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Prevalence and Impact of Coronary Artery Disease in Patients With Pulmonary Arterial Hypertension
Prevalence and Impact of Coronary Artery Disease in Patients With Pulmonary Arterial Hypertension Avi Shimony, MDa,b,c, Mark Jeffrey Eisenberg, MD, MPHa,b, Lawrence Glenn Rudski, MDa, Robert Schlesinger, MDa, Jonathan Afilalo, MD, MSca,b, Dominique Joyal, MDa, Leonidas Dragatakis, MDa, Andrew Hirsch, MDa, Kim Boutet, MDa, Benjamin Daniel Fox, MDa, and David Langleben, MDa,* The occurrence and impact of coronary artery disease (CAD) among patients with pulmonary arterial hypertension (PAH) are unknown. We aimed to determine the prevalence, clinical correlates, and effect of CAD in patients with PAH. We reviewed the medical records of consecutive patients diagnosed with PAH at a university-based referral center for pulmonary vascular disease from January 1990 to May 2010. The patients systematically underwent right heart catheterization and coronary angiography as a part of their evaluation. The patients with PAH with CAD (defined as >50% stenosis in >1 major epicardial coronary artery) were compared to patients without CAD. Among the 162 patients with PAH, the prevalence of CAD was 28.4%. The presence of CAD was associated with older age (66.6 ⴞ 11.5 vs 49.2 ⴞ 14.0 years, p <0.001), systemic hypertension, and dyslipidemia. The patients with PAH and CAD had a lower mean pulmonary arterial pressure (44.6 ⴞ 11.1 vs 49.2 ⴞ 14.0 mm Hg; p ⴝ 0.02) than patients without CAD. During a median follow-up of 36 months, 73 patients died. The presence of CAD was a predictor of all-cause mortality on univariate analysis (hazard ratio 1.97, 95% confidence interval 1.21 to 3.20) but not on multivariate analysis, which identified older age (hazard ratio 1.03, 95% confidence interval 1.01 to 1.05) and right atrial pressure (hazard ratio 1.08, 95% confidence interval 1.03 to 1.14) as the only independent predictors. In conclusion, our study has demonstrated that CAD is common among patients with PAH. CAD prevalence increases with age, dyslipidemia, and hypertension, but we did not detect an independent prognostic effect of CAD on mortality. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:460 – 464) A large registry from 54 United States centers (2,967 patients) has provided updated characteristics of patients with pulmonary arterial hypertension (PAH).1 A history of any ischemic cardiovascular event was noted in 10.2% of patients; however, the prevalence of coronary artery disease (CAD) was not reported. A recent systematic review was conducted to identify factors that predict mortality in patients with idiopathic PAH.2 A total of 54 publications describing 107 parameters reported to be associated with mortality in those with idiopathic PAH were reviewed. A reproducible association with mortality was demonstrated for 10 factors. The presence of CAD was not evaluated, and,
a
Center for Pulmonary Vascular Disease and bDivision of Clinical Epidemiology, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada; and cDivision of Cardiology, Soroka University Medical Center, Ben-Gurion University, Be’er-Sheva, Israel. Manuscript received February 14, 2011; manuscript received and accepted March 18, 2011. This work was supported by the Bank of Montreal Center for the Study of Heart Disease in Women and by the William and Ida Pencer Family Foundation at the Jewish General Hospital, Montreal, Quebec, Canada. Dr. Avi Shimony is supported by the Azrielli Fellowship Fund for research at the Jewish General Hospital, Montreal, Quebec, Canada. *Corresponding author: Tel: (514) 340-7531; fax: (514) 340-7534. E-mail address: [email protected] (D. Langleben). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.03.066
to our knowledge, the extent of overlap between PAH and CAD has never been explored. Because CAD is a leading cause of morbidity and mortality in the general population, we sought to establish the prevalence and clinical correlates of CAD among patients with PAH during their initial workup. We also aimed to determine whether underlying CAD affects the survival of patients with PAH. Methods The study population included a cohort of consecutive patients aged ⱖ18 years evaluated for PAH at a universitybased referral center for pulmonary vascular disease who underwent coronary angiography from January 1990 to May 2010. As routine in our center, every patient referred for evaluation of pulmonary hypertension underwent right and left cardiac catheterization (including coronary angiography) for diagnostic and prognostic purposes. In 19 patients (74% women), coronary angiography was not performed because of right heart catheterization and treatment started at another hospital (5 patients), patient too ill to undergo coronary angiography before treatment for PAH was initiated (5 patients), cognitive problems (1 patient), renal disease (1 patient), and reason not specified (7 patients). These patients were not included in the final analysis. All patients were longitudinally followed up at our center after their initial evaluation. www.ajconline.org
Miscellaneous/Impact of CAD on PAH
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Table 1 Baseline characteristics Variable
Age (years) Men Smoker Hypertension Diabetes mellitus Dyslipidemia* Body mass index ⱖ30 kg/m2 Body mass index Body surface area (m2) Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary artery bypass graft surgery
All (n ⫽ 162)
CAD
54.1 ⫾ 15.5 16.0% 48.6% 34.2% 12.3% 23.0% 24.8% 27.0 ⫾ 6.5 1.7 ⫾ 0.2 2.5% 3.7% 2.5%
p Value
No (n ⫽ 116)
Yes (n ⫽ 46)
49.2 ⫾ 14.0 13.8% 46.7% 23.5% 9.5% 14.7% 25.2% 27.3 ⫾ 7.0 1.8 ⫾ 0.2 0.9% 0.0% 0.0%
66.6 ⫾ 11.5 21.7% 53.5% 63.0% 19.6% 44.4% 23.9% 26.0 ⫾ 4.7 1.7 ⫾ 0.2 6.7% 13.0% 8.7%
⬍0.001 0.21 0.45 ⬍0.001 0.08 ⬍0.001 0.86 0.23 0.33 0.06 ⬍0.001 0.001
Data are presented as mean ⫾ SD or percentages. * Dyslipidemia defined as International Classification of Diseases, 9th edition, diagnostic codes 272.0 –272.4: pure hypercholesterolemia, pure hypertriglyceridemia, mixed hyperlipidemia, hyperchylomicronemia, and unspecified hyperlipidemia.
