Pulmonary Hypertension in the CREST Syndrome Variant of Progressive Systemic Sclerosis (Scleroderma) ROSEMARIE SALERNI, M.D.; GERALD P. RODNAN, M.D., F.A.C.P.; DONALD F. LEON, M.D., F.A.C.P.; and JAMES A. SHAVER, M.D., F.A.C.P.; Pittsburgh, Pennsylvania
Severe pulmonary hypertension without pulmonary fibrosis occurred in 10 patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia), reputedly a benign variant of progressive systemic sclerosis. Time from the initial symptom, Raynaud's phenomenon, to the recognition of pulmonary hypertension was as long as 40 years. Pulmonary hypertension and increased pulmonary vascular resistance was shown in all patients. Autopsy examination in three of six deaths attributable to pulmonary hypertension showed intimal proliferation with myxomatous change in the smalland medium-sized pulmonary arteries similar to changes in the digital arteries of patients with scleroderma and Raynaud's phenomenon, and interlobular renal arteries of those with "scleroderma kidney." It is concluded that the CREST syndrome is not entirely benign but may be complicated, after a long clinical course, by progressive pulmonary vascular obliteration, pulmonary hypertension, and death in the absence of significant pulmonary fibrosis.
I N 1964, WINTERBAUER (1) DESCRIBED seven patients with
a variant of progressive systemic sclerosis (scleroderma) characterized by relatively limited involvement of the skin (often confined to the fingers). He termed this the CRST syndrome based on the chief clinical features of calcinosis (C), Raynaud's phenomenon ( R ) , sclerodactyly ( S ) , and telangiectasia ( T ) , which permit ready identification of this disorder. These same clinical features occur in the classic form of progressive systemic sclerosis, which is marked by more diffuse, often global, scleroderma; but in the CRST syndrome the calcinosis is often much more extensive, the Raynaud's phenomenon more frequently complicated by digital ulcerations and gangrene, and the telangiectasia more profuse (2, 3 ) . Previous reports have emphasized the prolonged clinical course of these patients and stressed the "benign prognosis" of CRST syndrome compared with progressive systemic sclerosis (4, 5 ) . Prolonged observation, however, has shown that the CRST syndrome, although tending in general to pursue a very slowly progressive course, is associated in many instances with the • From the Divisions of Cardiology and Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine; and Presbyterian-University Hospital; Pittsburgh. Pennsylvania.
development of a set of serious and relatively distinctive internal disturbances ( 3 ) . The most frequent of these is esophageal dysfunction ( E ) , indistinguishable from that found in progressive systemic sclerosis, which tends to be more severe and appears in the majority of patients. It has been proposed, therefore, that CRST be amended to CREST syndrome ( 3 ) . In addition, there are at least two individual CREST cases reported with pulmonary hypertension, a well-recognized abnormality in progressive systemic sclerosis, described as a late complication (4, 5 ) . Although the hemodynamic evaluation of scleroderma patients with pulmonary hypertension has been reported ( 6 ) , pulmonary hypertension has not been evaluated in CREST patients and is the subject of this report. Materials and Methods During the past 20 years, we have had the opportunity to see more than 120 patients with CREST syndrome. Ten of these patients who had clinical evidence of pulmonary hypertension form the subjects of this report. Of this number, two had associated mitral valve disease, one having isolated severe mitral annulus calcification producing mitral orifice obstruction and incompetence and one having rheumatic heart disease with mitral stenosis and mild aortic regurgitation. Clinical histories, physical findings, chest X rays, and electrocardiograms were reviewed. Hemodynamic evaluation by right heart catheterization was done in all patients, and in six patients left heart catheterization was also done. Cardiac output was determined by the Fickor indicator dilution technique, or both, in seven patients. Total pulmonary resistance was calculated using cardiac output and mean pulmonary artery pressure and expressed as dynes * sec • cm"5 (normal 150 to 250 dynes • sec • cm"5). Pulmonary vascular or arteriolar resistance was calculated using the difference between pulmonary artery and pulmonary capillary or left atrial mean pressures and cardiac output (normal 45 to 120 dynes • sec • cm"5). Pulmonary function studies including carbon monoxide diffusing capacity were done in five patients. Survival and followup after hemodynamic evaluation was 1 to 38 months. The results of postmortem examination are available in three patients. Results CLINICAL COURSE AND FINDINGS
Clinical data are shown in Table 1. The patients ranged from 28 to 66 years of age at the time of hemodynamic evaluation. All were women with the exception of the two patients with mitral valve disease. Raynaud's phenomenon, which was the initial manifestation of the CREST syndrome in all cases, had been present from 3 to 40
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Figure 1. Serial roentgenograms of Patient 4 showing the progression of cardiac and pulmonary artery size. There is no evidence of interstitial pulmonary fibrosis. A. Initial study, with slight prominence of the pulmonary artery outflow tract (1968). B. Roentgenogram at the time of hemodynamic evaluation showing cardiomegaly, predominantly right atrium and ventricle, and enlarged proximal pulmonary arteries (1974).
