Rahaghi, Farbod N. MD, PhD*; van Beek, Edwin J.R. MD, PhD†; Washko, George R. MD*
Chronic obstructive pulmonary disease (COPD) is a syndrome encompassing a number of phenotypic subtypes with differing clinical features. These comorbid processes may be due to a mechanical interdependence with the lung (ie, hyperinflation and impaired ventricular filling), a localized or systemic inflammatory response to chronic tobacco smoke exposure (ie, atherosclerosis, cachexia), or potentially an admixture of the two.1 It is clear, however, that the presence and severity of such comorbidities has a significant impact on a patient’s health status and mortality, and a better understanding of the prevalence and etiology of such conditions may improve medical care. One such condition that has long been associated with increased health care costs and mortality in smokers is right-sided heart dysfunction and pulmonary vascular disease.2 Despite 50 years of clinical observations supporting this contention, however, there are still only limited tools available for assessing pulmonary vascular remodeling in smokers. The joint appearance of coronary artery disease in COPD, presenting either with cardiac or with pulmonary symptoms, is also being increasingly recognized as another potential manifestation of the relationship between COPD and circulation.3,4
The process by which chronic tobacco smoke exposure leads to pulmonary vascular remodeling is not clear. It has been observed clinically in subjects with severe emphysema and histopathologically even in smokers with normal lung function.5 Whereas the former may be due to compression of the intraparenchymal vasculature or even pruning of the vessels, the latter likely represents an inflammatory process that could be the precursor for clinically significant hemodynamic changes.6 Given the multitude of causes for this condition and the generally modest resultant increase in pulmonary arterial pressure, clinical and therapeutic investigation in this heterogenous cohort is challenging.
Thoracic imaging is playing an increasingly central role in screening for and monitoring pulmonary vascular disease and has potential to be used in a complementary manner with functional studies such as right heart catheterization (RHC). Such imaging includes assessment of extraparenchymal and intraparenchymal pulmonary vascular morphology, regional lung perfusion, and both right and left ventricular (LV) function. This article provides a brief overview of the mechanisms that may contribute to pulmonary vascular remodeling in smokers, followed by a more detailed description of the imaging techniques that are increasingly being used to refine our understanding of this disease. In addition, it offers a brief overview of the known interplay between COPD and coronary artery disease.
CLINICAL IMPLICATIONS OF PULMONARY VASCULAR DISEASE IN COPD
Estimates of the prevalence of clinically significant pulmonary vascular disease in patients with moderate to severe COPD ranges from 25% to >50%.2 For example, one study found that 63 of 105 patients in whom the right ventricular (RV) systolic pressure was estimated had pulmonary hypertension (PH).7 In another study, of the 215 patients with severe COPD referred for surgical therapy who were receiving cardiac catheterizations, 50% had elevated pulmonary artery (PA) pressure levels.8 In all, 91% of patients catheterized as part of the National Emphysema Treatment Trial had PA systolic pressures >20 mm Hg.9
Most patients with PH in COPD are categorized as mild, with one study finding 13.5% of patients with elevated pulmonary pressure >35 mm Hg8 and another finding 5.8% with more than mild elevation of pulmonary pressure. It is important, however, to consider the effect of mild PH when superimposed on the already existing activity limitations caused by COPD. In addition, resting PH may significantly underestimate the effect of PH on exercise tolerance in patients with COPD.10
Despite the heterogenous prevalence of PH, it is well known that it worsens exercise tolerance and is a predictor of hospitalization and mortality.11–13 Treatment with oxygen has been thought to improve at least the pulmonary vasoconstrictive effect of hypoxemia in COPD patients; however, despite treatment with long-term oxygen, PH continues to be predictive of mortality. The relationship between mortality and PH may in part be due to the observation that pulmonary pressure tends to particularly worsen during COPD exacerbations. The relationship between PH and other cardiac morbidities associated with COPD remains difficult to quantify.
MECHANISMS OF CARDIOPULMONARY COUPLING IN COPD
Increased pulmonary vascular resistance (PVR) and the accompanying RV dysfunction define a specific pathophysiological entity, cor pulmonale. The relationship of this process with airway disease, its selective progression, and the coupling of pulmonary vascular remodeling to RV failure remain areas of intense research.
Initial studies of pulmonary vascular disease in smokers focused on the mechanical effects of emphysema and hyperinflation on perfusion. This is thought to predominantly affect the more compressible vasculature, such as the alveolar capillary beds. Despite their peripheral anatomic location, interruption of blood flow at these sites has the potential for significant contribution to the overall vascular resistance.14 More recent data from the National Emphysema Treatment Trial, however, suggest that a reduction in hyperinflation through surgical lung volume reduction does not systematically result in a significant improvement in hemodynamics.15,16 It is possible that, although this mechanism plays a role in the development of vascular disease, it has led to irreversible changes in patients eligible for lung volume reduction surgery. Alternatively, surgical excision of intact vascular beds may in some cases offset any improvements in PVR caused by a reduction in vessel compression.
