State of artMechanisms of pulmonary hypertension in chronic obstructive pulmonary disease: A pathophysiologic review
Section snippets
Review methodology
The initial search was conducted using OVID Medline (from 1946) with the subject headings “Pulmonary Disease, Chronic Obstructive” and “Pulmonary Hypertension.” All abstracts were assessed for relevance and articles of the relevant studies were retrieved. Subsequent searches utilized the following combinations of subject headings: “Pulmonary Disease, Chronic Obstructive” or “Emphysema” or “Pulmonary Emphysema” or “Respiratory Mechanics” or “Lung Compliance” and “Hypertension, Pulmonary” or
Hypoxia
At present, there is broad agreement that hypoxia contributes to PHT via two mechanisms. First, alveolar (and perhaps low mixed venous saturation) hypoxia causes acute hypoxic pulmonary vasoconstriction of the small muscular pulmonary arteries,14 and in the setting of global hypoxia this mechanism may substantially increase pulmonary vascular resistance (PVR).15 Second, chronic hypoxia contributes to pulmonary vascular remodeling, resulting in intimal thickening and neo-muscularization of the
Hypercapnia/acidosis
Despite early studies showing a relationship between partial pressure of carbon dioxide (PaCO2) and mPAP in COPD subjects,27 the role of hypercapnia in contributing to PHT in COPD is unclear. From a range of physiologic studies exploring this relationship28, 29, 30 it has become apparent that hypercapnia increases cardiac output, which drives an increase in mPAP. However, changes in PVR depend on the balance between the dilatory forces (secondary to capillary recruitment resulting from
Pulmonary hyperinflation
It has been postulated that dynamic lung hyperinflation in COPD may contribute to the development of PHT through a combination of mechanisms, including increased lung volume,29 widened intrathoracic pressure swings,34, 35 cardiac effects,36, 37 altered gas exchange,29, 38 pulmonary vascular remodeling26 and even endothelial dysfunction.39
Many investigators have listed gas trapping and lung hyperinflation among the causes of PHT in COPD,8, 33, 40 but there is a lack of direct supporting
Airway resistance/airway obstruction
Studies have demonstrated a statistical correlation between forced expiratory volume in 1 second (FEV1; as a marker of airway obstruction) and mPAP.20, 44 However, this relationship is not always seen and FEV1 is not universally considered to be an independent predictor of pulmonary arterial pressure.3, 44 Further, Wright and Churg have demonstrated in an animal smoking model that raised pulmonary arterial pressure occurs prior to the development of emphysema.45 Thus, there is currently limited
Destruction of pulmonary vascular bed
It has long been held that emphysematous destruction of the pulmonary vascular bed contributes to the elevation of PAP and is often listed among the mechanisms of PHT in COPD.3, 33 The lack of substantial direct or indirect evidence to support this mechanism is surprising. For example, studies comparing computed tomography lung tissue density with pulmonary hemodynamics have not indicated any significant relationships.8, 46
Furthermore, resection of the pulmonary vascular bed in lung volume
Pulmonary vascular remodeling
A number of pathologic changes have been identified in the pulmonary vessels of patients with COPD-associated PHT, including variable medial hypertrophy, longitudinal muscle deposition, intimal hyperplasia, elastin and collagen deposition, muscularization of the pulmonary arterioles and in situ thrombosis.18, 26 Changes due to pulmonary vascular remodeling may alter the pulmonary vascular responsiveness and contribute to the development of PHT in COPD. However, studies have been inconsistent in
Inflammation
There has been renewed interest in the role of inflammation in the pathogenesis of pulmonary vascular remodeling and endothelial dysfunction in COPD.9 Increased numbers of leukocytes have been identified in the adventitia of muscular pulmonary arteries in COPD subjects compared with smoking controls and healthy controls, but with an inconsistent relationship between the inflammatory infiltrate and intimal thickness.23, 53 Nevertheless, this leads to speculation that inflammation may promote
Endothelial dysfunction
Pulmonary vascular endothelial dysfunction has been demonstrated to occur in idiopathic PAH54 involving numerous pathways, including prostacyclin, nitric oxide and endothelin.55 Although acutely these mediators and pathways may give rise to endothelial dysfunction, over time they contribute to pulmonary vascular remodeling. Endothelial dysfunction has been demonstrated in COPD subjects22, 56, 57 and appears to be mediated by pathways similar to those seen in idiopathic PAH.58, 59, 60 Other
Polycythemia
Polycythemia (with resultant increased blood viscosity) occurs in advanced COPD as a complication of chronic hypoxia. Although it may reflect COPD severity, polycythemia may be reduced by oxygen therapy, potentially masking any association of polycythemia to COPD-associated PHT. Not surprisingly, earlier work has provided inconsistent data regarding this relationship.67, 68, 69 Consequently, the role of polycythemia in the development of PHT remains unclear.
Genetics
Genetic predisposition appears to be important in the development of COPD, but only α1-anti-trypsin deficiency has been clearly shown as causative.70 There also appears to be genetic predisposition to the development of PHT in COPD subjects.9 Genetic polymorphisms of endothelial nitric oxide synthase and 5-hydroxytryptamine have been implicated in pulmonary vascular endothelial dysfunction and remodeling in COPD subjects.64, 71 Furthermore, genetic predisposition for PHT in COPD may also be
“Out-of-proportion” pulmonary hypertension
As discussed previously, PHT is frequently seen in moderate to severe COPD, but it is usually of mild severity.10 Moderate to severe elevations of PAP (i.e., mPAP > 35 mm Hg) have been documented to occur in up to 9.8% of subjects with advanced COPD.33 Patients with mild to moderate COPD (i.e., GOLD Stages I and II) with any severity PHT, and patients with more severe COPD (i.e., GOLD Stages III and IV) and moderate to severe PHT (i.e., PAP > 35 mm Hg) are unexpected. Consequently, such
Conclusions
The etiology of PHT in COPD is complex, multifaceted and due to both pre- and post-capillary mechanisms. Although the strength of the evidence to support the numerous pathogenic mechanisms is variable, this probably highlights that no single mechanism is responsible for PHT in all COPD subjects. Hypoxia clearly plays a pivotal role in the development of PHT in COPD patients, but the presence and magnitude of contributions by other pathogenic mechanisms remain unproven. Table 2 provides a
Disclosure statement
The authors have no conflicts of interests to disclose.
Funding was provided by the National Health and Medical Research Council of Australia (to J.P.W.).
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