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* From the Division of Rheumatology (Drs. Fischer and Meehan, and Ms. Ulrich), Department of Radiology (Drs. Misumi and Lynch), Department of Biostatistics (Dr. Curran-Everett), and Interstitial Lung Disease Program (Drs. Swigris, Frankel, Cosgrove, and Brown), National Jewish Medical and Research Center, Denver, CO.
Correspondence to: Aryeh Fischer, MD, Division of Rheumatology, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206; e-mail: fischera{at}njc.org
Abstract
Objectives: To determine the prevalence and significance of pericardial abnormalities in systemic sclerosis (SSc)-related interstitial lung disease (ILD).
Methods: Retrospective study of 41 subjects with SSc-related ILD who underwent evaluation including thoracic high-resolution CT (HRCT) imaging, transthoracic echocardiography (TTE), and pulmonary function testing. HRCT review evaluated the pericardium for the presence of pericardial effusion (PEf), thickness of the anterior pericardial recess (APR) [abnormal defined as > 10 mm], and pericardial thickening as calculated by total pericardial score (TPS) [abnormal defined as > 8 mm]. Pulmonary arterial hypertension (PAH) was defined as a pulmonary artery pressure > 35 mm Hg estimated by TTE.
Results: Fifty-nine percent had an abnormal pericardium, 49% had a PEf, 56% had an abnormal APR, and 49% had an abnormal TPS. An abnormal pericardium was more common in men than women. Subjects with and without pericardial abnormalities were otherwise similar with respect to age, SSc classification, autoantibodies, ILD radiographic pattern, and presence of esophageal dilation. Both groups had similar median percentage of predicted total lung capacity, percentage of predicted FVC, percentage of predicted FEV1, and percentage of predicted diffusion capacity of the lung for carbon monoxide. Subjects with pericardial abnormalities were more likely to have coexistent PAH (35% vs 75%; p = 0.02) and a higher median right ventricular systolic pressure (31 mm Hg vs 44 mm Hg; p = 0.03). Multiple logistic regression revealed that TPS was the best individual predictor of the presence of TTE-defined PAH.
Conclusions: In patients with SSc-related ILD, pericardial abnormalities are commonly seen on HRCT, and their presence is strongly associated with echocardiographically defined PAH, with abnormal TPS as the best individual predictor.
Key Words: interstitial lung disease • pericardial abnormalities • pulmonary arterial hypertension • systemic sclerosis
Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by skin thickening, Raynaud phenomenon, and varying degrees of internal organ involvement. Based on the extent of cutaneous involvement, patients are typically classified as having either limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). Fifty to 80% of all SSc patients have pulmonary disease, with pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) the most common manifestations and the leading causes of morbidity and mortality.1 In general, patients with lcSSc are at higher risk for PAH, while patients with dcSSc are more likely to have progressive ILD1; many patients will have both.2
In SSc patients with PAH, a pericardial effusion (PEf) is common34; in fact, Steen5 has suggested that a large PEf may be the presenting feature of PAH in SSc. In patients with hemodynamically severe idiopathic PAH, pericardial abnormalities, defined as pericardial thickening or PEf, are also common.
As the newer therapies for PAH improve symptoms, functional status, and may reduce mortality, early recognition of PAH in SSc patients is increasingly important. We hypothesized that in SSc patients with ILD, pericardial abnormalities identified on high-resolution CT (HRCT) would be associated with the presence of PAH. To test this hypothesis, we retrospectively evaluated a cohort of patients with SSc-related ILD to determine the prevalence and clinical significance of CT evidence of pericardial abnormalities.
Materials and Methods
Subjects
We identified 41 subjects who consented to enroll in our institutional review board-approved and Health Insurance Portability and Accountability Act-compliant ILD database with SSc-related ILD who had undergone a comprehensive evaluation that included the following: history and physical examination, rheumatologic serologic testing, pulmonary function testing, thoracic HRCT imaging, and transthoracic echocardiography (TTE). All were seen at National Jewish Medical and Research Center between 1998 and 2004. All subjects met current American College of Rheumatology criteria for the diagnosis of SSc.6 The diagnosis of ILD was made based on the presence of respiratory symptoms, abnormal pulmonary physiology, and diffuse parenchymal lung disease on thoracic HRCT. No subject had symptomatic or previously identified pericardial abnormalities prior to the evaluation.
Analysis of Pericardial Abnormalities
Two expert thoracic radiologists (S.M., D.A.L.), blinded to clinical information, performed measurements of the pericardium as described by Bacque-Juston et al.7 Briefly, using conventional mediastinal window settings (level, 50 Hounsfield units; width, 350 Hounsfield units; 5 mm slice thickness), the presence or absence of a PEf was recorded (Fig 1
, top left, A, and top right, B). Measurement of pericardial thickening was performed at the one level between the aortic root and the diaphragm that displayed the maximal circumferential extent of the pericardium. Thickness was measured at four points around the circumference: the anterior, posterior, left lateral, and right lateral pericardium. The total pericardial score (TPS) was calculated and defined as the sum of these four measurements, with > 8 mm defined as abnormal (Fig 1, center left, C, and center right, D). The sagittal dimension of the anterior pericardial recess (APR) was measured anteriorly between the ascending aorta and the pulmonary trunk (Fig 1, bottom left, E, and bottom right, F). An abnormal APR was defined as > 10 mm. The central pulmonary artery diameter (PAD) was assessed at its point of maximal dilation.
