Sleep Breath DOI 10.1007/s11325-015-1143-9
REVIEW
What can blood biomarkers tell us about cardiovascular risk in obstructive sleep apnea? Ivan Guerra de Araújo Freitas & Pedro Felipe Carvalhedo de Bruin & Lia Bittencourt & Veralice Meireles Sales de Bruin & Sérgio Tufik
Received: 12 November 2014 / Revised: 1 February 2015 / Accepted: 8 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Background Despite its high prevalence and frequent association with multiple comorbidities, including hypertension, heart disease, and stroke, obstructive sleep apnea (OSA) still lacks appropriate tools for cardiovascular risk assessment and stratification. Circulating biomarkers represent a safe, convenient, and inexpensive possibility, and several studies have been performed to define an ideal marker in this context. Additionally, biomarkers can provide insight into the pathological mechanisms of the disease and suggest new therapeutic approaches. Methods In the present review, the authors critically analyze the biomarkers of cardiovascular risk currently available and other potential markers, including brain natriuretic peptide, Creactive protein, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), cysteine, homocysteine, free fatty acids, 8isoprostane, gamma-glutamyl transferase, glycated hemoglobin, adipokines, and adhesion molecules. Conclusion The results clearly demonstrate that the relationship between specific biomarkers and OSA is often influenced by age, gender or ethnicity, which has hindered the identification of a unique marker for the evaluation of all patients with OSA. Moreover, given the frequency of comorbidities in OSA, which, by themselves, increase the cardiovascular risk, all confounding factors must be considered in the evaluation of these biomarkers. Keywords Biomarkers . Obstructive sleep apnea . Pathophysiology I. G. de Araújo Freitas : P. F. C. de Bruin (*) : V. M. S. de Bruin Department of Medicine, Universidade Federal do Ceará, Rua Prof. Costa Mendes, 1608/4° andar, 60430-140 Fortaleza, CE, Brazil e-mail: [email protected] L. Bittencourt : S. Tufik Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil
Introduction A biomarker is any measurable parameter that can represent a biological function, including anatomical, histological, biophysical, biochemical, and gene expression measurements, and is useful for screening, diagnosis, monitoring therapeutic response, prognosis, and risk prediction in specific clinical situations. The optimal biomarker should be easily accessible to the physician in terms of availability and cost, be involved in the main pathophysiological pathway of the disease, provide new information, exhibit dose–response behavior relative to the severity and treatment of the disease and exhibit sensitivity and specificity levels as well as predictive value that guide an appropriate management of the patient [1]. In practice, a biomarker that satisfactorily meets all of these criteria is very difficult to find.
Obstructive sleep apnea Obstructive sleep apnea (OSA) is a condition characterized by repeated interruptions in breathing during sleep caused by partial or complete obstruction of the upper airways. These breathing interruptions lead to transient reduction in oxyhemoglobin saturation and microarousals, which affect sleep architecture. Poor quality of sleep, hypoxia, and reoxygenation episodes, sympathetic hyperactivity, and large variations in pleural pressure are considered responsible for the many clinical consequences of OSA [2]. A significant set of evidence indicates an increased cardiovascular risk in OSA [3–5]. Excess cardiovascular mortality in these patients may occur due to an increased incidence of arrhythmias [6–8], heart failure [9], cerebrovascular disease [10], and coronary heart disease [11]. Hypertension, a traditional cardiovascular risk factor, exhibits a significant association with OSA. A causal relationship between OSA and
Sleep Breath
hypertension has been established, and the likelihood of developing hypertension has been shown to be positively related to the apnea–hypopnea index (AHI) [12]. The improvement of hypertension due to OSA treatment with positive airway pressure has already been shown [13]. Moreover, OSA is linked to dyslipidemia, inflammation, insulin resistance, and oxidative stress all of which play a role in atherosclerosis progression [14]. Hypoxia due to OSA may result in insufficient delivery of oxygen to the myocardium leading to nocturnal angina and arrhythmias. Hypoxemia with reoxygenation, as observed in OSA, resembles the ischemia–reperfusion phenomenon, with additional production of free radicals, increasing oxidative stress. Hypoxia also activates transcription factors with vasoconstrictor and inflammatory