Ravish Singhal, MD

 

Pulmonary hypertension (PH) is a progressive disease characterized by an increase in pulmonary arterial pressure and pulmonary vascular resistance (PVR) leading to right ventricular failure. Although substantial progress has been achieved in the treatment of PH, mostly due to improved pharmacotherapy, it remains a life-threatening disease with a poor prognosis. Increased pulmonary arterial pressure is a common feature of many chronic lung diseases, and chronic lung disease is the second most common cause of pulmonary hypertension. PH caused by chronic lung disease, including PH due to sleep-disordered breathing (SDB), is referred to as group 3 PH in the classification of pulmonary hypertension (Simonneau et al. J Am Coll Cardiol. 2013;62:D34 e41). Many reports since have linked pulmonary arterial hypertension to obstructive sleep apnea (OSA). These were validated in animal trials, when rodents were exposed to intermittent hypoxia for several hours over a few weeks, similar to what is seen in patients with OSA; this resulted in pulmonary vascular remodeling, sustained PH, and right ventricular hypertrophy. As with other chronic lung disease, prevalence rates of PH in SDB vary greatly, with some studies suggesting prevalence of pulmonary hypertension in OSA to be as high as 40%, although a lack of large-scale studies with clearly defined patient populations makes it difficult to determine the true prevalence rate. Most studies suggest that about 20% to 30% of patients with OSA have some degree of PH. OSA has been shown to be an independent causal factor for the development of PH (Hurdman et al. Eur Respir J. 2012; 39, 945–955). PH associated with OSA appears to be mild and may be due to a combination of precapillary and postcapillary factors, including pulmonary arteriolar remodeling, hyperreactivity to hypoxia, and left ventricular diastolic dysfunction resulting in left atrial enlargement. Despite differences in reported prevalence rates, most studies consistently reported mild increases in pulmonary arterial pressure with mPAP averaging less than 30 mm Hg. In one of the largest studies to date, the prevalence rate of PH in 220 patients with SDB was 17%, and the mPAP was 26 +/- 6 mm Hg (Chaouat et al. Chest. 1996;109[2]:380).

The other consistent finding in most studies was that PH correlated with the severity of obesity, daytime hypoxia and hypercapnia, obstructive airways disease, and nocturnal oxygen desaturation. PH seems to be more common and more severe in obesity hypoventilation syndrome (OHS) than in “pure” OSA patients (58% vs 9%) (Kessler et al. Chest. 2001;120[2]:369).

The incidence of OSA is rising in parallel with the rising global incide

nce of extreme obesity, and it is increasingly becoming a rapidly growing health problem in the United States and worldwide. It remains largely undiagnosed and has been linked to an increased incidence of stroke, heart failure, myocardial infarction, and arrhythmia. OSA is characterized by repetitive nocturnal arterial oxygen desaturations and hypercapnia, large intrathoracic pressure swings, and acute increases in pulmonary arterial pressure. PH in patients with OSA is thought to be due to hypoxia-related vasoconstriction that occurs during these apneic periods and can lead to progressive vascular damage resulting in accelerated inflammation and sympathetic activity; this eventually leads to subclinical myocardial injury and the potential development of biventricular systolic and diastolic dysfunction and resultant elevated cardiac biomarkers (Adegunsoye et al. Pulm Med. Published online 2012 Jul 11. doi: 10.1155/2012/273591). It is still unclear whether PH associated with chronic lung disease (CLD) and SDB is a direct consequence of hypoxemia (as seen in CLD and SDB) or whether this is due to a cascade of events that leads to pulmonary vascular disease that is separate from or out of proportion to the underlying lung injury from existing pulmonary processes.