The patients were evaluated for the presence of PAH (World Health Organization class 1) according to the current consensus criteria.3,4 The patients with PAH associated with other World Health Organization classes (class II-V) were excluded. CAD was defined as ⱖ50% stenosis of ⱖ1 major epicardial coronary arteries as visually assessed by the angiographer performing the study. The data were collected retrospectively by chart review, beginning with the initial screening visit at the clinic. The baseline demographic and, clinical data were documented for all subjects, including the cardiovascular risk factors. The 2-dimensional echocardiographic data included functional assessment of the right ventricle (normal vs any abnormality). The right and left heart catheterization data included hemodynamic measurements and the coronary angiographic results. In addition, it was noted whether the subjects had a history of CAD before their initial PAH evaluation. The Jewish General Hospital Research Ethics Committee approved the study. All-cause mortality was the primary outcome measure. For patients who survived during follow-up, the date of the last visit at the clinic (until May 2010) was used as the censoring date. The date of the initial clinic visit was considered the baseline from which survival time was measured, as has been done in other studies.5 The categorical variables were compared using the chisquare test or Fisher’s exact test, as appropriate, and are expressed as proportions and percentages. Continuous variables were compared using Student’s t test and are expressed as the mean ⫾ SD or median with the 25% to 75% interquartile range. Kaplan-Meier analysis was used to explore the association between significant CAD and mortality with the log-rank test to determine statistical significance. We used the Cox proportional hazard models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) and to examine the independent effect on survival of covariates associated with all-cause mortality on univariate analysis. The 2-sided level of significance was set at 0.05. The data were analyzed using a statistical software program
Table 2 Pulmonary arterial hypertension (PAH) subgroups Pulmonary Arterial Hypertension Etiology
Idiopathic Collagen vascular disease Congenital heart disease Portal hypertension Human immunodeficiency virus Familial disorders Anorexigenic drugs
All (n ⫽ 162)
CAD
p Value
No (n ⫽ 116)
Yes (n ⫽ 46)
42.6% 38.9%
41.4% 36.2%
45.7% 45.7%
0.62 0.27
9.3% 4.9% 3.1%
10.3% 6.9% 3.4%
6.5% 0.0% 2.2%
0.56 0.11 1.0
0.6% 0.6%
0.9% 0.9%
0.0% 0.0%
1.0 1.0
(Statistical Package for Social Sciences, version 16.0, SPSS, Chicago, Illinois). Results The study population consisted of 162 patients with PAH who underwent coronary angiography. Most of the patients were women (84.0%). The mean ⫾ SD age was 54.1 ⫾ 15.5 years and was similar for women and men (53.6 ⫾ 15.4 vs 57.0 ⫾ 15.7 years, respectively, p ⫽ 0.30). At the initial screening visit in the clinic, 80.0% and 9.3% of patients were in New York Heart Association functional class III and IV, respectively. The interval from symptom onset to the initial screening visit was available for 103 (63.6%) of the 162 patients. In these patients, the median interval was 12.0 months (25% to 75% interquartile range 7 to 30). CAD was present in 46 patients (28.4%, 95% CI 22.0% to 35.8%). The presence of CAD was associated with older age, hypertension, and dyslipidemia but not with gender, smoking, obesity, or PAH etiology. The demographics and co-morbid conditions of the 2 groups are summarized in Table 1.
