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Rheumatology Advance Access published online on May 25, 2008
Rheumatology, doi:10.1093/rheumatology/ken186
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Myocardial involvement in systemic sclerosis

L. Belloli1, N. Carlo-Stella1, G. Ciocia2, A. Chiti2, M. Massarotti1 and B. Marasini1

1Rheumatology Unit and 2Nuclear Medicine Unit, IRCCS Humanitas Clinical Institute, University of Milan, Milan, Italy.

Correspondence to: N. Carlo-Stella, Rheumatology Unit, IRCCS Humanitas Clinical Institute, University of Milan, Italy. E-mail: nickics{at}libero.it


   Abstract
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 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To identify clinical and/or laboratory characteristics that could be risk factors for myocardial microvascular involvement in patients with SSc.

Methods. Twenty-one SSc patients, clinically silent for cardiovascular disease, were consecutively evaluated for myocardial perfusion defects through 99m-Tc sestamibi gated myocardial perfusion SPECT with a stress–rest protocol.

Results. Eight patients (38%) had myocardial perfusion defects. Perfusion defects were related to skin scores (P < 0.0001), digital ulcers (P = 0.02) and oesophageal involvement (P = 0.046). A trend for anti-Scl 70 antibody positivity was observed in these patients (P = 0.09). Three SPECT-positive patients had re-establishment of normal myocardial perfusion after a course of prostanoid therapy. There were no significant associations between myocardial involvement and age, sex, diffuse/limited SSc, duration of RP or lung involvement.

Conclusions. Myocardial perfusion defects in SSc patients are frequent, and the presence of severe skin thickness, digital ulcers and perhaps oesophageal involvement might warrant screening for myocardial involvement. Further studies are necessary to evaluate the effect of prostanoid therapy on myocardial perfusion.

KEY WORDS: Myocardial perfusion, Systemic sclerosis, Prostanoid therapy


   Introduction
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 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Systemic sclerosis (scleroderma, SSc) is an autoimmune multisystem disorder, characterized by extensive microvascular abnormalities and fibrosis affecting the skin and internal organs. Primary myocardial disease (i.e. without systemic or pulmonary hypertension, and in the absence of renal or interstital lung involvement [1]) is common and is a severe prognostic factor, even worse than the idiopathic form, and along with pulmonary arterial hypertension (PAH) and pulmonary fibrosis, is one of the major causes of death [2]. The pathogenesis of primary myocardial involvement is still debated. Necropsy has established the presence of focal fibrosis randomly distributed throughout the myocardium, and myocardial contraction band necrosis, unrelated to epicardial coronary artery stenosis and considered the histological marker of SSc heart disease, is believed to be due to an intermittent vascular spasm of the intramural vessels (intramyocardial RP) [3]. Primary myocardial involvement seems to be more frequent in the dcSSc [4]. Moreover, perfusion defects as measured by gated myocardial SPECT are an early sign of cardiac dysfunction in SSc [5]. Patients have been reported to be usually anti-Scl70 antibody positive, to have a greater and more rapid progression in skin involvement and have a trend towards longer disease duration and severity [6]. However, the relationship between skin involvement, its progression and visceral complications has recently been reported to be more complex than previously thought [7].

On the basis of these data, we investigated whether it is possible to identify SSc patients at greater risk for myocardial microvascular disease.


   Patients and methods
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 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
The study group consisted of 21 patients (2 men and 19 women; mean age: 56 yrs, range 22–75 yrs) consecutively evaluated at our Institution. All patients met the American College of Rheumatology (ACR) classification criteria for SSc [8], and were classified as dcSSc or lcSSc based on the extent of skin thickness [9]. Skin thickness was measured using the modified Rodnan skin thickness score [10], and graded from 0 (normal) to 3 (severe) at 17 different cutaneous sites; these scores were then summed to obtain the maximum possible score of 51. The presence of SSc-related serum ANAs, including ACA and anti-Scl 70 (anti-topoisomerase I, Scl70) was determined by indirect IF and ELISA.