Other causes of increased PVR include hypoxemia and hypercapnia. These processes, often found in patients with sleep-disordered breathing and more severe expiratory airflow obstruction, appear to act synergistically to promote pulmonary vasoconstriction and remodeling. Under normoxic conditions, PVR will return to normal after transient changes in O2 and CO2. It has been suggested that prolonged exposure to hypoxemia may lead to irreversible remodeling of the vasculature; however, clinical observations suggest that the administration of supplemental oxygen attenuates the progression of PH in COPD. Additional factors such as tissue destruction with emphysema, increased viscosity due to polycythemia, and worsening acidosis may all contribute to the worsening PH.17
Despite the number of potential changes in the vascular environment associated with COPD, the irreversible remodeling of the pulmonary vasculature is thought to be the key common pathway marking disease progression.6,18 This process of remodeling has been extensively described and involves multiple stages thought to begin with endothelial dysfunction.19 Tobacco smoke exposure initiates an inflammatory cascade that results in thickening of the vessel walls (intimal hyperplasia), deposition of collagen, and ultimately in smooth muscle cell proliferation (Fig. 1).20 It is thought that this process precedes the development of PH in COPD6,18 as such vascular changes are also noted in smokers with normal lung function.5
Despite the presence of progressive vascular remodeling, the extent of PH and ventricular failure remains difficult to predict from the degree of vascular remodeling on histopathology.21 In addition, it has been noted that aberrant angiogenesis may play an additional role in increased PVR22 and that disturbance of the molecular constituents of the pulmonary vascular bed may play a key role in the development and progression of COPD.23,24 Recently, it was further appreciated that COPD may be considered a systemic disease and that impairments in metabolism and inflammatory cascades as a whole may lead to the many manifestations of this disease, including vascular changes and right heart failure, all of which may evolve together.23 For example, a study on 157 COPD patients showed a correlation between arterial stiffness as measured in the upper limb and the computed tomography (CT)-based extent of emphysema.18 In addition, Maclay et al25 demonstrated that there is systemic elastin degradation in COPD, which leads to loss of lung parenchyma and also has effects on the vasculature, with increased peripheral resistance, and on the skin, with loss of elasticity. All these effects compound on the increased PVR and right heart strain.
DIAGNOSIS AND MONITORING OF PULMONARY VASCULAR DISEASE IN COPD: ROLE OF IMAGING
RHC is the gold standard for the diagnosis of pulmonary vascular disease, but its invasiveness precludes its use in large study cohorts. Spirometry is used to diagnose COPD and monitor disease progression; however, studies have shown that the degree of expiratory airflow obstruction in smokers is neither sensitive nor specific for the presence of pulmonary vascular disease.17 The diffusion length of carbon monoxide can be reduced because of pulmonary vascular disease, but it is not reliable when emphysema is also present, which may alter the diffusion length of carbon monoxide independently.26 Imaging may provide a noninvasive tool for assessing pulmonary vascular morphology, lung perfusion, inflammation, and cardiac coupling. The following is a brief overview of multiple imaging modalities divided into the study of the RV, the pulmonary vascular anatomy (both proximal and distal), and finally imaging of lung perfusion.
Imaging of the RV
The hallmark radiographic findings suggestive of emphysema and hyperinflation include narrowing of the cardiac silhouette, suggestive of underfilling of the cardiac chambers.23 A subset of smokers, however, is found to have cardiomegaly with dilation of the RV. Although radiographs are insensitive to the detection of early-stage disease, it was historically well understood that by the time cardiomegaly is evident on conventional radiographs the prognosis was fairly poor.
The advent and availability of the echocardiogram has revolutionized screening and the diagnosis of PH in patients with COPD. Specifically, estimations of RV systolic pressure using tricuspid regurgitation27 have been explored extensively in patients with COPD.28,29 Most often, patients receive an echocardiogram as part of a workup for cardiac ischemic disease, heart failure, or dyspnea that appears out of proportion to their COPD. There remains concern, however, that echocardiography is inaccurate in detecting PH in patients with more severe COPD.30 This inaccuracy may be in part due to the rapid pressure changes in the chest cavity in the presence of significant parenchymal lung disease as well as inaccuracy introduced by increased distance between the probe and the heart.26,30
In addition to providing an estimate of pulmonary pressures, echocardiography has the advantage of providing a functional assessment of the RV. A decrease in RV ejection fraction and evidence of RV or right atrial dilation may be indicative of progressive right-sided heart failure and may prompt more aggressive treatment or further investigation by RHC. Recently, other more specific cardiac imaging markers have gained more widespread use in the assessment of PH. For example, the tricuspid annular plane systolic excursion, the distance travelled by the wall of the RV as defined by the plane of the tricuspid valve, is measured during systole31 and is thought to be a more reliable assessment of RV function compared with ejection fraction alone.32,33 Another functional echocardiographic parameter, the Myocardial Performance Index (also referred to as the Tei index), has been further developed from the concept of assessing the time that the right heart spends in isovolumetric contraction and isovolumetric relaxation compared with the time it spends actually pumping blood.34 This method has been studied in PH patients and has been found to have good prognostic potential.34,35
Despite such advances in echocardiography, there remains significant concern about not capturing the full mechanical effect of the pressure-volume relationship that governs cardiac function with a simple 2-dimensional (2D) geometric model of the RV. Such concerns may be addressed using 3D echocardiography36 and additional techniques such as tissue Doppler imaging, with the latter being leveraged to quantify the velocity of cardiac contraction and ejection of blood from the heart.37