Patients with OSA who have PH are more likely to be obese, have decreased respiratory function (FEV₁, vital capacity, and FEV₁/VC ratio), and lower oxygen saturation/higher carbon dioxide content in blood (Chaouat et al. Chest. 1996;109[2]:380). These patients frequently present with shortness of breath and dyspnea on exertion. Echocardiogram remains the main screening tool for evaluation of PH. With that said, right-sided heart catheterization remains the gold standard for the diagnosis of all classes of PH; however, use of right-sided heart catheterization in group 3 pulmonary hypertension is reserved for select patients. This is likely because PH in patients with OSA is accepted as a more benign prognostic marker compared with other group 3 forms. Furthermore, patients with OHS are more prone to developing PH and cor pulmonale compared with patients with isolated OSA. OSA with PH has lower survival rates than OSA without PH. Studies showed that patients with OHS tend to do worse than patients with OSA alone (Aljohara et al. J Thorac Dis. 2017;9[3]:779).

 

AHI and PH

Various studies have looked at different polysomnographic variables to understand the relationship between PH and OSA. Initial studies showed that the apnea hypopnea index (AHI) does not predict development of PH among patients with OSA. Decrements in nocturnal oxygen saturation, however, is predictive of the development of PH; the only predictor of developing PH among patients with OSA in one study was time spent with oxygen saturation below 70% during sleep (Wong et al. Eur Arch Otorhinolaryngol. 2017;74:2601). In addition, recent data suggest there is no statistically significant association between age, gender, body mass index, or AHI and chance for development of PH (Wong et al. 2017). It was found that the percentage of time during sleep with oxygen saturation below 90% was significant and independently associated with higher PAP. Furthermore, a recent study demonstrated that patients with moderate to severe OSA (AHI over 15/h) who develop PH tend to have worse hemodynamics (higher PVR and mPAP) and subclinical myocardial damage (evaluated by troponin T), as well as increased ventricular wall stress (assessed by proBNP) when compared with patients with mild OSA (AHI less than 15/h).

Treatment

The mainstay treatment for OSA and OHS is positive airway pressure (PAP). This therapy has been shown to improve sleep and respiratory parameters, including sleep quality, overall quality of life, as well as promote reduction in mean pulmonary arterial pressure. The regular use of noninvasive positive-pressure ventilation has also been shown to reverse daytime hypoxia and hypercapnia, as well as influence inflammatory markers: decrease circulating levels of endothelin-1, interleukin-6, and C-reactive protein, thereby improving vascular endothelial function and reducing platelet activation and aggregation (Yokoe et al. Circulation. 2003;107[8]:1129). Indeed, there is a decrease in mean pulmonary arterial pressure in some patients with long-term daily use of PAP, but, in some patients, both pulmonary and right ventricular dysfunction persists, suggesting vascular remodeling and/or endothelial dysfunction. These findings indicate the need for early recognition of OSA and early treatment for patients, thus preventing remodeling and further development of PH and right ventricular dysfunction. Adequate control of OSA/OHS has important long-term effects on overall health, because it significantly reduces the risk of systemic hypertension, congestive heart failure, arrhythmias, and stroke. It is imperative to control underlying SDB before considering PAH-specific medications to treat PH associated with OSA or OHS unless the patient is demonstrating signs of right-sided heart failure; in such cases, concomitant therapy may be considered upfront. It is recommended that

patients with SDB should have an assessment for PH before starting therapy for their SDB and then again after 3 to 4 months of effective PAP confirmed by device data monitoring. For patients who have persistent PH despite achieving adequate control of their SDB, pulmonary vasodilator therapy may be indicated following standard treatment guidelines for WHO group 1 PAH (Galie et al. J Am Coll Cardiol. 2013;62[suppl 25]:D60–72). Medications that are currently approved for the treatment of PAH have not been well studied in PH associated with SDB and, at present time, the available data do not demonstrate sustained benefit.

Dr. Singhal is a second-year fellow in Pulmonary/Critical Care and Dr. Minkin is Director, Pulmonary Hypertension Program, New York Presbyterian-Brooklyn Methodist Hospital. Dr. Minkin is also Assistant Professor of Clinical Medicine, Weill Cornell Medical College, New York.