Organ system involvement was also evaluated. Two types of pulmonary involvement were considered: (i) interstitial lung involvement [interstitial lung disease (ILD)], believed to be present if the following were found: restrictive lung disease without obstructive lung disease, <65% of predicted diffusing capacity for carbon monoxide (DLCO) or pulmonary fibrosis as seen on high-resolution CT and (ii) PAH defined by right ventricular systolic pressure >35 mmHg by echocardiography or right ventricular systolic pressure >25 mmHg measured by cardiac catheterization, not secondary to ILD. None of the patients had pleuritis or pericarditis. Major rhythm disturbances were excluded by EKG and EKG Holter. None of the patients had clinical evidence of renal involvement. Since, albeit any part of the gastrointestinal (GI) tract can be involved and oesophageal disease occurrence is the most typical among GI involvement [11], oesophageal abnormalities (cardiac incontinence, oesophagitis, ulcers, strictures and/or Barrett's oesophagus) have been considered representative of GI tract involvement. Oesophageal disease was evaluated by endoscopy and biopsy when necessary.

Risk factors for coronary artery disease (CAD) were considered and family history, total cholesterol blood levels (only one patient had hyperlipidaemia and was treated with statin therapy) and BMI (normal in all patients) were included. None of the patients had symptoms or signs of CAD. Patient characteristics can be seen in Table 1.


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  		TABLE 1. Patient characteristics

 
Myocardial perfusion using dipyridamole myocardial dual-head cardiac SPECT was performed as a single-day rest/stress imaging protocol by using 99m-Tc-sestamibi (MIBI, Bristol-Myers-Squibb, Rome, Italy) or 99m-Tc-tetrofosmin (Myoview, GE Healthcare, Milan, Italy) [12]. Because our cohort was small and some patients were elderly, this method was chosen because it guarantees that all of the patients could reach the end point of the test (a 2- to 3-fold coronary vasodilatation) with respect to the ergometric stress test (in which the target is to reach at least 85% of the theoretical maximum heart rate). At the stress study, a total of 0.56 mg/kg dipyridamole was infused over a 4-min period at stress, and consecutively, a technetiate flow tracer (360 MBq of 99m-Tc-MIBI or 360 MBq of 99m-Tc-tetrofosmin) was injected 3 min later. A rest study was conducted 5 h thereafter, by injection of the same technetiate tracer used at stress but with a higher activity (700 MBq) for the completion of imaging protocol. Images were examined with dedicated software [AutoQuant, released by Philips Healthcare (Monza, Italy) on Cedars-Sinai License, USA] and a Philips dual-head gamma camera (Philips Healthcare, Monza, Italy). The results of examination have been compared with a control database for number and intensity of perfusion defects. The sum of stress score (SSS) and the sum of rest score (SRS) were calculated. Because of their low number, the patients were divided into two groups: those with perfusion defects and those without perfusion defects. Three patients repeated gated myocardial SPECT 8–10 months after prostacyclin prostaglandin E2 analogue infusions (alprostadil 60 mcg e.v., once every 3 weeks).

Ethical considerations
Approval was obtained from the ethics committee of the Azienda Sanitaria Locale Milano 2 for this study to be carried out in the IRCCS Humanitas Institute (authorization no. 292 13/10/2005). Written informed consent was obtained from all patients.

