Summary
Heart involvement, including primary myocardial involvement, is very common in systemic sclerosis. There is strong evidence that primary myocardial involvement is related to repeat focal ischaemic injury causing subsequent irreversible myocardial fibrosis. Clinically evident cardiac involvement is recognized to be a poor prognostic factor; thus preclinical identification is highly encouraged. The severity of heart involvement has been confirmed recently. Echocardiography, including pulsed tissue Doppler echocardiography, is the cornerstone of routine heart assessment. Myocardial perfusion may be assessed by single photon emission computed tomography. If available, cardiac magnetic resonance imaging should be considered as it allows simultaneous measurement of ventricular volumes and function and myocardial perfusion, and assessment of possible inflammation and/or fibrosis. Biological variables, such as B-type natriuretic peptides, are highly relevant, valuable markers of global heart involvement in systemic sclerosis and should be considered for screening of patients and/or research purposes.
Résumé
Les complications cardiaques sont fréquentes chez les patients atteints de sclérodermie systémique, y compris l’atteinte myocardique primitive. Il existe de solides arguments pour affirmer que cette atteinte myocardique primitive est la conséquence d’épisode répétés d’ischémie focale génératrice de fibrose myocardique. L’atteinte cardiaque, lorsqu’elle est décelable cliniquement est de très mauvais pronostic ; son identification a un stade plus précoce, préclinique, est recommandée. La sévérité de l’atteinte cardiaque a été confirmée dans des études récentes. L’échocardiographie conventionnelle, incluant la mesure des vélocités annulaires par doppler pulsé tissulaire, est considérée comme la pierre angulaire de l’évaluation chez ces patients. La perfusion myocardique peut être étudiée par tomoscintigraphie myocardique. Lorsqu’elle est réalisable, l’IRM s’avère être un outil de choix car elle permet de mesurer les volumes ventriculaires, la fonction ventriculaire gauche et droite, la perfusion myocardique et la recherche d’une possible atteinte myocardique inflammatoire et/ou la fibrose myocardique. Certains paramètres biologiques, les peptides natriurétiques de type B, sont des marqueurs puissants d’atteinte cardiaque et pourraient être utiles pour la détection des patients devant bénéficier d’autres explorations cardiaques ou comme critère d’évaluation pour la recherche.
Abbreviations
CCB
calcium channel blocker
CI
confidence interval
LVEF
left ventricular ejection fraction
NT-pro-BNP
N-terminal prohormone brain natriuretic peptide
SSc
systemic sclerosis
TDE
tissue doppler echocardiography
Introduction
SSc is a connective tissue disease characterized by widespread vascular lesions and fibrosis of the skin and internal organs. Cardiac involvement is often clinically occult, but is recognized as a poor prognostic factor and is one of the leading causes of mortality in patients with SSc .
Cardiac involvement may affect the endocardium, myocardium and pericardium, separately or concomitantly. As a consequence, pericardial effusion, auricular and/or ventricular arrhythmias, conduction disease, valvular regurgitation, myocardial ischaemia, myocardial hypertrophy and heart failure have been reported. In addition, pulmonary arterial hypertension and renal and lung involvement can affect cardiac status adversely . In order to narrow the focus on specific involvement, most of the data we present in this review relate to primary myocardial involvement.
Prevalence and prognosis of overall cardiac involvement
The prevalence of overall cardiac disease varies between studies depending on the methods used for its assessment. Most available data are based upon clinical evaluation, electrocardiogram and thoracic X-ray. Several lines of evidence suggest that both cutaneous subtypes could be affected by cardiac involvement . However, an Italian epidemiological study suggested that heart involvement might be more prevalent in the diffuse subtype (32%) than in the limited form (23%) . Such an association has been confirmed recently in a study that focused on depressed LVEF and reported on more than 7000 patients . In addition, data from Perera et al. showed that antitopoisomerase I antibody-positive patients, with the limited or diffuse cutaneous subtype, and with rapid or intermediate skin thickness progression rate, are at considerable early risk of the occurrence of SSc-associated cardiac problems . Indeed, 41% of patients classified as being in the “rapid skin thickness progression subgroup” had cardiac involvement. Among those patients with cardiac involvement, 75% developed cardiac involvement within 3 years of the onset of skin thickening .
In an international meta-analysis, among 1645 cases, 578 deaths occurred over 11,521 person-years of follow-up. In multivariable analyses adjusted for age and sex, cardiac involvement (defined by major conduction disturbances, ventricular arrhythmia, heart failure or persistent moderate-to-large pericardial effusion detected by echocardiography) increased the risk of mortality (hazard ratio 2.8; 95% CI 2.1–3.8) as well as renal involvement (hazard ratio 1.9; 95% CI 1.4–2.5), pulmonary involvement (hazard ratio 1.6; 95% CI 1.3–2.2) and antitopoisomerase I antibodies (hazard ratio 1.3; 95% CI 1.0–1.6). Moreover, renal, cardiac and pulmonary involvement tended to occur concomitantly . Such a severity has been confirmed recently in a series of 366 Hungarian patients; 65% of the observed deaths were attributed to cardiopulmonary complications of the disease .
