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Thallium perfusion defects predict subsequent cardiac dysfunction in patients with systemic sclerosis.

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ARTHRITIS & RHEUMATISM
Vol. 39, No. 4, April 1996, pp 677-681
0 1996, American College of Rheumatology
677
THALLIUM PERFUSION DEFECTS PREDICT
SUBSEQUENT CARDIAC DYSFUNCTION IN
PATIENTS WITH SYSTEMIC SCLEROSIS
VIRGINIA D. STEEN, WILLIAM P. FOLLANSBEE, CLAUDIA G. CONTE, and
THOMAS A. MEDSGER, JR.
Objective. To determine the significance of thallium perfusion defects in patients with systemic sclerosis
(SSC).
Methods. This is a followup study of a series of 48
SSc patients who underwent thallium perfusion scans in
the early 1980s. Their cardiac history and survival
information over the last 10 years were obtained as part
of the Pittsburgh Databank’s yearly evaluation. We
determined the frequency of subsequent development of
arrhythmias requiring treatment or of congestive heart
failure through patient and physician information.
Results. Patients with larger thallium perfusion
defects had a significantly increased risk of developing
subsequent cardiac events or death. The size of the
initial thallium defect was the best predictor of later
adverse events compared with other disease-related
features, in a logistic regression analysis.
Conchion. We conclude that patients with SSc
who have significant thallium perfusion defects are at a
significantly increased risk of developing subsequent
cardiac disease or death.
Systemic sclerosis (SSc) is a connective tissue
disease characterized by multisystem visceral involvement. Although gastrointestinal and pulmonary dysfunction develop in a large proportion of patients, the
Supported by grants from the NIH (FR-00056, AM-21393,
and AM-01348), the RGK Foundation, Austin TX, and the Arthritis
Foundation, Western Pennsylvania Chapter (Shoemaker Fund).
Virginia D. Steen, MD, William P. Follansbee, MD, Claudia G. Conte, MA, MPH, Thomas A. Medsger, Jr., MD: University
of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Address reprint requests to Virginia D. Steen, MD, Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
Submitted for publication March 27, 1995; accepted in
revised form September 26, 1995.
less common developments of cardiac and renal involvement are the most life-threatening.
Cardiac abnormalities are frequently detected
by sensitive, noninvasive cardiac testing, but serious
clinical problems occur less often (1). Cardiac problems develop more commonly in patients with SSc and
diffuse scleroderma, but also occur in those with
limited cutaneous involvement. These problems can
occur at any time throughout the course of the disease.
Skeletal myositis has recently been shown to be associated with a high risk of cardiac complications (2), but
no other risk factors have been identified. Abnormalities demonstrated with noninvasive cardiac testing
have not yet been shown to identify patients at increased risk for future serious cardiac events.
In 1982-1983, we performed exercise thallium
scintigrams on 48 unselected SSc patients (3,4). Perfusion defects of the myocardium were found in the
majority of patients, but only 15% of these individuals
had any clinical evidence of cardiac involvement at
that time. The purpose of the present study was to
perform a followup evaluation of these 48 patients in
order to determine the predictive significance of myocardial perfusion defects.
PATIENTS AND METHODS
Patients. Forty-eight consecutive patients who were
willing to participate underwent a radionuclide myocardial
function study in 1982-1983 (3,4). Each had a complete
history and physical examination, a laboratory evaluation
for organ system involvement, including pulmonary function
tests, and a scleroderma-specific autoantibody profile performed. In addition, an electrocardiogram (EKG), chest
radiograph, planar exercise thallium scintigrams, and an
exercise radionuclide ventriculogram study were obtained.
Echocardiograms were not routinely performed.
Myocardial thallium uptake was quantified by a
circumferential count profile and compared with a normal
STEEN ET AL
678
patient data file from our laboratory. Perfusion defects were
defined as areas in which the count profile was >2 SD below
the normal range. Perfusion defects were summed and
expressed as a defect score (DS) for each patient (3). Since
this was the procedure we used 10 years ago, it would not be
easy to retrospectively change the evaluation approach and
determine the number or percentage of segments involved.
The median DS was 1.6, which is relatively mild, but 9
patients had extensive defects, with scores ranging from 3 to
9.5. Defects which were unchanged, comparing exercise
scans with followup redistribution scans, were considered to
be fixed defects consistent with fibrosis.
Followup. After the initial evaluation, patients completed annual questionnaires concerning symptoms, the status of organ system involvement, hospitalizations, laboratory testing, medications, drug toxicity, and functional
status using the Health Assessment Questionnaire (HAQ)
(5). After obtaining the patients' informed consent, information was gathered from hospital and physician records, as
well as death certificates, and then abstracted.
