| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
* From the Pat and Jim Calhoun Cardiology Center (Drs. Alkotob, Soltani, Katsetos, Hager, and Silverman), Division of Pulmonary Medicine and Critical Care (Drs. Sheatt and Foley), and the Division of Rheumatology (Dr. Rothfield), University of Connecticut School of Medicine. Farmington, CT.
Correspondence to: David I. Silverman, MD, Cardiology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-1305; e-mail: silverman{at}nso1.uchc.edu
Abstract
Objectives: We sought to determine the incidence of stress-induced pulmonary artery (PA) systolic hypertension in a referral population of patients with scleroderma, and to examine the relation between stress-induced pulmonary systolic hypertension and exercise capacity in this population.
Background: Early detection of patients with scleroderma at risk for pulmonary hypertension (PHTN) could lead to more timely intervention and thus reduce morbidity and improve mortality. The change in PA systolic pressure (PASP) with exercise provides a possible tool for such detection.
Methods: Sixty-five patients with scleroderma (9 men and 56 women; mean age 51 ± 12 years [SD]), normal resting PASP, and normal resting left ventricular function underwent exercise Doppler echocardiography using a standard Bruce protocol. Tricuspid regurgitation velocity was measured before and after exercise. Exercise variables including workload achieved in metabolic equivalents (METS), total exercise time, percentage of target heart rate achieved, and PASP at rest and within 60 s after exercise were recorded.
Results: Thirty patients (46%) demonstrated an increase in PASP to > 35 mm Hg plus an estimated right atrial pressure of 5 mm Hg. Postexercise PASP inversely correlated to both the maximum workload achieved (r = – 0.34, p = 0.006) and exercise time (r = – 0.31, p = 0.01). In women, the correlation was more significant (r = – 0.38, p = 0.003). Patients in the lowest quartile of exercise time, with the least cardiac workload achieved, produced the highest postexercise PASP.
Conclusion: Stress-induced PHTN is common in patients with scleroderma, even when resting PASP is normal. Stress Doppler echocardiography identifies scleroderma patients with an abnormal rise in PASP during exertion. Peak PASP is linearly related to exercise time and maximum workload achieved. Measurement of PASP during exercise may prove to be a useful tool for the identification of future resting PHTN.
Key Words: fibrosis • pulmonary arteriopathy • pulmonary hypertension • scleroderma • stress echocardiography • stress-induced hypertension
Pulmonary hypertension (PHTN) is a common complication of scleroderma that develops as the result of fibrosis and pulmonary arteriopathy,1 and produces much of its morbidity and mortality.2 Timely identification of PHTN, even in its earlier stages, may favorably alter disease management. Because the incidence and severity of PHTN is highly variable, a tool for early detection of this complication would be of value in identification of patients at risk for disease progression. While the "gold standard" for measurement of pulmonary artery (PA) pressure remains right-heart catheterization,3 quantification of tricuspid regurgitation velocity via Doppler echocardiography is a commonly employed, noninvasive alternative that correlates well with invasive measures.456 Neither method however, predicts exercise-induced PHTN in the presence of normal resting values.
A significant number of scleroderma patients have exertional dyspnea in the absence of elevated resting pulmonary pressures. To test the hypothesis that exercise-induced elevation of pulmonary pressure produces these symptoms, attempts have been made to look for evidence of PHTN occurring during exercise.7 In normal individuals, PA pressures with exercise have been reported to remain unchanged8 or increase slightly.9 In athletes, a greater increase was reported in one invasive study.10 In nonathletes, PA pressure increases at moderate workloads but begins to fall as the workload increases.11 A distinct tricuspid regurgitant Doppler flow pattern has also been reported in patients with exertional PHTN.12
In the aggregate, these data give rise to the hypothesis that an abnormal rise in PA systolic pressure (PASP) during exercise in selected patients with or without exertional dyspnea, but with normal or near-normal resting PA pressures, is a marker for the development of future resting PHTN.1314 To test this hypothesis, we used stress Doppler exercise testing to detect the development of stress-induced PHTN in a large group of patients with scleroderma and normal resting PASP.
