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Pericardial disease in scleroderma (systemic sclerosis)
Pericardial Disease in Scleroderma (Systemic Sclerosis)
JOHN E. McWHORTER,
IV, M.D.’
A review of the records of 210 patients with scleroderma seen between 1952 and 1972 revealed two clinical patterns of pericardial disease in 15 patients: (1) Chronic pericardial effusion (11 patients), confirmed by roentgenography and ultrasound, occurred in association with dyspnea, Raynaud’s syndrome, cardiomegaly, congestive heart failure and pleural effusion in the absence of renal failure. In three patients hemodynamic signs of pulsus paradoxus, Kussmaul’s sign or pulsus alternans developed. In six patients with chronic effusion renal failure developed within 6 months, an incidence severalfold higher than expected in the scleroderma population at large. (2) Acute pericarditis (four patients) was associated with dyspnea, chest pain, pericardial friction rub, fever, cardiomegaly and elevated latex fixation titers (in two of four patients). Pericardial disease is a recognizable clinical entity in scleroderma and should be considered in all patients with cardiomegaly, congestive heart failure or chest pain. In 34 autopsy studies, the incidence of peridardial involvement (62 per cent) exceeded the incidence of significant myocardial fibrosis (30 per cent); thus pericardial scleroderma represents a relatively common form of cardiac involvement in this diffuse connective tissue dis-
E. CARWILE LeROY, M.D. New York, New York
ease. Scleroderma (systemic sclerosis) is a multisystem disease of unknown etiology characterized by vascular and connective tissue abnormalities. Although hidebound skin and Raynaud’s syndrome are common features, visceral involvement determines prognosis in the individual patient. Renal, cardiac and pulmonary scleroderma have been associated with decreased survival in recent studies From the Department of Medicine, Columbia University College of Physicians & Surgeons, and the Edward Daniels Faulkner Arthritis Clinic, The Presbyterian Hospital, New York, New York. This investigation was supported by the New York and New Jersey Chapters of the Arthritis Foundation, the Charlotte and Sidney LifSchultz Foundation, and the Arthur K. Delson Medical Research Fund. Requests for reprints should be addressed to Dr. E. Carwile L&Roy, Department of Medicine, Columbia University College of Physicians 8 Surgeons, 630 West 168th Street, New York, New York 10032. Manuscriptaccepted January 18. 1974. *Present address: National Naval Medical Center, Bethesda, Maryland 20014.
566
October 1974
The American
[Il.
Scleroderma affects the heart in several ways. Diffuse myocardial fibrosis with or without heart block has been considered the predominant form of scleroderma heart disease [2-l I]. Recent controlled oostmortem studies have suaaested that clinicallv. sianifi“” I cant myocardial fibrosis is relatively uncommon [ 121; furthermore, physiologic studies have shown that pulmonary hypertension. pulmonary fibrosis and systemic hypertension with renal failure are maior determinants of scleroderma heart disease L 1131. 1 Althouah pericardial involvement has been noted in patients with scleroderma at postmortem [ 10,12,14,15] and in isolated case reports [2,4-g, 1S-19], the pericardium has generally been considered of little clinical importance in scleroderma heart disease. Stimulated by the prominence of pericardial effusion and peri-
Journal of Medicine
Volume 57
SYSTEMIC SCLEROSIS-McWHORTER, LeRoY
in several patients, we initially determined the incidence of pericardial disease in 210 patients with
carditis
scleroderma seen between 1952 and 1972. This review revealed two clinical presentations of pericardial disease in scleroderma, as well as an association between pericardial effusion and subsequent renal failure. We present both the patterns and the frequency of pericardial disease in scleroderma to emphasize that pericardial involvement should be searched for in every patient has cardiomegaly, congestive pain.
with scleroderma who heart failure or chest
al*effusion
was noted if greater
greater
than 360
patients
were
g in female
noted. Left ventricular
fined as left ventricle right ventricular wall thickness
greater
muscle revealed
analysis
of the medical
scleroderma tients
was assessed
was diagnosed
with oliguria,
mg/lOO
records
of 210 patients
between
azotemia
in whom
1952 and 1972.
(blood
ml) or the clinical syndrome
urea
Pa-
nitrogen
of uremia
>25
were
ex-
cluded from the study. All patients had clinical or biopsy evidence
of scleroder-
record was analyzed for age, sex and race. Symptoms noted included dyspnea. chest pain and Raynaud’s syndrome, defined as pallor and cyanosis on exposure to cold or stress with subsequent pain and suffusion. The physical measurements tabulated were blood
1.5 cm;
the following pathologic
le-
sions: (1) mild focal fibrosis (small and sparse areas of fibrosis in otherwise fibrosis (large small areas
normal
areas
(2) severe
focal
of fibrosis or multiple
of fibrosis), (3) diffuse fibrosis (interstitial fibro-
sis of the myocardium
concentric
myocardium),
circumscribed
replacing
(the presence
oles or renal cortical tal muscle involvement
effusion
for was
lesions consisted of
of the arterioles.
intimai proliferation
necrosis.
fibers)
inflamma-
was reviewed
Pleural
than 100 cc. Vascular either
myocardial
of numerous
fibrosis.
intimal proliferation
thology revealed
many
histopathology
of interstitial
noted if greater
by a retrospective
was de-
than
than 0.5 cm. Histologic examination
tory cells). The pulmonary
involvement
greater
was defined as right ventricle
of myocardial
the presence
Pericardial
and 410 g in male
hypertrophy
wall thickness
hypertrophy
and (4) myocarditis
METHODS
than 50 cc. Heart weights patients
Kidney pa-
of the arteri-
Gastrointestinal
and skele-
was defined as either muscle atro-
phy or fibrosis.
RESULTS
ma. Each patient’s
pressure, sence
temperature,
of edema,
pulse
rate,
the presence
In the cardiac
examination
particular
to pericardial
friction
pulsus
maul’s
rub,
sign (paradoxic
elevation
attention
of jugular
and
Kuss-
venous
pres-
Hypertension
diastolic
of 100 mm Hg or greater.
pressures
charted
(Westergren,
included
sis (especially
proteinuria)
Chest roentgenograms configuration,
and skin reactivity
sis on QRS axis (-I90
reviewed
to +30
+29
to -30
degrees
-90
degrees
= marked
evaluated
fibrosis
were =
Laboratory
sedimentation
rate
white blood cell count, urinaly-
were
pulmonary
Electrocardiograms
was defined as repeated
erythrocyte
uncorrected),
was given
paradoxus
sure on inspiration). data
or ab-
neck vein distention and hepatomegaly.
to tuberculin.
for heart size and
and
pleurat
effusions.
with particular
degrees
empha-
= no axis deviation,
left axis deviation,
and -31
to
left axis deviation) and T wave ab-
normalities. The appearance of low voltage (QRS voltage of less than 0.5 mv in all limb leads) or significant loss of voltage
(loss of more than 25 per cent of QRS voltage
limb leads)
in serial
221. Tests
used to confirm
effusion
electrocardiograms
right-sided
right atrial angiography or pericardiectomy. Postmortem data patients
the impression
included echocardiography
ide angiography,
[23,24],
cardiac
[ 17-18.25.261,
carried
noted
of pericardial carbon
dioxwith
pericardiocentesis autopsies
out between
1952
Age, sex, race, the presence
sence of Raynaud’s syndrome, uria were tabulated, as were
in
[20-
catheterization
on the 34 consecutive
with scleroderma
1972 were reviewed.
was
of and
or ab-
hypertension and proteinerythrocyte sedimentation
rates and blood urea nitrogen levels. Pathologic
examina-
tion of the viscera was analyzed. Abnormalities of the pericardium included either acute fibrinous material or fibrous pericarditis
(heavy fibrous bands and adhesions).
Pericardi-
The diagnosis of pericardial disease was made by clinical criteria [27-291 in 15 patients. These 15 patients were divided into two groups, each with a distinct clinical pattern: (1) pericardial effusion and congestive heart failure, and (2) acute pericarditis with friction rub. Clinical Picture. The 11 patients with chronic pericardial effusion and the 4 with acute inflammatory pericarditis (Table I) were similar in age at the onset of pericardial disease (Table II). Although there were more women than men and more whites than nonwhites among the patients with chronic effusion, only black women were seen with acute pericarditis. Dyspnea was an almost universal finding in both groups. Temperature greater than lOOoF and chest pain were frequent presenting complaints in those with acute pericarditis. Four patients with chronic pericardial effusion also had chest pain; in three of the four, the pain was exertional, substernal and typical of angina pectoris. Raynaud’s syndrome was seen in 10 of 11 patients with effusion but in only one patient with acute pericarditis. All patients with pericardial effusion had signs of altered cardiac function. Pedal edema, often marked, and hemodynamic abnormalities (Table Ill) were major findings in the patients with chronic pericardial effusion. Distended neck veins and liver enlargement were the most frequent findings in those with effusion. Early evidence of tampontide, i.e., pulsus paradoxus, Kussmaul’s sign and pulsus alternans, was seen in three patients; no patient required emergency intervention. In contrast to the patients with effusion, neck vein distention in one of four patients with acute pericarditis was the only evidence of altered cardiac function. Acute pericarditis was identified in these patients by
October 1974
The American Journal of Medicine
Volume 57
567
-__--
+
+
+
-
+
+
+
52,F,W
38,M,W
56,M,B
73,M.W
52,F,H
69,F,B
51, F,W
76, F,W
R.R.