 

Pulmonary hypertension (PH) is a progressive disease characterized by an increase in pulmonary arterial pressure and pulmonary vascular resistance (PVR) leading to right ventricular failure. Although substantial progress has been achieved in the treatment of PH, mostly due to improved pharmacotherapy, it remains a life-threatening disease with a poor prognosis. Increased pulmonary arterial pressure is a common feature of many chronic lung diseases, and chronic lung disease is the second most common cause of pulmonary hypertension. PH caused by chronic lung disease, including PH due to sleep-disordered breathing (SDB), is referred to as group 3 PH in the classification of pulmonary hypertension (Simonneau et al. J Am Coll Cardiol. 2013;62:D34 e41). Many reports since have linked pulmonary arterial hypertension to obstructive sleep apnea (OSA). These were validated in animal trials, when rodents were exposed to intermittent hypoxia for several hours over a few weeks, similar to what is seen in patients with OSA; this resulted in pulmonary vascular remodeling, sustained PH, and right ventricular hypertrophy. As with other chronic lung disease, prevalence rates of PH in SDB vary greatly, with some studies suggesting prevalence of pulmonary hypertension in OSA to be as high as 40%, although a lack of large-scale studies with clearly defined patient populations makes it difficult to determine the true prevalence rate. Most studies suggest that about 20% to 30% of patients with OSA have some degree of PH. OSA has been shown to be an independent causal factor for the development of PH (Hurdman et al. Eur Respir J. 2012; 39, 945–955). PH associated with OSA appears to be mild and may be due to a combination of precapillary and postcapillary factors, including pulmonary arteriolar remodeling, hyperreactivity to hypoxia, and left ventricular diastolic dysfunction resulting in left atrial enlargement. Despite differences in reported prevalence rates, most studies consistently reported mild increases in pulmonary arterial pressure with mPAP averaging less than 30 mm Hg. In one of the largest studies to date, the prevalence rate of PH in 220 patients with SDB was 17%, and the mPAP was 26 +/- 6 mm Hg (Chaouat et al. Chest. 1996;109[2]:380).

The other consistent finding in most studies was that PH correlated with the severity of obesity, daytime hypoxia and hypercapnia, obstructive airways disease, and nocturnal oxygen desaturation. PH seems to be more common and more severe in obesity hypoventilation syndrome (OHS) than in “pure” OSA patients (58% vs 9%) (Kessler et al. Chest. 2001;120[2]:369).

The incidence of OSA is rising in parallel with the rising global incide

nce of extreme obesity, and it is increasingly becoming a rapidly growing health problem in the United States and worldwide. It remains largely undiagnosed and has been linked to an increased incidence of stroke, heart failure, myocardial infarction, and arrhythmia. OSA is characterized by repetitive nocturnal arterial oxygen desaturations and hypercapnia, large intrathoracic pressure swings, and acute increases in pulmonary arterial pressure. PH in patients with OSA is thought to be due to hypoxia-related vasoconstriction that occurs during these apneic periods and can lead to progressive vascular damage resulting in accelerated inflammation and sympathetic activity; this eventually leads to subclinical myocardial injury and the potential development of biventricular systolic and diastolic dysfunction and resultant elevated cardiac biomarkers (Adegunsoye et al. Pulm Med. Published online 2012 Jul 11. doi: 10.1155/2012/273591). It is still unclear whether PH associated with chronic lung disease (CLD) and SDB is a direct consequence of hypoxemia (as seen in CLD and SDB) or whether this is due to a cascade of events that leads to pulmonary vascular disease that is separate from or out of proportion to the underlying lung injury from existing pulmonary processes.