Another more recently developed technique, speckle tracking, takes advantage of the stable tissue-based acoustic patterns that form, which do not change their relationship with respect to each other significantly during cardiac motion (Fig. 2).38 These natural markers or “speckles” are then tracked through the cardiac cycle, giving a representation of muscle movement throughout the cardiac chamber. Both Doppler tissue imaging and the refined speckle tracking can be used to estimate not only chamber anatomy but also a 2D or 3D strain pattern for the cardiac muscle.39 These dynamic measurements of strain complement measurements of chamber size in providing a more complete mechanical view of the right heart chamber, including estimation of pressure-volume relationships,40 and are currently under investigation for short-term monitoring and long-term prognostication in pulmonary vascular disease.41,42
Although echocardiograms have become widely available and are the standard for noninvasive monitoring of RV function, recent advances in cardiac magnetic resonance imaging (MRI) have made it a fast-growing alternative. Cardiac MRI naturally lends itself to 3D mapping of cardiac structure and function, and changes such as increases in RV mass and decreases in stroke volume can be readily quantified. Recently, it was observed that during exercise the RV stroke volume response was reduced in patients with COPD, likely due to exercise-induced increases in pulmonary vascular pressure (Fig. 3).44 These signs of pressure overload detectable by cardiac MRI may even be present before decreased ejection fraction is noted.45 For example, an index of adaptive change in RV measured by RV mass divided by RV end diastolic volume was significantly increased in mildly hypoxemic COPD patients as compared with normal controls, despite there being no difference in RV ejection fraction or estimated pulmonary pressure.43
The MRI data can further be used to estimate cardiac pressure and PVR.46 Other more sophisticated measures of cardiac myocyte workload, such as the kinetic energy contained in the muscle walls, can be derived.47 Finally, phase contrast methods can be used to estimate blood flow and can be combined with RHC to give a complete quantitative mechanical description of right heart function and its coupling to the pulmonary vasculature.48 Parameters such as PA capacitance, elasticity, distensibility, RV ejection fraction, RV end systolic volume, and RV work index can all be monitored simultaneously. Using these techniques, PA stiffness predicts RV dysfunction even when accounting for increased pulmonary pressure, suggesting that RV dysfunction may be driven in part by pulsatile workload.48
Imaging of the Pulmonary Vasculature
Early angiographic studies of the lungs of smokers suggested that emphysema was associated with distal vascular narrowing and pruning.5,20,49,50 Although providing some of the first in vivo assessments of pulmonary vascular morphology, such techniques are limited in the subjective data that they may provide. Multidetector CT (MDCT) scanning has made possible the volumetric acquisition of isotropic data in a single breath-hold. This improved acquisition time, resolution, and noise reduction, combined with increasing capabilities in storage and postprocessing software, has made this technology ideal for objective assessments of proximal and distal vascular structure.
Even in the early era of CT scans, precise measurements of the proximal PA were noted to be useful in predicting PH.51 This observation has been further refined by dividing the PA diameter by the diameter of the descending aorta, finding not only the presence of pulmonary arterial enlargement but also good correlation with invasive hemodynamic measurements.52 The result of these studies has yielded the general clinically used heuristic that a PA to aortic diameter ratio >1 should raise suspicion for clinically relevant PH. In a large multicenter trial with >3400 patients with COPD, analysis of this ratio was shown to be correlated with the frequency of exacerbations (Fig. 4).53
More dynamic assessments of proximal vascular morphology, such as PA distensibility, have been demonstrated to be predictive of the degree of pulmonary vascular disease,54,55 including in subjects with COPD.56 Although the exact pathophysiological sequence leading to changes in the size and mechanical properties of the proximal vasculature remains to be elucidated, such changes may precede the development of RV dysfunction or even be a risk factor for its development. Decreased vascular distensibility may lower the efficiency of the heart by mechanically decoupling the RV from the arterial bed.57,58
Quantitative assessment of microvascular morphology is generally beyond the resolution of most imaging modalities. Although gadolinium-enhanced MRI may provide measures of alveolar capillary perfusion, it cannot provide insight into the capillary structure. However, distal remodeling and luminal occlusion eventually lead to pruning and occlusion of more proximal vessels, and these can be visualized using CT and pulmonary angiography.59 This relationship was first leveraged by Matsuoka et al,60 who developed a technique for measuring the vascular cross-sectional area (CSA) on nonvolumetric axial high-resolution CT data in smokers. By limiting the structures of interest to those that appear circular in the axial plane, they were able to assess the aggregate CSA of vessels of different sizes. Using CT and RHC data from the National Emphysema Treatment Trial, the total CSA of vessels <5 mm2 was shown to correlate with pulmonary arterial pressures in patients with severe emphysema. Current MDCT technology allows volumetric acquisition and isotropic reconstruction of structural data in the chest, and it is now possible to objectively assess vascular 3D structures. Advanced postprocessing techniques have been developed that can identify blood vessels and the relative blood vessel volume as a function of aggregate vascular CSA.61 This measurement has been shown to have clinical implications in smokers beyond standard spirometric measures of lung function (Fig. 5).62 These tools may provide a basis for monitoring disease progression and treatment response using widely available imaging modalities in an anatomic site that is closer to where much of the pathophysiology may be taking place.