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Table 3 Hemodynamic, echocardiographic, and angiographic data Variable
Hemodynamic data Systolic pulmonary artery pressure (mm Hg) Diastolic pulmonary artery pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Right atrial pressure (mm Hg) Wedge pressure (mm Hg) Pulmonary vascular resistance (Wood units) Cardiac output (L/min)* Cardiac index (L/min/m2)* Echocardiographic data Abnormal right ventricular function Number of coronary arteries narrowed 1 2 3 Coronary artery narrowed† Left main Left anterior descending Left circumflex Right
All (n ⫽ 162)
CAD
p Value
No (n ⫽ 116)
Yes (n ⫽ 46)
76.6 ⫾ 18.8 30.4 ⫾ 9.5 48.1 ⫾ 11.8 8.6 ⫾ 5.6 8.5 ⫾ 3.4 11.2 ⫾ 5.9 4.2 ⫾ 1.5 2.4 ⫾ 0.9
77.3 ⫾ 18.9 31.9 ⫾ 9.7 49.5 ⫾ 11.9 9.1 ⫾ 5.8 8.6 ⫾ 3.5 11.8 ⫾ 6.3 4.2 ⫾ 1.6 2.4 ⫾ 0.9
74.9 ⫾ 18.6 26.7 ⫾ 8.0 44.6 ⫾ 11.2 7.3 ⫾ 5.1 8.4 ⫾ 3.1 9.8 ⫾ 4.5 4.3 ⫾ 1.3 2.5 ⫾ 0.7
0.46 0.001 0.02 0.06 0.64 0.07 0.89 0.69
79.4%
81.4%
74.4%
0.36
11.1% 12.3% 3.1%
— — —
41.8% 46.5% 11.7%
— — —
1.9% 17.3% 13.0% 17.3%
— — — —
6.5% 60.9% 45.7% 60.9%
— — — —
* Calculated by thermodilution at rest. † Significant CAD defined as ⱖ50% stenosis in ⱖ1 major epicardial coronary artery. Table 4 Unadjusted and adjusted Cox proportional hazard models for predictors of all-cause mortality over time
Figure 1. Kaplan-Meier analysis of survival time after first screening visit at the clinic. Comparison of patients with PAH and significant CAD to those without significant CAD.
The etiology of PAH stratified by the presence or absence of CAD is listed in Table 2. Most of the patients (81.5%) had idiopathic PAH or PAH associated with collagen vascular disease. Of the collagen vascular diseases, systemic sclerosis was the leading cause, present in 46 (73.0%) of the 63 patients. Of the congenital heart diseases, secundum atrial septal defect was the leading cause, present in 9 (60%) of the 15 patients.
Variable
Unadjusted HR (95% CI)
Adjusted HR* (95% CI)
Age (years) Men Significant coronary artery disease† Hypertension Obesity Smoker Diabetes mellitus Dyslipidemia Idiopathic pulmonary arterial hypertension Scleroderma-associated pulmonary arterial hypertension Normal right ventricular function on echocardiogram Mean pulmonary artery pressure (mm Hg) Right atrial pressure (mm Hg) Pulmonary vascular resistance (Wood units) Cardiac output (L/min) Cardiac index (L/min/m2)
1.03 (1.02–1.05) 1.66 (0.92–2.99) 1.97 (1.21–3.20) 1.38 (0.85–2.25) 1.58 (0.95–2.62) 1.23 (0.75–2.03) 1.24 (0.61–2.50) 1.23 (0.70–2.10) 1.09 (0.68–1.76)
1.02 (1.00–1.05) — 1.52 (0.84–2.74) — — — — — —
2.28 (1.37–3.77)
1.70 (0.95–3.06)
0.42 (0.20–0.86)
—
1.01 (0.99–1.03)
—
1.07 (1.02–1.11) 1.01 (0.97–1.05)
1.08 (1.03–1.14) —
0.84 (0.70–1.02) 0.70 (0.50–0.97)
— 0.77 (0.55–1.09)
* Adjustments were made for age, CAD, scleroderma-associated PAH, right atrial pressure, and cardiac index. † Significant CAD defined as ⱖ50% stenosis in ⱖ1 major epicardial coronary artery.
The hemodynamic and angiographic data at diagnosis, stratified by the presence or absence of CAD, are listed in Table 3. The patients with PAH and CAD had a lower mean pulmonary artery pressure than the patients without CAD.
Miscellaneous/Impact of CAD on PAH
No differences were found with respect to cardiac output, pulmonary capillary wedge pressure, pulmonary vascular resistance, and right atrial pressure. Two-vessel CAD was the most frequent diagnosis. Significant coronary stenoses were detected equally in the left anterior descending artery and right coronary artery and less often in the left circumflex artery. During the study period, 22.0% of patients with CAD underwent percutaneous coronary intervention. All through the follow-up period, myocardial infarction occurred in 4.4% and 0.0% of patients with and without CAD, respectively (p ⫽ 0.08). During a median follow-up of 36 months (25% to 75% interquartile range 17 to 71), 73 patients died. The survival estimate for all patients was 87.1%, 67.3%, and 58.5% at 1, 3, and 5 years, respectively. The Kaplan-Meier estimates for each group were compared and revealed worse survival for those patients with CAD (log-rank p ⫽ 0.005; Figure 1). On univariate analysis, age, CAD, scleroderma associated PAH, abnormal right ventricular function, right atrial pressure, and cardiac index were associated with all-cause mortality (Table 4). These parameters were entered into the multivariate analysis, with the exception of right ventricular function, because that is reflected in the right atrial pressure. The presence of CAD was a predictor for all-cause mortality on univariate analysis (HR 1.97, 95% CI 1.21 to 3.20). However, the multivariate Cox proportion hazard models suggested that only age (HR 1.03, 95% CI 1.01 to 1.05) and right atrial pressure (HR 1.08, 95% CI 1.03 to 1.14), were predictive of mortality (Table 4). Discussion The cohort of patients at our Center for Pulmonary Vascular Disease provided a rare opportunity to study the prevalence of CAD in a PAH population. With few exceptions, every 1 of our patients underwent coronary angiography at the baseline evaluation, enabling collection of sequential data. Thus, we were able to provide the prevalence, clinical correlates, and effect on mortality of CAD among our patients with PAH. We found that CAD is common. CAD prevalence increased with age, dyslipidemia, and hypertension, but we did not detect an independent prognostic effect of CAD on mortality. The true prevalence of CAD in the general population is unknown, because coronary angiography is not performed routinely in asymptomatic subjects. The estimates of the prevalence of CAD in patients ⱖ18 years old in the United States population range from 4.3% to 6.1%.6 Enbergs et al7 determined the prevalence of CAD in persons 40 to 70 years old referred for catheter electrophysiologic ablation therapy for arrhythmia. In 331 consecutive patients with a mean age of 53 ⫾ 7 years and a greater percentage of men (52.3%) compared to our study, the prevalence of CAD was 7.3%. These rates were much lower than those found in our cohort, although one might have expected a lower prevalence in our study owing to the greater female/male ratio than in the other studies. One explanation for the high rate in our cohort might be the shared pathogenic mechanisms between atherosclerosis and PAH, with similar inflammatory pathways in the coronary and pulmonary microvasculature advancing the progress of each disease.8,9 There could also be a causal