Patients with OSA who have PH are more likely to be obese, have decreased respiratory function (FEV₁, vital capacity, and FEV₁/VC ratio), and lower oxygen saturation/higher carbon dioxide content in blood (Chaouat et al. Chest. 1996;109[2]:380). These patients frequently present with shortness of breath and dyspnea on exertion. Echocardiogram remains the main screening tool for evaluation of PH. With that said, right-sided heart catheterization remains the gold standard for the diagnosis of all classes of PH; however, use of right-sided heart catheterization in group 3 pulmonary hypertension is reserved for select patients. This is likely because PH in patients with OSA is accepted as a more benign prognostic marker compared with other group 3 forms. Furthermore, patients with OHS are more prone to developing PH and cor pulmonale compared with patients with isolated OSA. OSA with PH has lower survival rates than OSA without PH. Studies showed that patients with OHS tend to do worse than patients with OSA alone (Aljohara et al. J Thorac Dis. 2017;9[3]:779).

 

AHI and PH

Various studies have looked at different polysomnographic variables to understand the relationship between PH and OSA. Initial studies showed that the apnea hypopnea index (AHI) does not predict development of PH among patients with OSA. Decrements in nocturnal oxygen saturation, however, is predictive of the development of PH; the only predictor of developing PH among patients with OSA in one study was time spent with oxygen saturation below 70% during sleep (Wong et al. Eur Arch Otorhinolaryngol. 2017;74:2601). In addition, recent data suggest there is no statistically significant association between age, gender, body mass index, or AHI and chance for development of PH (Wong et al. 2017). It was found that the percentage of time during sleep with oxygen saturation below 90% was significant and independently associated with higher PAP. Furthermore, a recent study demonstrated that patients with moderate to severe OSA (AHI over 15/h) who develop PH tend to have worse hemodynamics (higher PVR and mPAP) and subclinical myocardial damage (evaluated by troponin T), as well as increased ventricular wall stress (assessed by proBNP) when compared with patients with mild OSA (AHI less than 15/h).

Treatment

The mainstay treatment for OSA and OHS is positive airway pressure (PAP). This therapy has been shown to improve sleep and respiratory parameters, including sleep quality, overall quality of life, as well as promote reduction in mean pulmonary arterial pressure. The regular use of noninvasive positive-pressure ventilation has also been shown to reverse daytime hypoxia and hypercapnia, as well as influence inflammatory markers: decrease circulating levels of endothelin-1, interleukin-6, and C-reactive protein, thereby improving vascular endothelial function and reducing platelet activation and aggregation (Yokoe et al. Circulation. 2003;107[8]:1129). Indeed, there is a decrease in mean pulmonary arterial pressure in some patients with long-term daily use of PAP, but, in some patients, both pulmonary and right ventricular dysfunction persists, suggesting vascular remodeling and/or endothelial dysfunction. These findings indicate the need for early recognition of OSA and early treatment for patients, thus preventing remodeling and further development of PH and right ventricular dysfunction. Adequate control of OSA/OHS has important long-term effects on overall health, because it significantly reduces the risk of systemic hypertension, congestive heart failure, arrhythmias, and stroke. It is imperative to control underlying SDB before considering PAH-specific medications to treat PH associated with OSA or OHS unless the patient is demonstrating signs of right-sided heart failure; in such cases, concomitant therapy may be considered upfront. It is recommended that

patients with SDB should have an assessment for PH before starting therapy for their SDB and then again after 3 to 4 months of effective PAP confirmed by device data monitoring. For patients who have persistent PH despite achieving adequate control of their SDB, pulmonary vasodilator therapy may be indicated following standard treatment guidelines for WHO group 1 PAH (Galie et al. J Am Coll Cardiol. 2013;62[suppl 25]:D60–72). Medications that are currently approved for the treatment of PAH have not been well studied in PH associated with SDB and, at present time, the available data do not demonstrate sustained benefit.

Dr. Singhal is a second-year fellow in Pulmonary/Critical Care and Dr. Minkin is Director, Pulmonary Hypertension Program, New York Presbyterian-Brooklyn Methodist Hospital. Dr. Minkin is also Assistant Professor of Clinical Medicine, Weill Cornell Medical College, New York.