Functional Imaging: Perfusion
Pulmonary angiography has served as the gold standard for assessing proximal pulmonary anatomy as well as for providing insight into the relative perfusion of the various lung segments.63 It is an invasive procedure that requires placement of an RHC, followed by the fluoroscopic visualization of contrast medium injected directly into the pulmonary arteries (Fig. 6). Although this has significant clinical utility in the assessment of pulmonary embolism and extrinsic compression of the central vessels, it is limited to a series of 2D projections of 3D data, and the need for placement of an RHC precludes its use in large-scale studies.
With the advent of CT angiography and MR angiography, contrast injections are followed by high-resolution image acquisition and postprocessing, which give a similar visualization of the pulmonary vessels receiving blood (Fig. 7).64,65 However, because conventional angiography provides an animation of blood filling of the pulmonary vasculature, it can yield a nonquantitative but visual understanding of the relative perfusion of different segments.
Dual-energy CT imaging leverages tissue-specific absorption of photons and 2 sources of radiation at different energies to produce an image that can differentiate structures not discernable on standard CT scanning.66 In the lung, this can be exploited to measure the degree of penetration of contrast into the tissue and thus acquire a perfusion map of the lungs. Dual-energy CT scanning shows promise in the study of perfusion67 and has been explored in applications such as detection of pulmonary emboli and chronic thromboembolic disease (Fig. 8).69,70 This technique has also been applied in smokers, leading to the finding that lung perfusion is compromised in regions of emphysema proportional to the degree of parenchymal destruction.71 The use of inhaled contrast agents such as hyperpolarized noble gases also allows for direct observation ventilation. As a contrast agent, 129-xenon has the added benefit of being freely diffusible across that alveolar capillary boundary, which further enables assessment of the most basic function of the lung—ventilation and perfusion matching in health and disease.72,73
Similar to MDCT, contrast-enhanced MRI can be used to assess regional lung perfusion. With MRI, the progressive dilution of contrast can be followed, from which multiple markers of tissue perfusion can be derived, including time of transit of blood through the pulmonary circulation, pulmonary blood flow, and pulmonary blood volume (Fig. 9).74 This has been shown to correlate with disease severity in patients with PH.75 In addition, some correlation has been shown with invasive hemodynamic measurements in PH,76 and this method has also been demonstrated to be useful in distinguishing between patients with group 1 PH and those with chronic thromboembolic disease.77 For more information on this technique, also see the accompanying article by Swift and colleagues in this issue.
Another method that may be useful for quantifying perfusion is the use of radioisotope 15-oxygen to assess the degree of perfusion. Since the development of positron emission tomography, it has been investigated as a tool for studying the pulmonary vasculature78 and more recently to quantify parenchymal perfusion abnormalities in patients with asthma, pulmonary embolism, and COPD.79,80 One advantage of positron emission tomography scanning is that it allows for temporal monitoring of perfusion and ventilation during both quiescent observation and after therapeutic intervention (Fig. 10).
TREATMENT OF PULMONARY VASCULAR DISEASE IN COPD
Because of the known link between hypoxemia and pulmonary vasoconstriction, continuous oxygen therapy has been extensively studied as a therapeutic modality for PH in COPD. This is particularly true if hypoxemia is worsened by sleep-disordered breathing at night. Oxygen therapy has been shown to stabilize the progression of PH despite worsening airway disease and to offer minor improvement in hemodynamics81 as well as exercise tolerance.82 The treatment effects, however, have not led to complete amelioration of symptoms and progression, leading to a search for better therapeutic options.
Treatment with medications used in pulmonary arterial hypertension (World Health Organization group 1) has not yet been shown to be consistently beneficial in COPD patients. There have been conflicting reports of the utility of cyclooxygenase inhibitors in this context.83 An early small trial of prostacyclin in COPD patients in acute respiratory failure did not demonstrate improvement,84 but animal models have suggested that prostacyclin may have a protective effect in the development of PH in COPD.85 In addition, there has been a case report of prostacyclin being used in a COPD patient to treat disproportionate PH.86 A clinical trial of Bosentan, an endothelin antagonist FDA approved for the treatment of pulmonary arterial hypertension, did not show improvement in hemodynamics, functional capacity, or quality of life.87 Currently, no specific medication is FDA approved for use in PH in COPD.
Surgical treatment with lung volume reduction surgery can help relieve obstructive airway disease hyperinflation. However, there is no evidence that lung volume reduction surgery improves hemodynamics, although by this advanced disease stage vascular remodeling may be irremediable16 leaving lung transplantation as the only therapeutic option.88
Currently, the role of imaging in the treatment of PH in COPD has been limited to monitoring the progression of PH and the development of RV dysfunction as discussed above. Dynamic perfusion imaging with MRI or assessment of pulmonary parenchymal vascular morphology with MDCT may be useful in detecting pulmonary vascular abnormalities early, when treatment methods such as the use of oxygen may have a more protective effect. Furthermore, phenotypic characterization of pulmonary vascular anatomy and perfusion may be useful in characterizing subtypes that may respond to various therapies that have not yielded results in the general COPD population. Imaging-based animal models may be useful in assessing potential therapeutic targets as well as in monitoring treatment efficacy and safety in humans.