properties and inhibits production of nitric oxide, a vasodilator with antimitogenic features. Nitric oxide level is reduced in OSA patients and can be normalized by OSA treatment. Increased activity of the cyclooxygenase pathway also contributes to endothelial dysfunction in OSA. Nuclear factor kappa B upregulates levels of several proinflammatory genes and adhesion molecules, which mediate the recruitment of platelets and inflammatory cells leading to further endothelial insult. Chronic intermittent hypoxia enhances activity of nuclear factor kappa B in cardiovascular tissue of mice. Hypoxia also upregulates expression of hypoxia inducible factor 1, which has angiogenic and atherogenic properties [15]. In addition, intermittent hypoxia and arousals in OSA are related to surges in sympathetic activity and decrease in parasympathetic activity, increasing blood pressure and heart rate and reducing heart rate variability, a predictor of mortality [16]. Metabolic dysregulation ensues as a result of sympathetic overactivity and intermittent hypoxia. Also, OSA is characterized by large swings in intrathoracic pressure due to recurrent forced inspiration against the occluded airway. Such oscillations enhance transmural pressure of ventricles and large vessels, leading to increases in ventricular wall tension, left ventricle afterload, and myocardial oxygen consumption. Other consequences of negative intrathoracic pressure are increased venous return to right ventricle, displacement to the left of interventricular septum, resulting in reduced left ventricular filling and diminished cardiac output [17]. Currently, there is no consensus on the optimal marker of cardiovascular risk in OSA. Theoretically, a biomarker for OSA should reflect the increased swings in pleural pressure secondary to the repetitive respiratory efforts against a constricted airway, sleep fragmentation and the fluctuations in blood gases. These three events trigger pathophysiological changes in key domains, such as oxidative stress, inflammation, and sympathetic hyperactivity, and lead secondarily to increased hypoxia-inducible factor (HIF-α) and the release of adhesion molecules, adipokines, and free fatty acids [18]. Due to their confounding effect, the high frequency of
comorbidities in patients with OSA, including obesity, diabetes mellitus, and hypertension, hinders the identification of an optimal marker for this condition. In addition to these comorbidities, factors, such as age, gender, craniofacial alterations, and ethnicity, also affect this identification. For the purpose of this review, papers were searched in electronic databases, including Pubmed/Medline, for English language studies. In order to identify potentially useful circulating biomarkers, review articles from the previous 5 years were searched using “cardiac risk” and “biomarker” as search terms. We then combined the terms “sleep apnea” and each of the previously selected biomarkers as keywords. The references of retrieved articles were also reviewed to find further relevant studies. All papers were assessed for relevance and quality. A growing number of studies have been conducted to identify cardiovascular markers in OSA. The present review aimed to assess the applicability of these substances in clinical practice and their contribution to our current understanding of the pathophysiology of this condition. The term biomarker will be used hereinafter only to refer to substances in the circulating blood (Fig. 1).
Brain natriuretic peptide (BNP) and the N-terminal portion of the pro-brain natriuretic peptide [N-terminal pro-brain natriuretic peptide (NT-proBNP)] Natriuretic peptides constitute a family of molecules involved in the homeostatic control of blood volume, osmosis, and pressure regulation in the circulatory system. In humans, the following natriuretic peptides have been identified: the A-type or atrial natriuretic peptide (ANP), predominantly produced in the atria; the B-type or brain natriuretic peptide (BNP), originally described in the brain but mainly secreted by ventricular cardiomyocytes; and the C-type natriuretic peptide (CNP), which is expressed in the central nervous system, reproductive system, bone, and endothelial cells. Most of the biological effects of natriuretic peptides are well known. For BNP, these effects include vasodilation, natriuresis, and diuresis. BNP can also negatively regulate the renin–angiotensin–aldosterone system and exerts an antifibrotic effect on heart muscle. Stimuli to the secretion of BNP by the myocardium include mechanical stretch, ischemic injury/hypoxia, endothelin-1, angiotensin-2, interleukin-1β, and α-adrenergic and βadrenergic agonists [19]. BNP levels correlate with the severity of cardiac dysfunction [20] and guide the treatment of heart failure [21]. BNP secretion is also increased, to a lesser extent, in other conditions such as valvular heart disease, arrhythmias, myocardial hypertrophy, coronary disease, and pulmonary embolism [22]. NT-proBNP, a metabolically inactive product of the cleavage of prohormone pro-BNP, has also been shown to be a marker of cardiovascular risk, with some advantages
