Pulmonary Hypertension With COLD and Pulmonary Fibrosis
COPD is associated with a high incidence of pulmonary hypertension, linked with exercise limitation and a worse prognosis.
The prevalence of pulmonary hypertension in COPD is difficult to define as most of the studies have been conducted in patients with severe COPD, candidates for lung volume reduction surgery or lung transplantation. Several studies in patients with severe COPD showed that up to 90% of these patients have a mean pulmonary artery pressure (mPAP) of greater than 20 mmHg, with most ranging between 20 and 35 mmHg. However, subsets of COPD patients (3–5%) have severe pulmonary hypertension and share some similar features with pulmonary arterial hypertension (PAH).
The pathogenesis of pulmonary hypertension in COPD is complex and multifactorial. Destruction of the vascular bed and hypoxemia with pulmonary vasoconstriction has been classically considered to be the major pathogenic mechanism. However, the relationship between hypoxia and mPAP or pulmonary vascular resistance (PVR) is controversial. A recent study evaluating 95 patients with COPD observed that only partial pressure of oxygen in arterial blood (PaO2) was a significant predictor of mPAP. Pathological studies revealed that pulmonary vascular remodeling in COPD is more than just medial hypertrophy from long-lasting hypoxic vasoconstriction, and all vessel wall layers are involved with prominent intimal thickening, medial hypertrophy and muscularization of the small arterioles. Interestingly, similar changes have been reported in nonhypoxic patients with mild COPD and in smokers with no COPD, suggesting that vascular remodeling may be induced by other mechanisms such as tobacco smoke.
Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of pulmonary hypertension in COPD. Karmouty-Quintana et al. using human lung tissue demonstrated increased expression levels of the adenosine A2B receptor and a heightened deposition of hyaluronan (a component of the ECM) in the remodeled vessels of patients with pulmonary hypertension associated with COPD. Furthermore, blockade of adenosine A2B attenuated the development of a pulmonary hypertension phenotype that correlates with reduced levels of HA deposition in the vessels in an animal model of airspace enlargement and pulmonary hypertension. Another interestingly new look on the pathogenesis of pulmonary hypertension associated with COPD demonstrated a negative correlation between leukocyte telomere length and pulmonary hypertension severity in patients with COPD. Furthermore, pulmonary artery smooth muscle cell senescence caused by telomere shortening was found to be an important contributor to the process of pulmonary vascular remodeling that underlies pulmonary hypertension associated with COPD.
Genetic predisposition may explain the development of severe pulmonary hypertension in patients with COPD. A recent small study found a significant association between right ventricular systolic pressure measured by echocardiography in COPD patients and the NOS3-VNTR 4aa or 4ab genotype, which has been related through its effect on nitric oxide to vascular remodeling. The LL polymorphism of the serotonin transporter (5-hydroxy-tryptamine; 5-HTT), which plays a role in smooth muscle hyperplasia and vascular remodeling, was found to be associated with the presence of pulmonary hypertension in hypoxemic COPD patients and correlates with the severity of pulmonary hypertension. Ulasli et al. suggested that COPD patients with L allele of 5-HTT may have higher risk for the development of pulmonary hypertension and patients with LL genotype of 5-HTT may present higher pulmonary artery pressure (PAP). In contrast, the authors reported that eNOS and ACE gene polymorphisms are not associated with the development and severity of pulmonary hypertension in COPD. However, this was a small study including only 30 patients with COPD and pulmonary hypertension diagnosed on echocardiography.
Although severe airways obstruction was classically related to the development of pulmonary hypertension, previous studies demonstrated poor correlation between forced expiratory volume in the first second (FEV1) and mPAP, whereas mPAP was better related to the arterial partial pressure of oxygen and alveolar–arterial oxygen gradient. However, there is still significant variability in the degree of pulmonary hypertension seen in these patients.
Clinically, patients with COPD and severe pulmonary hypertension usually exhibit a distinctive pattern with severe effort dyspnea, mild-to-moderate airflow limitation with severely reduced diffusion capacity for carbon monoxide, severe hypoxemia and hypocapnia.
