REVIEW URRENT C OPINION
Pulmonary hypertension associated with chronic obstructive lung disease and idiopathic pulmonary fibrosis Yochai Adir a and Sergio Harari b
Purpose of review Severe pulmonary hypertension worsens the prognosis of patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). With the aim of better understanding the pathogenesis of this event and identifying the possible targets for therapeutic intervention, a great deal of clinical and translational research is now focused on this relevant field of medicine. Recent findings Some studies that were published last year have helped to better define the clinical and physiological profiles of patients with COPD or IPF and severe pulmonary hypertension. The importance of pulmonary rehabilitation was confirmed, particularly in patients with pulmonary hypertension associated with IPF. Information on the use of drugs approved for the treatment of pulmonary arterial hypertension is still very limited, because of some limitations and selection biases in the studies’ design. New strategies (i.e. the use of fasudil or sepiapterin in pulmonary hypertension associated with IPF) have been evaluated in animal models. Summary Pulmonary hypertension in COPD or IPF may range from mild to severe. When pulmonary hypertension is more advanced, it can drive a poor outcome. Therefore, future studies should focus on this subset. Keywords chronic obstructive pulmonary diseases, combined pulmonary fibrosis emphysema syndrome, idiopathic pulmonary fibrosis, pulmonary artery hypertension, pulmonary hypertension, rehabilitation
INTRODUCTION Pulmonary hypertension may complicate the course of idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and combined pulmonary fibrosis and emphysema (CPFE), and is increasingly recognized as a negative prognostic factor affecting the clinical manifestations, morbidity and mortality. IPF, COPD and CPFE are classified within the WHO group 3 pulmonary hypertension [1 ]. The degree of pulmonary hypertension in most patients will be mild to moderate, but a subgroup of patients will have a severe pulmonary hypertension. In the last 5th World Symposium on pulmonary hypertension [2 ], the following definition was suggested:
COPD=IPF=CPFE with severe PHðmPAP 35 mmHg or mPAP 25 mmHg with low cardiac index ðCI < 2:0 L=min=m2 Þ; severe PH-COPD; severe PH-IPF:
&&
&&
COPD=IPF=CPFE without PH ðmPAP < 25 mmHgÞ COPD=IPF=CPFE with PHðmPAP 25 mmHg; PH-COPD; PH-IPFÞ www.co-pulmonarymedicine.com
a
Pulmonary Division, Faculty of Medicine, Lady Davis Carmel Medical Center, The Technion, Institute of Technology, Haifa, Israel and bU.O. di Pneumologia e UTIR, Servizio di Fisiopatologia Respiratoria e di Emodinamica Polmonare, Ospedale San Giuseppe MultiMedica, Milan, Italy Correspondence to Yochai Adir, MD, Pulmonary Division, Faculty of Medicine, Lady Davis Carmel Medical Center, The Technion, Institute of Technology, 7 Michal Street, Haifa, Israel. Tel: +972 4 8258342; fax: +972 4 8258342; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:414–420 DOI:10.1097/MCP.0000000000000084 Volume 20 Number 5 September 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pulmonary hypertension Adir and Harari
KEY POINTS Pulmonary hypertension in advanced COPD and IPF is common, and usually is mild to moderate. A small subset of patients may have severe pulmonary hypertension which shares some similarities to PAH. The pathogenesis of pulmonary hypertension in IPF and COPD is complex involving structural vascular changes and remodeling, and is not the result of hypoxemia. Pulmonary hypertension in COPD and IPF increased morbidity and mortality. Right heart catheterization is the gold standard for diagnosis. Empirical PAH approved therapy is commonly used without adequate studies to support this approach. Long-term RCT focusing on patients with severe pulmonary hypertension and chronic obstructive or restrictive lung diseases are needed, in order to provide reliable data as to the use of PAH approved drugs.
be the major pathogenic mechanism [5]. However, the relationship between hypoxia and mPAP or pulmonary vascular resistance (PVR) is controversial. A recent study [6] 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 [7 ,8 ]. 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 [9,10]. 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. [11 ] 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 [12]. 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 [13]. 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 [14]. Ulasli et al. [15 ] suggested &
&
&
The focus of this review is to describe the prevalence, pathogenesis, clinical implication and therapeutic approach to patients with pulmonary hypertension associated with COPD and IPF, with emphasis on the recent findings.