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relation. The pathogenic proliferative cytokines produced in PAH such as endothelin-1 might advance the atherosclerotic processes in the coronary arteries.10 –12 We compared the demographic, clinical, and hemodynamic data in patients with PAH who did or did not have CAD on their initial workup. The age at diagnosis for the whole cohort was similar to that reported in the recent Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL) registry.1 The patients with CAD, however, were older than those without CAD, reflecting the expected development of coronary atherosclerosis with increasing age. Also, our registry demonstrated a female preponderance with a 3.6:1 and 6.3:1 female/male ratio among those patients with PAH and with or without CAD, respectively. This marked female preponderance in those with PAH observed in our study is consistent with that observed in previous reports.1,13 Also, unlike a prevalence study of CAD in a general population that would detect a male predominance, the gender bias of PAH toward women likely introduced a female referral bias to our center. As expected, patients with CAD were more likely to have common cardiovascular risk factors such as hypertension and dyslipidemia or a history of previous myocardial infarction and coronary procedures. However, the prevalence of CAD in our cohort was much greater than that found in a population with similar mean age and risk factors.7 Therefore, the tendency to develop CAD in this unique population might not be predicted only by measuring the established cardiovascular risk factors but might represent a possible association between PAH and CAD. Only a few patients with CAD underwent percutaneous coronary intervention during the follow-up period, reflecting the conservative approach to asymptomatic CAD in our center. Also, the 20-year span of the study, beginning in 1990, covered a period from the infancy of coronary angioplasty through to the routine use of angioplasty and stenting of high-risk lesions, and the clinical practice has evolved accordingly. Because of the small number of patients, we were not able to identify a beneficial effect of percutaneous coronary intervention in patients with PAH and CAD. It is not surprising that no difference was found in the pulmonary artery wedge pressure between the patients with and without CAD— by definition, PAH excludes left heart disease, systolic or diastolic, and any patient with an elevated wedge pressure was excluded from the PAH population a priori. The most common PAH-associated diagnosis were idiopathic or collagen vascular disease in both groups, similar to other reports.1 No apparent association was found between the PAH types and the presence of CAD. The significant differences in pulmonary artery pressure between the 2 groups in our study were not anticipated. Because of the small number of patients in each group, these findings should be interpreted with caution, and any interpretation must be speculative. These results might have resulted from unrecognized confounders such as the medications given for each group or a potential intolerance to greater pulmonary artery pressure in the presence of CAD, resulting in a selection bias. The observed differences could also have resulted from chance. In any case, they are of questionable clinical relevance because of the small mean difference between the 2 groups.
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CAD is a leading cause of death.6 Nevertheless, our results suggest that patients with PAH and documented CAD do not have worse mortality outcomes than those without. Our survival estimates were in line with those of other studies, which showed that the long-term prognosis of patients with PAH is poor, even with treatment.3,14,15 In the presence of PAH, which will most strongly drive the survival outcome, stable CAD might have little effect, if any. Moreover, as in previous studies, age and right atrial pressure were independent predictors for mortality. We were unable to detect an independent prognostic value for other clinical, demographic, and hemodynamic variables. This might reflect the lesser importance of these variables when adjusted in a multivariate model or reduced power to detect differences owing to our cohort size. The present study had a number of limitations. First, our study could have been affected by the changing classification of PAH during the past 20 years. However, we had complete diagnostic data on the patients, and the limitation was addressed by adjusting the patient diagnosis to contemporary PAH definitions. Furthermore, interpretation of the data was limited by the uncontrolled nature of an observational retrospective single-center study. However, owing to the similarity in the basic characteristics of patients with PAH with larger studies and the lengthy follow-up, we believe that the results are relevant to those of other PAH populations. Also, human immunodeficiency virus infection induces CAD, and the human immunodeficiency virus population had the potential to skew our reported frequency of CAD in those with PAH. However, we had only a few patients with the human immunodeficiency virus, and no increase in CAD was found in the human immunodeficiency virus group. Finally, we did not examine the effect of PAHand CAD-specific medications, the use of which might have had affected the outcomes. However, because of the evolving practice during the 20-year period, it would have been difficult to interpret the results.