years at the time of study. All patients had sclerodactyly, and, in addition, Patient 1 had minimal induration of facial skin and Patient 3 had generalized hyperpigmentation. Calcinosis, present predominantly in the hands, was evident clinically in four patients and was shown only roentgenographically in a fifth. Telangiectasia was most prominent on the fingers, palms, lips, face, and oral mucous membranes. Six patients had roentgenographic evidence of esophageal dysfunction without clinical symptoms except for esophageal reflux in one patient. Clinical evidence for other visceral manifestations of progressive systemic sclerosis involving the heart, lungs, and kidneys was notably absent. The most common cardiovascular symptom was exertional dyspnea, which had been present in all patients from 6 months to 2 years before hemodynamic evaluation. There was clinical evidence of pulmonary hypertension in all patients, consisting of an increased intensity of the pulmonic component of the second heart sound and a palpable parasternal heave. Five patients with the most severe pulmonary hypertension showed tricuspid regurgitation. At the time of study, four individuals had congestive heart failure with right ventricular decompensation secondary to pulmonary hypertension. A fifth patient with only minimal tricuspid regurgitation at the time of study subsequently developed congestive failure within 6 months after hemodynamic evaluation. Electrocardiographic evidence of right ventricular hypertrophy was present in eight patients. Roentgenographic examination disclosed mild cardiomegaly in nine patients and more marked enlargement in one patient (Patient 7) who had a large pericardial effusion. The most prominent abnormality was enlargement of the main and proximal pulmonary arteries. Figure 1 illustrates the progression of the pulmonary arterial changes in Patient 4. None of the patients had roentgenographic evidence of pulmonary interstitial fibrosis. Pulmonary carbon monoxide diffusing capacity was diminished in the five patients so tested. This was accompanied by a minimal decrease in lung volumes in two patients without significant restrictive or obstructive
spirometric abnormalities. In four patients with CREST syndrome death was directly attributable to pulmonary hypertension, and a fifth patient died suddenly 5 days postoperatively after a cholecystectomy. In a sixth patient (Patient 7 ) , it is possible that cardiac tamponade rather than pulmonary hypertension alone was responsible for death. These deaths occurred from 1 to 38 months after hemodynamic evaluation. HEMODYNAMIC DATA
A summary of the hemodynamic data is presented in Table 2. All patients had significant pulmonary hypertension, with pulmonary artery mean pressures of 32 to 65 mm Hg. Pulmonary capillary pressure was normal in six patients and only minimally elevated in one patient. There was no evidence of either left ventricular dysfunction or mitral valve disease and the left ventricular enddiastolic pressure was normal in one patient in whom a satisfactory pulmonary capillary pressure could not be obtained. The two patients with mitral valve disease had an expected elevation of their pulmonary capillary pressure. The cardiac output ranged from normal to severely depressed, with the most severely pulmonary hypertensive patients having the lower cardiac outputs. Total pulmonary resistance was elevated in each of the patients in whom this was measured. The major component of this was pulmonary vascular or arteriolar resistance, which ranged from 409 to 2413 dynes • sec • c m 5 . The two patients with mitral valve disease also had elevated postcapillary resistance with a proportionally lower component of pulmonary arteriolar resistance when compared with the other patients with CREST syndrome. Both patients with mitral stenosis had a mean diastolic gradient of 11 mm Hg across the mitral valve, and the degree of elevation of pulmonary artery pressure and resistance was compatible with the severity of their mitral stenosis. PATHOLOGY
Postmortem examination in Patient 1 showed a markedSalerni
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Table 1. Clinical Data*
Patient
Sex
Age
Duration of Raynaud's Phenomenon at Time of Study
Calcinosis
Sclerodactyly
Telangiectasia
Esophageal Dysfunction
4-
+ + + + + + + + + +
+
yrs
yrs 1 2
60 41
F F
19 9
+
3 4 5 6 7 8 9 10
56 69 64 66 28 48 61 46
F F F F F F M M
24 3 40 30 18 9 3 23
0 0
0
+ +0 0
+ +
+ + + + + + + + +
0
0
+ +0 +0 + -f
* + = present, O = absent, — = not available, + = expired. RVH = right ventricular hypertrophy, LVH = left ventricular hypertrophy, LBBB = left bundle branch block.
intimal change and focal areas of medial atrophy. Immunofluorescent staining of lung sections for immunoglobulin G (IgG), IgM, IgA, Clq, C3, C4, fibrin, albumin, transferrin, and alpha-2-macroglobulin showed deposits of IgG (trace-l + ), C l q (trace), and fibrin (1 + ) in the vascular intima. Concentric intimal proliferation was found in the smaller pulmonary arteries and arterioles. Elastic tissue stains showed an increased content of elastica in the vessel walls and reduplication of both the internal and external elastic membranes. The interlobular renal arteries showed minimal intimal proliferation similar to that in the pulmonary arteries of comparable size. Deposition of IgG, and Clq, IgM, and fibrin (trace-l + ) was also seen in the intima of renal arcuate and interlobular arteries by immunofluorescent study. At postmortem examination in Patient 7 the enlarged pericardial sac, which was under a minimal amount of tension, contained 1100 ml of serous fluid. The heart weighed 350 g and right ventricle hypertrophy was present (thickness, 1.1 c m ) . On microscopic examination of the lung only minimal, if any, interstitial fibrosis was seen. The pulmonary arteries and arterioles exhibited marked intimal thickening. There was slight to moderate thicken-
ly dilated and hypertrophied right ventricle (thickness, 0.5 cm). The heart weighed 360 g and the right ventricle composed the apex of the heart. There was no microscopic evidence of significant myocardial fibrosis. Grossly, the pulmonary arteries showed marked atherosclerosis. On microscopic examination, the walls of the small- and medium-sized pulmonary arteries were markedly thickened with striking intimal proliferation causing concentric luminal narrowing (Figure 2A). Minimal if any interstitial fibrosis was present in some areas (viewed by three pathologists); however, the extent and location of parenchymal fibrosis did not correspond to the severity of the vascular abnormalities. A minimal degree of intimal proliferation was present in the interlobular renal arteries. In Patient 3 the heart weighed 450 g and the right ventricle was also markedly dilated and hypertrophied (thickness, 0.6 cm). Moderate-to-severe pulmonary atherosclerosis was noted on gross examination. There was no evidence of pulmonary parenchymal fibrosis on microscopic examination (Figure IB). Various pulmonary arterial abnormalities were seen. In the larger- and mediumsized arteries extensive intimal proliferation and fibrosis were present. In the latter there were also myxomatous
Table 2. Hemodynamic Data*
Patient mRA
RV
PA
mm Hg 1 2 3 4 5 6 7 8
t9 tio
CO.