A.D.
A.M.
A.B.
T.C.5
CT.’
F.P.”
B.0.s
+
+
52,M,W
Raynaud’s SynAge (yr), Sex and Race drome _ --__
- __
+
-
i-
+
+
+
+
-I-
-t-
Dyspnea
1+
2+
-
+
2+
2+
+
-
2+
-
-
-
4c
-
4+
4+
-
+
Pedal Edema __-__
Chest Pain ~-__-
and Pericardial
- - ~-__~__
Patients with Scleroderma
--
R.L.
Patient __-
TABLE I
-
-
-
-
-
-
-
-
-
-
-
-I-
-
-
i-
-
-
~~___
99.2
9
120
36
99.8 100.0
37
29
18
32
56
34
-___
Cardiomegaly Cardiomegaly
5,500
11,650
Cardiomegaly
2+
8,000
-
NAD, low voltage, AF, T wave abnormalities
MLAD, low volt. age incorn. plete RBBB
MLAD, T wave abnormalities
LAD, low voltage, T wave abnormalities
LAD, low voltage, T wave abnormalities
Electrocard\ogrami
-__
NAD, voltage loss, AF, T wave abnormalities
NAD, low voltage
NAD, T wave abnormalities
Cardiomegaly, in- LAD, low voltage, T wave creased pulabnormalities monary markings, bilateral pleural effusion
Cardiomegaly
Cardiomegaly, increased pulmonary markings
Cardiomegaly, increased pulmonary markings
Cardiomegaly, increased pulmonary mark. ings, bilateral pleurat effusion
Cardiomegaly, left pleural effusion
l-i-
1+
-
1+
1+
2+
Chest Roentgenogram __I~
22,000
5,400
7,000
6,600
9,000
12,800
--__-
Proteinuna
Effusion
White Blood count (/mmP)
with Pericardial
Erythrocyte Sedimentation Rate (mm/hr) _~__-__~-
102.0
98.0
99.0
98.6
101.8
98.0
Pericarditis
(“0 -__
Temperature
~___.____
Hypertension* _~__
Chronic
.Pericardial Friction Rub
Disease
co2 pos
PC pos PP pos
coz pos PC pas
Echo pos
ND
Echo pas
Echo pos CC pos
Echo pos cc pos PB pos
Echo pas
OtherS
-
ND
-
ND
-
ND
-
+
(PPD)
Tuberculin Skin Test
F n 2
I 8 3 2 ?J
?I $ z
r
52,F,W
50,F,B,
79,F,B
32,F,B
40,F,B
L.G.$
N.C.
B.G.
D.T.§
A.Mc.$
-
+
-
-
+
+
+
+
+
+
+
+
-
-
-
-
-
4+
1+
+
+
-I-
-
+
+
+
+
-4
-
-
102.0
100.4
-
-
99.4
-
104.0
Inflammatory
101.0
-
Acute -
98.0
-
20,700
6,300
45
10
30
115
4,750
12) 500
4,500
19.400
Pericarditis
71
18
2+
1+
-
2+
2+
3+
Cardiomegaly, increased pulmonacy markings
Cardiomegaly
Cardiomegaly, increased pul. monary markings
Cardiomegaly, increased pulmonary markings
pleural effusion
Cardiomegaly, increased pulmonary markings, bilateral
Cardiomegaly, left pleural effusion, increased pulmonary markings
LAD, low voltage, T wave abnormalities
LAD, voltage loss, T wave abnormalities
LAD, T wave abnormalities
LAD. voltage loss, T wave abnormalities
MLAD, T wave abnormalities
MLAD, low voltage, RBBB
Echo neg
Echo neg CO? neg
COn neg
ND
Echo pos
Echo pos
+
+
ND
NOTE: W = white; B = black; H = hispanic; + = present; - = absent; ND = not done. * Diastolic pressure greater than 100 mm Fig. 1 NAD = no axis deviation (+90” to +30”); LAD = left axis deviation (+29O to -3OO); MLAD = marked left axis deviation (-30” to -90”); Voltage loss = significant loss of voltage; AF = atrial fibrillation; RBBB = right bundle branch block; Inc= incomplete. $ Echo = echocardiogram; CC = cardiac catheterization; PB = pericardial biopsy; CO* = CO, angiogram; PC = pericardiocentesis; PP = pneumopericardium; pos = positive; neg = negative. $ Autopsy data in Table V. ” Reported by Meltzer [16].
41,F,B
M.R.a
s’
9
!
$ 0
w L
SYSTEMIC
TABLE II
SCLEROSIS-McWHORTER,
LeROY
Summary of Clinical Data on Patients with Pericardial Disease Data
Age (yr), mean (range) Sex (male/female) Race White Black Hispanic Raynaud’s syndrome Dyspnea Chest pain Pericardial friction rub Fever (>lOO”F) Hypertension (diastolic Chest roentgenogram Cardiomegaly
~-~-~____-__
Chronic Effusion 53 (39-76) 4/7
>lOO mm Hg)
Increased pulmonary markings Pleural effusion Electrocardiogram Low voltage Loss of voltage T wave abnormalities Leukocytosis (>lO,OOO/mm”) Erythrocyte sedimentation rate (>25) Rapid renal failure within 6 months
Acute Pericarditis
7111 3/11 l/11 lO/ll lO/ll 4/11 o/11 4/11 2/11
O/4 414 O/4 l/4 4/4 314 414 3/4 O/4
ll/ll 6/11 6/11
414 314 O/4
7111 l/4 l/11 214 8/11 3/4 4111 214 7111 414 6/11 O/4 ~_ .~_.._
~~~~~_
Hemodynamic Signs Signs ~~
.~_.~
Congestive failure 1. Pedal edema 2. Distended neck veins 3. Hepatomegaly 4. Tachycardia without fever Either 1, 2, 3 or 4 Pericardial signs 5. Pulsus paradoxus 6. Kussmaul’s sign 7. Pulsus alternans Either 5, 6 or 7
O/4
341, the electrocardiogram was not useful either in making the initial diagnosis of pericardial involvement or in making the distinction between acute pericarditis and chronic effusion. There was no pattern of deviation of the electrical axis. Although right axis deviation would be expected with the high incidence of pulmonary fibrosis seen at postmortem [21], right axis deviation was not seen in either group. Low voltage was seen more frequently in those with chronic pericardial effur;ion; when patients with significant loss of voltage on sequential tracings were taken into account, the two groups were similar (Table II). Low voltage has been described as a frequent finding in patients with scleroderma [35]. Nonspecific T wave abnormalities were seen frequently in both groups and were of no diagnostic significance. The white blood cell count was Laboratory Data. not helpful in differentiating patients with acute periOctober 1974
~
50 (32-79)
the presence of fever, chest pain and a pericardial friction rub. Chest Roentgenogram. Cardiomegaly was found in all patients in both groups but was generally more pronounced in those with pericardial effusion (Table II). Increased interstitial markings were a frequent manifestation of both groups whereas pleural effusion was seen only in those with chronic pericardial effusion. These findings are similar to those of previous investigators who described cardiomegaly and pulmonary infiltrates as common manifestations of scleroderma [ 30-321. As in previous studies [33, Electrocardiograms.
570
TABLE III
Chronic Effusion
Acute Pericarditis
lO/ll 8/11 7111 3/11 ll/ll
O/4 l/4 O/4 O/4 l/4
l/11 2111 2111 3/11
O/4 O/4 O/4 O/4
.~~
-
carditis from those with chronic effusion (Table II); also, the erythrocyte sedimentation rate was frequently elevated in both groups. Only one of the patients with chronic effusion had a slightly decreased serum complement level, and no patient from either group had a positive lupus erythematosus preparation or a biologic false-positive serologic test. Although latex fixation titers have been reported to be elevated in up to 35 per cent of the patients with scleroderma [36], only two patients with acute inflammatory pericarditis had elevated titers: both of these patients died suddenly during hospitalization. Clinical Course. Within 6 months of the onset of symptoms leading to the diagnosis of pericardial effusion, 6 of the 11 patients had died from renal failure (55 per cent). All patients with pericardial effusion were treated with digitalis and diuretics. As an example, the mean weight loss in the six patients in whom renal failure
subsequently
developed
was 13 per cent
of body weight. This incidence of renal failure (55 per cent) was considerably higher than expected in the general population with scleroderma in which the incidence of azotemia was 19 per cent (40 of 210 patients), the incidence of hypertension was 24 per cent (50 of 2 10 patients), the incidence of proteinuria was 36 per cent (76 of 210 patients), and the combined incidence of any one of these renal markers (azotemia, hypertension or proteinuria) was 45 per cent (94 of 2 10 patients). Since only azotemia defines renal failure, the 55 per cent incidence of renal failure in patients with pericardial effusion is most appropriately compared with a 19 per cent incidence of azotemia in the over-all scleroderma population. The mechanism for the increased incidence of renal failure in patients with pericardial effusion is unclear. Two of the four patients with acute inflammatory pericarditis died suddenly during the acute illness, presumably from a cardiac arrhythmia. In the remaining two patients, the acute pericarditis resolved and they were able to function for several years. Renal failure was not observed in these four patients.