These patients have limited exercise capacity in part because of the severely elevated PAP, which further limits the reduced exercise capacity caused by the obstructive ventilator impairment. A recent study reported that COPD patients with severe pulmonary hypertension show an exhausted circulatory reserve at the end of exercise with maintained breathing reserve, as opposed to COPD patients with moderate or no pulmonary hypertension who were limited by ventilatory impairment. This study suggested that circulatory impairment in COPD patients with severe pulmonary hypertension markedly adds to the limitation in exercise capacity. Hilde et al. demonstrated that higher resting mPAP is associated with impaired functional capacity (6-min walking distance; 6MWD) independent of demographics, pulmonary capillary wedge pressure and GOLD. The authors reported the peak exercise PVR and pulmonary artery compliance were negatively correlated to the maximum workload or 6MWD, which indirectly suggests that excessive afterloading of the right ventricle would limit the exercise capacity. It may be that the right ventricle limits the exercise capacity only in COPD patients with severe pulmonary hypertension, who present with preserved ventilatory reserve, hypocapnia, hypoxemia and very low mixed venous oxygenation at maximal exercise. These patients might be candidates for trials of targeted therapies with PAH approved drugs.
Pulmonary hypertension in COPD has a negative prognostic effect. Hurdman et al. identified age, DLCO, SvO2 and WHO functional class as independent predictors of survival in a cohort of 101 patients with pulmonary hypertension associated with COPD. SvO2 or less 65% and DLCO or less 27% were considered as a better threshold to define poor outcome in pulmonary hypertension associated with COPD. Interestingly, FEV1, BMI and exercise capacity did not independently predict survival. This finding implies that conventional COPD prognostic models may not apply in patients with pulmonary hypertension associated with COPD. A recent study reported that echocardiographic evidence of pulmonary hypertension is associated with increased 1-year mortality in patients admitted with COPD exacerbation. Furthermore, the presence of pulmonary hypertension was found to be a predictive factor of hospitalization for acute COPD exacerbation, and enlarged pulmonary artery diameter, as detected by computed tomography (CT) scan, predicts the hospitalization caused by acute COPD exacerbation.
Doppler echocardiography is the best method for noninvasive diagnosis of pulmonary hypertension. However, lung hyperinflation may preclude optimal visualization with high rate of inaccurate PAP measurements. Hilde et al. in an echocardiography study showed that impaired right ventricular systolic function, hypertrophy and dilation were present even at a slight increase of mPAP, which indicates an early impact on right ventricular function and structure in patients with COPD.
Recent studies investigate the efficacy of other noninvasive tools. A small study on COPD patients being evaluated for lung transplantation reported that relative pulmonary artery enlargement measured on chest CT scan was correlated to mPAP but not to systolic pulmonary artery pressure (SPAP) and actually outperforms echocardiography for pulmonary hypertension diagnosis Minai et al. found that PaO2, DLCO and FEV1 may be helpful in screening patients for precapillary pulmonary hypertension in severe emphysema, but none is reliably predictive of its presence.
Right heart catheterization (RHC) is the gold standard for the diagnosis of pulmonary hypertension. However, there are no data demonstrating the value of routine use of RHC in patients with advanced COPD.
During RHC, pulmonary artery wedge pressure measurements may be largely affected by swings in the intrathoracic pressure, especially in patients with lung disease. Furthermore, hyperinflation and air-trapping with increased positive end-expiratory pressure (auto-PEEP) may variably affect pulmonary artery wedge pressure by altering intravascular pressures. These changes also depend on lung compliance. Therefore, RHC should be performed meticulously in patients with lung disease and in specific circumstances left ventricular end-diastolic pressure should also be measured.
It should be emphasized that although pulmonary hypertension was found to be mildly elevated, it may markedly increase during exercise or COPD exacerbation because of increasing hypoxemia or the inability of the noncompliant pulmonary vasculature to cope with the increased pulmonary blood flow.
In patients with severe pulmonary hypertension and mild-to-moderate airway obstruction, a major dilemma is whether the pulmonary hypertension is secondary to or concomitant with COPD. COPD is a common disease and development of pulmonary hypertension in such patients may not necessarily be the result of the COPD. Notably, IPAH patients may also display mild-to-moderate ventilatory impairment in the absence of any evidence for lung airway or parenchymal disease, mainly in the form of airway obstruction. Normal or mild airway obstruction, absence or modest abnormalities on chest CT scan and features of exhausted circulatory reserve support group I PAH, whereas moderate-to-severe airway obstruction, characteristic abnormalities on CT scan and exhausted ventilator reserve suggest that the pulmonary hypertension is secondary to COPD.