 

Pulmonary hypertension (PH) is a progressive disease characterized by an increase in pulmonary arterial pressure and pulmonary vascular resistance (PVR) leading to right ventricular failure. Although substantial progress has been achieved in the treatment of PH, mostly due to improved pharmacotherapy, it remains a life-threatening disease with a poor prognosis. Increased pulmonary arterial pressure is a common feature of many chronic lung diseases, and chronic lung disease is the second most common cause of pulmonary hypertension. PH caused by chronic lung disease, including PH due to sleep-disordered breathing (SDB), is referred to as group 3 PH in the classification of pulmonary hypertension (Simonneau et al. J Am Coll Cardiol. 2013;62:D34 e41). Many reports since have linked pulmonary arterial hypertension to obstructive sleep apnea (OSA). These were validated in animal trials, when rodents were exposed to intermittent hypoxia for several hours over a few weeks, similar to what is seen in patients with OSA; this resulted in pulmonary vascular remodeling, sustained PH, and right ventricular hypertrophy. As with other chronic lung disease, prevalence rates of PH in SDB vary greatly, with some studies suggesting prevalence of pulmonary hypertension in OSA to be as high as 40%, although a lack of large-scale studies with clearly defined patient populations makes it difficult to determine the true prevalence rate. Most studies suggest that about 20% to 30% of patients with OSA have some degree of PH. OSA has been shown to be an independent causal factor for the development of PH (Hurdman et al. Eur Respir J. 2012; 39, 945–955). PH associated with OSA appears to be mild and may be due to a combination of precapillary and postcapillary factors, including pulmonary arteriolar remodeling, hyperreactivity to hypoxia, and left ventricular diastolic dysfunction resulting in left atrial enlargement. Despite differences in reported prevalence rates, most studies consistently reported mild increases in pulmonary arterial pressure with mPAP averaging less than 30 mm Hg. In one of the largest studies to date, the prevalence rate of PH in 220 patients with SDB was 17%, and the mPAP was 26 +/- 6 mm Hg (Chaouat et al. Chest. 1996;109[2]:380).

The other consistent finding in most studies was that PH correlated with the severity of obesity, daytime hypoxia and hypercapnia, obstructive airways disease, and nocturnal oxygen desaturation. PH seems to be more common and more severe in obesity hypoventilation syndrome (OHS) than in “pure” OSA patients (58% vs 9%) (Kessler et al. Chest. 2001;120[2]:369).

The incidence of OSA is rising in parallel with the rising global incide

nce of extreme obesity, and it is increasingly becoming a rapidly growing health problem in the United States and worldwide. It remains largely undiagnosed and has been linked to an increased incidence of stroke, heart failure, myocardial infarction, and arrhythmia. OSA is characterized by repetitive nocturnal arterial oxygen desaturations and hypercapnia, large intrathoracic pressure swings, and acute increases in pulmonary arterial pressure. PH in patients with OSA is thought to be due to hypoxia-related vasoconstriction that occurs during these apneic periods and can lead to progressive vascular damage resulting in accelerated inflammation and sympathetic activity; this eventually leads to subclinical myocardial injury and the potential development of biventricular systolic and diastolic dysfunction and resultant elevated cardiac biomarkers (Adegunsoye et al. Pulm Med. Published online 2012 Jul 11. doi: 10.1155/2012/273591). It is still unclear whether PH associated with chronic lung disease (CLD) and SDB is a direct consequence of hypoxemia (as seen in CLD and SDB) or whether this is due to a cascade of events that leads to pulmonary vascular disease that is separate from or out of proportion to the underlying lung injury from existing pulmonary processes.