The American Journalof Medicine Volume 57
SYSTEMIC SCLEROSIS-McWHORTER, L&OY
Postmortem
34 patients
Results.
between
Autopsies were performed on 1952 and 1972; the mean age
at autopsy was 53 years (Tables IV and V). The patients seen most frequently at postmortem were female and white. Pericardial disease, defined as either fibrinous or fibrous adhesions, or a pericardial effusion of 50 cc or greater, was found in 19 patients (56 per cent). Two patients (A.D., R.L., Table I) had no pericardial disease at postmortem but had documented pericardial effusion prior to death when their blood urea nitrogen level was normal. If we include these two patients, the adjusted incidence of pericardial disease is 62 per cent. Twelve patients were found to have pericardial effusion without pericarditis, eight had pericarditis without effusion and one had pericarditis with effusion. After excluding patients with terminal blood urea nitrogen values of 46 to 163 mg/lOO ml, the incidence of pericardial disease (55 per cent) did not change significantly. Examination of the heart revealed increased heart weight in 63 per cent of the autopsy patients. Left ventricular hypertrophy was present in 47 per cent of patients and right ventricular hypertrophy in 28 per cent. Biventricular hypertrophy was present in 25 per cent of the autopsy patients; in eight of nine patients with right ventricular hypertrophy, the left ventricle was also thickened. Left ventricular hypertrophy at postmortem examination could not be correlated with hypertension and/or uremia prior to death; similarly, right ventricular hypertrophy could not be correlated with pulmonary fibrosis. Thus, the present postmortem series does not add support to previous correlations of this type [ 13,141. Histopathologic examination of the myocardium revealed significant myocardial fibrosis (severe or diffuse, see “Methods”) in 30 per cent of the autopsy patients. As in previous series, a few small areas of fibrosis were observed in an otherwise normal myocardium in 21 per cent of the patients and were not considered significant fibrosis. In this study, the incidence of pericardial involvement (62 per cent) was greater than the incidence of myocardial fibrosis (30 per cent). Examination of the other viscera revealed pulmonary fibrosis in 65 per cent and pleural effusions (> 100 cc) in 59 per cent. The gastrointestinal tract was involved in 62 per cent and the skeletal muscle in 21 per cent. lntimal proliferation of the small arteries or arterioles was the most frequent pathologic finding at autopsy (76 per cent) and was seen often in numerous
organ systems.
COMMENTS
The present study outlines two clinical patterns of pericardial disease in scleroderma: acute pericarditis and chronic pericardial effusion. Furthermore, at postmortem pericardial disease was found to be more common than myocardial fibrosis. Subsequent
TABLE IV
Summary of Data on 34 Postmortem ClinicalData
.Total Series
Age (yr), mean (range) Sex (male/female) Race White Black Hispanic
Postmortem Data Heart Pericardium Pericardial disease (total) at postmortem Adjusted incidence of pericardial disease (total)? Pericardial effusion without pericerditis Pericarditis without effusion Pericarditis with effusion
Patients
53 (39.-76) 7.‘27 21134 (620/,)
1l/34 (32%) .!/34 (6%) Without Arotemla*
19,‘34 (56%) U/22 (55%)
:1/34 (62%)
7122 (32%)
12/34 (35%)
4/22 (18%)
8/34 (24%)
l/22 (5%)
l/34 (3%)
Myocardium Fibrosis, diffuse Fibrosis, focal, severe Fibrosis, focal, mild increased heart weight Left ventricular hypertrophy Right ventricular hypertrophy Biventricular hypertrophy Lung Fibrosis Pleural effusion (>lOO cc) Gastrointestinal Skeletal muscle Vascular
4/34 (12%) 6134 (18%) 7/34 (21%) TO/32 (63%)1 I.5132 (47%)$ 9/32 (28%)t 8/3? (25%): :?2/34 (65%) ;20/34 (59%) ?I/34 (62%) 7;34 ~217~) 26,‘34 (76%)
* Adjusted for two patients (L.G. and T.C., Table I) who had documented pericardial effusion when thetr blood urea nitrogen level was normal. i Addition of two patients (A.D. and R.L., Table I) who had documented pericardial effusion prior to death during period of normal blood urea nitrogen. f. This determination was not made in iwo postmortem examinations.
renal failure occurred in 6 of 11 patients with pericardial effusion. In this context the development of thought concerning cardiac involvement in scleroderma and its possible bearing on future renal involvement is reviewed. In 1895 Lewin and Heller [37] reviewed the previously reported cases of scleroderma and found pericardial disease in 7 of 28 autopsy cases; Matsui [ 381, in 1924, reported two cases of pericardial effusion in six autopsy cases. In 1943 Weiss et al. 121, using the term scleroderma heart disease, described nine patients with Raynaud’s phenomenon, dyspnea on exertion and prominent pedal edema. The chest roentgenograms showed an enlarged triangle-shaped heart consistent with pericardial effusion. In these two autopsy cases pericardial effusions were significant, but these investigators considered the major
October 1974
The American Journal of Medicine
Volume 57
571
SYSTEMIC SCLEROSIS-McWHORTER,
TABLE
Data on Patients
V
L&OY
with Pericardial
Disease
at Postmortem
Autopsy Organ involvement*
Patient
Age (yr), Sex, Race
Blood Urea Nttrogen (rng/100 ml)
T.J. Z.D. K.G. M.M.
44,M,W 55,F,W 64,F,W 42,F,B
104 163 29 60
K.A.
66,F,W
15
4O,F,B 32,F,B 6O,F,B 52, F, H 63, F,W 42,F,W 76,F,W 41,F.B 40, F, H 67,F,B 43,F,W 54,F.W 40, F,W 52,F,W
19 11 117 60 110 116 14 20 27: 49 12 57 46 74
A.Mc. D.T.i
1
C.Th. T.C. H.M. M.E. B.0.i M.R.j E.R. B.M. S.F. F.D. M.A. L.G.j
Lung Pencardrum Effusion
Heart
Acute fibrinous Acute fibrinous Acute fibrinous Frbrous--with inflammation Fibrous
-
-
Fibrous Fibrous Fibrous Acute fibrinous -
-
Perrcardrtrs
MFF
-
MC MFF SFF DF -
+ + f + + + + + + + +
-
SFF MFF DF MFF DF SFF MFF MC SFF
NOTE: W = whrte; B = black; H = hispanic; + = present; - = absent. * See methods for criteria1 of organ rnvolvement. MFF = mild focal fibrosis; MC = myocarditis. i SeeTable I for clinical data. 1 Nonprotein nitrogen (normal = 15-35 mg/lOO ml).
pathologic feature to be “myocardial scarring of an unusual iype.” Over the next several years, several workers (Bevans in 1944 171, Mathison et al. in 1947 [9J, Goetz in 1951 14). Hurly et al. in 1951 [5] and Beigelman et al. in 1953 IS]) reported cases in which myocardiai fibrosis was described as the predominant form of scleroderma heart disease. Of these, several were associated with pericardial disease which was thought to be an incidental finding ]2,491. In 1954, Leinwand et al. [39] reviewed 150 cases of scleroderma and concluded that pericardial disease was rarely, if ever, found. In 1956, pericardial effusion as a primary form of scleroderma heart disease was first described by Meltzer f 161 in two cases (Table I). Utilizing angiography, Steinberg and Rothbard [ 17,181 reported five cases of pericardial effusion in two reports. In 1964, Sackner et al. [ 131 demonstrated pulmonary hypertension by cardiac catheterization as the most common cardiopulmonary finding in scleroderma; in reviewing 65 patients and 25 postmortem examinations, Sackner concluded that myocardial fibrosis rarely contributed to heart disease in scleroderma. Excluding focal fibrosis, he found 3 of 25 patients with diffuse fibrosis and noted
572
October
1974
The American
Journal of Medicine
Pleural GastroEffusion Fibrosis Kidney Vascular Intestinal
-
Muscle
+ + + +
+ + -
+ -
-
-
+ + +
+
-
+
+
+
-
+
+
+
+
+
+
-
+ -
-
+ + + + + + + + + + + + +
+ -
+ +
+ + + + + + + + + +
+ + + + + + + + +
+ + + + + + + + + +
SFF = severe focal fibrosis;
+ + + + + + + +
DF = diffuse
+ + -
fibrosis:
the high frequency of this finding in other disease states in this age group. Sackner attributed scleroderma heart disease either to pulmonary hypertension or to systemic hypertension with scleroderma renal involvement. He also noted pericardial disease as a common pathologic feature in 18 of 25 postmortem studies [ 151. D’Angelo et al. compared 58 autopsy patients with scleroderma with 58 matched controls and found pericardial lesions in 53 per cent compared with 12 per cent in controls. The incidence of pericardial effusion was the same as in controls; however, the size of effusion was greater in those with scleroderma. In patients over 40 years of age, no significant difference in myocardial fibrosis could be determined between those with scleroderma and control subjects. In patients under 40 years of age, myocardial fibrosis was more common in those with scleroderma [ 121. Endocardial lesions have been only rarely reported in scleroderma. Four reports ascribed a nodular thickening of the mitral valve to scleroderma [39-421; however, D’Angelo et al. [ 121 found an equal incidence of this abnormality in matched controls. Involvement of the pericardium is therefore fre-
Volume 57
SYSTEMIC SCLEROSIS-McWHORTER,
quent and well known in autopsy studies of scleroderma; still, the diagnosis is often unrecognized clinically. There is general agreement that approximately 50 to 70 per cent of patients (62 per cent present study, 53 per cent D’Angelo, 72 per cent Sackner) show evidence of pericardial involvement at postmortem examination. Renal failure and uremia are frequent terminal events in patients with scleroderma [43-481. Since uremia frequently produces pericardial disease 1491, all patients studied at autopsy were reevaluated to determine whether eliminating those patients in whom pericardial disease could not be clearly separated from uremia would alter the incidence. An incidence of 55 per cent was found for pericardial disease unrelated to uremia, which was not significantly different from the over-all incidence of pericardial disease (62 per cent). A comparison of the clinical patient series and the postmortem data in the present study indicates that pericardial disease can be detected clinically in the patient with scleroderma with chest pain or congestive heart failure. In this comparison, 32 per cent of pericardial disease demonstrated at autopsy was documented prior to death. The etiology of pericardial disease in scleroderma remains unclear. Patients with chronic pericardial effusion presented with Raynaud’s syndrome and congestive heart failure which was manifested by dyspnea. neck vein distention, hepatomegaly and pedal edema. Signs of cardiac tamponade effect were present in a few patients but did not require intervention. It was not possible to determine from this retrospective study whether pericardial effusion was caused by antecedent heart failure secondary to pulmonary hypertension or myocardial disease, or whether primary involvement of the pericardium causing effusion precipitated congestive heart failure. The presence of pericardial effusion and congestive failure was associated with the subsequent development of renal failure in a disquietingly large proportion of patients (6 of 11). The mechanism of the association between pericardial effusion, congestive failure and renal failure is not clear; several mechanisms may be operative [50-521. First, it is known from other studies of this same patient population that renal failure in scleroderma is associated with a marked reduction in renal cortical blood flow 1541; renal cortical blood flow determinations in 6 of the 11 patients with pericardial effusion were low, with a mean cortical flow of less than 100 ml/ 100 g/min (normal >350 ml/100 g/min). Pericardial effusion, congestive failure and its therapy, all contribute to renal cortical vasoconstriction by several mechanisms. Decreased cardiac output decreases renal cortical flow 1531; increased renal venous pressure
October
also
contributes
to renal
cortical
vasospasm.