Sleep Breath Arousals/ Sleep fragmentation
Hypoxia-reoxygenation
↑ Oscilations in intrathoracic pressure
Sympathetic overactivity Inflammation Metabolic dysregulation
Oxidative stress
CRP IL-6 TNF-α, adipokines
HbA1C Free fatty acids Hypercoagulability
Homocystein Cystein
8-Isoprostane Gamma-glutamyl
Elevated LV transmural pressures BNP
transferase
Endothelial dysfunction Adhesion molecules
Increased Cardiovascular risk Coronary disease Stroke LV dysfunction Arrythmias
Fig. 1 Flowchart of pathways leading to cardiovascular risk in obstructive sleep apnea. BNP brain natriuretic peptide, CRP C-reactive protein, TNF-α tumor necrosis factor-α, IL-6 interleukin-6, HbA1C glycated hemoglobin
over BNP, particularly, in the technical aspects of measurement [23]. In untreated OSA, a significant change in the secretion of natriuretic peptides would be expected due to the excessive oscillation in pleural pressure during sleep and the consequent effect on the myocardial wall tension. In patients with OSA and heart failure, increased BNP is well demonstrated [24] and is recognized as a poor prognostic factor [25]. However, it remains controversial whether individuals with OSA generally exhibit elevated BNP and, likewise, elevated NT-proBNP (Table 1). A positive association was observed by Kita et al. [26]. These researchers observed a progressive increase in plasma BNP levels between the beginning and the end of the sleep period in 14 patients with OSA. On the subsequent night, the use of continuous positive airway pressure (CPAP) in the same individuals promoted an acute reduction of these levels [26]. Koga et al. [27] studied 27 patients with moderately severe to severe OSA and 22 controls without OSA using echocardiography and measurements of BNP levels before the treatment and 1 and 3 months after treatment with CPAP. The authors observed a reduction in BNP levels after 3 months of treatment. There was also an improvement in ventricular function, as assessed by the Tei index, calculated as the ratio of time intervals [(a−b)/b], where a is the interval between cessation and onset of mitral inflow, and b is ejection time of left ventricular outflow. The Tei index is generally considered a reliable method for the evaluation of left ventricular systolic and diastolic performance, and an earlier indicator of improvement than other echocardiographic indices [27]. A community-based study conducted in Uppsala, Sweden, showed positive correlation between OSA and BNP levels in 349 women, with a dose–response relationship between
morning BNP and severity of sleep apnea [28]. Tasci et al. [29] evaluated the impact of CPAP treatment on the NTproBNP levels in 60 patients with OSA, 34 of which were hypertensive and 26 of which were normotensive. Nine normotensive controls without OSA were also studied. Although the results did not demonstrate differences in pretreatment baseline NT-proBNP levels between the three groups, the application of CPAP resulted in a significant reduction in the levels of this marker in patients with OSA [29]. Sanchez et al. [30] did not observe increased NT-proBNP levels in 27 patients with severe OSA when compared with 15 patients with mild to moderate OSA and 14 normal controls. However, these researchers noted that the main factor affecting the NT-proBNP levels in subjects with OSA was the percentage of sleep time with oxygen saturation below 90 %. A decreased NT-proBNP concentration due to the CPAP treatment was not observed [30]. In contrast, other studies in adults did not find any relationship between the presence of OSA and BNP levels or changes in these levels resulting from treatment [31–38]. Moller et al. [31] did not observe differences between the morning levels of BNP in 24 cases of OSA when compared with 18 controls. In the same study, a subset of 13 patients with OSA, restudied after 14 months of CPAP therapy, did not demonstrate any reduction in BNP levels [31]. Svatikova et al. [32] compared plasma BNP levels in ten patients with OSA without cardiovascular disease (CVD), 13 patients with OSA and concomitant CVD (including five cases of heart failure) and ten normal controls (without OSA and without CVD) during overnight polysomnography using the “split-night” protocol (first part of the exam without CPAP and final portion with CPAP). These researchers were unable to identify increases in BNP