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Statistical Analysis
We assessed differences between groups using Fisher exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. Multiple logistic regression analysis included the following variables: PEf, APR, TPS, rank TPS, PAD, esophageal dilation, ILD pattern, percentage of predicted total lung capacity, percentage of predicted FVC (ppFVC), percentage of predicted FEV1, percentage of predicted diffusion capacity of the lung for carbon monoxide (ppDLCO), ppDLCO/alveolar volume, gender, age, and SSc type (lcSSc, dcSSc).
Results
Twenty four of 41 subjects (59%) had an abnormal pericardium by HRCT. Twenty of 41 subjects (49%) had a PEf, 23 of 41 subjects (56%) had an abnormal APR, and 20 of 41 subjects (49%) had an abnormal TPS.
An abnormal pericardium was more common in men than women. Subjects with and without pericardial abnormalities were otherwise similar with respect to age, SSc classification, autoantibodies, ILD pattern, presence of esophageal dilation, and pulmonary physiology (Table 1 ). Subjects with pericardial abnormalities were more likely to have a higher median right ventricular systolic pressure (RVSP) and coexistent TTE-defined PAH (Table 2 ). Patients with TTE-defined PAH demonstrated similar pulmonary physiology but were more likely to have a PEf, an abnormal APR, and an abnormal TPS (Table 3 ).
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). Discussion
SSc patients commonly have asymptomatic pericardial abnormalities (reviewed by Deswal and Follansbee8), with autopsy series reporting a prevalence of 33 to 72%.8910111213 Fibrinous pericarditis, fibrous pericarditis, pericardial adhesions, and pericardial effusions have all been described.11 Screening echocardiographic evaluations have shown a prevalence of asymptomatic PEf of 13 to 55%.814151617 The prevalence of symptomatic pericardial abnormalities is much less prevalent, with studies8101112151819 reporting a prevalence of 4 to 16%. To our knowledge, this is the first study to evaluate the prevalence and clinical significance of asymptomatic pericardial abnormalities in patients with SSc-related ILD.
We found asymptomatic pericardial abnormalities in the majority of patients with SSc-related ILD. A widened APR, a PEf, and an abnormal TPS were all common. The presence of a PEf, an APR > 10 mm, or a TPS > 8 mm was strongly associated with the presence of echocardiographically defined PAH. Of these, TPS was the best individual predictor of coexistent PAH.
These findings are supported by previous studies34720 showing that an asymptomatic PEf is associated with both idiopathic and secondary forms of PAH. The presence of a PEf in patients with idiopathic PAH has been reported to be associated with right-heart failure, impaired exercise tolerance, and increased mortality.34 Similarly, it has been shown that the presence of a large PEf (> 200 mL) in patients with SSc is associated with a poor prognosis.15
It is not known why patients with PAH have pericardial abnormalities. In our subjects, we found a high concordance rate among PEf, a wide APR, and a wide TPS, and believe that they share a mechanistic link reflecting the presence of PAH. Increased right atrial pressure could contribute to the production of PEf via the direct drainage of some cardiac veins into the right atrium.7 Alternatively, pericardial fluid accumulation could be a passive transudative process resulting from increased pulmonary artery pressure.21
Steen and Medsger14 have shown that an isolated low or falling diffusion capacity is the best feature to predict the future development of PAH. However, in patients with progressive ILD, diffusion capacity may be low due to parenchymal lung disease and thus less predictive of pulmonary vasculopathy. Indeed, in our cohort of subjects with SSc-related ILD, we found no meaningful differences in the diffusion capacity or FVC/diffusion capacity ratio among those with or without PAH.
Patients with PAH are at risk for the development of right-heart failure and death from hypoxemia and ventricular arrhythmia.14 As medications such as bosentan, epoprostenol, sitaxsentan, and sildenafil have shown beneficial effects in patients with PAH, and may even alter the natural history of SSc-associated PAH, the early identification of those most likely to acquire PAH is of increasing importance.14
This study has limitations. This was a prospectively enrolled cohort of subjects with SSc and ILD who had been referred for further evaluation of their ILD and may not be typical for those seen in a general or specialized rheumatology practice. While the pericardial HRCT abnormalities were analyzed and collected in a blinded fashion, all TTE data were obtained by retrospective data review. The lack of right-heart catheterization to confirm cases of echocardiographically defined PAH adds a level of uncertainty regarding the presence of clinically significant PAH. While Doppler echocardiography has proven to be a convenient, noninvasive, and relatively accurate tool for evaluating PAH, the correlation between TTE-estimated PAH and right-heart catheterization may be variable.222324252627
In conclusion, we report that HRCT-defined pericardial abnormalities are common and clinically meaningful in patients with SSc-related ILD. The presence of pericardial abnormalities predicts the presence of echocardiographically defined PAH and should prompt a more definitive evaluation. Prospective studies are needed to confirm our findings and to establish whether the presence of pericardial abnormalities in patients with SSc-related ILD have prognostic implications.
Footnotes
Abbreviations: APR = anterior pericardial recess; dcSSc = diffuse cutaneous systemic sclerosis; HRCT = high-resolution CT; ILD = interstitial lung disease; lcSSc = limited cutaneous systemic sclerosis; PAD = pulmonary artery diameter; PAH = pulmonary arterial hypertension; PEf = pericardial effusion; ppDLCO = percentage of predicted diffusion capacity of the lung for carbon monoxide; ppFVC = percentage of predicted FVC; RVSP = right ventricular systolic pressure; SSc = systemic sclerosis; TPS = total pericardial score; TTE = transthoracic echocardiography
None of the authors have any financial or other potential conflicts of interest to disclose.
Received for publication September 19, 2006. Accepted for publication December 13, 2006.
References
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