Long-term oxygen therapy (LTOT) improves survival in hypoxic COPD patients and is associated with a mild improvement in pulmonary hemodynamics. As LTOT treatment does not result in normalization of the increased PAP and reversal of vascular remodeling, the use of PAH approved drugs in patients with COPD and pulmonary hypertension, especially severe pulmonary hypertension, seems appealing. However, vasodilator may worsen gas exchange because of the presence of low ventilation perfusion areas in the lung and interference with the hypoxic vasoconstriction mechanism. Recently, few studies have evaluated the role of PAH approved drugs in these patients population. However, most studies were small and uncontrolled, with controversial results and demonstrated a deleterious effect on gas exchanges. Inhaled therapy may be selective and may improve pulmonary hemodynamics without deterioration of gas exchange; however, long-term clinical trials using inhaled prostanoids have not been reported. Currently, there are no data to support the use of PAH approved therapy in pulmonary hypertension associated with COPD and large randomized controlled trials (RCTs) are needed. An interesting study recently reported that bosentan effectively decreased the endothelin receptor overexpression elicited by cigarette smoke extracts in human pulmonary artery smooth muscle cells and small intrapulmonary arteries. This direct inhibitory effect may support its use in pulmonary hypertension associated with COPD. Other treatment approaches were evaluated in two small studies. Elevated rho-kinase activity has been demonstrated in various animal models of PAH, with rho-kinase inhibitors associated with pulmonary vasodilatation and regression of PAH. Liu et al. reported that fasudil (a rho-kinase inhibitor) increased the number and enhanced the function of the late endothelial progenitor cells in the peripheral blood of COPD patients with pulmonary hypertension and reduced PAP measured by echocardiography. Another small study tested the effect of dehydroepiandrosterone (DHEA), which in animal studies reverses chronic-hypoxia-induced pulmonary hypertension, on eight patients with pulmonary hypertension associated with COPD. DHEA treatment significantly improves 6-min walking test (6MWT) distance, pulmonary hemodynamics and DLCO of patients with pulmonary hypertension associated with COPD, without worsening gas exchange.
Chronic Obstructive Pulmonary Disease
COPD is associated with a high incidence of pulmonary hypertension, linked with exercise limitation and a worse prognosis.
Prevalence
The prevalence of pulmonary hypertension in COPD is difficult to define as most of the studies have been conducted in patients with severe COPD, candidates for lung volume reduction surgery or lung transplantation. Several studies in patients with severe COPD showed that up to 90% of these patients have a mean pulmonary artery pressure (mPAP) of greater than 20 mmHg, with most ranging between 20 and 35 mmHg. However, subsets of COPD patients (3–5%) have severe pulmonary hypertension and share some similar features with pulmonary arterial hypertension (PAH).
Pathogenesis
The pathogenesis of pulmonary hypertension in COPD is complex and multifactorial. Destruction of the vascular bed and hypoxemia with pulmonary vasoconstriction has been classically considered to be the major pathogenic mechanism. However, the relationship between hypoxia and mPAP or pulmonary vascular resistance (PVR) is controversial. A recent study evaluating 95 patients with COPD observed that only partial pressure of oxygen in arterial blood (PaO2) was a significant predictor of mPAP. Pathological studies revealed that pulmonary vascular remodeling in COPD is more than just medial hypertrophy from long-lasting hypoxic vasoconstriction, and all vessel wall layers are involved with prominent intimal thickening, medial hypertrophy and muscularization of the small arterioles. Interestingly, similar changes have been reported in nonhypoxic patients with mild COPD and in smokers with no COPD, suggesting that vascular remodeling may be induced by other mechanisms such as tobacco smoke.
Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of pulmonary hypertension in COPD. Karmouty-Quintana et al. using human lung tissue demonstrated increased expression levels of the adenosine A2B receptor and a heightened deposition of hyaluronan (a component of the ECM) in the remodeled vessels of patients with pulmonary hypertension associated with COPD. Furthermore, blockade of adenosine A2B attenuated the development of a pulmonary hypertension phenotype that correlates with reduced levels of HA deposition in the vessels in an animal model of airspace enlargement and pulmonary hypertension. Another interestingly new look on the pathogenesis of pulmonary hypertension associated with COPD demonstrated a negative correlation between leukocyte telomere length and pulmonary hypertension severity in patients with COPD. Furthermore, pulmonary artery smooth muscle cell senescence caused by telomere shortening was found to be an important contributor to the process of pulmonary vascular remodeling that underlies pulmonary hypertension associated with COPD.