AHI
REVIEW
What can blood biomarkers tell us about cardiovascular risk in obstructive sleep apnea? Ivan Guerra de Araújo Freitas & Pedro Felipe Carvalhedo de Bruin & Lia Bittencourt & Veralice Meireles Sales de Bruin & Sérgio Tufik
Received: 12 November 2014 / Revised: 1 February 2015 / Accepted: 8 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Background Despite its high prevalence and frequent association with multiple comorbidities, including hypertension, heart disease, and stroke, obstructive sleep apnea (OSA) still lacks appropriate tools for cardiovascular risk assessment and stratification. Circulating biomarkers represent a safe, convenient, and inexpensive possibility, and several studies have been performed to define an ideal marker in this context. Additionally, biomarkers can provide insight into the pathological mechanisms of the disease and suggest new therapeutic approaches. Methods In the present review, the authors critically analyze the biomarkers of cardiovascular risk currently available and other potential markers, including brain natriuretic peptide, Creactive protein, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), cysteine, homocysteine, free fatty acids, 8isoprostane, gamma-glutamyl transferase, glycated hemoglobin, adipokines, and adhesion molecules. Conclusion The results clearly demonstrate that the relationship between specific biomarkers and OSA is often influenced by age, gender or ethnicity, which has hindered the identification of a unique marker for the evaluation of all patients with OSA. Moreover, given the frequency of comorbidities in OSA, which, by themselves, increase the cardiovascular risk, all confounding factors must be considered in the evaluation of these biomarkers. Keywords Biomarkers . Obstructive sleep apnea . Pathophysiology I. G. de Araújo Freitas : P. F. C. de Bruin (*) : V. M. S. de Bruin Department of Medicine, Universidade Federal do Ceará, Rua Prof. Costa Mendes, 1608/4° andar, 60430-140 Fortaleza, CE, Brazil e-mail: [email protected] L. Bittencourt : S. Tufik Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil
Introduction A biomarker is any measurable parameter that can represent a biological function, including anatomical, histological, biophysical, biochemical, and gene expression measurements, and is useful for screening, diagnosis, monitoring therapeutic response, prognosis, and risk prediction in specific clinical situations. The optimal biomarker should be easily accessible to the physician in terms of availability and cost, be involved in the main pathophysiological pathway of the disease, provide new information, exhibit dose–response behavior relative to the severity and treatment of the disease and exhibit sensitivity and specificity levels as well as predictive value that guide an appropriate management of the patient [1]. In practice, a biomarker that satisfactorily meets all of these criteria is very difficult to find.
Obstructive sleep apnea Obstructive sleep apnea (OSA) is a condition characterized by repeated interruptions in breathing during sleep caused by partial or complete obstruction of the upper airways. These breathing interruptions lead to transient reduction in oxyhemoglobin saturation and microarousals, which affect sleep architecture. Poor quality of sleep, hypoxia, and reoxygenation episodes, sympathetic hyperactivity, and large variations in pleural pressure are considered responsible for the many clinical consequences of OSA [2]. A significant set of evidence indicates an increased cardiovascular risk in OSA [3–5]. Excess cardiovascular mortality in these patients may occur due to an increased incidence of arrhythmias [6–8], heart failure [9], cerebrovascular disease [10], and coronary heart disease [11]. Hypertension, a traditional cardiovascular risk factor, exhibits a significant association with OSA. A causal relationship between OSA and
Sleep Breath
hypertension has been established, and the likelihood of developing hypertension has been shown to be positively related to the apnea–hypopnea index (AHI) [12]. The improvement of hypertension due to OSA treatment with positive airway pressure has already been shown [13]. Moreover, OSA is linked to dyslipidemia, inflammation, insulin resistance, and oxidative stress all of which play a role in atherosclerosis progression [14]. Hypoxia due to OSA may result in insufficient delivery of oxygen to the myocardium leading to nocturnal angina and arrhythmias. Hypoxemia with reoxygenation, as observed in OSA, resembles the ischemia–reperfusion phenomenon, with additional production of free radicals, increasing oxidative stress. Hypoxia also activates transcription factors with vasoconstrictor and inflammatory properties and inhibits