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) [2 ,3,4]. &&
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
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&
www.co-pulmonarymedicine.com
415
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Disorders of the pulmonary circulation
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 [16]. 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-tomoderate airflow limitation with severely reduced diffusion capacity for carbon monoxide, severe hypoxemia and hypocapnia [17,18 ]. 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 [19] 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. [20 ] 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 &
&&
416
www.co-pulmonarymedicine.com
oxygenation at maximal exercise. These patients might be candidates for trials of targeted therapies with PAH approved drugs [21 ]. &&
Prognosis Pulmonary hypertension in COPD has a negative prognostic effect [2 ,18 ,22]. Hurdman et al. [18 ] 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 [22]. 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 [23]. &&
&
&
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 [2 ]. Hilde et al. [24 ] 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 [25 ] Minai et al. [26 ] 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 [2 ]. However, there are no data demonstrating &&
&
&
&
&&
Volume 20 Number 5 September 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pulmonary hypertension Adir and Harari
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 airtrapping 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 [27]. 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 [2 ]. 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-tosevere airway obstruction, characteristic abnormalities on CT scan and exhausted ventilator reserve suggest that the pulmonary hypertension is secondary to COPD [2 ]. &&
However, most studies were small and uncontrolled, with controversial results and demonstrated a deleterious effect on gas exchanges [2 ,28]. Inhaled therapy may be selective and may improve pulmonary hemodynamics without deterioration of gas exchange [29]; 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 [30]. Other treatment approaches were evaluated in two small studies. Elevated rhokinase 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. [31] 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 [32] 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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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.
IDIOPATHIC PULMONARY FIBROSIS The occurrence of severe pulmonary hypertension in patients suffering from IPF is a rare event; however, it may significantly affect the clinical outcome. The pathophysiology of pulmonary hypertension in parenchymal lung diseases is attributable to the destruction and distortion of the vascular bed and to hypoxia. Usually, patients present with mild or moderate degrees of pulmonary hypertension; however, a severe pulmonary hypertension, which cannot be solely explained by hypoxia and parenchymal injury, may occasionally develop in patients with IPF [33]. The pathogenesis of this event is still unclear and is an object of controversy. Interesting findings were published last year by Calabrese et al. [34 ], who found that the prevalence of herpes virus infection (as detected by molecular analysis) in the
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Disorders of the pulmonary circulation
lungs of 55 IPF patients was higher than that in the lungs of 44 control patients. Viral infection was also associated with a higher mPAP, suggesting the role of herpes virus in the remodeling of the lung vessels: thus, such hypothesis now takes back to the potential role of HIV and inflammation in the development of HIV-PAH and opens new interesting scenario framework for research. Recently, as already mentioned, the proceedings of the 5th World Symposium on Pulmonary Hypertension, which was held in Nice, France, in February 2013, have been published in the Journal of the American College of Cardiology. The task force on ‘Chronic Lung diseases’ addressed the issue on the appropriateness of considering pulmonary hypertension as disproportionate in relation to the severity of parenchymal lung disease [2 ]. The experts also add three important considerations. In fact, they stated that ‘the ‘‘severe pulmonary hypertension group’’ includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilator reserve underlies the limitation of exercise capacity’. The experts also claimed that ‘for discrimination between group 1 pulmonary hypertension patients with concomitant respiratory abnormalities and group 3 pulmonary hypertension patients (pulmonary hypertension caused by lung disease), patients should be transferred to a center with expertise in both pulmonary hypertension and lung diseases for comprehensive evaluation’. The task force concluded by stating that ‘studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on this severe PH group’ [2 ]. These concerns can also explain the disappointing results of all clinical trials carried out so far in patients with IPF and pulmonary hypertension treated with medications commonly used for PAH (e.g. ambrisentan) [35 ]. In fact, as patients were considered eligible even if they had a slight increase in pulmonary hypertension, two distinct disease phenotypes (one comprising IPF patients with mild-to-moderate pulmonary hypertension secondary to hypoxia and progression of the scarring process because of the fibrotic disarrangement of the vascular bed, and the other one comprising patients who presented with minor or moderate fibrotic alterations, yet had severe pulmonary hypertension) were included in the study and, thus, selection bias might have occurred. The role of functional tests for the screening of pulmonary hypertension in IPF was evaluated in &&
