiac and renal function | |
| Left ventricular ejection fraction (%) | 59 ± 9 |
| Glomerular filtration rate, mL/min | 121 ± 53 |
| Polysomnography data (baseline) | |
| Apnea hypopnea index, no./h | 53 ± 21 |
| Oxygen saturation nadir, % | 71 ± 12 |
| Sleep time with SaO2 < 90%, % | 18 ± 17 |
| Sleep time with SaO2 < 80%, % | 2 ± 4 |
| Maximal duration of sleep‐related breathing disorders, s | 89 ± 56 |
Abbreviations: ACE, angiotensin‐converting enzyme; COPD, chronic obstructive pulmonary disease.
Data are presented as mean ± standard deviation or number (%).
The levels and distribution of the cardiac markers hs‐TropT and NT‐proBNP in untreated patients were not significantly different before and after sleep, when diagnostic polysomnography was performed. We found no correlation between the severity of OSA expressed as the AHI and the levels of hs‐TropT and NT‐proBNP. Hs‐TropT was detectable (≥ 3 ng/L) in 18 (86%) patients before as well as after polysomnography. Mean hs‐TropT levels before and after sleep were 10 ± 7 ng/L and 10 ± 9 ng/L, respectively.
None of the patients showed clinical signs and symptoms of heart failure. Echocardiography revealed normal systolic left ventricular function (LVEF ≥ 50%) in 19 patients. In 2 patients, ventricular function was reduced (LVEF 40%). Mean NT‐proBNP levels before and after sleep were 499 ± 758 pg/mL and 400 ± 592 pg/mL, respectively. ST‐segment analysis revealed no significant ST depression (≥100 μV) suspicious of myocardial ischemia at the time of the deepest oxygen desaturation.
In these patients, CPAP significantly reduced NT‐proBNP levels from 475 ± 654 pg/mL before sleep to 353 ± 573 pg/mL after sleep (Figure 2). CPAP also attenuated ST‐segment depression during sleep, but the difference compared to baseline polysomnography was no significant (Figure 3). The levels of hs‐TropT were not altered by CPAP (Figure 4).
Figure 2.
NT‐proBNP levels pre‐ and post‐PSG and pre‐ and post‐CPAP therapy. Middle horizontal line inside the box indicates median. Bottom and top of the box are 25th and 75th percentiles, and the error bars outside the box represent maximum and minimum values, respectively. Abbreviations: CPAP, continuous positive airway pressure; ns = not significant; PSG, polysomnography.
Figure 3.
ST‐segment depression at the time point of maximum nocturnal oxygen desaturation. Middle horizontal line inside the box indicates median. Bottom and top of the box are 25th and 75th percentiles, and the error bars outside the box represent maximum and minimum values, respectively. Abbreviations: CPAP, continuous positive airway pressure; ns = not significant; PSG, polysomnography.
Figure 4.
High‐sensitivity troponin T levels pre‐ and post‐PSG and pre‐ and post‐CPAP therapy. Middle horizontal line inside the box indicates median. Bottom and top of the box are 25th and 75th percentiles, and the error bars outside the box represent maximum and minimum values, respectively. Abbreviations: CPAP, continuous positive airway pressure; ns = not significant; PSG, polysomnography.
Discussion
It is well known that OSA is associated with adverse effects on cardiac structure and function, although the underlying mechanisms are not well understood. Previous studies have suggested that the main risk factor for myocardial ischemia in patients with OSA is inadequate oxygen supply in the presence of CAD, whereas others assume an increase in oxygen demand due to tachycardia and sympathetic activation following the rebreathing phase after an apnea event.15, 16, 17, 18
In the current study, we found no myocardial ischemia with myocyte necrosis in patients with severe OSA and coexisting CAD evidenced by significantly elevated hs‐TropT levels or significant ST‐segment depression. Increased NT‐proBNP levels were significantly reduced after a single night of CPAP therapy.
The results of previously presented studies that investigated the relation between OSA and myocardial damage measured by different troponins are not univocal. Similar to our findings, other studies reported no myocardial injury detectable by a troponin T assay despite the fact that patients with OSA and concomitant CAD experienced nocturnal ischemia. In a study by Gami et al, the AHI was comparable to our study, but the mean nocturnal oxygen saturation nadir was less distinct (83% ± 6%).19 In a study including 505 subjects drawn from the general population, the proportion of subjects with detectable hs‐TropT (≥3 ng/L) increased with increasing severity of OSA. But after adjustment for significant univariate predictors of detectable hs‐TropT, the association between AHI and hs‐TropT was no longer statistically significant, and this association was likely to be caused by a clustering of cardiovascular risk factors among subjects with OSA.20 On the other hand, Querejeta Roca et al found higher hs‐TropT levels independently correlated with OSA severity in middle‐aged and older individuals free of coronary heart disease and heart failure, suggesting that subclinical myocardial injury may play a role in the association between OSA and risk of heart failure.21 A limitation of this study is that hs‐TropT was not measured coincident with polysomnography and therefore makes no statement on changes of hs‐TropT levels shortly after nocturnal ischemia. In contrast a study by Einvik et al of 514 patients showed an independent association between OSA severity and higher concentrations of high‐sensitivity troponin I, suggesting that frequent apneas or hypoxemia in OSA may cause low‐grade myocardial injury.22 The divergent study results may be partially due to the different sensitivity and low‐range analytical precision of the different assays, but it could also be due to true biological differences.