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5.
6.
7.
8. 9. 10.
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12.
Acknowledgment: We thank the nurses and technicians of the cardiac catheterization laboratory, and the pulmonary hypertension clinic coordinators at the Jewish General Hospital for their tender care provided to our patients and the many hours involved in collection of the data. 1. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010;137: 376 –387. 2. Swiston JR, Johnson SR, Granton JT. Factors that prognosticate mortality in idiopathic pulmonary arterial hypertension: A systematic review of the literature. Respir Med 2010;104:1588 –1607. 3. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J; American College of Cardiology Foundation, Task Force on Expert Consensus Documents, American Heart Association, American College of Chest Physicians, American Thoracic Society, Inc., Pulmonary Hypertension Association. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension a
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report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573–1619. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493– 2537. Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J 2010;35:1079 –1087. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O’Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, Hong Y; American Heart Association, Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics— 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;119: e21–181. Enbergs A, Bürger R, Reinecke H, Borggrefe M, Breithardt G, Kerber S. Prevalence of coronary artery disease in a general population without suspicion of coronary artery disease: angiographic analysis of subjects aged 40 to 70 years referred for catheter ablation therapy. Eur Heart J 2000;21:45–52. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999;340:115–126. Sluimer JC, Daemen MJ. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol 2009;218:7–29. Reriani M, Raichlin E, Prasad A, Mathew V, Pumper GM, Nelson RE, Lennon R, Rihal C, Lerman LO, Lerman A. Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis. Circulation 2010;122:958 – 966. Lerman A, Edwards BS, Hallett JW, Heublein DM, Sandberg SM, Burnett JC Jr. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991;325:997–1001. Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP, Hoeffken G. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001;120:1562–1569. Walker AM, Langleben D, Korelitz JJ, Rich S, Rubin LJ, Strom BL, Gonin R, Keast S, Badesch D, Barst RJ, Bourge RC, Channick R, Frost A, Gaine S, McGoon M, McLaughlin V, Murali S, Oudiz RJ, Robbins IM, Tapson V, Abenhaim L, Constantine G. Temporal trends and drug exposures in pulmonary hypertension: an American experience. Am Heart J 2006;152:521–526. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hypertension: insights from the Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL). Circulation 2010;122:164 –172. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaïci A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Cottin V, Degano B, Jaïs X, Montani D, Souza R, Simonneau G. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156 –163.
a
Center for Pulmonary Vascular Disease and bDivision of Clinical Epidemiology, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada; and cDivision of Cardiology, Soroka University Medical Center, Ben-Gurion University, Be’er-Sheva, Israel. Manuscript received February 14, 2011; manuscript received and accepted March 18, 2011. This work was supported by the Bank of Montreal Center for the Study of Heart Disease in Women and by the William and Ida Pencer Family Foundation at the Jewish General Hospital, Montreal, Quebec, Canada. Dr. Avi Shimony is supported by the Azrielli Fellowship Fund for research at the Jewish General Hospital, Montreal, Quebec, Canada. *Corresponding author: Tel: (514) 340-7531; fax: (514) 340-7534. E-mail address: [email protected] (D. Langleben). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.03.066
to our knowledge, the extent of overlap between PAH and CAD has never been explored. Because CAD is a leading cause of morbidity and mortality in the general population, we sought to establish the prevalence and clinical correlates of CAD among patients with PAH during their initial workup. We also aimed to determine whether underlying CAD affects the survival of patients with PAH. Methods The study population included a cohort of consecutive patients aged ⱖ18 years evaluated for PAH at a universitybased referral center for pulmonary vascular disease who underwent coronary angiography from January 1990 to May 2010. As routine in our center, every patient referred for evaluation of pulmonary hypertension underwent right and left cardiac catheterization (including coronary angiography) for diagnostic and prognostic purposes. In 19 patients (74% women), coronary angiography was not performed because of right heart catheterization and treatment started at another hospital (5 patients), patient too ill to undergo coronary angiography before treatment for PAH was initiated (5 patients), cognitive problems (1 patient), renal disease (1 patient), and reason not specified (7 patients). These patients were not included in the final analysis. All patients were longitudinally followed up at our center after their initial evaluation. www.ajconline.org
Miscellaneous/Impact of CAD on PAH
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Table 1 Baseline characteristics Variable
Age (years) Men Smoker Hypertension Diabetes mellitus Dyslipidemia* Body mass index ⱖ30 kg/m2 Body mass index Body surface area (m2) Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary artery bypass graft surgery
All (n ⫽ 162)
CAD
54.1 ⫾ 15.5 16.0% 48.6% 34.2% 12.3% 23.0% 24.8% 27.0 ⫾ 6.5 1.7 ⫾ 0.2 2.5% 3.7% 2.5%
p Value
No (n ⫽ 116)
Yes (n ⫽ 46)
49.2 ⫾ 14.0 13.8% 46.7% 23.5% 9.5% 14.7% 25.2% 27.3 ⫾ 7.0 1.8 ⫾ 0.2 0.9% 0.0% 0.0%
66.6 ⫾ 11.5 21.7% 53.5% 63.0% 19.6% 44.4% 23.9% 26.0 ⫾ 4.7 1.7 ⫾ 0.2 6.7% 13.0% 8.7%
⬍0.001 0.21 0.45 ⬍0.001 0.08 ⬍0.001 0.86 0.23 0.33 0.06 ⬍0.001 0.001
Data are presented as mean ⫾ SD or percentages. * Dyslipidemia defined as International Classification of Diseases, 9th edition, diagnostic codes 272.0 –272.4: pure hypercholesterolemia, pure hypertriglyceridemia, mixed hyperlipidemia, hyperchylomicronemia, and unspecified hyperlipidemia.