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two interesting studies. In a study conducted on 38 patients with IPF, van der Plas et al. [36] evaluated the predictive value of noninvasive exercise parameters that were associated with elevated SPAP and survival. The authors found that V0 E/V0 CO2 was the only cardiopulmonary exercise test (CPET) parameter associated with elevated systolic PAP (as evaluated by echocardiography) and appeared as a potentially useful noninvasive screening test to be used in IPF patients for the early detection of pulmonary hypertension development. Gla¨ser et al. [37 ] attained similar results in a multicenter study conducted on 135 IPF patients who underwent CPET, right heart catheterization, and pulmonary function test during their initial evaluation. Pulmonary hypertension (which was diagnosed in 73 patients) was best predicted by gas exchange efficiency during exercise and peak oxygen uptake; in addition, oxygen uptake at peak exercise was a good predictor of survival. The combined pulmonary emphysema and fibrosis (CPFE) syndrome, including radiological findings of upper lobe emphysema and lower lobe fibrosis, typically occurs in male smokers and is characterized by subnormal spirometry, severely impaired DLCO and poor prognosis [38]. CPFE has also been described as a distinct pulmonary manifestation within the spectrum of CTD-associated lung diseases, such as rheumatoid arthritis and systemic scleroderma [39]. Cottin et al. [38] reported that 47% of CPFE patients had systolic PAP of at least 45 mmHg, as estimated by echocardiography. Pulmonary hypertension seems to be more frequent in patients with CPFE than in IPF patients without emphysema and is a determinant of their prognosis [40]. Drugs used for group I PAH patients such as bosentan, sildenafil or inhaled iloprost did not show any significant beneficial effect in these patients [41]. Nowadays, the only supportive therapy for these patients is oxygen therapy and an early referral for lung transplantation is strongly recommended [42 ]. The role of pulmonary rehabilitation in patients with interstitial lung diseases has been the subject of long-standing controversy; recently, a study published in the European Respiratory Journal has helped clarify the issue. The authors evaluated 402 consecutive patients with interstitial lung disease who were admitted to a specialized pulmonary rehabilitation center (over a period of 12 months): they observed that the 6-MWT markedly improved (by 46 3 m) after 30 days of rehabilitation, whereas dyspnea rating did not change and lung function tests only showed marginal improvement. In addition, patients with signs of pulmonary hypertension also seemed to benefit from rehabilitation [43 ]. &
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Volume 20 Number 5 September 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pulmonary hypertension Adir and Harari Table 1. Management of pulmonary hypertension in the setting of chronic lung disease mPAP
Pulmonary hypertension associated with chronic obstructive lung disease and idiopathic pulmonary fibrosis Yochai Adir a and Sergio Harari b
Purpose of review Severe pulmonary hypertension worsens the prognosis of patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). With the aim of better understanding the pathogenesis of this event and identifying the possible targets for therapeutic intervention, a great deal of clinical and translational research is now focused on this relevant field of medicine. Recent findings Some studies that were published last year have helped to better define the clinical and physiological profiles of patients with COPD or IPF and severe pulmonary hypertension. The importance of pulmonary rehabilitation was confirmed, particularly in patients with pulmonary hypertension associated with IPF. Information on the use of drugs approved for the treatment of pulmonary arterial hypertension is still very limited, because of some limitations and selection biases in the studies’ design. New strategies (i.e. the use of fasudil or sepiapterin in pulmonary hypertension associated with IPF) have been evaluated in animal models. Summary Pulmonary hypertension in COPD or IPF may range from mild to severe. When pulmonary hypertension is more advanced, it can drive a poor outcome. Therefore, future studies should focus on this subset. Keywords chronic obstructive pulmonary diseases, combined pulmonary fibrosis emphysema syndrome, idiopathic pulmonary fibrosis, pulmonary artery hypertension, pulmonary hypertension, rehabilitation
INTRODUCTION Pulmonary hypertension may complicate the course of idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and combined pulmonary fibrosis and emphysema (CPFE), and is increasingly recognized as a negative prognostic factor affecting the clinical manifestations, morbidity and mortality. IPF, COPD and CPFE are classified within the WHO group 3 pulmonary hypertension [1 ]. The degree of pulmonary hypertension in most patients will be mild to moderate, but a subgroup of patients will have a severe pulmonary hypertension. In the last 5th World Symposium on pulmonary hypertension [2 ], the following definition was suggested:
COPD=IPF=CPFE with severe PHðmPAP 35 mmHg or mPAP 25 mmHg with low cardiac index ðCI < 2:0 L=min=m2 Þ; severe PH-COPD; severe PH-IPF:
&&
&&
COPD=IPF=CPFE without PH ðmPAP < 25 mmHgÞ COPD=IPF=CPFE with PHðmPAP 25 mmHg; PH-COPD; PH-IPFÞ www.co-pulmonarymedicine.com
a
Pulmonary Division, Faculty of Medicine, Lady Davis Carmel Medical Center, The Technion, Institute of Technology, Haifa, Israel and bU.O. di Pneumologia e UTIR, Servizio di Fisiopatologia Respiratoria e di Emodinamica Polmonare, Ospedale San Giuseppe MultiMedica, Milan, Italy Correspondence to Yochai Adir, MD, Pulmonary Division, Faculty of Medicine, Lady Davis Carmel Medical Center, The Technion, Institute of Technology, 7 Michal Street, Haifa, Israel. Tel: +972 4 8258342; fax: +972 4 8258342; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:414–420 DOI:10.1097/MCP.0000000000000084 Volume 20 Number 5 September 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pulmonary hypertension Adir and Harari
KEY POINTS Pulmonary hypertension in advanced COPD and IPF is common, and usually is mild to moderate. A small subset of patients may have severe pulmonary hypertension which shares some similarities to PAH. The pathogenesis of pulmonary hypertension in IPF and COPD is complex involving structural vascular changes and remodeling, and is not the result of hypoxemia. Pulmonary hypertension in COPD and IPF increased morbidity and mortality. Right heart catheterization is the gold standard for diagnosis. Empirical PAH approved therapy is commonly used without adequate studies to support this approach. Long-term RCT focusing on patients with severe pulmonary hypertension and chronic obstructive or restrictive lung diseases are needed, in order to provide reliable data as to the use of PAH approved drugs.
be the major pathogenic mechanism [5]. However, the relationship between hypoxia and mPAP or pulmonary vascular resistance (PVR) is controversial. A recent study [6] 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 [7 ,8 ]. 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 [9,10]. 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. [11 ] 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 [12]. 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 [13]. 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 [14]. Ulasli et al. [15 ] suggested &
&
&
The focus of this review is to describe the prevalence, pathogenesis, clinical implication and therapeutic approach to patients with pulmonary hypertension associated with COPD and IPF, with emphasis on the recent findings.
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) [2 ,3,4]. &&
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
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-pulmonarymedicine.com
415
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Disorders of the pulmonary circulation
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 [16]. 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-tomoderate airflow limitation with severely reduced diffusion capacity for carbon monoxide, severe hypoxemia and hypocapnia [17,18 ]. 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 [19] 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. [20 ] 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 &
&&
416
www.co-pulmonarymedicine.com
oxygenation at maximal exercise. These patients might be candidates for trials of targeted therapies with PAH approved drugs [21 ]. &&
Prognosis Pulmonary hypertension in COPD has a negative prognostic effect [2 ,18 ,22]. Hurdman et al. [18 ] 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 [22]. 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 [23]. &&
&
&
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 [2 ]. Hilde et al. [24 ] 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 [25 ] Minai et al. [26 ] 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 [2 ]. However, there are no data demonstrating &&
&
&
&
&&
Volume 20 Number 5 September 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pulmonary hypertension Adir and Harari
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 airtrapping 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 [27]. 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 [2 ]. 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-tosevere airway obstruction, characteristic abnormalities on CT scan and exhausted ventilator reserve suggest that the pulmonary hypertension is secondary to COPD [2 ]. &&
However, most studies were small and uncontrolled, with controversial results and demonstrated a deleterious effect on gas exchanges [2 ,28]. Inhaled therapy may be selective and may improve pulmonary hemodynamics without deterioration of gas exchange [29]; 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 [30]. Other treatment approaches were evaluated in two small studies. Elevated rhokinase 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. [31] 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 [32] 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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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.