LeROY
All
these hemodynamic bases for renal vasoconstriction contribute to the higher incidence of renal failure in scleroderma complicated by pericardial effusion and congestive failure. Furthermore, the histopathologic process of scleroderma, the etiology of which is unknown, may lead to simultaneous and essentially coincidental pericardial and renal involvement [ 55 1. As a third mechanism, the therapy of the antecedent pericardial effusion and congestive failure may enhance and hasten the development of renal scleroderma. Diuretic therapy of increasing potency could reduce blood volume (volume depletion) sufficient to induce visceral vasoconstriction and a selective reduction in renal cortical blood flow; it is also possible that the renin-angiotensin system participates in these vasoconstrictive phenomena. Thus the patient with scleroderma has three potential causes of reduced renal cortical flow and therefore of glomerular perfusion: the microvascular lesion of scleroderma; the cardiac involvement be it pericardial, myocardial or pulmonary; and volume depletion by diuretic therapy. The additive effect of these three mechanisms may explain the high incidence of subsequent renal failure in patients with scleroderma and pericardial involvement. Since the mechanism of reduced cortical perfusion in congestive heart failure is unclear, scleroderma may provide a useful setting to study the influence of efferent arteriolar vasoconstriction (Raynaud’s phenomenon of the kidney) on renal function in anatomically separate regions of nephrons. Acute inflammatory pericarditis in scleroderma was characterized by fever, chest pain and pericardial friction rub without evidence of congestive heart failure or tamponade. This syndrome could not be distinguished from acute idiopathic or viral pericarditis. Pericarditis is seen commonly in systemic lupus erythematosus [56] and less commonly in rheumatoid arthritis [ 571. The significance of elevated latex fixation titers in two of four patients with acute pericarditis in scleroderma remains unclear but suggests a possible immune complex etiology. Because two of four patients died during their hospitalization, it was not possible to assess the effect of acute pericarditis on subsequent organ involvement. In the two surviving patients kidney involvement did not develop. ACKNOWLEDGMENT
We are indebted to Dr. M. Irene Ferrer for review of the electrocardiograms and for her advice, to Dr. Kent Ellis for review of the chest roentgenogram and to Edna Farrington, R.N., for assistance with patient records. We wish to thank Drs. Charles A. Ragan, Jr., Stanley E. Bradley, J. Thomas Bigger, Jay I. Meltzer and Paul J. Cannon for helpful suggestions.
1974
The American
Journal
of Medicine
Volume 57
573
SYSTEMIC SCLEROSIS-McWHORTER,
LeROY
REFERENCES
2.
3.
8. 9. 10. 11.
12.
13.
14.
15. 16. 17.
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Medsger TA, Masi AT, Rodnan GP, Benedek TG, Robinson H: Survival with systemic sclerosis (scleroderma). A lifetable analysis of clinical and demographic factors in 309 patients. Ann Intern Med 75: 369, 197 1. Weiss S. Stead EA, Warren JV. Bailey OT: Scleroderma heart disease, with a consideration of certain other visceral manifestations of scleroderma. Arch Intern Med 71: 749. 1943. Rodnan GP: The natural history of progressive systemic sclerosis (diffuse scleroderma). Bull Rheum Dis 13: 301, 1963. Goetz RH: The heart in generalized scleroderma. Progressive systemic sclerosis. Angiology 2: 555, 195 1. Hurly J, Billings M, Coe J, Weber L: Scleroderma heart disease. Am Heart J 42: 758, 1951. Beigelman PM, Goldner F, Bayles TB: Progressive systemic sclerosis (scleroderma). N Engl J Med 249: 45, 1953. Bevans M: Pathology of scleroderma with special reference to the changes in the gastrointestinal tract. Am J Pathol 21: 25, 1945. Piper WN, Helwig EB: Progressive systemic sclerosis. Arch Dermatol 72: 535, 1955. Mathisen AK, Palmer JD: Diffuse scleroderma with involvement of the heart. Am Heart J 33: 366, 1947. Oram S, Stokes W: The heart in scleroderma. Br Heart J 23: 243, 1961. Orabona ML, Albano 0: Progressive systemic sclerosis (or visceral scleroderma). Review of literature and report of cases. Acta Med Stand 160 (suppl333): I. 1958. D’Angelo WA, Fries JF, Masi AT, Shulman LE: Pathologic observations in systemic sclerosis (scleroderma). A study of 58 autopsy cases and 58 matched controls. Am J Med 46: 428, 1969. Sackner MA, Akgun N. Kimbel P, Lewis DH: The pathophysiology of scleroderma involving the heart and respiratory system. Ann Intern Med 60: 6 1 I, 1964. Sackner MA: Cardiac manifestations of scleroderma. Scleroderma Proceedings of an International Symposium Sponsored by the World Health Organization (Delbarre F, Saporta L, eds), Paris, Masson et Cie. 1972, p 7 1. Sackner MA, Heinz ER, Steinberg AJ: The heart in scleroderma. Am J Cardiol 17, 542, 1966. Meltzer JI: Pericardial effusion in generalized scleroderma. Am J Med 20: 638, 1956. Steinberg I, Rothbard S: Pericardial effusion and car pulmonale in progressive systemic sclerosis (scleroderma). Role of angiocardiography in diagnosis in two cases. Am J Cardiol 9: 953, 1962. Steinberg I, Rothbard S: Roentgen features of sclerodermal pericarditis with effusion. Radiology 83: 292, 1964. Godeau P, Herreman G, Siguier F: Les pericardites sclerodermiques. Scleroderma Proceedings of an International Symposium Sponsored by the World Health Organization (Defbarre F, Saporta L, eds), Paris, Masson et Cie, 1972, p 81. Criteria Committee of the N.Y. Heart Association: Diseases of the Heart and Great Vessels: Nomenclature and Criteria for Diagnosis, 7th ed, Boston, Little, Brown & Co., 1973. Kilcoyne MM, Davis AL, Ferrer Ml: A dynamic electrocardiographic concept useful in the diagnosis of car pulmonale. Result of a survey of 200 patients with chronic obstructive pulmonary disease. Circulation 42: 903, 1970. Ferrer Ml: Personal communication, 1973. Feigenbaum H, Zaky A, Waldhausen JA: Use of ultrasound in the diagnosis of pericardial effusion. Ann Intern Med 65: 443, 1966.
October
1974
The American
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37. 38.
39.