Apart from cardiac involvement, pulmonary hypertension may also have a negative effect on the prognosis of patients with SSc. Indeed, two recent studies included patients with mean pulmonary arterial pressure ranging from 40 to 50 mmHg . Three-year survival ranged from 28 to 48% in these studies and was reduced significantly compared with primary pulmonary hypertension or systemic lupus erythematosus-associated pulmonary hypertension . As pulmonary hypertension is often associated with both right and left ventricular involvement in SSc, one may speculate whether such specific cardiac involvement contributes to the observed high mortality rate .
Different manifestations of cardiac involvement in SSc and their prevalence
SSc may be complicated by several distinct cardiac manifestations. Of these, depressed myocardial contractility is supposed to be specific, and the “hallmark” of primary myocardial involvement. However, its existence and prevalence is still a matter of debate, as most studies have reported a low prevalence of reduced LVEF . One French multicentre study, which included 570 patients, reported a 1.4% prevalence of left ventricular systolic dysfunction . Other authors have reported a low prevalence of depressed LVEF at rest, although up to 46% of patients had left ventricular dysfunction when LVEF was also measured during exercise . More recently, the EUSTAR registry provided robust estimates of the prevalence of left ventricular dysfunction. The EUSTAR registry is a multicentre, international database that has been described in detail . LVEF was classified as depressed when <50% or 55%, according to each echocardiographic laboratory. The EUSTAR registry collected data from 7073 consecutive patients (mean age 56 ± 14 years) and demonstrated an overall 5.4% prevalence of reduced LVEF .
We have reported previously the observation of reduced left ventricular contractility despite a normal LVEF, using radial strain rate determined by TDE, suggesting that the prevalence of depressed myocardial contractility may be underestimated . In a more recent study, we investigated 100 consecutive patients with SSc and matched controls, using conventional echocardiography implemented by pulsed TDE mitral and tricuspid annular velocity measurements . Using this simple and widely available method, we demonstrated that 14% and 15% of patients with SSc had reduced left and right ventricular contractility, respectively .
The presence of diastolic dysfunction in patients with SSc has been demonstrated extensively . However, the distinction between pathological findings and age-related changes or other confounding factors may be hard to ascertain. In the largest study, the authors reported the presence of diastolic abnormalities in 101 of 570 patients (17.7%) . However, 48 (8.4%) patients had a restrictive mitral flow pattern, which is unequivocally abnormal, while 53 (9.3%) patients had delayed diastolic relaxation, which, in the absence of a control group, does not allow formal conclusions to be made . In our controlled study, using pulsed TDE, we found that 30 of 100 patients had definite abnormal left ventricular filling . Overall, the prevalence of diastolic dysfunction was increased compared with age- and sex-matched controls , and ranged from 17 to 30% .
Primary pulmonary arterial hypertension is assumed to be rare but is one of the most severe complications of SSc. In one of the largest series, the French ITINERAIR cohort, its prevalence was 7.85% . Other series reported similar results, and its prevalence ranges from 8 to 12% overall, according to the various series .
Pericardial effusion has been noted in 33 of 77 (43%) SSc patients versus two of 45 (4%) controls, but only 11 of 77 (14%) had a significant effusion, according to a controlled study . In our study, 15 of 100 (15%) patients compared with one of 26 (4%) controls had pericardial effusion (difference not significant) . In addition, we demonstrated that SSc patients had a higher prevalence of aortic regurgitation (18%) and a trend towards more prevalent mitral regurgitation; however, valvular regurgitations were associated with age, and most patients had grade I aortic or mitral regurgitation, or both (a benign finding) .
Pathophysiology of primary myocardial involvement
SSc vascular lesions result in general impairment of the microcirculation. Despite the predominance of vascular abnormalities and documented ischaemia, some studies do not support a higher prevalence of atherosclerotic coronary artery disease in SSc patients than in the general population ; however, the exact prevalence of atherosclerotic coronary artery disease remains to be determined. Myocardial fibrosis is thought to occur after repeated focal ischaemia, resulting from abnormal vasoreactivity, with or without associated structural vascular disease. Studies demonstrating the effect of vasodilator agents on perfusion abnormalities further emphasize the potential role of coronary vasospasm. The observations by SPECT of myocardial perfusion defects unrelated to coronary artery distribution and the reversibility of some perfusion defects after vasodilator treatment, which coexist with fixed defects, do suggest the coexistence of ischaemic lesions such as vasospasm and irreversible lesions such as organic vessel disease or myocardial fibrosis . Indeed, some histological examinations have revealed diffuse patchy fibrosis, with contraction band necrosis unrelated to epicardial coronary artery stenosis , whereas other studies have revealed concentric intimal hypertrophy associated with fibrinoid necrosis of intramural coronary arteries . Typical pathological findings include disseminated plaques of myocardial fibrosis, normal epicardial coronary arteries but arteriolar concentric intimal hypertrophy, which leads to impaired coronary reserve ( Fig. 1 ).