Materials and Methods
Patients
The study included consecutive patients from February 2003 to April 2004 18 years old with a rheumatologist-established diagnosis of scleroderma by standard criteria.15 Patients were referred as part of their routine follow-up care. Both, patients with diffuse systemic sclerosis or limited scleroderma (CREST syndrome [calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia]) were accepted. PASP was normal or only mildly elevated at rest (PASP 
35 mm Hg plus estimated right atrial pressure of 5 mm Hg) when evaluated by continuous-wave Doppler echocardiography. All patients had normal left ventricular systolic function (ejection fraction > 55%) and no echocardiographic evidence of significant right ventricular dysfunction. Patients were excluded from the study if there was heart failure on physical examination, if tricuspid regurgitation was absent, if the tricuspid regurgitation velocity could not be determined accurately, or if ischemic ECG changes occurred during exercise. The study was approved by the University of Connecticut Health Center Institutional Review Board.
Study Protocol
A complete resting echocardiographic examination was performed immediately prior to exercise. Special care was given to determine tricuspid regurgitation velocity. Evidence (or lack thereof) of congestive heart failure by physical examination was documented prior to exercise. Sixty-three patients followed a standard Bruce protocol, and the remainder (n = 2) underwent a modified Bruce protocol because of musculoskeletal limitations due to their scleroderma. Patients were counseled to exercise until they believed they could go no further, and the exercise test was terminated when patients reached their maximum capacity. A repeat continuous-wave Doppler echocardiographic evaluation was performed with immediate focus on postexercise tricuspid regurgitation velocity in the four-chamber view. All repeat tests were completed within 60 s after exercise. Exercise data were recorded with the maximum workload estimated by standard metabolic equivalents (METS). Echocardiographic data were recorded during the examination and reviewed later for confirmation. One investigator (Dr. Silverman) reviewed all studies.
Study Objectives and Definitions
The primary objective of the study was to measure the frequency of stress-induced PHTN in this patient population. The secondary objective was to determine the relation (if any) between the maximum workload achieved and the maximum PASP measured at peak exercise.
Data Analysis
All data are reported as mean ± SD unless otherwise stated. A correlation analysis comparing PASP with workload and exercise time was performed measuring Pearson correlation coefficient. Assuming a 25% change in PASP and an SD of 4 min across the entire distribution of exercise times, a sample size of n = 44 achieves 81% power at a significance level (
) of 0.05. Data analysis was performed using statistical software (SPSS, version 12.0; SPSS; Chicago, IL).
Results
All patients had normal wall motion at baseline. There were no clinical signs of heart failure on physical examination. The vast majority of patients had no left ventricular hypertrophy. Diabetes (n = 1) and hypertension (n = 6) were infrequent. Resting diastolic function was normal (Table 1 ). Pulmonary function data were available for 57 patients (87%; Table 1). Right atrial pressure was estimated at 5 mm Hg for all patients. No patients complained of exertional chest pain. Thirty patients (46%) produced an abnormal rise in PASP (> 40 mm Hg) during exercise. Of these 30 patients, two thirds (n = 20) had CREST syndrome, and one third (n = 10) had diffuse systemic sclerosis. Exercise time, workload, and postexercise PASP varied widely (Table 1). Forty-five patients (69%) achieved a heart rate (HR) > 85% of their age-predicted maximum. Mean overall increase in PASP was 14 ± 8 mm Hg.
|
No difference was noted, however, in either resting PASP (20 ± 8 mm Hg vs 18 ± 10 mm Hg) or PASP at peak exercise (30 ± 11 mm Hg vs 34 ± 13 mm Hg). Seventeen of 36 patients with limited scleroderma (3 men and 33 women; mean age, 51 ± 12 years) were anti-centromere autoantibody positive. Nine of these patients (53%) demonstrated an abnormal increase in PASP (> 40 mm Hg) during exercise, compared to 4 of 19 patients with negative anti-centromere autoantibodies (
2 = 4.79, p < 0.05).
Because energy exerted varies with each stage of Bruce protocol, separate analyses for both exercise time and workload achieved in METS were performed. Workload achieved in METs was significantly correlated to all four lung function parameters: FVC, FEV1, total lung capacity (TLC), and diffusion capacity of the lung for carbon monoxide (DLCO) [r = –0.32 or greater; p < 0.001 for FEV1; p = 0.004 for FVC; p = 0.016 for TLC; and p = 0.006 for DLCO]. Total exercise time was correlated with FEV1, FVC, and DLCO (r = 0.3 or greater; p = 0.014 for FEV1; p = 0.022 for FVC; and p = 0.03 for DLCO) compared with exercise time. PASP was not significantly correlated to any PFT variable.