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Volume 57
Feigenbaum H: Echocardiographic diagnosis of pericardial effusion. Am J Cardiol 26: 475, 1970. Bauer GE: Scleroderma heart failure. Australas Ann Med 4: 149, 1955. Conner PK, Bashour FA: Cardiopulmonary changes in scleroderma. A physiologic study. Am Heart J 61: 494, 1961. Spodick DH: Acute Pericarditis, New York and London, Grune & Stratton, Inc., 1959. Spodick DH: Acute cardiac tamponade. Pathologic physiology, diagnosis and management. Prog Cardiovasc Dis IO: 64, 1967. Spodick DH: Differential diagnosis of acute pericarditis. Prog Cardiovasc Dis 14: 192. 1971. Boyd JA, Patrick SI, Reeves RJ: Roentgen changes observed in generalized scleroderma. Report of 63 cases, Arch Intern Med 94: 248, 1954. Gondos B: Roentgen manifestations in progressive systemic sclerosis (diffuse scleroderma). Am J Roentgen01 Radium Ther Nucl Med 84: 235, 1960. Harper RAK. Jackson DC: Progressive systemic sclerosis. Br J Radio1 38: 825, 1965. Bianchi FA, Bistue AR, Wendt VE. Puro HE, Keech MK: Analysis of 27 cases of progressive systemic sclerosis (including 2 with combined systemic lupus erythematosus) and a review of the literature. J Chron Dis 19: 953, 1966. Windesheim JH, Parkin TW: Electrocardiograms of ninety patients with acrosclerosis and progressive diffuse sclerosis (scleroderma). Circulation 17: 874, 1958. Escudero J, McDevitt E: The electrocardiogram in scleroderma. Analysis of 60 cases and review of the literature. Am Heart J 56: 846, 1958. Clark JA, Winkelmann RK, Ward LE: Serologic alterations in scleroderma and sclerodermatomyositis. Mayo Clin Proc 46: 104. 1971. Lewin G, Heller J: Die Sclerodermie. Berlin, August Hirschwald, 1895. Matsui S: Ueber die Pathologie and Pathogenese von Sclerodermia Universalis. Mitt med Fak K Univ Tokyo 3 1: 55, 1924. Leinwand I, Duryee AW, Richter MN: Scleroderma (based on a study of over 150 cases). Ann Intern Med 4 1: 1003, 1954. Osler W: The Principles and Practice of Medicine, Edinburgh and London, Young J. Pentland, 1892, p 993. Jones EW: Valvular disease of the heart in systemic scleroderma. Br J Dermatol 74: 183, 1962. Roth LM, Kissane JM: Panaortitis and aortic valvulitis in progressive systemic sclerosis (scleroderma). Report of a case with perforation of an aortic cusp. Am J Clin Pathol 41: 287, 1964. Moore HC, Sheehan HL: The kidney in scleroderma. Lancet 1: 68, 1952. Rodnan GP, Schreiner GE, Black RL: Renal involvement in progressive systemic sclerosis (generalized scleroderma). Am J Med 23: 445, 1957. Hannigan CA, Hannigan MH, Scott EL: Scleroderma of the kidneys. Am J Med 20: 793, 1956. East T, Oram S: The heart in scleroderma. Br Heart J 9: 167. 1947. Sharnoff JG. Carideo HL, Stein ID: Cortisone-treated scleroderma. Report of a case with autopsy findings. JAMA 145: 1230, 1951. Nasser WK. Mishkin ME, Rosenbaum D, Genovese PD: Pericardial and myocardial disease in progressive systemic sclerosis. Am J Cardiol 22: 538. 1968.
SYSTEMIC
49. 50.
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Comty CM, Cohen SL. Shapiro FL: Pericarditis in chronic uremia and its sequels. Ann Intern Med 75: 173, 1971. Bradley SE, Blake WD: Pathogenesis of renal dysfunction during congestive heart failure. Am J Med 6: 470, 1949. Fishman AP, Stamler J, Katz LN, Miller AJ, Silber EN, Rubenstein L: Mechanisms of edema formation in chronic experimental pericarditis with effusion. J Clin Invest 29: 521, 1950. Shabetai R, Fowler NO, Guntheroth WG: The hemodynamits of cardiac tamponade and constrictive pericarditis. Am J Cardiol 26: 480, 1970. Kilcoyne MM, Schmidt DH, Cannon PJ: lntrarenal blood flow in congestive heart failure. Circulation 47: 786, 1973.
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October 1974
SCLEROSIS-McWHORTER.
LeROY
Cannon PJ, Hassar M, Case DB, Casarella WJ, Sommers SC, LeRoy EC: The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of renal cortical circulation. Medicine (Baltimore) 53: 1. 1974. Norton WL. Nardo JM: Vascular disease in progressive systemic sclerosis (scleroderma). Ann Intern Med 73: 317. 1970. Estes D, Christian CL: The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 50: 85, 1971. Franc0 AE, Levine HD, Hall AP: Rheumatoid pericarditis. Report of 17 cases diagnosed clinically. Ann Intern Med 77: 837, 1972.
The American Journal of Medicine
Volume 57
575
JOHN E. McWHORTER,
IV, M.D.’
A review of the records of 210 patients with scleroderma seen between 1952 and 1972 revealed two clinical patterns of pericardial disease in 15 patients: (1) Chronic pericardial effusion (11 patients), confirmed by roentgenography and ultrasound, occurred in association with dyspnea, Raynaud’s syndrome, cardiomegaly, congestive heart failure and pleural effusion in the absence of renal failure. In three patients hemodynamic signs of pulsus paradoxus, Kussmaul’s sign or pulsus alternans developed. In six patients with chronic effusion renal failure developed within 6 months, an incidence severalfold higher than expected in the scleroderma population at large. (2) Acute pericarditis (four patients) was associated with dyspnea, chest pain, pericardial friction rub, fever, cardiomegaly and elevated latex fixation titers (in two of four patients). Pericardial disease is a recognizable clinical entity in scleroderma and should be considered in all patients with cardiomegaly, congestive heart failure or chest pain. In 34 autopsy studies, the incidence of peridardial involvement (62 per cent) exceeded the incidence of significant myocardial fibrosis (30 per cent); thus pericardial scleroderma represents a relatively common form of cardiac involvement in this diffuse connective tissue dis-
E. CARWILE LeROY, M.D. New York, New York
ease. Scleroderma (systemic sclerosis) is a multisystem disease of unknown etiology characterized by vascular and connective tissue abnormalities. Although hidebound skin and Raynaud’s syndrome are common features, visceral involvement determines prognosis in the individual patient. Renal, cardiac and pulmonary scleroderma have been associated with decreased survival in recent studies From the Department of Medicine, Columbia University College of Physicians & Surgeons, and the Edward Daniels Faulkner Arthritis Clinic, The Presbyterian Hospital, New York, New York. This investigation was supported by the New York and New Jersey Chapters of the Arthritis Foundation, the Charlotte and Sidney LifSchultz Foundation, and the Arthur K. Delson Medical Research Fund. Requests for reprints should be addressed to Dr. E. Carwile L&Roy, Department of Medicine, Columbia University College of Physicians 8 Surgeons, 630 West 168th Street, New York, New York 10032. Manuscriptaccepted January 18. 1974. *Present address: National Naval Medical Center, Bethesda, Maryland 20014.
566
October 1974
The American
[Il.
Scleroderma affects the heart in several ways. Diffuse myocardial fibrosis with or without heart block has been considered the predominant form of scleroderma heart disease [2-l I]. Recent controlled oostmortem studies have suaaested that clinicallv. sianifi“” I cant myocardial fibrosis is relatively uncommon [ 121; furthermore, physiologic studies have shown that pulmonary hypertension. pulmonary fibrosis and systemic hypertension with renal failure are maior determinants of scleroderma heart disease L 1131. 1 Althouah pericardial involvement has been noted in patients with scleroderma at postmortem [ 10,12,14,15] and in isolated case reports [2,4-g, 1S-19], the pericardium has generally been considered of little clinical importance in scleroderma heart disease. Stimulated by the prominence of pericardial effusion and peri-
Journal of Medicine
Volume 57
SYSTEMIC SCLEROSIS-McWHORTER, LeRoY
in several patients, we initially determined the incidence of pericardial disease in 210 patients with
carditis
scleroderma seen between 1952 and 1972. This review revealed two clinical presentations of pericardial disease in scleroderma, as well as an association between pericardial effusion and subsequent renal failure. We present both the patterns and the frequency of pericardial disease in scleroderma to emphasize that pericardial involvement should be searched for in every patient has cardiomegaly, congestive pain.
with scleroderma who heart failure or chest
al*effusion
was noted if greater
greater
than 360
patients
were
g in female
noted. Left ventricular
fined as left ventricle right ventricular wall thickness
greater
muscle revealed
analysis
of the medical
scleroderma tients
was assessed
was diagnosed
with oliguria,
mg/lOO
records
of 210 patients
between
azotemia
in whom
1952 and 1972.
(blood
ml) or the clinical syndrome
urea
Pa-
nitrogen
of uremia
>25
were
ex-
cluded from the study. All patients had clinical or biopsy evidence
of scleroder-
record was analyzed for age, sex and race. Symptoms noted included dyspnea. chest pain and Raynaud’s syndrome, defined as pallor and cyanosis on exposure to cold or stress with subsequent pain and suffusion. The physical measurements tabulated were blood
1.5 cm;
the following pathologic
le-
sions: (1) mild focal fibrosis (small and sparse areas of fibrosis in otherwise fibrosis (large small areas
normal
areas
(2) severe
focal
of fibrosis or multiple
of fibrosis), (3) diffuse fibrosis (interstitial fibro-
sis of the myocardium
concentric
myocardium),
circumscribed
replacing
(the presence
oles or renal cortical tal muscle involvement
effusion
for was
lesions consisted of
of the arterioles.
intimai proliferation
necrosis.
fibers)
inflamma-
was reviewed
Pleural
than 100 cc. Vascular either
myocardial
of numerous
fibrosis.
intimal proliferation
thology revealed
many
histopathology
of interstitial
noted if greater
by a retrospective
was de-
than
than 0.5 cm. Histologic examination
tory cells). The pulmonary
involvement
greater
was defined as right ventricle
of myocardial
the presence
Pericardial
and 410 g in male
hypertrophy
wall thickness
hypertrophy
and (4) myocarditis
METHODS
than 50 cc. Heart weights patients
Kidney pa-
of the arteri-
Gastrointestinal
and skele-
was defined as either muscle atro-
phy or fibrosis.