All 48 patients in the original study were accounted
for during 191-1993. All patients had at least 1 repeat EKG
and some had other cardiac tests, the results of which were
obtained for review. Thallium scans were not repeated
because many of the patients had died, some were not from
the Pittsburgh area, and comparing the old and new thallium
scans and techniques would be difficult.
Definitions of cardiac abnormalities. Only myocardial
and conducting system abnormalities were included in this
study. Pericardial disease (pericarditis, pericardial effusions)
was not included as an abnormality since the focus was on
myocardial function and perfusion. Patients with known
atherosclerotic heart disease had been excluded from the
original study, and those with symptoms or thallium scan
abnormalities suggestive of coronary disease underwent
coronary arteriography to rule out coronary artery problems
prior to inclusion in the original study. All 8 patients so
studied had normal coronary arteries.
Cardiac disease was defined by the presence of
clinical cardiac events (symptomatic) and by the demonstration of objective, noninvasive cardiac abnormalities in the
absence of symptoms (asymptomatic). The following definitions were used and recorded at any point during a patient's
illness. Asymptomatic heart disease: abnormal cardiac test
results but no cardiac symptoms and no cardiac medications.
(a) Conduction defects: right bundle branch block, left
bundle branch block, left anterior hemiblock, etc. (b) Arrhythmia: frequent or multiple atrial or ventricular premature contractures on routine EKG. (c) Myocardial dysfunction: cardiomegaly on chest radiography or evidence of left
ventricular dysfunction on echocardiography. Symptomatic
heart disease: one or more cardiac symptoms, including
dizziness, syncope, persistent palpitations, orthopnea, dyspnea, or edema (congestive heart failure [CHF]), that required medication or pacemaker insertion, plus one of the
following: (a) conduction defects: bradycardia or complete
heart block; (b) arrhythmias atrial or ventricular: or (c) CHF.
Statistical analysis. We used standard MEDLOG
statistics programs, Kaplan-Meier survival analysis, and
stepwise logistic regression.
Table 1. Cardiac findings in 47 systemic sclerosis patients at initial
thallium scan and during followup
At
initial scan
During
followup
18
8
2
0
2
4
Asymptomatic heart disease
No. of patients
Conduction defects
Arrhythmias, atrial
Arrhythmias, ventricular
Myocardial dysfunction
Symptomatic heart disease
No. of patients
Conduction defects
Arrhythmias, atrial
Arrhythmias, ventricular
Congestive heart failure
8
1
2
10
I
0
5
3
3
8
2
3
0
5
RESULTS
The mean age of the 48 patients was 51 years at
the time of the original study (3,4). Seventy-seven
percent were female and 54% (n = 26) had diffuse
cutaneous involvement. The mean disease duration at
the time of the initial study was 8.2 years (4.3 years for
those with diffuse SSc). Thirty-four of the 48 patients
had abnormal thallium scintigram findings, 26 with
fixed perfusion defects and 10 with exercise-induced
defects (2 patients had both defects). Eight of the 10
patients with exercise-induced perfusion abnormalities
underwent coronary angiography , the findings of
which were normal in all 8 patients. One patient who
died at the time of the initial evaluation had severe
coronary artery disease at autopsy and was excluded
from the analysis. The mean followup time for the
remaining 47 patients was 7.5 years.
Table 1 summarizes the cardiac findings in the
patients at the time of the 1982-1983 thallium scan and
any additional findings which occurred during followup. Eighteen patients initially had asymptomatic
heart disease. Eight patients had conduction defects, 3
had arrhythmias (I atrial and 2 ventricular), and 10
patients had objective myocardial dysfunction without
symptoms of CHF. Three patients had more than one
of these abnormalities. During followup, 8 of the
original patients with normal findings developed new
asymptomatic abnormalities, including 4 with EKG
abnormalities (2 with conduction defects and 2 with
ventricular arrhythmias) and 4 with myocardial dysfunction.
Seven patients had symptomatic heart disease
at the time of initial study, including 5 with supraventricular tachycardias or atrial arrhythmias, 3 with
ventricular arrhythmias, and 3 with CHF. During the
CARDIAC DYSFUNCTION IN SSc
679
Table 2. Association of initial thallium perfusion defect scores
with cardiac abnormalities during the course of systemic sclerosis'
At initial scan
Age, mean years
Disease duration, mean years
Diffuse scleroderma, %
LV ejection fraction (lowest), %
At initial scan or during followup
Any resting EKG abnormality, %
LV ejection fraction (lowest), 9%
SvmDtomatic heart disease. %
Dkaih, %
DS 21.6
(n = 16)
DS <1.6
(n = 31)
52
5.4
65
60
50
9.8
45
67
0.01
69
56
56
69
32
67
26
19
0.05
0.01
0.05
0.002
* DS = defect scores; N S = not significant; LV
EKG = electrocardiogram.