Neither exercise time nor workload achieved were significantly correlated with age alone. PASP after exercise correlated to workload achieved (r = – 0.34, p = 0.0006; Fig 1 ). The higher the postexercise PA pressure observed, the lower the workload achieved. Total exercise time and PASP after exercise were also significantly correlated (r = – 0.31, p = 0.01). Among women, the correlation between PASP and workload (r = – 0.38, p = 0.003; Fig 2 ) and PASP and exercise time (r = – 0.35, p = 0.008) was greater than the entire population. When the subset of patients with stress-induced PHTN (n = 30) was analyzed, correlation between total exercise time or METS and PASP did not improve. HR, expressed as a fraction of age-predicted maximum, was also correlated with cardiac workload (r = 0.46, p = 0.001). Neither maximum HR nor peak double product, however, correlated with PASP. Neither absolute change in PASP nor percentage change in PASP from baseline significantly correlated with workload achieved or total exercise time. When patients without pulmonary fibrosis were analyzed, however, total exercise time and stress PASP were significantly correlated (r = – 0.35, p = 0.018). Quartiles analysis demonstrated that patients in the lowest quartile of exercise time had the highest postexercise PASP (Fig 3 ). Univariate analysis assigning workload achieved in METS as the dependent variable and age, sex, double product at peak exercise, peak HR, resting PASP, poststress PASP, FEV1, FVC/FEV1, and adjusted DLCO covariants identified only peak HR as significantly predictive (F = 4.6, p = 0.04).
|
|
|
In this study, we demonstrate that stress-induced pulmonary systolic hypertension in patients with scleroderma is highly prevalent, and is associated with reduced exercise capacity, decreased maximum cardiac workload, and decreased adjusted DLCO. While our data do not directly examine the mechanism underlying these relations, they do suggest that determinants of exercise capacity in scleroderma patients may vary from those variables that govern more traditional populations undergoing exercise tolerance testing, including normal subjects16 and patients undergoing screening for ischemic heart disease.17 The incidence of PHTN in systemic sclerosis varies from 6 to 60%,1819 as PHTN can develop in either the limited or diffuse forms of this disease. The wide variability in reported incidence may be explained by the different populations studied. Patients with the limited form of scleroderma (CREST syndrome) more commonly acquire PHTN compared to those with the diffuse form of systemic sclerosis, who more frequently manifest interstitial lung disease. To add to the complexity, PHTN can also develop secondary to, or simultaneous with, interstitial lung disease.1819 Critically, why some patients with scleroderma acquire PHTN and others do not is unknown. Regardless of pathogenesis, our data give rise to the tantalizing hypothesis that the presence of stress-induced PHTN in scleroderma patients identifies a subset at high risk for resting PHTN over time.
Factors that determine exercise capacity have been studied extensively in both healthy populations16 and in patients with a variety of disease states.202122 Age, gender, muscle mass, level of adrenergic response, and baseline fitness all play a significant role in limiting maximum exercise capacity in normal individuals. For most patients with coronary artery disease, ischemia secondary to coronary atherosclerosis is the major determinant of exercise tolerance.17 While systolic BP normally rises with exercise as a function of increased cardiac output, pulmonary vascular resistance falls as the result of pulmonary vasodilatation, resulting in little or no change in PA pressure.23 Normal gas exchange increases linearly with cardiac workload and the minute ventilation/carbon dioxide production ratio falls. In contrast, patients with severe resting PHTN demonstrate maximum gas exchange at a much lower maximum work rate, and the minute ventilation/carbon dioxide production ratio rises with exercise.24 The combination of reduced carbon dioxide exchange secondary to pulmonary hypoperfusion and depleted energy stores because of increased anaerobic metabolism with subsequent rising lactate levels and muscle fatigue all combine to produce the dyspnea characteristic of PHTN.23 The loss of normal vasodilatation alone, in the face of increasing cardiac output, will produce a fixed pulmonary vascular resistance and a rise in PASP. By whatever mechanism, the dynamic increase in PASP seen in our patients mimics the pathophysiologic effects of patients with resting PHTN and results in an analogous reduction in exercise capacity.