The patients were evaluated for the presence of PAH (World Health Organization class 1) according to the current consensus criteria.3,4 The patients with PAH associated with other World Health Organization classes (class II-V) were excluded. CAD was defined as ⱖ50% stenosis of ⱖ1 major epicardial coronary arteries as visually assessed by the angiographer performing the study. The data were collected retrospectively by chart review, beginning with the initial screening visit at the clinic. The baseline demographic and, clinical data were documented for all subjects, including the cardiovascular risk factors. The 2-dimensional echocardiographic data included functional assessment of the right ventricle (normal vs any abnormality). The right and left heart catheterization data included hemodynamic measurements and the coronary angiographic results. In addition, it was noted whether the subjects had a history of CAD before their initial PAH evaluation. The Jewish General Hospital Research Ethics Committee approved the study. All-cause mortality was the primary outcome measure. For patients who survived during follow-up, the date of the last visit at the clinic (until May 2010) was used as the censoring date. The date of the initial clinic visit was considered the baseline from which survival time was measured, as has been done in other studies.5 The categorical variables were compared using the chisquare test or Fisher’s exact test, as appropriate, and are expressed as proportions and percentages. Continuous variables were compared using Student’s t test and are expressed as the mean ⫾ SD or median with the 25% to 75% interquartile range. Kaplan-Meier analysis was used to explore the association between significant CAD and mortality with the log-rank test to determine statistical significance. We used the Cox proportional hazard models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) and to examine the independent effect on survival of covariates associated with all-cause mortality on univariate analysis. The 2-sided level of significance was set at 0.05. The data were analyzed using a statistical software program
Table 2 Pulmonary arterial hypertension (PAH) subgroups Pulmonary Arterial Hypertension Etiology
Idiopathic Collagen vascular disease Congenital heart disease Portal hypertension Human immunodeficiency virus Familial disorders Anorexigenic drugs
All (n ⫽ 162)
CAD
p Value
No (n ⫽ 116)
Yes (n ⫽ 46)
42.6% 38.9%
41.4% 36.2%
45.7% 45.7%
0.62 0.27
9.3% 4.9% 3.1%
10.3% 6.9% 3.4%
6.5% 0.0% 2.2%
0.56 0.11 1.0
0.6% 0.6%
0.9% 0.9%
0.0% 0.0%
1.0 1.0
(Statistical Package for Social Sciences, version 16.0, SPSS, Chicago, Illinois). Results The study population consisted of 162 patients with PAH who underwent coronary angiography. Most of the patients were women (84.0%). The mean ⫾ SD age was 54.1 ⫾ 15.5 years and was similar for women and men (53.6 ⫾ 15.4 vs 57.0 ⫾ 15.7 years, respectively, p ⫽ 0.30). At the initial screening visit in the clinic, 80.0% and 9.3% of patients were in New York Heart Association functional class III and IV, respectively. The interval from symptom onset to the initial screening visit was available for 103 (63.6%) of the 162 patients. In these patients, the median interval was 12.0 months (25% to 75% interquartile range 7 to 30). CAD was present in 46 patients (28.4%, 95% CI 22.0% to 35.8%). The presence of CAD was associated with older age, hypertension, and dyslipidemia but not with gender, smoking, obesity, or PAH etiology. The demographics and co-morbid conditions of the 2 groups are summarized in Table 1.