Statistical analysis
The StatView statistical package (SAS Software, NC, USA) was used. Continuous data were expressed as mean (S.D., range). Differences in the contingency table were examined using the chi-square test. Differences between mean values were examined using the Student's t-test. Differences between continuous data and nominal variables were studied using analysis of variance. A P-value <0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Of the 21 patients studied, 8 (38%) had perfusion defects. All of these eight patients (100%) had digital ulcers compared with 7 of 13 patients (54%) with digital ulcers but a negative myocardial perfusion SPECT (P = 0.02). Skin scores were significantly higher in SPECT-positive patients [25.9 ± 9.1 vs 9.8 ± 5.4 (mean ± S.D.), P < 0.0001] (Fig. 1). Oesophageal abnormalities were found in 71% of the patients, including all of the eight patients with perfusion defects and 7 of 13 patients (54%) without perfusion defects (P = 0.046). A trend for positivity of the Scl70 antibody was observed in patients with perfusion defects compared with patients without perfusion defects (37.5% vs 7.7%, P = 0.09), but no relationship was observed for presence of ACA (36% vs 40%, SPECT-positive vs SPECT-negative). There were no significant associations between myocardial perfusion abnormalities and average age (55 yrs for patients with normal myocardial perfusion with respect to 58 yrs for patients with perfusion defects), sex (perfusion defects in 50% males and in 39% females with respect to 50% males and 61% females with normal SPECT), dcSSC/lcSSc skin type (60% of dcSSc and 31.2% of lcSSc had a positive SPECT), duration of RP (14.9 yrs in patients with a normal SPECT with respect to 15.5 yrs in patients with pathological SPECT), lung involvement (ILD or PAH, data not shown). The only patient with hyperlipidaemia had a negative myocardial perfusion SPECT. Three patients with perfusion defects who repeated gated myocardial SPECT after alprostadil, showed a re-establishment of normal perfusion.


Figure 1
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  		FIG. 1. Relationship between skin scores and myocardial perfusion.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Early functional myocardial impairment using different imaging techniques has already been described in SSc patients [5, 12]. We have found that perfusion defects are present among our patients with a frequency (38%) similar to that of previous studies (18–52%) [5, 12]. We did not find a relationship with respect to disease duration in accordance with the report by Sulli et al. [13]. We have instead found a correlation with respect to modified Rodnan total skin score in agreement with Nakajima et al. [5]. The association we have found between myocardial perfusion defects and the presence of digital ulcers can be regarded as a manifestation of more severe RP in these patients; moreover, this finding might also be consistent with an abnormal vaso-reactivity as a possible pathogenetic mechanism linking cutaneous and myocardial microcirculatory involvement in SSc. To this effect, the three patients who had re-established normal coronary flow reserve after alprostadil support an endothelial damage underlying coronary microcirculation abnormalities.

Several studies have demonstrated beneficial effects of vasodilators, such as calcium channel blockers and angiotensin-converting enzyme inhibitors, in SSc patients [14, 15] but, as far as we know, no study has evaluated the effects of prostanoids on myocardial perfusion abnormalities. However, beneficial effects of prostaglandins on ventricular repolarization have been reported [16].

The majority of patients (87.5%) with oesophageal abnormalities had myocardial perfusion defects. The observation that oesophageal dysfunction was strongly associated with the presence of RP [17] is consistent with our data and with a study performed in 125 SSc Italian patients investigated by radiological, endoscopic, manometric and pH-metric techniques that found 100% incidence of oesophagitis in patients with more severe cutaneous involvement [18]. To our knowledge, there are no studies investigating the association between SSc heart disease and GI disease.

In SPECT-positive patients, we have found a trend for positivity of the anti-Scl-70 antibody, the hallmark of dcSSc. This finding is in agreement with certain studies that have found a significant positive association between cardiomyopathy and anti-Scl-70 antibody [19]. However, the data of a large Italian epidemiological study reporting that heart involvement was not significantly different between patients with limited vs diffuse disease [4], might suggest that genetic factors may be associated with distinct SSc phenotypes and may predispose to myocardial disease [20].

One of the limitations of this study is the small number of patients; to overcome this, multi-centre trials are warranted.

In conclusion, our study has found that myocardial perfusion defects in patients with SSc are frequent and that there is a significant association with those patients who have a history of digital ulcers, severe skin thickness and upper GI involvement. We have also confirmed that Scl-70 antibody-positive patients may be at risk for myocardial microcirculatory abnormalities. Further studies seem to be necessary in order to clarify the possible consequences of prostanoid therapy on myocardial perfusion.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Kahan A, Allanore Y. Primary myocardial involvement in systemic sclerosis. Rheumatol (2006) 45:iv14–7.[Abstract/Free Full Text]
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Submitted 8 January 2008; revised version accepted 10 April 2008.
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