CORONARY ARTERY DISEASE AND COPD
The correlation between COPD and coronary artery disease, which is likely a direct reflection of the systemic effects of cigarette smoking, is noteworthy. With the use of large-scale studies screening for coronary artery calcification as a marker for coronary artery disease, it became apparent that many patients have comorbid disease of emphysema.3 Similarly, large cohort studies evaluating the extent of COPD have found many patients who demonstrate coronary artery calcification.4,89 Furthermore, several studies have shown that this relationship is responsible for significant comorbidity and affects the outcome of patients with COPD and coronary artery disease.
Several studies demonstrated a correlation between COPD and cardiovascular fatal and nonfatal events.33,35 The Multi-Ethnic Study of Atherosclerosis (MESA), a large cohort study of 2816 asymptomatic subjects being screened for coronary artery disease, showed a linear relationship between increasing CT-determined emphysema and decreasing MRI-determined LV function.3 An MRI study evaluating LV function also showed that LV function was diminished in patients with emphysema.90 The same research group had also shown in a previous study that LV function improved after lung volume reduction surgery,29 supporting the hypothesis that hyperinflation may play a role in worsening heart function. A further study on 138 COPD patients showed that the size of cardiac chambers decreased with more severe COPD and that impaired LV diastolic filling pattern negatively impacted the 6-minute walking distance.31 Finally, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, which evaluated the extent of COPD using CT in relation to smoking history, demonstrated that coronary artery calcification was directly correlated with COPD as assessed by CT, the degree of dyspnea, exercise capacity, and all-cause mortality.32
Pulmonary vascular disease and subsequent right heart failure is a key mechanism of cardiopulmonary coupling in COPD. It has high prevalence, has been associated with symptomatic and functional impairment, and is a poor prognostic sign. The mechanism by which it develops includes hypoxemia, inflammation, vascular deformation due to hyperinflation, remodeling, and loss of vessels, all of which may lead to RV dysfunction and failure. In addition, coronary artery disease and COPD are directly correlated, likely due to a common etiology, with smoking history as a key factor.
Imaging has been integrated into standard clinical practice, and echocardiography is commonly used to screen for pulmonary vascular disease in smokers. Coronary artery calcium scoring with CT is commonly utilized in patients with risk factors for coronary artery atherosclerosis and will also yield pulmonary parenchymal information. In addition, phenotypic markers derived from anatomic and functional examination of the lung parenchyma are becoming increasingly available. These include 3D reconstruction of the intraparenchymal vasculature and objective assessments of lung ventilation and perfusion. These phenotypic markers may be used in the future to assess potential therapeutic targets, to identify more homogenous subsets of disease for therapeutic investigation, and as an intermediate study endpoint for clinical investigation.
1. Divo M, Cote C, de Torres JP, et al .Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2012; 186:155–161.
2. Minai OA, Chaouat A, Adnot S .Pulmonary hypertension in COPD: epidemiology, significance, and management: pulmonary vascular disease: the global perspective.Chest. 2010; 137:suppl 39S–51S.
3. Barr RG, Ahmed FS, Carr JJ, et al .Subclinical atherosclerosis, airflow obstruction and emphysema: the MESA Lung Study.Eur Respir J. 2012; 39:846–854.
4. Budoff MJ, Nasir K, Kinney GL, et al .Coronary artery and thoracic calcium on noncontrast thoracic CT scans: comparison of ungated and gated examinations in patients from the COPD Gene cohort.J Cardiovasc Comput Tomogr. 2011; 5:113–118.
5. Santos S, Peinado VI, Ramirez J, et al .Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD.Eur Respir J. 2002; 19:632–638.
6. Barbera JA .Mechanisms of development of chronic obstructive pulmonary disease-associated pulmonary hypertension.Pulm Circ. 2013; 3:160–164.
7. Fayngersh V, Drakopanagiotakis F, Dennis McCool F, et al .Pulmonary hypertension in a stable community-based COPD population.Lung. 2011; 189:377–382.
8. Thabut G, Dauriat G, Stern JB, et al .Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation.Chest. 2005; 127:1531–1536.
9. Scharf SM, Iqbal M, Keller C, et al .Hemodynamic characterization of patients with severe emphysema.Am J Respir Crit Care Med. 2002; 166:314–322.
10. Weitzenblum E, Kessler R, Oswald M, et al .Medical treatment of pulmonary hypertension in chronic lung disease.Eur Respir J. 1994; 7:148–152.
11. Oswald-Mammosser M, Weitzenblum E, Quoix E, et al .Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure.Chest. 1995; 107:1193–1198.
12. Kessler R, Faller M, Weitzenblum E, et al .“Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease.Am J Respir Crit Care Med. 2001; 164:219–224.
13. Sims MW, Margolis DJ, Localio AR, et al .Impact of pulmonary artery pressure on exercise function in severe COPD.Chest. 2009; 136:412–419.
14. Shepard JM, Gropper MA, Nicolaysen G, et al .Lung microvascular pressure profile measured by micropuncture in anesthetized dogs.J Appl Physiol (1985). 1988; 64:874–879.