production of nitric oxide, a vasodilator with antimitogenic features. Nitric oxide level is reduced in OSA patients and can be normalized by OSA treatment. Increased activity of the cyclooxygenase pathway also contributes to endothelial dysfunction in OSA. Nuclear factor kappa B upregulates levels of several proinflammatory genes and adhesion molecules, which mediate the recruitment of platelets and inflammatory cells leading to further endothelial insult. Chronic intermittent hypoxia enhances activity of nuclear factor kappa B in cardiovascular tissue of mice. Hypoxia also upregulates expression of hypoxia inducible factor 1, which has angiogenic and atherogenic properties [15]. In addition, intermittent hypoxia and arousals in OSA are related to surges in sympathetic activity and decrease in parasympathetic activity, increasing blood pressure and heart rate and reducing heart rate variability, a predictor of mortality [16]. Metabolic dysregulation ensues as a result of sympathetic overactivity and intermittent hypoxia. Also, OSA is characterized by large swings in intrathoracic pressure due to recurrent forced inspiration against the occluded airway. Such oscillations enhance transmural pressure of ventricles and large vessels, leading to increases in ventricular wall tension, left ventricle afterload, and myocardial oxygen consumption. Other consequences of negative intrathoracic pressure are increased venous return to right ventricle, displacement to the left of interventricular septum, resulting in reduced left ventricular filling and diminished cardiac output [17]. Currently, there is no consensus on the optimal marker of cardiovascular risk in OSA. Theoretically, a biomarker for OSA should reflect the increased swings in pleural pressure secondary to the repetitive respiratory efforts against a constricted airway, sleep fragmentation and the fluctuations in blood gases. These three events trigger pathophysiological changes in key domains, such as oxidative stress, inflammation, and sympathetic hyperactivity, and lead secondarily to increased hypoxia-inducible factor (HIF-α) and the release of adhesion molecules, adipokines, and free fatty acids [18]. Due to their confounding effect, the high frequency of
comorbidities in patients with OSA, including obesity, diabetes mellitus, and hypertension, hinders the identification of an optimal marker for this condition. In addition to these comorbidities, factors, such as age, gender, craniofacial alterations, and ethnicity, also affect this identification. For the purpose of this review, papers were searched in electronic databases, including Pubmed/Medline, for English language studies. In order to identify potentially useful circulating biomarkers, review articles from the previous 5 years were searched using “cardiac risk” and “biomarker” as search terms. We then combined the terms “sleep apnea” and each of the previously selected biomarkers as keywords. The references of retrieved articles were also reviewed to find further relevant studies. All papers were assessed for relevance and quality. A growing number of studies have been conducted to identify cardiovascular markers in OSA. The present review aimed to assess the applicability of these substances in clinical practice and their contribution to our current understanding of the pathophysiology of this condition. The term biomarker will be used hereinafter only to refer to substances in the circulating blood (Fig. 1).
Brain natriuretic peptide (BNP) and the N-terminal portion of the pro-brain natriuretic peptide [N-terminal pro-brain natriuretic peptide (NT-proBNP)] Natriuretic peptides constitute a family of molecules involved in the homeostatic control of blood volume, osmosis, and pressure regulation in the circulatory system. In humans, the following natriuretic peptides have been identified: the A-type or atrial natriuretic peptide (ANP), predominantly produced in the atria; the B-type or brain natriuretic peptide (BNP), originally described in the brain but mainly secreted by ventricular cardiomyocytes; and the C-type natriuretic peptide (CNP), which is expressed in the central nervous system, reproductive system, bone, and endothelial cells. Most of the biological effects of natriuretic peptides are well known. For BNP, these effects include vasodilation, natriuresis, and diuresis. BNP can also negatively regulate the renin–angiotensin–aldosterone system and exerts an antifibrotic effect on heart muscle. Stimuli to the secretion of BNP by the myocardium include mechanical stretch, ischemic injury/hypoxia, endothelin-1, angiotensin-2, interleukin-1β, and α-adrenergic and βadrenergic agonists [19]. BNP levels correlate with the severity of cardiac dysfunction [20] and guide the treatment of heart failure [21]. BNP secretion is also increased, to a lesser extent, in other conditions such as valvular heart disease, arrhythmias, myocardial hypertrophy, coronary disease, and pulmonary embolism [22]. NT-proBNP, a metabolically inactive product of the cleavage of prohormone pro-BNP, has also been shown to be a marker of cardiovascular risk, with some advantages