Pressures
14 7 4 14 10 5 8 12 7 5
100/0(15) 80/0 (7) 60/0 (8) 100/0(15) 94/0(12) 60/0 (6)
70/0 (7) ' 55/4 (7)
m
Total
m Wedge or LA litres/min
mm Hg 98/37 80/25 65/20 100/40 87/36 60/16 75/35 60/30 72/25 55/24
Pulmonar / Resistance
C.I.
63 40 35 65 43 32 50 40 36
6 8 8 5* 15 6 8 16 18
1.89 5.29 4.85 3.21 1.50
...
6.66 3.52
2
litres /min/m
dynes • sec -cm~5
1.16 3.19 2.89 1.95 1.19
2667 605 577 1620 2293
...
... ...
3.41 1.89
Vascular
480 818
2413 484 445 2027
... 288 409
* m = mean pressure, RA = right atrium, RV = right ventricle, number in ( ) = end-diastolic pressure, PA = pulmonary artery, LA = left atrium, CO = cardiac output, CI = cardiac index. t Mitral annulus calcification. t Rheumatic heart disease with mitral stenosis and mild aortic insufficiency.
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Table 1. (Continued)
Pulmonary Fibrosis (Roentgenogram)
Pulmonary Diffusing Capacity Percent of Predicted
0 0
38
RVH RVH
11/ 14/
0 0 0 0 0 0 0 0
50
RVH RVH RVH Sick sinus RVH RVH LBBB RVH/LVH
38/
Electrocardiogram
Follow-Up from Time of Study
Associated Diseases
months
52 42 37
— —
ing of the small- and medium-sized renal arterioles. Discussion
The CREST syndrome as originally described was felt to be a variant of progressive systemic sclerosis with only limited cutaneous involvement and a protracted clinical course ( 1 ) . It has become clear, however, with long-term follow-up, that patients with CREST syndrome often develop severe esophageal malfunction and intestinal disease characteristic of progressive systemic sclerosis. Early authors, while emphasizing the relatively benign and prolonged course of CREST syndrome, described the late development of pulmonary hypertension, resulting in death after 40 years in one patient (4) and in signs of cor pulmonale with congestive heart failure after 14 years in another ( 5 ) . Pulmonary hypertension, a well-recognized abnormality in progressive systemic sclerosis, was originally thought to be related to pulmonary interstitial fibrosis. In more recent studies, however, obliterative vascular disease has become recognized as a major cause of pulmonary hypertension (6, 7 ) . Sackner and associates (6) found poor correlation between the presence and severity of pulmonary hyper-
Hashimoto's thyroiditis Hypothyroidism (? Hashimoto's thyroiditis) ? Sjogren's syndrome ? Sjogren's syndrome
U 5/ 20 4/ 6 34 37
Sjogren's syndrome Sjogren's syndrome Calcified mitral annulus Rheumatic heart disease
tension in progressive systemic sclerosis, as ascertained by hemodynamic evaluation, and physiologic or roentgenographic evidence of pulmonary fibrosis, or both, and restrictive pulmonary disease. The severity of pulmonary hypertension and the presence of electrocardiographic evidence of right ventricular hypertrophy correlated best with the degree of proximal pulmonary artery enlargement. When categorized according to the clinical severity of pulmonary hypertension from those having no clinical evidence of pulmonary hypertension to those with cor pulmonale and at least one episode of right ventricular decompensation, the patients studied showed increasing elevation of pulmonary artery pressure and vascular resistance. In our study also, the patients with cor pulmonale and right ventricular decompensation exhibited the highest levels of pulmonary artery pressure and pulmonary vascular resistance. Patients with CREST syndrome without clinical evidence of pulmonary hypertension have not yet been assessed with respect to pulmonary vascular resistance. We presume that elevated pulmonary vascular resistance would be found in some patients with CREST syndrome not suspected of having pulmonary hypertension as is found in patients with classical progressive systemic sclerosis.