15. Sciurba FC, Rogers RM, Keenan RJ, et al .Improvement in pulmonary function and elastic recoil after lung-reduction surgery for diffuse emphysema.N Engl J Med. 1996; 334:1095–1099.
16. Criner GJ, Scharf SM, Falk JA, et al .Effect of lung volume reduction surgery on resting pulmonary hemodynamics in severe emphysema.Am J Respir Crit Care Med. 2007; 176:253–260.
17. Chaouat A, Naeije R, Weitzenblum E .Pulmonary hypertension in COPD.Eur Respir J. 2008; 32:1371–1385.
18. McAllister DA, Maclay JD, Mills NL, et al .Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2007; 176:1208–1214.
19. Barr RG .The epidemiology of vascular dysfunction relating to chronic obstructive pulmonary disease and emphysema.Proc Am Thorac Soc. 2011; 8:522–527.
20. Hale KA, Niewoehner DE, Cosio MG .Morphologic changes in the muscular pulmonary arteries: relationship to cigarette smoking, airway disease, and emphysema.Am Rev Respir Dis. 1980; 122:273–278.
21. Wright JL, Petty T, Thurlbeck WM .Analysis of the structure of the muscular pulmonary arteries in patients with pulmonary hypertension and COPD: National Institutes of Health nocturnal oxygen therapy trial.Lung. 1992; 170:109–124.
22. Hopkins N, McLoughlin P .The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis? J Anat. 2002; 201:335–348.
23. Van Beek EJR, Mirsadraee S, Murchison JT. A M.P.a.H .Radiology of chronic obstructive pulmonary disease.A Colour Atlas for COPD. 2013; .NY:Clinical Publishing
24. Voelkel NF, Douglas IS, Nicolls M .Angiogenesis in chronic lung disease.Chest. 2007; 131:874–879.
25. Maclay JD, McAllister DA, Rabinovich R, et al .Systemic elastin degradation in chronic obstructive pulmonary disease.Thorax. 2012; 67:606–612.
26. Fisher MR, Criner GJ, Fishman AP, et al .Estimating pulmonary artery pressures by echocardiography in patients with emphysema.Eur Respir J. 2007; 30:914–921.
27. Yock PG, Popp RL .Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation.Circulation. 1984; 70:657–662.
28. Tramarin R, Torbicki A, Marchandise B, et al .Doppler echocardiographic evaluation of pulmonary artery pressure in chronic obstructive pulmonary disease. A European multicentre study. Working Group on Noninvasive Evaluation of Pulmonary Artery Pressure. European Office of the World Health Organization, Copenhagen.Eur Heart J. 1991; 12:103–111.
29. Jorgensen K, Houltz E, Westfelt U, et al .Effects of lung volume reduction surgery on left ventricular diastolic filling and dimensions in patients with severe emphysema.Chest. 2003; 124:1863–1870.
30. Arcasoy SM, Christie JD, Ferrari VA, et al .Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease.Am J Respir Crit Care Med. 2003; 167:735–740.
31. Watz H, Waschki B, Meyer T, et al .Decreasing cardiac chamber sizes and associated heart dysfunction in COPD: role of hyperinflation.Chest. 2010; 138:32–38.
32. Williams MC, Murchison J, Edwards LD, et al .Artery calcification is increased in patients with COPD and associated with increased mortality and morbidity.Thorax. 2013;
33. Mapel DW, Dedrick D, Davis K .Trends and cardiovascular co-morbidities of COPD patients in the Veterans Administration Medical System, 1991-1999.COPD. 2005; 2:35–41.
34. Tei C, Nishimura RA, Seward JB, et al .Noninvasive Doppler-derived myocardial performance index: correlation with simultaneous measurements of cardiac catheterization measurements.J Am Soc Echocardiogr. 1997; 10:169–178.
35. Curkendall SM, DeLuise C, Jones JK, et al .Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients.Ann Epidemiol. 2006; 16:63–70.
36. Di Bello V, Conte L, Delle Donne MG, et al .Advantages of real time three-dimensional echocardiography in the assessment of right ventricular volumes and function in patients with pulmonary hypertension compared with conventional two-dimensional echocardiography.Echocardiography. 2013; 30:820–828.
37. Rajagopalan N, Simon MA, Shah H, et al .Utility of right ventricular tissue Doppler imaging: correlation with right heart catheterization.Echocardiography. 2008; 25:706–711.
38. Leitman M, Lysyansky P, Sidenko S, et al .Two-dimensional strain-a novel software for real-time quantitative echocardiographic assessment of myocardial function.J Am Soc Echocardiogr. 2004; 17:1021–1029.
39. Leong DP, Grover S, Molaee P, et al .Nonvolumetric echocardiographic indices of right ventricular systolic function: validation with cardiovascular magnetic resonance and relationship with functional capacity.Echocardiography. 2012; 29:455–463.
40. Russell K, Eriksen M, Aaberge L, et al .A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work.Eur Heart J. 2012; 33:724–733.
41. Hardegree EL, Sachdev A, Villarraga HR, et al .Role of serial quantitative assessment of right ventricular function by strain in pulmonary arterial hypertension.Am J Cardiol. 2013; 111:143–148.