IDIOPATHIC PULMONARY FIBROSIS The occurrence of severe pulmonary hypertension in patients suffering from IPF is a rare event; however, it may significantly affect the clinical outcome. The pathophysiology of pulmonary hypertension in parenchymal lung diseases is attributable to the destruction and distortion of the vascular bed and to hypoxia. Usually, patients present with mild or moderate degrees of pulmonary hypertension; however, a severe pulmonary hypertension, which cannot be solely explained by hypoxia and parenchymal injury, may occasionally develop in patients with IPF [33]. The pathogenesis of this event is still unclear and is an object of controversy. Interesting findings were published last year by Calabrese et al. [34 ], who found that the prevalence of herpes virus infection (as detected by molecular analysis) in the
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Disorders of the pulmonary circulation
lungs of 55 IPF patients was higher than that in the lungs of 44 control patients. Viral infection was also associated with a higher mPAP, suggesting the role of herpes virus in the remodeling of the lung vessels: thus, such hypothesis now takes back to the potential role of HIV and inflammation in the development of HIV-PAH and opens new interesting scenario framework for research. Recently, as already mentioned, the proceedings of the 5th World Symposium on Pulmonary Hypertension, which was held in Nice, France, in February 2013, have been published in the Journal of the American College of Cardiology. The task force on ‘Chronic Lung diseases’ addressed the issue on the appropriateness of considering pulmonary hypertension as disproportionate in relation to the severity of parenchymal lung disease [2 ]. The experts also add three important considerations. In fact, they stated that ‘the ‘‘severe pulmonary hypertension group’’ includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilator reserve underlies the limitation of exercise capacity’. The experts also claimed that ‘for discrimination between group 1 pulmonary hypertension patients with concomitant respiratory abnormalities and group 3 pulmonary hypertension patients (pulmonary hypertension caused by lung disease), patients should be transferred to a center with expertise in both pulmonary hypertension and lung diseases for comprehensive evaluation’. The task force concluded by stating that ‘studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on this severe PH group’ [2 ]. These concerns can also explain the disappointing results of all clinical trials carried out so far in patients with IPF and pulmonary hypertension treated with medications commonly used for PAH (e.g. ambrisentan) [35 ]. In fact, as patients were considered eligible even if they had a slight increase in pulmonary hypertension, two distinct disease phenotypes (one comprising IPF patients with mild-to-moderate pulmonary hypertension secondary to hypoxia and progression of the scarring process because of the fibrotic disarrangement of the vascular bed, and the other one comprising patients who presented with minor or moderate fibrotic alterations, yet had severe pulmonary hypertension) were included in the study and, thus, selection bias might have occurred. The role of functional tests for the screening of pulmonary hypertension in IPF was evaluated in &&
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two interesting studies. In a study conducted on 38 patients with IPF, van der Plas et al. [36] evaluated the predictive value of noninvasive exercise parameters that were associated with elevated SPAP and survival. The authors found that V0 E/V0 CO2 was the only cardiopulmonary exercise test (CPET) parameter associated with elevated systolic PAP (as evaluated by echocardiography) and appeared as a potentially useful noninvasive screening test to be used in IPF patients for the early detection of pulmonary hypertension development. Gla¨ser et al. [37 ] attained similar results in a multicenter study conducted on 135 IPF patients who underwent CPET, right heart catheterization, and pulmonary function test during their initial evaluation. Pulmonary hypertension (which was diagnosed in 73 patients) was best predicted by gas exchange efficiency during exercise and peak oxygen uptake; in addition, oxygen uptake at peak exercise was a good predictor of survival. The combined pulmonary emphysema and fibrosis (CPFE) syndrome, including radiological findings of upper lobe emphysema and lower lobe fibrosis, typically occurs in male smokers and is characterized by subnormal spirometry, severely impaired DLCO and poor prognosis [38]. CPFE has also been described as a distinct pulmonary manifestation within the spectrum of CTD-associated lung diseases, such as rheumatoid arthritis and systemic scleroderma [39]. Cottin et al. [38] reported that 47% of CPFE patients had systolic PAP of at least 45 mmHg, as estimated by echocardiography. Pulmonary hypertension seems to be more frequent in patients with CPFE than in IPF patients without emphysema and is a determinant of their prognosis [40]. Drugs used for group I PAH patients such as bosentan, sildenafil or inhaled iloprost did not show any significant beneficial effect in these patients [41]. Nowadays, the only supportive therapy for these patients is oxygen therapy and an early referral for lung transplantation is strongly recommended [42 ]. The role of pulmonary rehabilitation in patients with interstitial lung diseases has been the subject of long-standing controversy; recently, a study published in the European Respiratory Journal has helped clarify the issue. The authors evaluated 402 consecutive patients with interstitial lung disease who were admitted to a specialized pulmonary rehabilitation center (over a period of 12 months): they observed that the 6-MWT markedly improved (by 46 3 m) after 30 days of rehabilitation, whereas dyspnea rating did not change and lung function tests only showed marginal improvement. In addition, patients with signs of pulmonary hypertension also seemed to benefit from rehabilitation [43 ]. &
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Pulmonary hypertension Adir and Harari Table 1. Management of pulmonary hypertension in the setting of chronic lung disease mPAP