Genetic predisposition may explain the development of severe pulmonary hypertension in patients with COPD. A recent small study found a significant association between right ventricular systolic pressure measured by echocardiography in COPD patients and the NOS3-VNTR 4aa or 4ab genotype, which has been related through its effect on nitric oxide to vascular remodeling. The LL polymorphism of the serotonin transporter (5-hydroxy-tryptamine; 5-HTT), which plays a role in smooth muscle hyperplasia and vascular remodeling, was found to be associated with the presence of pulmonary hypertension in hypoxemic COPD patients and correlates with the severity of pulmonary hypertension. Ulasli et al. suggested that COPD patients with L allele of 5-HTT may have higher risk for the development of pulmonary hypertension and patients with LL genotype of 5-HTT may present higher pulmonary artery pressure (PAP). In contrast, the authors reported that eNOS and ACE gene polymorphisms are not associated with the development and severity of pulmonary hypertension in COPD. However, this was a small study including only 30 patients with COPD and pulmonary hypertension diagnosed on echocardiography.
Clinical Presentation and Significance
Although severe airways obstruction was classically related to the development of pulmonary hypertension, previous studies demonstrated poor correlation between forced expiratory volume in the first second (FEV1) and mPAP, whereas mPAP was better related to the arterial partial pressure of oxygen and alveolar–arterial oxygen gradient. However, there is still significant variability in the degree of pulmonary hypertension seen in these patients.
Clinically, patients with COPD and severe pulmonary hypertension usually exhibit a distinctive pattern with severe effort dyspnea, mild-to-moderate airflow limitation with severely reduced diffusion capacity for carbon monoxide, severe hypoxemia and hypocapnia.
These patients have limited exercise capacity in part because of the severely elevated PAP, which further limits the reduced exercise capacity caused by the obstructive ventilator impairment. A recent study reported that COPD patients with severe pulmonary hypertension show an exhausted circulatory reserve at the end of exercise with maintained breathing reserve, as opposed to COPD patients with moderate or no pulmonary hypertension who were limited by ventilatory impairment. This study suggested that circulatory impairment in COPD patients with severe pulmonary hypertension markedly adds to the limitation in exercise capacity. Hilde et al. demonstrated that higher resting mPAP is associated with impaired functional capacity (6-min walking distance; 6MWD) independent of demographics, pulmonary capillary wedge pressure and GOLD. The authors reported the peak exercise PVR and pulmonary artery compliance were negatively correlated to the maximum workload or 6MWD, which indirectly suggests that excessive afterloading of the right ventricle would limit the exercise capacity. It may be that the right ventricle limits the exercise capacity only in COPD patients with severe pulmonary hypertension, who present with preserved ventilatory reserve, hypocapnia, hypoxemia and very low mixed venous oxygenation at maximal exercise. These patients might be candidates for trials of targeted therapies with PAH approved drugs.
Prognosis
Pulmonary hypertension in COPD has a negative prognostic effect. Hurdman et al. identified age, DLCO, SvO2 and WHO functional class as independent predictors of survival in a cohort of 101 patients with pulmonary hypertension associated with COPD. SvO2 or less 65% and DLCO or less 27% were considered as a better threshold to define poor outcome in pulmonary hypertension associated with COPD. Interestingly, FEV1, BMI and exercise capacity did not independently predict survival. This finding implies that conventional COPD prognostic models may not apply in patients with pulmonary hypertension associated with COPD. A recent study reported that echocardiographic evidence of pulmonary hypertension is associated with increased 1-year mortality in patients admitted with COPD exacerbation. Furthermore, the presence of pulmonary hypertension was found to be a predictive factor of hospitalization for acute COPD exacerbation, and enlarged pulmonary artery diameter, as detected by computed tomography (CT) scan, predicts the hospitalization caused by acute COPD exacerbation.
Diagnosis
Doppler echocardiography is the best method for noninvasive diagnosis of pulmonary hypertension. However, lung hyperinflation may preclude optimal visualization with high rate of inaccurate PAP measurements. Hilde et al. in an echocardiography study showed that impaired right ventricular systolic function, hypertrophy and dilation were present even at a slight increase of mPAP, which indicates an early impact on right ventricular function and structure in patients with COPD.