42. Motoji Y, Tanaka H, Fukuda Y, et al .Efficacy of right ventricular free-wall longitudinal speckle-tracking strain for predicting long-term outcome in patients with pulmonary hypertension.Circ J. 2013; 77:756–763.
43. Vonk-Noordegraaf A, Marcus JT, Holverda S, et al .Early changes of cardiac structure and function in COPD patients with mild hypoxemia.Chest. 2005; 127:1898–1903.
44. Holverda S, Rietema H, Westerhof N, et al .Stroke volume increase to exercise in chronic obstructive pulmonary disease is limited by increased pulmonary artery pressure.Heart. 2009; 95:137–141.
45. Marcus JT, Vonk Noordegraaf A, De Vries PM, et al .MRI evaluation of right ventricular pressure overload in chronic obstructive pulmonary disease.J Magn Reson Imaging. 1998; 8:999–1005.
46. Swift AJ, Rajaram S, Hurdman J, et al .Noninvasive estimation of PA pressure, flow, and resistance with CMR imaging: derivation and prospective validation study from the ASPIRE registry.JACC Cardiovasc Imaging. 2013; 6:1036–1047.
47. Carlsen J, Hasseriis Andersen K, Boesgaard S, et al .Pulmonary arterial lesions in explanted lungs after transplantation correlate with severity of pulmonary hypertension in chronic obstructive pulmonary disease.J Heart Lung Transplant. 2013; 32:347–354.
48. Stevens GR, Garcia-Alvarez A, Sahni S, et al .RV dysfunction in pulmonary hypertension is independently related to pulmonary artery stiffness.JACC Cardiovasc Imaging. 2012; 5:378–387.
49. Jacobson G, Turner AF, Balchum OJ, et al .Vascular changes in pulmonary emphysema. The radiologic evaluation by selective and peripheral pulmonary wedge angiography.Am J Roentgenol Radium Ther Nucl Med. 1967; 100:374–396.
50. Magee F, Wright JL, Wiggs BR, et al .Pulmonary vascular structure and function in chronic obstructive pulmonary disease.Thorax. 1988; 43:183–189.
51. Kuriyama K, Gamsu G, Stern RG, et al .CT-determined pulmonary artery diameters in predicting pulmonary hypertension.Invest Radiol. 1984; 19:16–22.
52. Ng CS, Wells AU, Padley SP .A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter.J Thorac Imaging. 1999; 14:270–278.
53. Wells JM, Washko GR, Han MK, et al .Pulmonary arterial enlargement and acute exacerbations of COPD.N Engl J Med. 2012; 367:913–921.
54. Revel MP, Faivre JB, Remy-Jardin M, et al .Pulmonary hypertension: ECG-gated 64-section CT angiographic evaluation of new functional parameters as diagnostic criteria.Radiology. 2009; 250:558–566.
55. Paz R, Mohiaddin RH, Longmore DB .Magnetic resonance assessment of the pulmonary arterial trunk anatomy, flow, pulsatility and distensibility.Eur Heart J. 1993; 14:1524–1530.
56. Ertan C, Tarakci N, Ozeke O, et al .Pulmonary artery distensibility in chronic obstructive pulmonary disease.Echocardiography. 2013; 30:940–944.
57. Fourie PR, Coetzee AR, Bolliger CT .Pulmonary artery compliance: its role in right ventricular-arterial coupling.Cardiovasc Res. 1992; 26:839–844.
58. Vonk Noordegraaf A, Naeije R .Right ventricular function in scleroderma-related pulmonary hypertension.Rheumatology (Oxford). 2008; 47:suppl 5 v42–v43.
59. Engelke C, et al .High-resolution CT and CT angiography of peripheral pulmonary vascular disorders.Radiographics. 2002; 22:739–764.
60. Matsuoka S, Washko GR, Yamashiro T, et al .Pulmonary hypertension and computed tomography measurement of small pulmonary vessels in severe emphysema.Am J Respir Crit Care Med. 2010; 181:218–225.
61. Estepar RS, Ross JC, Krissian K, et al .Computational vascular morphometry for the assessment of pulmonary vascular disease based on scale-space particles.Proc IEEE Int Symp Biomed Imaging. 2012; 1479–1482.
62. Estepar RS, Kinney GL, Black-Shinn JL, et al .Computed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications.Am J Respir Crit Care Med. 2013; 188:231–239.
63. Rabinovitch M, Keane JF, Fellows KE, et al .Quantitative analysis of the pulmonary wedge angiogram in congenital heart defects. Correlation with hemodynamic data and morphometric findings in lung biopsy tissue.Circulation. 1981; 63:152–164.
64. Junqueira FP, Lima CM, Coutinho AC Jr, et al .Pulmonary arterial hypertension: an imaging review comparing MR pulmonary angiography and perfusion with multidetector CT angiography.Br J Radiol. 2012; 85:1446–1456.
65. Schoepf UJ, Savino G, Lake DR, et al .The age of CT pulmonary angiography.J Thorac Imaging. 2005; 20:273–279.
66. Johnson TR, Krauss B, Sedlmair M, et al .Material differentiation by dual energy CT: initial experience.Eur Radiol. 2007; 17:1510–1517.