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Table 3 Hemodynamic, echocardiographic, and angiographic data Variable
Hemodynamic data Systolic pulmonary artery pressure (mm Hg) Diastolic pulmonary artery pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Right atrial pressure (mm Hg) Wedge pressure (mm Hg) Pulmonary vascular resistance (Wood units) Cardiac output (L/min)* Cardiac index (L/min/m2)* Echocardiographic data Abnormal right ventricular function Number of coronary arteries narrowed 1 2 3 Coronary artery narrowed† Left main Left anterior descending Left circumflex Right
All (n ⫽ 162)
CAD
p Value
No (n ⫽ 116)
Yes (n ⫽ 46)
76.6 ⫾ 18.8 30.4 ⫾ 9.5 48.1 ⫾ 11.8 8.6 ⫾ 5.6 8.5 ⫾ 3.4 11.2 ⫾ 5.9 4.2 ⫾ 1.5 2.4 ⫾ 0.9
77.3 ⫾ 18.9 31.9 ⫾ 9.7 49.5 ⫾ 11.9 9.1 ⫾ 5.8 8.6 ⫾ 3.5 11.8 ⫾ 6.3 4.2 ⫾ 1.6 2.4 ⫾ 0.9
74.9 ⫾ 18.6 26.7 ⫾ 8.0 44.6 ⫾ 11.2 7.3 ⫾ 5.1 8.4 ⫾ 3.1 9.8 ⫾ 4.5 4.3 ⫾ 1.3 2.5 ⫾ 0.7
0.46 0.001 0.02 0.06 0.64 0.07 0.89 0.69
79.4%
81.4%
74.4%
0.36
11.1% 12.3% 3.1%
— — —
41.8% 46.5% 11.7%
— — —
1.9% 17.3% 13.0% 17.3%
— — — —
6.5% 60.9% 45.7% 60.9%
— — — —
* Calculated by thermodilution at rest. † Significant CAD defined as ⱖ50% stenosis in ⱖ1 major epicardial coronary artery. Table 4 Unadjusted and adjusted Cox proportional hazard models for predictors of all-cause mortality over time
Figure 1. Kaplan-Meier analysis of survival time after first screening visit at the clinic. Comparison of patients with PAH and significant CAD to those without significant CAD.
The etiology of PAH stratified by the presence or absence of CAD is listed in Table 2. Most of the patients (81.5%) had idiopathic PAH or PAH associated with collagen vascular disease. Of the collagen vascular diseases, systemic sclerosis was the leading cause, present in 46 (73.0%) of the 63 patients. Of the congenital heart diseases, secundum atrial septal defect was the leading cause, present in 9 (60%) of the 15 patients.
Variable
Unadjusted HR (95% CI)
Adjusted HR* (95% CI)
Age (years) Men Significant coronary artery disease† Hypertension Obesity Smoker Diabetes mellitus Dyslipidemia Idiopathic pulmonary arterial hypertension Scleroderma-associated pulmonary arterial hypertension Normal right ventricular function on echocardiogram Mean pulmonary artery pressure (mm Hg) Right atrial pressure (mm Hg) Pulmonary vascular resistance (Wood units) Cardiac output (L/min) Cardiac index (L/min/m2)
1.03 (1.02–1.05) 1.66 (0.92–2.99) 1.97 (1.21–3.20) 1.38 (0.85–2.25) 1.58 (0.95–2.62) 1.23 (0.75–2.03) 1.24 (0.61–2.50) 1.23 (0.70–2.10) 1.09 (0.68–1.76)
1.02 (1.00–1.05) — 1.52 (0.84–2.74) — — — — — —
2.28 (1.37–3.77)
1.70 (0.95–3.06)
0.42 (0.20–0.86)
—
1.01 (0.99–1.03)
—
1.07 (1.02–1.11) 1.01 (0.97–1.05)
1.08 (1.03–1.14) —
0.84 (0.70–1.02) 0.70 (0.50–0.97)
— 0.77 (0.55–1.09)
* Adjustments were made for age, CAD, scleroderma-associated PAH, right atrial pressure, and cardiac index. † Significant CAD defined as ⱖ50% stenosis in ⱖ1 major epicardial coronary artery.
The hemodynamic and angiographic data at diagnosis, stratified by the presence or absence of CAD, are listed in Table 3. The patients with PAH and CAD had a lower mean pulmonary artery pressure than the patients without CAD.
Miscellaneous/Impact of CAD on PAH
No differences were found with respect to cardiac output, pulmonary capillary wedge pressure, pulmonary vascular resistance, and right atrial pressure. Two-vessel CAD was the most frequent diagnosis. Significant coronary stenoses were detected equally in the left anterior descending artery and right coronary artery and less often in the left circumflex artery. During the study period, 22.0% of patients with CAD underwent percutaneous coronary intervention. All through the follow-up period, myocardial infarction occurred in 4.4% and 0.0% of patients with and without CAD, respectively (p ⫽ 0.08). During a median follow-up of 36 months (25% to 75% interquartile range 17 to 71), 73 patients died. The survival estimate for all patients was 87.1%, 67.3%, and 58.5% at 1, 3, and 5 years, respectively. The Kaplan-Meier estimates for each group were compared and revealed worse survival for those patients with CAD (log-rank p ⫽ 0.005; Figure 1). On univariate analysis, age, CAD, scleroderma associated PAH, abnormal right ventricular function, right atrial pressure, and cardiac index were associated with all-cause mortality (Table 4). These parameters were entered into the multivariate analysis, with the exception of right ventricular function, because that is reflected in the right atrial pressure. The presence of CAD was a predictor for all-cause mortality on univariate analysis (HR 1.97, 95% CI 1.21 to 3.20). However, the multivariate Cox proportion hazard models suggested that only age (HR 1.03, 95% CI 1.01 to 1.05) and right atrial pressure (HR 1.08, 95% CI 1.03 to 1.14), were predictive of mortality (Table 4). Discussion The cohort of patients at our Center for Pulmonary Vascular Disease provided a rare opportunity to study the prevalence of CAD in a PAH population. With few exceptions, every 1 of our patients underwent coronary angiography at the baseline evaluation, enabling collection of sequential data. Thus, we were able to provide the prevalence, clinical correlates, and effect on mortality of CAD among our patients with PAH. We found that CAD is common. CAD prevalence increased with age, dyslipidemia, and hypertension, but we did not detect an independent prognostic effect of CAD on mortality. The true prevalence of CAD in the general population is unknown, because coronary angiography is not performed routinely in asymptomatic subjects. The estimates of the prevalence of CAD in patients ⱖ18 years old in the United States population range from 4.3% to 6.1%.6 Enbergs et al7 determined the prevalence of CAD in persons 40 to 70 years old referred for catheter electrophysiologic ablation therapy for arrhythmia. In 331 consecutive patients with a mean age of 53 ⫾ 7 years and a greater percentage of men (52.3%) compared to our study, the prevalence of CAD was 7.3%. These rates were much lower than those found in our cohort, although one might have expected a lower prevalence in our study owing to the greater female/male ratio than in the other studies. One explanation for the high rate in our cohort might be the shared pathogenic mechanisms between atherosclerosis and PAH, with similar inflammatory pathways in the coronary and pulmonary microvasculature advancing the progress of each disease.8,9 There could also be a causal