Figure 2A. Photomicrograph of lung, Patient 1. Medium-sized pulmonary artery with marked intimal proliferation and reduplication of the elastic membrane. (Verhoeff-Van Gieson stain; original magnification: microscopic, x 208, photographic, x 104.) B. Photomicrograph of lung, Patient 3. The parenchyma is normal without pulmonary fibrosis. There is intimal proliferation and reduplication of the elastic membrane in the pulmonary artery. (Trichrome-Verhoeff-Van Gieson stain; original magnification: microscopic, X 60, photographic, x 30.) Salerni
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Although right ventricular hypertrophy and pulmonary arterial abnormalities in scleroderma were initially described in 1887 ( 8 ) , it was not until 1924 that the importance of these pulmonary vascular changes was first emphasized by Matsui ( 9 ) . Several more recent reviews have described the vascular changes in the lungs as well as in other organs (10-14). As with the clinical and hemodynamic findings, there has been no correlation between the severity or extent of pulmonary vascular changes and the degree of parenchymal pulmonary fibrosis. The degree of elevation of pulmonary artery pressure and pulmonary vascular resistance is out of proportion to the degree of fibrosis present, as was seen microscopically in the patients in this report. The characteristic microscopic finding involving the small- and medium-sized pulmonary arteries and arterioles is intimal proliferation or thickening with narrowing of the vessel lumen, leading at times to nearly complete obliteration. Although medial hypertrophy may be seen, this is much less prominent than the intimal alteration and there is often a decreased thickness with areas of focal medial atrophy. These changes are similar if not identical to those found in the digital vessels of patients with progressive systemic sclerosis and Raynaud's phenomenon (11, 14), and in the interlobular renal arteries of patients with "scleroderma kidney" (2, 15). Pulmonary vascular lesions have also been described in patients with scleroderma who had no clinical evidence of pulmonary hypertension (12) indicating that these changes are the cause and not the result of pulmonary hypertension. The finding of immune globulin IgG and complement component Clq in the pulmonary vessels suggests the possibility the immune complexes may be deposited in the vessel walls. The role that immune complexes may play in the genesis of the intimal changes is not known. Such deposits have also been described in the interlobular renal arteries in scleroderma (16-18). Pulmonary hypertension associated with pulmonary arterial disease has been reported in other connective tissue diseases including systemic lupus erythematosus (19-23), dermatomyostitis (24), and rheumatoid arthritis (25-27). Pulmonary vascular abnormalities similar to those found in our three patients and others noted in the literature are seen in primary pulmonary hypertension with the addition of dilatation and plexiform lesions in the vessels of patients with the most severe hypertension (28, 29). Raynaud's phenomenon has been reported to occur in as many as 30% of patients with primary pulmonary hypertension (29-35). In reviewing these reports it is clear that a significant number include descriptions of cutaneous abnormalities present in the CREST syndrome (sclerodactyly and telangiectasia). Although some patients were felt to have connective tissue disease as well as primary pulmonary hypertension, the conclusion that there is an association between these disorders was not drawn perhaps because in the earlier literature the emphasis was placed on pulmonary fibrosis rather than arterial disease as the cause of pulmonary hypertension in progressive systemic sclerosis. In addition, the cutaneous manifestations of scleroderma in 398
the CREST syndrome variant may be subtle and confined to minimal sclerodactyly and telangiectasia and therefore overlooked. In one case description, for example, scleroderma was clearly present at postmortem examination yet no mention of this was made in the clinical presentation (36). Primary pulmonary hypertension is not a homogenous disease with respect to its clinical presentation and may represent one part of the connective tissue disease spectrum in which vascular abnormalities, specifically those of the pulmonary circulation, predominate. In our experience, the most severe degree of pulmonary hypertension associated with progressive systemic sclerosis has occurred most often in patients with the CREST syndrome variant, and pulmonary hypertension has been a major cause of death in these patients. In more than 350 patients with classical progressive systemic sclerosis we have seen no patients with pulmonary hypertension without pulmonary fibrosis or left ventricular dysfunction. The severity of pulmonary hypertension found in five patients who had hemodynamic evaluation was less than in the patients with CREST syndrome with pulmonary artery pressures of 21 to 48 mm Hg and pulmonary vascular resistance of 155 to 922 dynes • sec • cnr 5 . In the reports of Treli ( 7 ) , Case 2-1972 of the Massachusetts General Hospital (37), and two patients described by Opie (38), pulmonary hypertension is described in patients who clearly had the CREST variant of progressive systemic sclerosis. It is possible that the relatively high frequency of severe pulmonary hypertension in the CREST syndrome is related to prolonged survival of these individuals compared with patients with the classic form of progressive systemic sclerosis. The capacity of the pulmonary vascular bed is so great that many years may be necessary before pulmonary arterial changes lead to hemodynamically significant elevation of pulmonary vascular resistance and clinical pulmonary hypertension. It should be noted that in most of our patients with CREST syndrome, evidence of pulmonary hypertension first appeared long after (as many as 40 years) the onset of Raynaud's phenomenon. The CREST syndrome appears to be a subset of the connective tissue disease progressive systemic sclerosis with predominantly vascular manifestations. The origin of pulmonary hypertension in the CREST syndrome is obliterative vascular disease, and, although the clinical course is generally prolonged, severe progressive pulmonary hypertension can develop and lead to death. ACKNOWLEDGMENTS: The authors thank Dr. Martin Cohen and Dr. Stuart N. Novack for providing information on Patients 5 and 6 and giving their permission to include these patients in this report, and Dr. Francis S. Perrone for referring and providing follow-up information on Patient 7. Grant support: in part by Grant 5 TOl HL 05678-10 from the National Heart and Lung Institute, the RGK Foundation and the U.S. Public Health Service Grant FR-00056 from the National Institutes of Health. Presented in part at the 46th Session of the American Heart Association, 8 through 11 November, Atlantic City, New Jersey. Received 16 August 1976; revision accepted 17 December 1976. • Requests for reprints should be addressed to Rosemarie Salerni, M.D.; 789 Scaife Hall, University of Pittsburgh School of Medicine; Pittsburgh, PA 15261. References
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1. WINTERBAUER RH: Multiple telangiectasia, Raynaud's phenom-
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12. D'ANGELO WA, FRIES JF, MASI AT, et al: Pathologic obser-
vations in systemic sclerosis (scleroderma). Am J Med 46:428440, 1969 13. WEAVER AL, DIVERTIE MP, TITUS JL: Pulmonary scleroderma.