Recent studies investigate the efficacy of other noninvasive tools. A small study on COPD patients being evaluated for lung transplantation reported that relative pulmonary artery enlargement measured on chest CT scan was correlated to mPAP but not to systolic pulmonary artery pressure (SPAP) and actually outperforms echocardiography for pulmonary hypertension diagnosis Minai et al. found that PaO2, DLCO and FEV1 may be helpful in screening patients for precapillary pulmonary hypertension in severe emphysema, but none is reliably predictive of its presence.
Right heart catheterization (RHC) is the gold standard for the diagnosis of pulmonary hypertension. However, there are no data demonstrating the value of routine use of RHC in patients with advanced COPD.
During RHC, pulmonary artery wedge pressure measurements may be largely affected by swings in the intrathoracic pressure, especially in patients with lung disease. Furthermore, hyperinflation and air-trapping with increased positive end-expiratory pressure (auto-PEEP) may variably affect pulmonary artery wedge pressure by altering intravascular pressures. These changes also depend on lung compliance. Therefore, RHC should be performed meticulously in patients with lung disease and in specific circumstances left ventricular end-diastolic pressure should also be measured.
It should be emphasized that although pulmonary hypertension was found to be mildly elevated, it may markedly increase during exercise or COPD exacerbation because of increasing hypoxemia or the inability of the noncompliant pulmonary vasculature to cope with the increased pulmonary blood flow.
In patients with severe pulmonary hypertension and mild-to-moderate airway obstruction, a major dilemma is whether the pulmonary hypertension is secondary to or concomitant with COPD. COPD is a common disease and development of pulmonary hypertension in such patients may not necessarily be the result of the COPD. Notably, IPAH patients may also display mild-to-moderate ventilatory impairment in the absence of any evidence for lung airway or parenchymal disease, mainly in the form of airway obstruction. Normal or mild airway obstruction, absence or modest abnormalities on chest CT scan and features of exhausted circulatory reserve support group I PAH, whereas moderate-to-severe airway obstruction, characteristic abnormalities on CT scan and exhausted ventilator reserve suggest that the pulmonary hypertension is secondary to COPD.
Treatment
Long-term oxygen therapy (LTOT) improves survival in hypoxic COPD patients and is associated with a mild improvement in pulmonary hemodynamics. As LTOT treatment does not result in normalization of the increased PAP and reversal of vascular remodeling, the use of PAH approved drugs in patients with COPD and pulmonary hypertension, especially severe pulmonary hypertension, seems appealing. However, vasodilator may worsen gas exchange because of the presence of low ventilation perfusion areas in the lung and interference with the hypoxic vasoconstriction mechanism. Recently, few studies have evaluated the role of PAH approved drugs in these patients population. However, most studies were small and uncontrolled, with controversial results and demonstrated a deleterious effect on gas exchanges. Inhaled therapy may be selective and may improve pulmonary hemodynamics without deterioration of gas exchange; however, long-term clinical trials using inhaled prostanoids have not been reported. Currently, there are no data to support the use of PAH approved therapy in pulmonary hypertension associated with COPD and large randomized controlled trials (RCTs) are needed. An interesting study recently reported that bosentan effectively decreased the endothelin receptor overexpression elicited by cigarette smoke extracts in human pulmonary artery smooth muscle cells and small intrapulmonary arteries. This direct inhibitory effect may support its use in pulmonary hypertension associated with COPD. Other treatment approaches were evaluated in two small studies. Elevated rho-kinase activity has been demonstrated in various animal models of PAH, with rho-kinase inhibitors associated with pulmonary vasodilatation and regression of PAH. Liu et al. reported that fasudil (a rho-kinase inhibitor) increased the number and enhanced the function of the late endothelial progenitor cells in the peripheral blood of COPD patients with pulmonary hypertension and reduced PAP measured by echocardiography. Another small study tested the effect of dehydroepiandrosterone (DHEA), which in animal studies reverses chronic-hypoxia-induced pulmonary hypertension, on eight patients with pulmonary hypertension associated with COPD. DHEA treatment significantly improves 6-min walking test (6MWT) distance, pulmonary hemodynamics and DLCO of patients with pulmonary hypertension associated with COPD, without worsening gas exchange.
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