Patients with OSA who have PH are more likely to be obese, have decreased respiratory function (FEV₁, vital capacity, and FEV₁/VC ratio), and lower oxygen saturation/higher carbon dioxide content in blood (Chaouat et al. Chest. 1996;109[2]:380). These patients frequently present with shortness of breath and dyspnea on exertion. Echocardiogram remains the main screening tool for evaluation of PH. With that said, right-sided heart catheterization remains the gold standard for the diagnosis of all classes of PH; however, use of right-sided heart catheterization in group 3 pulmonary hypertension is reserved for select patients. This is likely because PH in patients with OSA is accepted as a more benign prognostic marker compared with other group 3 forms. Furthermore, patients with OHS are more prone to developing PH and cor pulmonale compared with patients with isolated OSA. OSA with PH has lower survival rates than OSA without PH. Studies showed that patients with OHS tend to do worse than patients with OSA alone (Aljohara et al. J Thorac Dis. 2017;9[3]:779).

 

AHI and PH

Various studies have looked at different polysomnographic variables to understand the relationship between PH and OSA. Initial studies showed that the apnea hypopnea index (AHI) does not predict development of PH among patients with OSA. Decrements in nocturnal oxygen saturation, however, is predictive of the development of PH; the only predictor of developing PH among patients with OSA in one study was time spent with oxygen saturation below 70% during sleep (Wong et al. Eur Arch Otorhinolaryngol. 2017;74:2601). In addition, recent data suggest there is no statistically significant association between age, gender, body mass index, or AHI and chance for development of PH (Wong et al. 2017). It was found that the percentage of time during sleep with oxygen saturation below 90% was significant and independently associated with higher PAP. Furthermore, a recent study demonstrated that patients with moderate to severe OSA (AHI over 15/h) who develop PH tend to have worse hemodynamics (higher PVR and mPAP) and subclinical myocardial damage (evaluated by troponin T), as well as increased ventricular wall stress (assessed by proBNP) when compared with patients with mild OSA (AHI less than 15/h).

Treatment

The mainstay treatment for OSA and OHS is positive airway pressure (PAP). This therapy has been shown to improve sleep and respiratory parameters, including sleep quality, overall quality of life, as well as promote reduction in mean pulmonary arterial pressure. The regular use of noninvasive positive-pressure ventilation has also been shown to reverse daytime hypoxia and hypercapnia, as well as influence inflammatory markers: decrease circulating levels of endothelin-1, interleukin-6, and C-reactive protein, thereby improving vascular endothelial function and reducing platelet activation and aggregation (Yokoe et al. Circulation. 2003;107[8]:1129). Indeed, there is a decrease in mean pulmonary arterial pressure in some patients with long-term daily use of PAP, but, in some patients, both pulmonary and right ventricular dysfunction persists, suggesting vascular remodeling and/or endothelial dysfunction. These findings indicate the need for early recognition of OSA and early treatment for patients, thus preventing remodeling and further development of PH and right ventricular dysfunction. Adequate control of OSA/OHS has important long-term effects on overall health, because it significantly reduces the risk of systemic hypertension, congestive heart failure, arrhythmias, and stroke. It is imperative to control underlying SDB before considering PAH-specific medications to treat PH associated with OSA or OHS unless the patient is demonstrating signs of right-sided heart failure; in such cases, concomitant therapy may be considered upfront. It is recommended that

patients with SDB should have an assessment for PH before starting therapy for their SDB and then again after 3 to 4 months of effective PAP confirmed by device data monitoring. For patients who have persistent PH despite achieving adequate control of their SDB, pulmonary vasodilator therapy may be indicated following standard treatment guidelines for WHO group 1 PAH (Galie et al. J Am Coll Cardiol. 2013;62[suppl 25]:D60–72). Medications that are currently approved for the treatment of PAH have not been well studied in PH associated with SDB and, at present time, the available data do not demonstrate sustained benefit.

Dr. Singhal is a second-year fellow in Pulmonary/Critical Care and Dr. Minkin is Director, Pulmonary Hypertension Program, New York Presbyterian-Brooklyn Methodist Hospital. Dr. Minkin is also Assistant Professor of Clinical Medicine, Weill Cornell Medical College, New York.