67. Remy-Jardin M, Faivre JB, Pontana F, et al .Thoracic applications of dual energy.Radiol Clin North Am. 2010; 48:193–205.
68. Ghaye B, Monville J-F .“Case 2 - Assessment of Perfusion Defects”, Appearing in Brochure “Dual Energy CT: SOMATOM Definition” Order No. A91CT-00615-04C1-7600. 2008; .Erlangen Germany:Siemens AG.
69. Hoey ET, Mirsadraee S, Pepke-Zaba J, et al .Dual-energy CT angiography for assessment of regional pulmonary perfusion in patients with chronic thromboembolic pulmonary hypertension: initial experience.Am J Roentgenol. 2011; 196:524–532.
70. Pontana F, Faivre JB, Remy-Jardin M, et al .Lung perfusion with dual-energy multidetector-row CT (MDCT): feasibility for the evaluation of acute pulmonary embolism in 117 consecutive patients.Acad Radiol. 2008; 15:1494–1504.
71. Pansini V, Remy-Jardin M, Faivre JB, et al .Assessment of lobar perfusion in smokers according to the presence and severity of emphysema: preliminary experience with dual-energy CT angiography.Eur Radiol. 2009; 19:2834–2843.
72. Lu GM, Zhao Y, Zhang LJ, et al .Dual-energy CT of the lung.Am J Roentgenol. 2012; 199:suppl S40–S53.
73. Washko GR, Parraga G, Coxson HO .Quantitative pulmonary imaging using computed tomography and magnetic resonance imaging.Respirology. 2012; 17:432–444.
74. Ohno Y, Hatabu H, Murase K, et al .Quantitative assessment of regional pulmonary perfusion in the entire lung using three-dimensional ultrafast dynamic contrast-enhanced magnetic resonance imaging: Preliminary experience in 40 subjects.J Magn Reson Imaging. 2004; 20:353–365.
75. Ohno Y, Hatabu H, Murase K, et al .Primary pulmonary hypertension: 3D dynamic perfusion MRI for quantitative analysis of regional pulmonary perfusion.Am J Roentgenol. 2007; 188:48–56.
76. Ley S, Mereles D, Puderbach M, et al .Value of MR phase-contrast flow measurements for functional assessment of pulmonary arterial hypertension.Eur Radiol. 2007; 17:1892–1897.
77. Ley S, Fink C, Zaporozhan J, et al .Value of high spatial and high temporal resolution magnetic resonance angiography for differentiation between idiopathic and thromboembolic pulmonary hypertension: initial results.Eur Radiol. 2005; 15:2256–2263.
78. Schuster DP, Mintun MA .Studying the pulmonary circulation with positron emission tomography.J Thorac Imaging. 1988; 3:15–24.
79. Harris RS, Schuster DP .Visualizing lung function with positron emission tomography.J Appl Physiol (1985). 2007; 102:448–458.
80. Vidal Melo MF, Winkler T, Harris RS, et al .Spatial heterogeneity of lung perfusion assessed with (13)N PET as a vascular biomarker in chronic obstructive pulmonary disease.J Nucl Med. 2010; 51:57–65.
81. Zielinski J, Tobiasz M, Hawrylkiewicz I, et al .Effects of long-term oxygen therapy on pulmonary hemodynamics in COPD patients: a 6-year prospective study.Chest. 1998; 113:65–70.
82. Fujimoto K, Matsuzawa Y, Yamaguchi S, et al .Benefits of oxygen on exercise performance and pulmonary hemodynamics in patients with COPD with mild hypoxemia.Chest. 2002; 122:457–463.
83. Park J, Song JH, Park DA, et al .Systematic review and meta-analysis of pulmonary hypertension specific therapy for exercise capacity in chronic obstructive pulmonary disease.J Korean Med Sci. 2013; 28:1200–1206.
84. Archer SL, Mike D, Crow J, et al .A placebo-controlled trial of prostacyclin in acute respiratory failure in COPD.Chest. 1996; 109:750–755.
85. Nana-Sinkam SP, Lee JD, Sotto-Santiago S, et al .Prostacyclin prevents pulmonary endothelial cell apoptosis induced by cigarette smoke.Am J Respir Crit Care Med. 2007; 175:676–685.
86. Shimizu M, Imanishi J, Takano T, et al .Disproportionate pulmonary hypertension in a patient with early-onset pulmonary emphysema treated with specific drugs for pulmonary arterial hypertension.Intern Med. 2011; 50:2341–2346.
87. Stolz D, Rasch H, Linka A, et al .A randomised, controlled trial of bosentan in severe COPD.Eur Respir J. 2008; 32:619–628.
88. Bjortuft O, Simonsen S, Geiran OR, et al .Pulmonary haemodynamics after single-lung transplantation for end-stage pulmonary parenchymal disease.Eur Respir J. 1996; 9:2007–2011.
89. Romme EA, Murchison JT, Edwards LD, et al .CT-measured bone attenuation in patients with chronic obstructive pulmonary disease: relation to clinical features and outcomes.J Bone Miner Res. 2013; 28:1369–1377.
90. Jorgensen K, Muller MF, Nel J, et al .Reduced intrathoracic blood volume and left and right ventricular dimensions in patients with severe emphysema: an MRI study.Chest. 2007; 131:1050–1057.