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hypertension. Am J Med 49:70-79, 1970 30. TAFT EB, MALLORY GK: Primary pulmonary vascular sclerosis. Arch Pathol 42:630-634, 1946 31. SMITH WM, KROOP IG: Raynaud's disease in primary pulmonary hypertension. JAMA 165:1245-1248, 1957 32. WADE G, BALL J: Unexplained pulmonary hypertension. Q J Med 26:83-119, 1957
Dis Chest 54:490-498, 1968 14. NORTON WL, NARDO JM: Vascular disease in progressive systemic sclerosis (scleroderma). Ann Intern Med 73:317-324, 1970
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deposits in scleroderma. Pathology 3:145-150, 1971 17. SCOTT DG, ROWELL NR: Immunohistological studies of the
kidney in systemic lupus erythematosus and systemic sclerosis using antisera to IgC, C3, fibrin, and human renal glomeruli. Ann Rheum Dis 33:473-481, 1974 18. GERBER MA: Immunohistochemical findings in the renal vascular lesions of progressive systemic sclerosis. Hum Pathol 6: 343-347, 1975 19. AITCHISON JD, WILLIAMS AW: Pulmonary changes in disseminated lupus erythematosus. Ann Rheum Dis 15:26-32, 1956
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Salerni et al. • CREST Syndrome
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Severe pulmonary hypertension without pulmonary fibrosis occurred in 10 patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia), reputedly a benign variant of progressive systemic sclerosis. Time from the initial symptom, Raynaud's phenomenon, to the recognition of pulmonary hypertension was as long as 40 years. Pulmonary hypertension and increased pulmonary vascular resistance was shown in all patients. Autopsy examination in three of six deaths attributable to pulmonary hypertension showed intimal proliferation with myxomatous change in the smalland medium-sized pulmonary arteries similar to changes in the digital arteries of patients with scleroderma and Raynaud's phenomenon, and interlobular renal arteries of those with "scleroderma kidney." It is concluded that the CREST syndrome is not entirely benign but may be complicated, after a long clinical course, by progressive pulmonary vascular obliteration, pulmonary hypertension, and death in the absence of significant pulmonary fibrosis.
I N 1964, WINTERBAUER (1) DESCRIBED seven patients with
a variant of progressive systemic sclerosis (scleroderma) characterized by relatively limited involvement of the skin (often confined to the fingers). He termed this the CRST syndrome based on the chief clinical features of calcinosis (C), Raynaud's phenomenon ( R ) , sclerodactyly ( S ) , and telangiectasia ( T ) , which permit ready identification of this disorder. These same clinical features occur in the classic form of progressive systemic sclerosis, which is marked by more diffuse, often global, scleroderma; but in the CRST syndrome the calcinosis is often much more extensive, the Raynaud's phenomenon more frequently complicated by digital ulcerations and gangrene, and the telangiectasia more profuse (2, 3 ) . Previous reports have emphasized the prolonged clinical course of these patients and stressed the "benign prognosis" of CRST syndrome compared with progressive systemic sclerosis (4, 5 ) . Prolonged observation, however, has shown that the CRST syndrome, although tending in general to pursue a very slowly progressive course, is associated in many instances with the • From the Divisions of Cardiology and Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine; and Presbyterian-University Hospital; Pittsburgh. Pennsylvania.
development of a set of serious and relatively distinctive internal disturbances ( 3 ) . The most frequent of these is esophageal dysfunction ( E ) , indistinguishable from that found in progressive systemic sclerosis, which tends to be more severe and appears in the majority of patients. It has been proposed, therefore, that CRST be amended to CREST syndrome ( 3 ) . In addition, there are at least two individual CREST cases reported with pulmonary hypertension, a well-recognized abnormality in progressive systemic sclerosis, described as a late complication (4, 5 ) . Although the hemodynamic evaluation of scleroderma patients with pulmonary hypertension has been reported ( 6 ) , pulmonary hypertension has not been evaluated in CREST patients and is the subject of this report. Materials and Methods During the past 20 years, we have had the opportunity to see more than 120 patients with CREST syndrome. Ten of these patients who had clinical evidence of pulmonary hypertension form the subjects of this report. Of this number, two had associated mitral valve disease, one having isolated severe mitral annulus calcification producing mitral orifice obstruction and incompetence and one having rheumatic heart disease with mitral stenosis and mild aortic regurgitation. Clinical histories, physical findings, chest X rays, and electrocardiograms were reviewed. Hemodynamic evaluation by right heart catheterization was done in all patients, and in six patients left heart catheterization was also done. Cardiac output was determined by the Fickor indicator dilution technique, or both, in seven patients. Total pulmonary resistance was calculated using cardiac output and mean pulmonary artery pressure and expressed as dynes * sec • cm"5 (normal 150 to 250 dynes • sec • cm"5). Pulmonary vascular or arteriolar resistance was calculated using the difference between pulmonary artery and pulmonary capillary or left atrial mean pressures and cardiac output (normal 45 to 120 dynes • sec • cm"5). Pulmonary function studies including carbon monoxide diffusing capacity were done in five patients. Survival and followup after hemodynamic evaluation was 1 to 38 months. The results of postmortem examination are available in three patients. Results CLINICAL COURSE AND FINDINGS
Clinical data are shown in Table 1. The patients ranged from 28 to 66 years of age at the time of hemodynamic evaluation. All were women with the exception of the two patients with mitral valve disease. Raynaud's phenomenon, which was the initial manifestation of the CREST syndrome in all cases, had been present from 3 to 40
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Annals of Internal Medicine 86:394-399, 1977
Figure 1. Serial roentgenograms of Patient 4 showing the progression of cardiac and pulmonary artery size. There is no evidence of interstitial pulmonary fibrosis. A. Initial study, with slight prominence of the pulmonary artery outflow tract (1968). B. Roentgenogram at the time of hemodynamic evaluation showing cardiomegaly, predominantly right atrium and ventricle, and enlarged proximal pulmonary arteries (1974).