=
P
NS
2;
left ventricular;
decade of followup, 8 additional patients developed
symptomatic heart disease, including 2 who required
pacemakers for the treatment of complete heart block,
3 who had atrial arrhythmias, and 5 who had CHF.
Two of these persons initially had asymptomatic heart
disease, and 2 had more than one abnormality.
There was a wide range of defect scores on the
original thallium perfusion scans in these patients.
Fourteen of 22 patients (64%)with limited scleroderma
and 20 of 26 patients (77%) with diffuse scleroderma
had perfusion defects. The mean DS in the patients
with diffuse scleroderma was significantly greater than
that in patients with limited scleroderma (3.5 versus
1.4; P < 0.01) (3,4). The median DS for patients with
a defect was 1.6, which is a relatively mild amount of
decreased perfusion, but the high DS group had many
patients with severe perfusion defects (3).
Patients with higher DSs ( 21.6) were compared
with those with lower DSs (<1.6). There were no
statistically significant differences in age, disease duration, or percentage of patients with diffuse scleroderma between the high and low DS groups at the time
of the scan, although the high DS group had more (but
not significantly more) patients with diffuse scleroderma and a shorter mean disease duration (Table 2).
When abnormalities acquired during followup
were added to the initial findings, a high initial DS was
significantly associated with EKG abnormalities and
reduced left ventricular ejection fraction throughout
the entire illness. Most importantly, patients with a
high DS significantly more frequently had symptomatic heart disease (56% versus 26%; P < 0.05) or died
(of any cause) during followup (69% versus 19%; P <
0.002) compared with those in the low DS group.
Additionally, when patients who later devel-
oped symptomatic heart disease or died during followup were
with those who did not develop
new heart problems and were alive, the former group
had a significantly larger DS at the time of initial evaluation. Patients with a high initial DS had a significantly
greater risk for the subsequent development of several
important conditions, including new symptomatic
heart disease (relative risk [RR] 3.6, 95% confidence
interval [95% CI] 1.05-22.25, P = 0.02), cardiac death
(RR 7.8, 95% CI 0.94-63.71, P = O M ) , or death from
any cause (RR 3.5, 95% CI 1.61-7.83, P = 0.001).
Using a Cox multiple logistic regression model
that included sex, scleroderma subtype, and values at
time of initial thallium scan for age, disease duration,
extent of skin thickening, blood pressure, pulse rate,
left ventricular ejection fraction, EKG abnormalities,
and thallium DS, only the defect score was significantly independently associated with subsequent
death (P = 0.007).
Figure 1 shows the time to onset of new symptomatic heart disease in patients with high and low DS
who did not have symptomatic heart disease at the
time of the initial thallium study. The group with a high
DS developed new symptomatic heart disease significantly more rapidly than did those with a low DS (P=
0.002). Likewise, Figure 2 shows that the patients with
a high DS had a reduced survival compared with those
with a low DS. The 5-year cumulative survival rate
from the time of the initial thallium test was 90% for
the low DS group and 60% for the high DS group (P=
0.0002), independent of scleroderma subtype.
In the high DS group, 5 of the 11 deaths were
from cardiac causes (but not coronary artery disease),
100,
HIGH DS (n=ll) v
LOW DS (11-27)
I
P-0.002
1
3
::
0
0
1
2
3
4
5
I
7
I
P
10
TIME FROM THALLIUM SCAN (YEARS)
Figure 1. Cumulative rate of development of symptomatic heart
disease from the time of initial thallium perfusion study in patients
with high and low defect scores (DS) on initial thallium testing.
STEEN ET AL
680
100
n
\r
-\.
(h
90
80
cl
4
70
a
g
5
f
\.-.
60
zw
so
3
30
LO.
HIGH
DS
US (n-31)
&is)
U
\-\ I
P-o.oooz
.
.-.
20
lo
1
o l
0
1
2
3
4
5
6
7
8
9
10
TIME FROM THALLIUM SCAN (YEARS)
Figure 2. Cumulative survival from the time of initial thallium
perfusion study in patients with high and low defect scores (DS) on
initial thallium testing.
and 5 were from other causes related to scleroderma.
In the low DS group, 1 of the 6 deaths was from a
cardiac cause, 3 were from other scleroderma problems, and 2 were from unrelated causes.