The lack of correlation of total exercise time with the change in PASP suggests that multiple factors in these patients determine exercise tolerance, with no one factor predominant. The presence of pulmonary fibrosis, for example, clearly reduced exercise time without affecting peak PASP, and anti-centromere autoantibody-positive patients demonstrated a higher frequency of stress-induced PHTN than those whose antibody titers were normal. Lung volumes and DLCO were correlated to workload but not total exercise time and, as with other variables, did not remain statistically significant when subjected to univariate analysis. Furthermore, percentage change, or 
PASP, does not sufficiently account for baseline PASP pressure because patients whose changes fall within the normal range will obscure the importance of PASP in those who manifest an abnormal response. For instance, a patient beginning at a PA pressure of 15 mm Hg and rising to 35 mm Hg has produced a normal response, while a patient beginning at 35 mm Hg and rising to 55 mm Hg has just as clearly produced a response that is abnormal. Both changes, however, are the same. Such factors notwithstanding, the weight of the data suggest that an abnormal rise is PASP is an important variable in determining the ability to do cardiac work.
The successful creation of a program of serial stress Doppler exercise testing in this population also lays the foundation for prospective examination of the relation between the development and/or progression of stress-induced PHTN and the ultimate appearance of PHTN at rest. Several groups125 have reported the use of resting tricuspid flow as a screening tool for PHTN in scleroderma, but this report, to our knowledge, represents the first demonstration of stress Doppler for this purpose. Since 2001, the Rheumatology, Pulmonary Medicine and Cardiology Divisions of the University of Connecticut Health Center have initiated annual serial stress Doppler testing for all scleroderma patients. Patients who demonstrate a markedly abnormal response to exercise undergo right-heart catheterization in the traditional fashion with the addition of provocative isotonic exercise testing. Thus far, two patients with stress-induced PHTN and normal resting PA pressures at initial catheterization have acquired resting PHTN within the 3-year period. Resting PASP in one patient rose from 41 to 68 mm Hg within a 12-month period, and from 40 to 60 mm Hg in the second patient within 6 months. No patient to date with a normal stress Doppler response to exercise has acquired resting PHTN. While the total number of normal patients in whom pulmonary vascular response to exercise has been studied remains limited,11 the marked rise seen in our patients clearly lies outside of any normal distribution that has been, or is likely to be, reported.
Factors other than pulmonary vascular response to exercise undoubtedly contributed to determination of total exercise capacity, and may explain in part the relatively weak, although significant correlation between total cardiac workload and peak PASP. Age, variability of pulmonary involvement, and other comorbidities must be considered. Arthralgia, myalgia, inflammatory arthritis, and sclerodactyly itself are well-described complications within the broad spectrum of the disease26 that could limit exercise capacity out of proportion to any measurable hemodynamic effect. The ability of a majority of our patients to achieve age-adjusted target HR, and the strong correlation between fraction of target HR achieved and cardiac workload suggest that increased catecholamines (sympathetic drive), by some mechanism, may play a greater role in limiting exercise tolerance in our population than in normal subjects.
The emergence of several new therapies for PHTN, including epoprostenol, the prostacyclin analog trepopostinil, and the endothelin receptor antagonist bosentan, has increased the importance of timely diagnosis and identification of patients who may respond to therapy. The ability to measure PASP at peak exercise provides a potential tool for the evaluation of existent as well as potential therapies, and for gauging the timing of therapy. The experience described herein demonstrates that stress Doppler echocardiography exercise testing with determination of PASP at rest and at peak exercise represents an important first step in use of this tool for diagnosis, prognosis and evaluation of therapy in this challenging group of patients.
Acknowledgements
The authors thank Dr. Irfan Yusufzai for his assistance in data collection and management.
Footnotes
Abbreviations: CREST = calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia; DLCO = diffusion capacity of the lung for carbon monoxide; HR = heart rate; METS = metabolic equivalent; PA = pulmonary artery; PASP = pulmonary artery systolic pressure; PHTN = pulmonary hypertension; TLC = total lung capacity
Supported in part by National Institutes of Health General Clinical Research Center grant MO1RR06192.
There are no conflicts of interest or financial disclosures for any of the authors.
Received for publication August 5, 2005. Accepted for publication January 3, 2006.
References
Related Article
This article has been cited by other articles:
|
|
 |
|
  V. Steen, M. Chou, V. Shanmugam, M. Mathias, T. Kuru, and R. Morrissey Exercise-Induced Pulmonary Arterial Hypertension in Patients With Systemic Sclerosis Chest, July 1, 2008; 134(1): 146 - 151. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