We observed elevated NT‐proBNP levels in untreated patients with severe OSA and CAD before and after sleep. Interestingly, 1 night of CPAP therapy significantly decreased NT‐proBNP in these patients. In untreated OSA patients, respiratory effort during obstruction of the upper airways can generate substantial intrathoracic pressure fluctuations followed by right heart volume overload and secretion of natriuretic peptides. CPAP abolishes negative intrathoracic pressure swings. That could explain a decrease in NT‐proBNP secretion.
Other studies also found higher serum NT‐proBNP values in patients with OSA, although this finding has not been universal.21, 23, 24, 25, 26 NT‐proBNP is also an independent predictor for patients with CAD.27 In patients with stable angina pectoris, NT‐proBNP serum concentrations showed a close relation to the extent of coronary artery disease and inducible myocardial ischemia.28, 29 CPAP is the first‐line treatment for moderate‐to‐severe OSA.30 A significant improvement in LVEF was noted with CPAP in patients with sleep‐disordered breathing and heart failure.31 Conflicting data exist regarding the effects of CPAP on cardiac markers like natriuretic peptides and troponins in OSA patients. In some studies, CPAP therapy showed to decreased elevated NT‐ProBNP and atrial natriuretic peptide levels.24, 32, 33, 34 In contrast, Cifci et al evaluated the effect of CPAP in 33 unselected patients with OSA and found no difference in pro‐BNP after 6 months of CPAP.26 Similar results were reported by Colish et al, who found no changes in the levels of NT‐proBNP and troponin following 12 months of CPAP in 47 patients with OSA despite improvement in cardiovascular remodeling.35 A study by Barcelo et al provided evidence that treatment with CPAP is followed by a rise in hs‐TropT concentrations, indicating that CPAP therapy might induce a potential degree of cardiac stress.36
We found only minor ST‐segment depression (<1 mm) during sleep at the time point of maximum oxygen desaturation in patients suffering from severe OSA and CAD. Other studies have noted ST‐segment depression (>1 mm) in about a third of OSA patients with CAD during apneas and decreases in oxygen saturation.16, 17 Nocturnal ischemia predominantly occurred during the rebreathing phase of the apneas, and it was characterized by raised heart rate and blood pressure, indicating an increase in myocardial oxygen consumption. CPAP significantly ameliorated the nocturnal ST depression time. A study, including 226 patients referred for coronary angiogram because of angina pectoris, found nocturnal ST‐segment depression (≥1 mm, ≥1 min) within 2 minutes after an apnea‐hypopnea or desaturation only in 12% of patients.37 Apnea‐associated ST‐segment depression was often preceded by a significant increase in heart rate, repetitive apneas, and severe oxygen desaturation. A temporal relationship between sleep‐disordered breathing and myocardial ischemia was present only in a minority of patients. Hanly et al also found asymptomatic ST depression during sleep even in 30% of patients with OSA who did not have a history of CAD.38
The mechanism of ST segment depression during sleep in patients with OSA is not fully understood. Inspiration against occluded upper airways causing periodic negative changes in intrathoracal pressure and alterations in cardiac preload and afterload may result in myocardial ischemia in the absence of hypoxemia.39 OSA often is accompanied by hypoxemia, and thereby enhances the risk of myocardial ischemia especially in patients with CAD.
The present study did have some limitations that deserve comment. First is the small number of the study group, which limits interpretation of the results, in particular the P values. Second, other mechanisms like sympathetic activation with increased heart rate and blood pressure were not considered in exploring the relationship between OSA and myocardial injury, because most of the patients with OSA and coexisting CAD were on medications (β‐blockers, angiotensin‐converting enzyme inhibitors), which may confound these findings. Third, it is possible that the chosen time point for the analysis of ST‐segment depression after oxygen saturation nadir might not represent the time of most severe myocardial ischemia. ST depression may have been more pronounced during postapnea tachycardia. We also did not take into account the duration of hypoxemia. Most of the CAD patients were status postintervention, which may also affect ischemic thresholds.
Conclusion
The present study showed that in patients with severe OSA and coexisting CAD, repeated nocturnal oxygen desaturation did not result in myocardial necrosis evidenced by elevation of hs‐TropT after sleep. At the time of maximum oxygen desaturation during sleep, we could not find a significant ST segment depression. Patients with OSA and CAD revealed higher NT‐proBNP serum levels. A single night of CPAP significantly reduced NT‐proBNP. The mechanism of cardiovascular injury in patients with significant OSA seems to be independent from direct ischemia‐induced myocardial necrosis even in patients with manifest CAD.
Acknowledgments
The authors thank Simone Rack and all staff members of the Center of Sleep Medicine at Sachsenhausen Hospital for their assistance and data acquisition.
The authors have no funding, financial relationships, or conflicts of interest to disclose.
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