RESULTS
ma. Each patient’s
pressure, sence
temperature,
of edema,
pulse
rate,
the presence
In the cardiac
examination
particular
to pericardial
friction
pulsus
maul’s
rub,
sign (paradoxic
elevation
attention
of jugular
and
Kuss-
venous
pres-
Hypertension
diastolic
of 100 mm Hg or greater.
pressures
charted
(Westergren,
included
sis (especially
proteinuria)
Chest roentgenograms configuration,
and skin reactivity
sis on QRS axis (-I90
reviewed
to +30
+29
to -30
degrees
-90
degrees
= marked
evaluated
fibrosis
were =
Laboratory
sedimentation
rate
white blood cell count, urinaly-
were
pulmonary
Electrocardiograms
was defined as repeated
erythrocyte
uncorrected),
was given
paradoxus
sure on inspiration). data
or ab-
neck vein distention and hepatomegaly.
to tuberculin.
for heart size and
and
pleurat
effusions.
with particular
degrees
empha-
= no axis deviation,
left axis deviation,
and -31
to
left axis deviation) and T wave ab-
normalities. The appearance of low voltage (QRS voltage of less than 0.5 mv in all limb leads) or significant loss of voltage
(loss of more than 25 per cent of QRS voltage
limb leads)
in serial
221. Tests
used to confirm
effusion
electrocardiograms
right-sided
right atrial angiography or pericardiectomy. Postmortem data patients
the impression
included echocardiography
ide angiography,
[23,24],
cardiac
[ 17-18.25.261,
carried
noted
of pericardial carbon
dioxwith
pericardiocentesis autopsies
out between
1952
Age, sex, race, the presence
sence of Raynaud’s syndrome, uria were tabulated, as were
in
[20-
catheterization
on the 34 consecutive
with scleroderma
1972 were reviewed.
was
of and
or ab-
hypertension and proteinerythrocyte sedimentation
rates and blood urea nitrogen levels. Pathologic
examina-
tion of the viscera was analyzed. Abnormalities of the pericardium included either acute fibrinous material or fibrous pericarditis
(heavy fibrous bands and adhesions).
Pericardi-
The diagnosis of pericardial disease was made by clinical criteria [27-291 in 15 patients. These 15 patients were divided into two groups, each with a distinct clinical pattern: (1) pericardial effusion and congestive heart failure, and (2) acute pericarditis with friction rub. Clinical Picture. The 11 patients with chronic pericardial effusion and the 4 with acute inflammatory pericarditis (Table I) were similar in age at the onset of pericardial disease (Table II). Although there were more women than men and more whites than nonwhites among the patients with chronic effusion, only black women were seen with acute pericarditis. Dyspnea was an almost universal finding in both groups. Temperature greater than lOOoF and chest pain were frequent presenting complaints in those with acute pericarditis. Four patients with chronic pericardial effusion also had chest pain; in three of the four, the pain was exertional, substernal and typical of angina pectoris. Raynaud’s syndrome was seen in 10 of 11 patients with effusion but in only one patient with acute pericarditis. All patients with pericardial effusion had signs of altered cardiac function. Pedal edema, often marked, and hemodynamic abnormalities (Table Ill) were major findings in the patients with chronic pericardial effusion. Distended neck veins and liver enlargement were the most frequent findings in those with effusion. Early evidence of tampontide, i.e., pulsus paradoxus, Kussmaul’s sign and pulsus alternans, was seen in three patients; no patient required emergency intervention. In contrast to the patients with effusion, neck vein distention in one of four patients with acute pericarditis was the only evidence of altered cardiac function. Acute pericarditis was identified in these patients by
October 1974
The American Journal of Medicine
Volume 57
567
-__--
+
+
+
-
+
+
+
52,F,W
38,M,W
56,M,B
73,M.W
52,F,H
69,F,B
51, F,W
76, F,W
R.R.
A.D.
A.M.
A.B.
T.C.5
CT.’
F.P.”
B.0.s
+
+
52,M,W
Raynaud’s SynAge (yr), Sex and Race drome _ --__
- __
+
-
i-
+
+
+
+
-I-
-t-
Dyspnea
1+
2+
-
+
2+
2+
+
-
2+
-
-
-
4c
-
4+
4+
-
+
Pedal Edema __-__
Chest Pain ~-__-
and Pericardial
- - ~-__~__
Patients with Scleroderma
--
R.L.
Patient __-
TABLE I
-
-
-
-
-
-
-
-
-
-
-
-I-
-
-
i-
-
-
~~___
99.2
9
120
36
99.8 100.0
37
29
18
32
56
34
-___
Cardiomegaly Cardiomegaly
5,500
11,650
Cardiomegaly
2+
8,000
-
NAD, low voltage, AF, T wave abnormalities
MLAD, low volt. age incorn. plete RBBB
MLAD, T wave abnormalities
LAD, low voltage, T wave abnormalities
LAD, low voltage, T wave abnormalities
Electrocard\ogrami
-__
NAD, voltage loss, AF, T wave abnormalities
NAD, low voltage
NAD, T wave abnormalities
Cardiomegaly, in- LAD, low voltage, T wave creased pulabnormalities monary markings, bilateral pleural effusion
Cardiomegaly
Cardiomegaly, increased pulmonary markings
Cardiomegaly, increased pulmonary markings
Cardiomegaly, increased pulmonary mark. ings, bilateral pleurat effusion
Cardiomegaly, left pleural effusion
l-i-
1+
-
1+
1+
2+
Chest Roentgenogram __I~
22,000
5,400
7,000
6,600
9,000
12,800
--__-
Proteinuna
Effusion
White Blood count (/mmP)
with Pericardial
Erythrocyte Sedimentation Rate (mm/hr) _~__-__~-
102.0
98.0
99.0
98.6
101.8
98.0
Pericarditis
(“0 -__
Temperature
~___.____
Hypertension* _~__
Chronic
.Pericardial Friction Rub
Disease
co2 pos
PC pos PP pos
coz pos PC pas
Echo pos
ND
Echo pas
Echo pos CC pos
Echo pos cc pos PB pos
Echo pas
OtherS
-
ND
-
ND
-
ND
-
+
(PPD)
Tuberculin Skin Test
F n 2
I 8 3 2 ?J
?I $ z
r
52,F,W
50,F,B,
79,F,B
32,F,B
40,F,B
L.G.$
N.C.
B.G.
D.T.§
A.Mc.$
-
+
-
-
+
+
+
+
+
+
+
+
-
-
-
-
-
4+
1+
+
+
-I-
-
+
+
+
+
-4
-
-
102.0
100.4
-
-
99.4
-
104.0
Inflammatory
101.0
-
Acute -
98.0
-
20,700
6,300
45
10
30
115
4,750
12) 500
4,500
19.400
Pericarditis
71
18
2+
1+
-
2+
2+
3+
Cardiomegaly, increased pulmonacy markings
Cardiomegaly
Cardiomegaly, increased pul. monary markings
Cardiomegaly, increased pulmonary markings
pleural effusion
Cardiomegaly, increased pulmonary markings, bilateral
Cardiomegaly, left pleural effusion, increased pulmonary markings
LAD, low voltage, T wave abnormalities
LAD, voltage loss, T wave abnormalities
LAD, T wave abnormalities
LAD. voltage loss, T wave abnormalities
MLAD, T wave abnormalities
MLAD, low voltage, RBBB
Echo neg
Echo neg CO? neg
COn neg
ND
Echo pos
Echo pos
+
+
ND
NOTE: W = white; B = black; H = hispanic; + = present; - = absent; ND = not done. * Diastolic pressure greater than 100 mm Fig. 1 NAD = no axis deviation (+90” to +30”); LAD = left axis deviation (+29O to -3OO); MLAD = marked left axis deviation (-30” to -90”); Voltage loss = significant loss of voltage; AF = atrial fibrillation; RBBB = right bundle branch block; Inc= incomplete. $ Echo = echocardiogram; CC = cardiac catheterization; PB = pericardial biopsy; CO* = CO, angiogram; PC = pericardiocentesis; PP = pneumopericardium; pos = positive; neg = negative. $ Autopsy data in Table V. ” Reported by Meltzer [16].
41,F,B
M.R.a
s’
9
!