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relation. The pathogenic proliferative cytokines produced in PAH such as endothelin-1 might advance the atherosclerotic processes in the coronary arteries.10 –12 We compared the demographic, clinical, and hemodynamic data in patients with PAH who did or did not have CAD on their initial workup. The age at diagnosis for the whole cohort was similar to that reported in the recent Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL) registry.1 The patients with CAD, however, were older than those without CAD, reflecting the expected development of coronary atherosclerosis with increasing age. Also, our registry demonstrated a female preponderance with a 3.6:1 and 6.3:1 female/male ratio among those patients with PAH and with or without CAD, respectively. This marked female preponderance in those with PAH observed in our study is consistent with that observed in previous reports.1,13 Also, unlike a prevalence study of CAD in a general population that would detect a male predominance, the gender bias of PAH toward women likely introduced a female referral bias to our center. As expected, patients with CAD were more likely to have common cardiovascular risk factors such as hypertension and dyslipidemia or a history of previous myocardial infarction and coronary procedures. However, the prevalence of CAD in our cohort was much greater than that found in a population with similar mean age and risk factors.7 Therefore, the tendency to develop CAD in this unique population might not be predicted only by measuring the established cardiovascular risk factors but might represent a possible association between PAH and CAD. Only a few patients with CAD underwent percutaneous coronary intervention during the follow-up period, reflecting the conservative approach to asymptomatic CAD in our center. Also, the 20-year span of the study, beginning in 1990, covered a period from the infancy of coronary angioplasty through to the routine use of angioplasty and stenting of high-risk lesions, and the clinical practice has evolved accordingly. Because of the small number of patients, we were not able to identify a beneficial effect of percutaneous coronary intervention in patients with PAH and CAD. It is not surprising that no difference was found in the pulmonary artery wedge pressure between the patients with and without CAD— by definition, PAH excludes left heart disease, systolic or diastolic, and any patient with an elevated wedge pressure was excluded from the PAH population a priori. The most common PAH-associated diagnosis were idiopathic or collagen vascular disease in both groups, similar to other reports.1 No apparent association was found between the PAH types and the presence of CAD. The significant differences in pulmonary artery pressure between the 2 groups in our study were not anticipated. Because of the small number of patients in each group, these findings should be interpreted with caution, and any interpretation must be speculative. These results might have resulted from unrecognized confounders such as the medications given for each group or a potential intolerance to greater pulmonary artery pressure in the presence of CAD, resulting in a selection bias. The observed differences could also have resulted from chance. In any case, they are of questionable clinical relevance because of the small mean difference between the 2 groups.
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CAD is a leading cause of death.6 Nevertheless, our results suggest that patients with PAH and documented CAD do not have worse mortality outcomes than those without. Our survival estimates were in line with those of other studies, which showed that the long-term prognosis of patients with PAH is poor, even with treatment.3,14,15 In the presence of PAH, which will most strongly drive the survival outcome, stable CAD might have little effect, if any. Moreover, as in previous studies, age and right atrial pressure were independent predictors for mortality. We were unable to detect an independent prognostic value for other clinical, demographic, and hemodynamic variables. This might reflect the lesser importance of these variables when adjusted in a multivariate model or reduced power to detect differences owing to our cohort size. The present study had a number of limitations. First, our study could have been affected by the changing classification of PAH during the past 20 years. However, we had complete diagnostic data on the patients, and the limitation was addressed by adjusting the patient diagnosis to contemporary PAH definitions. Furthermore, interpretation of the data was limited by the uncontrolled nature of an observational retrospective single-center study. However, owing to the similarity in the basic characteristics of patients with PAH with larger studies and the lengthy follow-up, we believe that the results are relevant to those of other PAH populations. Also, human immunodeficiency virus infection induces CAD, and the human immunodeficiency virus population had the potential to skew our reported frequency of CAD in those with PAH. However, we had only a few patients with the human immunodeficiency virus, and no increase in CAD was found in the human immunodeficiency virus group. Finally, we did not examine the effect of PAHand CAD-specific medications, the use of which might have had affected the outcomes. However, because of the evolving practice during the 20-year period, it would have been difficult to interpret the results.
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8. 9. 10.
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