years at the time of study. All patients had sclerodactyly, and, in addition, Patient 1 had minimal induration of facial skin and Patient 3 had generalized hyperpigmentation. Calcinosis, present predominantly in the hands, was evident clinically in four patients and was shown only roentgenographically in a fifth. Telangiectasia was most prominent on the fingers, palms, lips, face, and oral mucous membranes. Six patients had roentgenographic evidence of esophageal dysfunction without clinical symptoms except for esophageal reflux in one patient. Clinical evidence for other visceral manifestations of progressive systemic sclerosis involving the heart, lungs, and kidneys was notably absent. The most common cardiovascular symptom was exertional dyspnea, which had been present in all patients from 6 months to 2 years before hemodynamic evaluation. There was clinical evidence of pulmonary hypertension in all patients, consisting of an increased intensity of the pulmonic component of the second heart sound and a palpable parasternal heave. Five patients with the most severe pulmonary hypertension showed tricuspid regurgitation. At the time of study, four individuals had congestive heart failure with right ventricular decompensation secondary to pulmonary hypertension. A fifth patient with only minimal tricuspid regurgitation at the time of study subsequently developed congestive failure within 6 months after hemodynamic evaluation. Electrocardiographic evidence of right ventricular hypertrophy was present in eight patients. Roentgenographic examination disclosed mild cardiomegaly in nine patients and more marked enlargement in one patient (Patient 7) who had a large pericardial effusion. The most prominent abnormality was enlargement of the main and proximal pulmonary arteries. Figure 1 illustrates the progression of the pulmonary arterial changes in Patient 4. None of the patients had roentgenographic evidence of pulmonary interstitial fibrosis. Pulmonary carbon monoxide diffusing capacity was diminished in the five patients so tested. This was accompanied by a minimal decrease in lung volumes in two patients without significant restrictive or obstructive
spirometric abnormalities. In four patients with CREST syndrome death was directly attributable to pulmonary hypertension, and a fifth patient died suddenly 5 days postoperatively after a cholecystectomy. In a sixth patient (Patient 7 ) , it is possible that cardiac tamponade rather than pulmonary hypertension alone was responsible for death. These deaths occurred from 1 to 38 months after hemodynamic evaluation. HEMODYNAMIC DATA
A summary of the hemodynamic data is presented in Table 2. All patients had significant pulmonary hypertension, with pulmonary artery mean pressures of 32 to 65 mm Hg. Pulmonary capillary pressure was normal in six patients and only minimally elevated in one patient. There was no evidence of either left ventricular dysfunction or mitral valve disease and the left ventricular enddiastolic pressure was normal in one patient in whom a satisfactory pulmonary capillary pressure could not be obtained. The two patients with mitral valve disease had an expected elevation of their pulmonary capillary pressure. The cardiac output ranged from normal to severely depressed, with the most severely pulmonary hypertensive patients having the lower cardiac outputs. Total pulmonary resistance was elevated in each of the patients in whom this was measured. The major component of this was pulmonary vascular or arteriolar resistance, which ranged from 409 to 2413 dynes • sec • c m 5 . The two patients with mitral valve disease also had elevated postcapillary resistance with a proportionally lower component of pulmonary arteriolar resistance when compared with the other patients with CREST syndrome. Both patients with mitral stenosis had a mean diastolic gradient of 11 mm Hg across the mitral valve, and the degree of elevation of pulmonary artery pressure and resistance was compatible with the severity of their mitral stenosis. PATHOLOGY
Postmortem examination in Patient 1 showed a markedSalerni
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Table 1. Clinical Data*
Patient
Sex
Age
Duration of Raynaud's Phenomenon at Time of Study
Calcinosis
Sclerodactyly
Telangiectasia
Esophageal Dysfunction
4-
+ + + + + + + + + +
+
yrs
yrs 1 2
60 41
F F
19 9
+
3 4 5 6 7 8 9 10
56 69 64 66 28 48 61 46
F F F F F F M M
24 3 40 30 18 9 3 23
0 0
0
+ +0 0
+ +
+ + + + + + + + +
0
0
+ +0 +0 + -f
* + = present, O = absent, — = not available, + = expired. RVH = right ventricular hypertrophy, LVH = left ventricular hypertrophy, LBBB = left bundle branch block.
intimal change and focal areas of medial atrophy. Immunofluorescent staining of lung sections for immunoglobulin G (IgG), IgM, IgA, Clq, C3, C4, fibrin, albumin, transferrin, and alpha-2-macroglobulin showed deposits of IgG (trace-l + ), C l q (trace), and fibrin (1 + ) in the vascular intima. Concentric intimal proliferation was found in the smaller pulmonary arteries and arterioles. Elastic tissue stains showed an increased content of elastica in the vessel walls and reduplication of both the internal and external elastic membranes. The interlobular renal arteries showed minimal intimal proliferation similar to that in the pulmonary arteries of comparable size. Deposition of IgG, and Clq, IgM, and fibrin (trace-l + ) was also seen in the intima of renal arcuate and interlobular arteries by immunofluorescent study. At postmortem examination in Patient 7 the enlarged pericardial sac, which was under a minimal amount of tension, contained 1100 ml of serous fluid. The heart weighed 350 g and right ventricle hypertrophy was present (thickness, 1.1 c m ) . On microscopic examination of the lung only minimal, if any, interstitial fibrosis was seen. The pulmonary arteries and arterioles exhibited marked intimal thickening. There was slight to moderate thicken-
ly dilated and hypertrophied right ventricle (thickness, 0.5 cm). The heart weighed 360 g and the right ventricle composed the apex of the heart. There was no microscopic evidence of significant myocardial fibrosis. Grossly, the pulmonary arteries showed marked atherosclerosis. On microscopic examination, the walls of the small- and medium-sized pulmonary arteries were markedly thickened with striking intimal proliferation causing concentric luminal narrowing (Figure 2A). Minimal if any interstitial fibrosis was present in some areas (viewed by three pathologists); however, the extent and location of parenchymal fibrosis did not correspond to the severity of the vascular abnormalities. A minimal degree of intimal proliferation was present in the interlobular renal arteries. In Patient 3 the heart weighed 450 g and the right ventricle was also markedly dilated and hypertrophied (thickness, 0.6 cm). Moderate-to-severe pulmonary atherosclerosis was noted on gross examination. There was no evidence of pulmonary parenchymal fibrosis on microscopic examination (Figure IB). Various pulmonary arterial abnormalities were seen. In the larger- and mediumsized arteries extensive intimal proliferation and fibrosis were present. In the latter there were also myxomatous
Table 2. Hemodynamic Data*
Patient mRA
RV
PA
mm Hg 1 2 3 4 5 6 7 8
t9 tio
CO.