$ 0
w L
SYSTEMIC
TABLE II
SCLEROSIS-McWHORTER,
LeROY
Summary of Clinical Data on Patients with Pericardial Disease Data
Age (yr), mean (range) Sex (male/female) Race White Black Hispanic Raynaud’s syndrome Dyspnea Chest pain Pericardial friction rub Fever (>lOO”F) Hypertension (diastolic Chest roentgenogram Cardiomegaly
~-~-~____-__
Chronic Effusion 53 (39-76) 4/7
>lOO mm Hg)
Increased pulmonary markings Pleural effusion Electrocardiogram Low voltage Loss of voltage T wave abnormalities Leukocytosis (>lO,OOO/mm”) Erythrocyte sedimentation rate (>25) Rapid renal failure within 6 months
Acute Pericarditis
7111 3/11 l/11 lO/ll lO/ll 4/11 o/11 4/11 2/11
O/4 414 O/4 l/4 4/4 314 414 3/4 O/4
ll/ll 6/11 6/11
414 314 O/4
7111 l/4 l/11 214 8/11 3/4 4111 214 7111 414 6/11 O/4 ~_ .~_.._
~~~~~_
Hemodynamic Signs Signs ~~
.~_.~
Congestive failure 1. Pedal edema 2. Distended neck veins 3. Hepatomegaly 4. Tachycardia without fever Either 1, 2, 3 or 4 Pericardial signs 5. Pulsus paradoxus 6. Kussmaul’s sign 7. Pulsus alternans Either 5, 6 or 7
O/4
341, the electrocardiogram was not useful either in making the initial diagnosis of pericardial involvement or in making the distinction between acute pericarditis and chronic effusion. There was no pattern of deviation of the electrical axis. Although right axis deviation would be expected with the high incidence of pulmonary fibrosis seen at postmortem [21], right axis deviation was not seen in either group. Low voltage was seen more frequently in those with chronic pericardial effur;ion; when patients with significant loss of voltage on sequential tracings were taken into account, the two groups were similar (Table II). Low voltage has been described as a frequent finding in patients with scleroderma [35]. Nonspecific T wave abnormalities were seen frequently in both groups and were of no diagnostic significance. The white blood cell count was Laboratory Data. not helpful in differentiating patients with acute periOctober 1974
~
50 (32-79)
the presence of fever, chest pain and a pericardial friction rub. Chest Roentgenogram. Cardiomegaly was found in all patients in both groups but was generally more pronounced in those with pericardial effusion (Table II). Increased interstitial markings were a frequent manifestation of both groups whereas pleural effusion was seen only in those with chronic pericardial effusion. These findings are similar to those of previous investigators who described cardiomegaly and pulmonary infiltrates as common manifestations of scleroderma [ 30-321. As in previous studies [33, Electrocardiograms.
570
TABLE III
Chronic Effusion
Acute Pericarditis
lO/ll 8/11 7111 3/11 ll/ll
O/4 l/4 O/4 O/4 l/4
l/11 2111 2111 3/11
O/4 O/4 O/4 O/4
.~~
-
carditis from those with chronic effusion (Table II); also, the erythrocyte sedimentation rate was frequently elevated in both groups. Only one of the patients with chronic effusion had a slightly decreased serum complement level, and no patient from either group had a positive lupus erythematosus preparation or a biologic false-positive serologic test. Although latex fixation titers have been reported to be elevated in up to 35 per cent of the patients with scleroderma [36], only two patients with acute inflammatory pericarditis had elevated titers: both of these patients died suddenly during hospitalization. Clinical Course. Within 6 months of the onset of symptoms leading to the diagnosis of pericardial effusion, 6 of the 11 patients had died from renal failure (55 per cent). All patients with pericardial effusion were treated with digitalis and diuretics. As an example, the mean weight loss in the six patients in whom renal failure
subsequently
developed
was 13 per cent
of body weight. This incidence of renal failure (55 per cent) was considerably higher than expected in the general population with scleroderma in which the incidence of azotemia was 19 per cent (40 of 210 patients), the incidence of hypertension was 24 per cent (50 of 2 10 patients), the incidence of proteinuria was 36 per cent (76 of 210 patients), and the combined incidence of any one of these renal markers (azotemia, hypertension or proteinuria) was 45 per cent (94 of 2 10 patients). Since only azotemia defines renal failure, the 55 per cent incidence of renal failure in patients with pericardial effusion is most appropriately compared with a 19 per cent incidence of azotemia in the over-all scleroderma population. The mechanism for the increased incidence of renal failure in patients with pericardial effusion is unclear. Two of the four patients with acute inflammatory pericarditis died suddenly during the acute illness, presumably from a cardiac arrhythmia. In the remaining two patients, the acute pericarditis resolved and they were able to function for several years. Renal failure was not observed in these four patients.
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SYSTEMIC SCLEROSIS-McWHORTER, L&OY
Postmortem
34 patients
Results.
between
Autopsies were performed on 1952 and 1972; the mean age
at autopsy was 53 years (Tables IV and V). The patients seen most frequently at postmortem were female and white. Pericardial disease, defined as either fibrinous or fibrous adhesions, or a pericardial effusion of 50 cc or greater, was found in 19 patients (56 per cent). Two patients (A.D., R.L., Table I) had no pericardial disease at postmortem but had documented pericardial effusion prior to death when their blood urea nitrogen level was normal. If we include these two patients, the adjusted incidence of pericardial disease is 62 per cent. Twelve patients were found to have pericardial effusion without pericarditis, eight had pericarditis without effusion and one had pericarditis with effusion. After excluding patients with terminal blood urea nitrogen values of 46 to 163 mg/lOO ml, the incidence of pericardial disease (55 per cent) did not change significantly. Examination of the heart revealed increased heart weight in 63 per cent of the autopsy patients. Left ventricular hypertrophy was present in 47 per cent of patients and right ventricular hypertrophy in 28 per cent. Biventricular hypertrophy was present in 25 per cent of the autopsy patients; in eight of nine patients with right ventricular hypertrophy, the left ventricle was also thickened. Left ventricular hypertrophy at postmortem examination could not be correlated with hypertension and/or uremia prior to death; similarly, right ventricular hypertrophy could not be correlated with pulmonary fibrosis. Thus, the present postmortem series does not add support to previous correlations of this type [ 13,141. Histopathologic examination of the myocardium revealed significant myocardial fibrosis (severe or diffuse, see “Methods”) in 30 per cent of the autopsy patients. As in previous series, a few small areas of fibrosis were observed in an otherwise normal myocardium in 21 per cent of the patients and were not considered significant fibrosis. In this study, the incidence of pericardial involvement (62 per cent) was greater than the incidence of myocardial fibrosis (30 per cent). Examination of the other viscera revealed pulmonary fibrosis in 65 per cent and pleural effusions (> 100 cc) in 59 per cent. The gastrointestinal tract was involved in 62 per cent and the skeletal muscle in 21 per cent. lntimal proliferation of the small arteries or arterioles was the most frequent pathologic finding at autopsy (76 per cent) and was seen often in numerous
organ systems.
COMMENTS
The present study outlines two clinical patterns of pericardial disease in scleroderma: acute pericarditis and chronic pericardial effusion. Furthermore, at postmortem pericardial disease was found to be more common than myocardial fibrosis. Subsequent
TABLE IV
Summary of Data on 34 Postmortem ClinicalData
.Total Series
Age (yr), mean (range) Sex (male/female) Race White Black Hispanic
Postmortem Data Heart Pericardium Pericardial disease (total) at postmortem Adjusted incidence of pericardial disease (total)? Pericardial effusion without pericerditis Pericarditis without effusion Pericarditis with effusion
Patients
53 (39.-76) 7.‘27 21134 (620/,)
1l/34 (32%) .!/34 (6%) Without Arotemla*
19,‘34 (56%) U/22 (55%)
:1/34 (62%)
7122 (32%)
12/34 (35%)
4/22 (18%)
8/34 (24%)
l/22 (5%)
l/34 (3%)
Myocardium Fibrosis, diffuse Fibrosis, focal, severe Fibrosis, focal, mild increased heart weight Left ventricular hypertrophy Right ventricular hypertrophy Biventricular hypertrophy Lung Fibrosis Pleural effusion (>lOO cc) Gastrointestinal Skeletal muscle Vascular
4/34 (12%) 6134 (18%) 7/34 (21%) TO/32 (63%)1 I.5132 (47%)$ 9/32 (28%)t 8/3? (25%): :?2/34 (65%) ;20/34 (59%) ?I/34 (62%) 7;34 ~217~) 26,‘34 (76%)
* Adjusted for two patients (L.G. and T.C., Table I) who had documented pericardial effusion when thetr blood urea nitrogen level was normal. i Addition of two patients (A.D. and R.L., Table I) who had documented pericardial effusion prior to death during period of normal blood urea nitrogen. f. This determination was not made in iwo postmortem examinations.
renal failure occurred in 6 of 11 patients with pericardial effusion. In this context the development of thought concerning cardiac involvement in scleroderma and its possible bearing on future renal involvement is reviewed. In 1895 Lewin and Heller [37] reviewed the previously reported cases of scleroderma and found pericardial disease in 7 of 28 autopsy cases; Matsui [ 381, in 1924, reported two cases of pericardial effusion in six autopsy cases. In 1943 Weiss et al. 121, using the term scleroderma heart disease, described nine patients with Raynaud’s phenomenon, dyspnea on exertion and prominent pedal edema. The chest roentgenograms showed an enlarged triangle-shaped heart consistent with pericardial effusion. In these two autopsy cases pericardial effusions were significant, but these investigators considered the major
October 1974
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Volume 57
571
SYSTEMIC SCLEROSIS-McWHORTER,
TABLE
Data on Patients
V
L&OY
with Pericardial
Disease
at Postmortem
Autopsy Organ involvement*
Patient
Age (yr), Sex, Race
Blood Urea Nttrogen (rng/100 ml)
T.J. Z.D. K.G. M.M.