Sleep Breath Arousals/ Sleep fragmentation
Hypoxia-reoxygenation
↑ Oscilations in intrathoracic pressure
Sympathetic overactivity Inflammation Metabolic dysregulation
Oxidative stress
CRP IL-6 TNF-α, adipokines
HbA1C Free fatty acids Hypercoagulability
Homocystein Cystein
8-Isoprostane Gamma-glutamyl
Elevated LV transmural pressures BNP
transferase
Endothelial dysfunction Adhesion molecules
Increased Cardiovascular risk Coronary disease Stroke LV dysfunction Arrythmias
Fig. 1 Flowchart of pathways leading to cardiovascular risk in obstructive sleep apnea. BNP brain natriuretic peptide, CRP C-reactive protein, TNF-α tumor necrosis factor-α, IL-6 interleukin-6, HbA1C glycated hemoglobin
over BNP, particularly, in the technical aspects of measurement [23]. In untreated OSA, a significant change in the secretion of natriuretic peptides would be expected due to the excessive oscillation in pleural pressure during sleep and the consequent effect on the myocardial wall tension. In patients with OSA and heart failure, increased BNP is well demonstrated [24] and is recognized as a poor prognostic factor [25]. However, it remains controversial whether individuals with OSA generally exhibit elevated BNP and, likewise, elevated NT-proBNP (Table 1). A positive association was observed by Kita et al. [26]. These researchers observed a progressive increase in plasma BNP levels between the beginning and the end of the sleep period in 14 patients with OSA. On the subsequent night, the use of continuous positive airway pressure (CPAP) in the same individuals promoted an acute reduction of these levels [26]. Koga et al. [27] studied 27 patients with moderately severe to severe OSA and 22 controls without OSA using echocardiography and measurements of BNP levels before the treatment and 1 and 3 months after treatment with CPAP. The authors observed a reduction in BNP levels after 3 months of treatment. There was also an improvement in ventricular function, as assessed by the Tei index, calculated as the ratio of time intervals [(a−b)/b], where a is the interval between cessation and onset of mitral inflow, and b is ejection time of left ventricular outflow. The Tei index is generally considered a reliable method for the evaluation of left ventricular systolic and diastolic performance, and an earlier indicator of improvement than other echocardiographic indices [27]. A community-based study conducted in Uppsala, Sweden, showed positive correlation between OSA and BNP levels in 349 women, with a dose–response relationship between
morning BNP and severity of sleep apnea [28]. Tasci et al. [29] evaluated the impact of CPAP treatment on the NTproBNP levels in 60 patients with OSA, 34 of which were hypertensive and 26 of which were normotensive. Nine normotensive controls without OSA were also studied. Although the results did not demonstrate differences in pretreatment baseline NT-proBNP levels between the three groups, the application of CPAP resulted in a significant reduction in the levels of this marker in patients with OSA [29]. Sanchez et al. [30] did not observe increased NT-proBNP levels in 27 patients with severe OSA when compared with 15 patients with mild to moderate OSA and 14 normal controls. However, these researchers noted that the main factor affecting the NT-proBNP levels in subjects with OSA was the percentage of sleep time with oxygen saturation below 90 %. A decreased NT-proBNP concentration due to the CPAP treatment was not observed [30]. In contrast, other studies in adults did not find any relationship between the presence of OSA and BNP levels or changes in these levels resulting from treatment [31–38]. Moller et al. [31] did not observe differences between the morning levels of BNP in 24 cases of OSA when compared with 18 controls. In the same study, a subset of 13 patients with OSA, restudied after 14 months of CPAP therapy, did not demonstrate any reduction in BNP levels [31]. Svatikova et al. [32] compared plasma BNP levels in ten patients with OSA without cardiovascular disease (CVD), 13 patients with OSA and concomitant CVD (including five cases of heart failure) and ten normal controls (without OSA and without CVD) during overnight polysomnography using the “split-night” protocol (first part of the exam without CPAP and final portion with CPAP). These researchers were unable to identify increases in BNP
AHI