Pressures
14 7 4 14 10 5 8 12 7 5
100/0(15) 80/0 (7) 60/0 (8) 100/0(15) 94/0(12) 60/0 (6)
70/0 (7) ' 55/4 (7)
m
Total
m Wedge or LA litres/min
mm Hg 98/37 80/25 65/20 100/40 87/36 60/16 75/35 60/30 72/25 55/24
Pulmonar / Resistance
C.I.
63 40 35 65 43 32 50 40 36
6 8 8 5* 15 6 8 16 18
1.89 5.29 4.85 3.21 1.50
...
6.66 3.52
2
litres /min/m
dynes • sec -cm~5
1.16 3.19 2.89 1.95 1.19
2667 605 577 1620 2293
...
... ...
3.41 1.89
Vascular
480 818
2413 484 445 2027
... 288 409
* m = mean pressure, RA = right atrium, RV = right ventricle, number in ( ) = end-diastolic pressure, PA = pulmonary artery, LA = left atrium, CO = cardiac output, CI = cardiac index. t Mitral annulus calcification. t Rheumatic heart disease with mitral stenosis and mild aortic insufficiency.
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Table 1. (Continued)
Pulmonary Fibrosis (Roentgenogram)
Pulmonary Diffusing Capacity Percent of Predicted
0 0
38
RVH RVH
11/ 14/
0 0 0 0 0 0 0 0
50
RVH RVH RVH Sick sinus RVH RVH LBBB RVH/LVH
38/
Electrocardiogram
Follow-Up from Time of Study
Associated Diseases
months
52 42 37
— —
ing of the small- and medium-sized renal arterioles. Discussion
The CREST syndrome as originally described was felt to be a variant of progressive systemic sclerosis with only limited cutaneous involvement and a protracted clinical course ( 1 ) . It has become clear, however, with long-term follow-up, that patients with CREST syndrome often develop severe esophageal malfunction and intestinal disease characteristic of progressive systemic sclerosis. Early authors, while emphasizing the relatively benign and prolonged course of CREST syndrome, described the late development of pulmonary hypertension, resulting in death after 40 years in one patient (4) and in signs of cor pulmonale with congestive heart failure after 14 years in another ( 5 ) . Pulmonary hypertension, a well-recognized abnormality in progressive systemic sclerosis, was originally thought to be related to pulmonary interstitial fibrosis. In more recent studies, however, obliterative vascular disease has become recognized as a major cause of pulmonary hypertension (6, 7 ) . Sackner and associates (6) found poor correlation between the presence and severity of pulmonary hyper-
Hashimoto's thyroiditis Hypothyroidism (? Hashimoto's thyroiditis) ? Sjogren's syndrome ? Sjogren's syndrome
U 5/ 20 4/ 6 34 37
Sjogren's syndrome Sjogren's syndrome Calcified mitral annulus Rheumatic heart disease
tension in progressive systemic sclerosis, as ascertained by hemodynamic evaluation, and physiologic or roentgenographic evidence of pulmonary fibrosis, or both, and restrictive pulmonary disease. The severity of pulmonary hypertension and the presence of electrocardiographic evidence of right ventricular hypertrophy correlated best with the degree of proximal pulmonary artery enlargement. When categorized according to the clinical severity of pulmonary hypertension from those having no clinical evidence of pulmonary hypertension to those with cor pulmonale and at least one episode of right ventricular decompensation, the patients studied showed increasing elevation of pulmonary artery pressure and vascular resistance. In our study also, the patients with cor pulmonale and right ventricular decompensation exhibited the highest levels of pulmonary artery pressure and pulmonary vascular resistance. Patients with CREST syndrome without clinical evidence of pulmonary hypertension have not yet been assessed with respect to pulmonary vascular resistance. We presume that elevated pulmonary vascular resistance would be found in some patients with CREST syndrome not suspected of having pulmonary hypertension as is found in patients with classical progressive systemic sclerosis.