44,M,W 55,F,W 64,F,W 42,F,B
104 163 29 60
K.A.
66,F,W
15
4O,F,B 32,F,B 6O,F,B 52, F, H 63, F,W 42,F,W 76,F,W 41,F.B 40, F, H 67,F,B 43,F,W 54,F.W 40, F,W 52,F,W
19 11 117 60 110 116 14 20 27: 49 12 57 46 74
A.Mc. D.T.i
1
C.Th. T.C. H.M. M.E. B.0.i M.R.j E.R. B.M. S.F. F.D. M.A. L.G.j
Lung Pencardrum Effusion
Heart
Acute fibrinous Acute fibrinous Acute fibrinous Frbrous--with inflammation Fibrous
-
-
Fibrous Fibrous Fibrous Acute fibrinous -
-
Perrcardrtrs
MFF
-
MC MFF SFF DF -
+ + f + + + + + + + +
-
SFF MFF DF MFF DF SFF MFF MC SFF
NOTE: W = whrte; B = black; H = hispanic; + = present; - = absent. * See methods for criteria1 of organ rnvolvement. MFF = mild focal fibrosis; MC = myocarditis. i SeeTable I for clinical data. 1 Nonprotein nitrogen (normal = 15-35 mg/lOO ml).
pathologic feature to be “myocardial scarring of an unusual iype.” Over the next several years, several workers (Bevans in 1944 171, Mathison et al. in 1947 [9J, Goetz in 1951 14). Hurly et al. in 1951 [5] and Beigelman et al. in 1953 IS]) reported cases in which myocardiai fibrosis was described as the predominant form of scleroderma heart disease. Of these, several were associated with pericardial disease which was thought to be an incidental finding ]2,491. In 1954, Leinwand et al. [39] reviewed 150 cases of scleroderma and concluded that pericardial disease was rarely, if ever, found. In 1956, pericardial effusion as a primary form of scleroderma heart disease was first described by Meltzer f 161 in two cases (Table I). Utilizing angiography, Steinberg and Rothbard [ 17,181 reported five cases of pericardial effusion in two reports. In 1964, Sackner et al. [ 131 demonstrated pulmonary hypertension by cardiac catheterization as the most common cardiopulmonary finding in scleroderma; in reviewing 65 patients and 25 postmortem examinations, Sackner concluded that myocardial fibrosis rarely contributed to heart disease in scleroderma. Excluding focal fibrosis, he found 3 of 25 patients with diffuse fibrosis and noted
572
October
1974
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Journal of Medicine
Pleural GastroEffusion Fibrosis Kidney Vascular Intestinal
-
Muscle
+ + + +
+ + -
+ -
-
-
+ + +
+
-
+
+
+
-
+
+
+
+
+
+
-
+ -
-
+ + + + + + + + + + + + +
+ -
+ +
+ + + + + + + + + +
+ + + + + + + + +
+ + + + + + + + + +
SFF = severe focal fibrosis;
+ + + + + + + +
DF = diffuse
+ + -
fibrosis:
the high frequency of this finding in other disease states in this age group. Sackner attributed scleroderma heart disease either to pulmonary hypertension or to systemic hypertension with scleroderma renal involvement. He also noted pericardial disease as a common pathologic feature in 18 of 25 postmortem studies [ 151. D’Angelo et al. compared 58 autopsy patients with scleroderma with 58 matched controls and found pericardial lesions in 53 per cent compared with 12 per cent in controls. The incidence of pericardial effusion was the same as in controls; however, the size of effusion was greater in those with scleroderma. In patients over 40 years of age, no significant difference in myocardial fibrosis could be determined between those with scleroderma and control subjects. In patients under 40 years of age, myocardial fibrosis was more common in those with scleroderma [ 121. Endocardial lesions have been only rarely reported in scleroderma. Four reports ascribed a nodular thickening of the mitral valve to scleroderma [39-421; however, D’Angelo et al. [ 121 found an equal incidence of this abnormality in matched controls. Involvement of the pericardium is therefore fre-
Volume 57
SYSTEMIC SCLEROSIS-McWHORTER,
quent and well known in autopsy studies of scleroderma; still, the diagnosis is often unrecognized clinically. There is general agreement that approximately 50 to 70 per cent of patients (62 per cent present study, 53 per cent D’Angelo, 72 per cent Sackner) show evidence of pericardial involvement at postmortem examination. Renal failure and uremia are frequent terminal events in patients with scleroderma [43-481. Since uremia frequently produces pericardial disease 1491, all patients studied at autopsy were reevaluated to determine whether eliminating those patients in whom pericardial disease could not be clearly separated from uremia would alter the incidence. An incidence of 55 per cent was found for pericardial disease unrelated to uremia, which was not significantly different from the over-all incidence of pericardial disease (62 per cent). A comparison of the clinical patient series and the postmortem data in the present study indicates that pericardial disease can be detected clinically in the patient with scleroderma with chest pain or congestive heart failure. In this comparison, 32 per cent of pericardial disease demonstrated at autopsy was documented prior to death. The etiology of pericardial disease in scleroderma remains unclear. Patients with chronic pericardial effusion presented with Raynaud’s syndrome and congestive heart failure which was manifested by dyspnea. neck vein distention, hepatomegaly and pedal edema. Signs of cardiac tamponade effect were present in a few patients but did not require intervention. It was not possible to determine from this retrospective study whether pericardial effusion was caused by antecedent heart failure secondary to pulmonary hypertension or myocardial disease, or whether primary involvement of the pericardium causing effusion precipitated congestive heart failure. The presence of pericardial effusion and congestive failure was associated with the subsequent development of renal failure in a disquietingly large proportion of patients (6 of 11). The mechanism of the association between pericardial effusion, congestive failure and renal failure is not clear; several mechanisms may be operative [50-521. First, it is known from other studies of this same patient population that renal failure in scleroderma is associated with a marked reduction in renal cortical blood flow 1541; renal cortical blood flow determinations in 6 of the 11 patients with pericardial effusion were low, with a mean cortical flow of less than 100 ml/ 100 g/min (normal >350 ml/100 g/min). Pericardial effusion, congestive failure and its therapy, all contribute to renal cortical vasoconstriction by several mechanisms. Decreased cardiac output decreases renal cortical flow 1531; increased renal venous pressure
October
also
contributes
to renal
cortical
vasospasm.
LeROY
All
these hemodynamic bases for renal vasoconstriction contribute to the higher incidence of renal failure in scleroderma complicated by pericardial effusion and congestive failure. Furthermore, the histopathologic process of scleroderma, the etiology of which is unknown, may lead to simultaneous and essentially coincidental pericardial and renal involvement [ 55 1. As a third mechanism, the therapy of the antecedent pericardial effusion and congestive failure may enhance and hasten the development of renal scleroderma. Diuretic therapy of increasing potency could reduce blood volume (volume depletion) sufficient to induce visceral vasoconstriction and a selective reduction in renal cortical blood flow; it is also possible that the renin-angiotensin system participates in these vasoconstrictive phenomena. Thus the patient with scleroderma has three potential causes of reduced renal cortical flow and therefore of glomerular perfusion: the microvascular lesion of scleroderma; the cardiac involvement be it pericardial, myocardial or pulmonary; and volume depletion by diuretic therapy. The additive effect of these three mechanisms may explain the high incidence of subsequent renal failure in patients with scleroderma and pericardial involvement. Since the mechanism of reduced cortical perfusion in congestive heart failure is unclear, scleroderma may provide a useful setting to study the influence of efferent arteriolar vasoconstriction (Raynaud’s phenomenon of the kidney) on renal function in anatomically separate regions of nephrons. Acute inflammatory pericarditis in scleroderma was characterized by fever, chest pain and pericardial friction rub without evidence of congestive heart failure or tamponade. This syndrome could not be distinguished from acute idiopathic or viral pericarditis. Pericarditis is seen commonly in systemic lupus erythematosus [56] and less commonly in rheumatoid arthritis [ 571. The significance of elevated latex fixation titers in two of four patients with acute pericarditis in scleroderma remains unclear but suggests a possible immune complex etiology. Because two of four patients died during their hospitalization, it was not possible to assess the effect of acute pericarditis on subsequent organ involvement. In the two surviving patients kidney involvement did not develop. ACKNOWLEDGMENT
We are indebted to Dr. M. Irene Ferrer for review of the electrocardiograms and for her advice, to Dr. Kent Ellis for review of the chest roentgenogram and to Edna Farrington, R.N., for assistance with patient records. We wish to thank Drs. Charles A. Ragan, Jr., Stanley E. Bradley, J. Thomas Bigger, Jay I. Meltzer and Paul J. Cannon for helpful suggestions.
1974
The American
Journal
of Medicine
Volume 57
573
SYSTEMIC SCLEROSIS-McWHORTER,
LeROY
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Cannon PJ, Hassar M, Case DB, Casarella WJ, Sommers SC, LeRoy EC: The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of renal cortical circulation. Medicine (Baltimore) 53: 1. 1974. Norton WL. Nardo JM: Vascular disease in progressive systemic sclerosis (scleroderma). Ann Intern Med 73: 317. 1970. Estes D, Christian CL: The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 50: 85, 1971. Franc0 AE, Levine HD, Hall AP: Rheumatoid pericarditis. Report of 17 cases diagnosed clinically. Ann Intern Med 77: 837, 1972.
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