There were no detectable differences in the
outcome of patients with a high DS who were and were
not treated with vasodilators. However, the numbers
were small, and a significant benefit of such treatment
could have been missed.
DISCUSSION
The heart is one of the major target organs of
systemic sclerosis. Although pericardial involvement
is common (H),
abnormalities of the conducting
system and myocardium are more likely to be associated with a poor prognosis.
Clinically significant myocardial dysfunction in
the absence of extramural coronary artery disease
occurs in about 10% of patients with diffuse scleroderma and is unusual in patients with limited scleroderma (9). This complication must be distinguished
from secondary forms of heart disease, such as the left
ventricular hypertrophy seen in “scleroderma renal
crisis” and right ventricular hypertrophy and failure
due to pulmonary arterial hypertension. The vast
majority of SSc patients who develop myocardial
involvement die within 3-5 years. Previous studies
have shown an uncertain correlation of asymptomatic
left ventricular dysfunction, as demonstrated by
echocardiogram, with clinical outcome (8).
Conduction defects and heart rhythm abnormalities are well-known manifestations of scleroderma
heart disease (10,ll). As many as 50% of patients are
reported to have one or more EKG abnormality (12),
including a variety of conduction disturbances, right or
left ventricular hypertrophy, or atrial or ventricular
ectopy. A septa1 infarction pattern has been demonstrated in scleroderma (12). Interestingly, patients
with a normal resting EKG rarely have any significant
myocardial dysfunction if further sophisticated testing
is performed at the same visit (12).
The detection of cardiac conducting system and
myocardial disease is increased when noninvasive
testing is used compared with clinical assessment,
resting EKG, and chest radiography only. An increased prevalence of arrhythmias can be detected by
using a 24-hour ambulatory EKG monitor, which was
not done in our study group (13). Echocardiograms
and radionuclide ventriculograms often demonstrate
left ventricular dysfunction in the absence of clinical
evidence of CHF (3,8,14). Abnormalities noted on
EKG are commonly without symptoms (12,13,15).
Symptomatic severe cardiac involvement can present
with depressed left ventricular ejection fraction, spontaneous or exercise-induced arrhythmias (12), or sudden death (16). The significance and the prognostic
implications of these cardiac abnormalities have not
been clearly established.
In the present study, we evaluated the result of
one noninvasive test, an exercise thallium scintigram,
on subsequent outcome after a mean followup of 7.5
years. A thallium defect score above the median was
significantly associated with an adverse outcome, including the end points of new symptomatic cardiac
disease, death from a cardiac cause, or death from any
cause. The thallium defect score was the only covariant in a multiple regression analysis including age,
disease subtype, disease duration, and selected cardiac findings that was a statistically significant predictor of death. Thus, this evidence for decreased cardiac
perfusion may be a manifestation of present or future
severe heart disease. Since there were non-cardiac
deaths in this high DS group, it may suggest increased
risk of any severe scleroderma.
Myocardial fibrosis has been found at autopsy
in SSc patients (17). It is distributed randomly
throughout the myocardium, unrelated to the extramural vessels (18). Fixed thallium perfusion defects likely
reflect this patchy fibrosis. There is speculation that
areas of fibrosis result from vasospasm of small intramural arteries (17). Contraction band necrosis, a
CARDIAC DYSFUNCTION IN SSc
pathologic finding associated with experimental ischemia followed by reperfusion, has been found in some
SSc patients, particularly those with left ventricular
dysfunction in the absence of systemic hypertension
(1,17,19). It has been suggested to be a marker of
vasospasm with ischemic injury followed by a “myocardial Raynaud’s phenomenon. ” Cold challenge has
led to the presence of reperfusion abnormalities on the
thallium scan (20,21), again suggesting that vascular
change and/or spasm may be the primary etiology of
perfusion defects. Newer techniques for evaluating
decreased cardiac perfusion may be more helpful in
better understanding the pathogenesis of this puzzling
disease.
Reduction in thallium perfusion defects in SSc
patients has been observed after a single dose of
nicardipine (22). nifedipine (23), and captopril (24),
suggesting that they are not fixed fibrotic defects.
However, there has been no documentation of any
clinically significant effect of such drugs. These
changes in perfusion may just be from the surrounding
area and not actually affecting the fibrotic areas.
We conclude that patients with SSc who have
thallium perfusion defects are at significantly increased risk of developing subsequent symptomatic
serious cardiac disease and early death. Identification
of a high-risk subgroup of patients provides the potential to intervene and possibly prevent permanent myocardial damage. This high-risk subgroup would be
ideal for prospective therapeutic trials, possibly including vasodilator drugs.
68 1
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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