Figure 2A. Photomicrograph of lung, Patient 1. Medium-sized pulmonary artery with marked intimal proliferation and reduplication of the elastic membrane. (Verhoeff-Van Gieson stain; original magnification: microscopic, x 208, photographic, x 104.) B. Photomicrograph of lung, Patient 3. The parenchyma is normal without pulmonary fibrosis. There is intimal proliferation and reduplication of the elastic membrane in the pulmonary artery. (Trichrome-Verhoeff-Van Gieson stain; original magnification: microscopic, X 60, photographic, x 30.) Salerni
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Although right ventricular hypertrophy and pulmonary arterial abnormalities in scleroderma were initially described in 1887 ( 8 ) , it was not until 1924 that the importance of these pulmonary vascular changes was first emphasized by Matsui ( 9 ) . Several more recent reviews have described the vascular changes in the lungs as well as in other organs (10-14). As with the clinical and hemodynamic findings, there has been no correlation between the severity or extent of pulmonary vascular changes and the degree of parenchymal pulmonary fibrosis. The degree of elevation of pulmonary artery pressure and pulmonary vascular resistance is out of proportion to the degree of fibrosis present, as was seen microscopically in the patients in this report. The characteristic microscopic finding involving the small- and medium-sized pulmonary arteries and arterioles is intimal proliferation or thickening with narrowing of the vessel lumen, leading at times to nearly complete obliteration. Although medial hypertrophy may be seen, this is much less prominent than the intimal alteration and there is often a decreased thickness with areas of focal medial atrophy. These changes are similar if not identical to those found in the digital vessels of patients with progressive systemic sclerosis and Raynaud's phenomenon (11, 14), and in the interlobular renal arteries of patients with "scleroderma kidney" (2, 15). Pulmonary vascular lesions have also been described in patients with scleroderma who had no clinical evidence of pulmonary hypertension (12) indicating that these changes are the cause and not the result of pulmonary hypertension. The finding of immune globulin IgG and complement component Clq in the pulmonary vessels suggests the possibility the immune complexes may be deposited in the vessel walls. The role that immune complexes may play in the genesis of the intimal changes is not known. Such deposits have also been described in the interlobular renal arteries in scleroderma (16-18). Pulmonary hypertension associated with pulmonary arterial disease has been reported in other connective tissue diseases including systemic lupus erythematosus (19-23), dermatomyostitis (24), and rheumatoid arthritis (25-27). Pulmonary vascular abnormalities similar to those found in our three patients and others noted in the literature are seen in primary pulmonary hypertension with the addition of dilatation and plexiform lesions in the vessels of patients with the most severe hypertension (28, 29). Raynaud's phenomenon has been reported to occur in as many as 30% of patients with primary pulmonary hypertension (29-35). In reviewing these reports it is clear that a significant number include descriptions of cutaneous abnormalities present in the CREST syndrome (sclerodactyly and telangiectasia). Although some patients were felt to have connective tissue disease as well as primary pulmonary hypertension, the conclusion that there is an association between these disorders was not drawn perhaps because in the earlier literature the emphasis was placed on pulmonary fibrosis rather than arterial disease as the cause of pulmonary hypertension in progressive systemic sclerosis. In addition, the cutaneous manifestations of scleroderma in 398
the CREST syndrome variant may be subtle and confined to minimal sclerodactyly and telangiectasia and therefore overlooked. In one case description, for example, scleroderma was clearly present at postmortem examination yet no mention of this was made in the clinical presentation (36). Primary pulmonary hypertension is not a homogenous disease with respect to its clinical presentation and may represent one part of the connective tissue disease spectrum in which vascular abnormalities, specifically those of the pulmonary circulation, predominate. In our experience, the most severe degree of pulmonary hypertension associated with progressive systemic sclerosis has occurred most often in patients with the CREST syndrome variant, and pulmonary hypertension has been a major cause of death in these patients. In more than 350 patients with classical progressive systemic sclerosis we have seen no patients with pulmonary hypertension without pulmonary fibrosis or left ventricular dysfunction. The severity of pulmonary hypertension found in five patients who had hemodynamic evaluation was less than in the patients with CREST syndrome with pulmonary artery pressures of 21 to 48 mm Hg and pulmonary vascular resistance of 155 to 922 dynes • sec • cnr 5 . In the reports of Treli ( 7 ) , Case 2-1972 of the Massachusetts General Hospital (37), and two patients described by Opie (38), pulmonary hypertension is described in patients who clearly had the CREST variant of progressive systemic sclerosis. It is possible that the relatively high frequency of severe pulmonary hypertension in the CREST syndrome is related to prolonged survival of these individuals compared with patients with the classic form of progressive systemic sclerosis. The capacity of the pulmonary vascular bed is so great that many years may be necessary before pulmonary arterial changes lead to hemodynamically significant elevation of pulmonary vascular resistance and clinical pulmonary hypertension. It should be noted that in most of our patients with CREST syndrome, evidence of pulmonary hypertension first appeared long after (as many as 40 years) the onset of Raynaud's phenomenon. The CREST syndrome appears to be a subset of the connective tissue disease progressive systemic sclerosis with predominantly vascular manifestations. The origin of pulmonary hypertension in the CREST syndrome is obliterative vascular disease, and, although the clinical course is generally prolonged, severe progressive pulmonary hypertension can develop and lead to death. ACKNOWLEDGMENTS: The authors thank Dr. Martin Cohen and Dr. Stuart N. Novack for providing information on Patients 5 and 6 and giving their permission to include these patients in this report, and Dr. Francis S. Perrone for referring and providing follow-up information on Patient 7. Grant support: in part by Grant 5 TOl HL 05678-10 from the National Heart and Lung Institute, the RGK Foundation and the U.S. Public Health Service Grant FR-00056 from the National Institutes of Health. Presented in part at the 46th Session of the American Heart Association, 8 through 11 November, Atlantic City, New Jersey. Received 16 August 1976; revision accepted 17 December 1976. • Requests for reprints should be addressed to Rosemarie Salerni, M.D.; 789 Scaife Hall, University of Pittsburgh School of Medicine; Pittsburgh, PA 15261. References
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