This article appears in the following Rheumatology issue: Update in systemic sclerosis [View the issue table of contents]
Outcome measures for heart involvement in systemic sclerosis
1Department of Rheumatology A and 2Department of Cardiology, Paris Descartes University, Cochin Hospital, AP-HP, Paris, France.
Correspondence to: Y. Allanore, Service de Rhumatologie A, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France. E-mail: yannick.allanore{at}cch.aphp.fr
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Primary myocardial involvement is common in SSc. Increasing evidence strongly suggests that this involvement is related to repeat focal ischaemic injury causing irreversible myocardial fibrosis. Clinically evident cardiac involvement is recognized to be a poor prognostic factor, thus pre-clinical identification is highly encouraged. Echocardiography, if possible coupled to pulsed tissue Doppler, is the cornerstone of heart assessment even if radionuclide ventriculography remains the gold standard for evaluation of ventricular function. Myocardial perfusion may be assessed by single photon emission CT, but cardiac MRI will probably supplant this technique; it, furthermore, offers the possibility to concomitantly determine, ventricular function, myocardial perfusion and tissular parameters (i.e. myocarditis or burden of fibrosis). Conduction system abnormalities are common but not serious, while arrhythmias may be life-threatening, necessitating 24-h ambulatory Holter ECG. Natriuretic peptides have been used mainly when the heart has been involved secondary to pulmonary arterial hypertension, but may also be useful for the identification of early heart dysfunction. Their predictive value should also be investigated when there is primary heart involvement.
KEY WORDS: Systemic sclerosis, Heart, Myocardiopathy, Tissular Doppler echocardiography, Cardiac magnetic resonance imaging, Vasospasm, Microcirculation, Right ventricule, Contractility
SSc is a CTD characterized by widespread vascular lesions and fibrosis of the skin and internal organs. Although cardiac involvement is often clinically occult, myocardial involvement is common in SSc and when sensitive tools are used, it has been estimated to occur in up to 100% of SSc patients. Once cardiac involvement is clinically evident, it is recognized as a poor patient prognostic factor [1].
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. Renal and pulmonary involvement can also adversely affect cardiac status. However, this report will focus on primary myocardial involvement in patients without systemic or pulmonary hypertension and without significant renal or pulmonary involvement, and specific to SSc and will discuss the hallmark vascular lesion associated with this disease.
The prevalence of cardiac disease varies depending on the definition used. Most of the data available are based on clinical symptoms or common investigations such as ECG and thoracic X-ray. These examinations together with clinical evaluation have been proposed as candidate variables for routine cardiac assessment [2]. However, these indexes have a poor sensitivity and do not allow a prompt diagnosis at a pre-clinical stage, when therapeutics are supposed to be more effective. To this end, ECG has been found to be the cornerstone of heart evaluation. Although radionuclide ventriculography remains the gold standard for the assessment of heart function, it has been supplanted by ECG; its indication is limited to patients with poor echogenicity (<5%) and for research purposes.
Myocardial fibrosis is the hallmark of established myocardial involvement in SSc; fibrotic lesions are patchy, distributed in both ventricles and are inconsistent with regards coronary artery distribution. Most studies used conventional echocardiography for assessment and report only few patients with depressed left ventricular (LV) contractility, though up to 40% of relaxation abnormalities, frequent valvular regurgitation and possible right ventricular (RV) involvement [3]. In contrast, a high prevalence of reduced LV and/or RV contractility has been observed in patients suffering from SSc with new methods, such as strain rate (SR) determined by tissue-Doppler ECG (TDE) or MRI [4–7]. TDE is a recently developed ultrasound technique that allows direct measurement of myocardial velocities and SR, and offers several modalities of measurements. Indeed, previous studies demonstrated that SR is reproducible, is a powerful indicator of myocardial contraction, independent of myocardial translational motion and far more sensitive than conventional echocardiography. In addition, its application in the context of SSc has recently been suggested. Indeed, in a recent study, we compared 17 consecutive SSc patients with normal cardiac function on examination, pulmonary artery pressures and radionuclide LV ejection fractions, with 15 matched controls, using SR [4]. SSc patients had lower systolic SRs than controls (1.6 ± 0.5 vs 3.8 ± 1.7 per cm, respectively, P < 0.0001), and lower diastolic SR (3.7 ± 1.5 vs 5.6 ± 1.2 per cm, P = 0.0004) which suggests both reduced contractility and relaxation in SSc; in addition, 10/17 SSc patients had reduced systolic SR (<1.5 per cm). Beyond the accuracy of SR determined by TDE, this study suggests that abnormal myocardial dysfunction may be present in patients with SSc despite normal echocardiographic and radionuclide LV ejection fractions, highlighting the need for close follow-up of these patients.
Recent technological advances have made pulsed TDE widely available, enabling the online measurements of velocities with excellent temporal resolution, and the routine evaluation of longitudinal LV and RV function. Using these latter modalities, in addition to conventional echocardiographic measurements, we investigated SSc patients [free of pulmonary arterial hypertension (PAH) or clinical symptoms of heart failure] in a controlled study [3]. We observed that, when compared with controls, SSc patients had a wider mean left atrial diameter, impaired LV ventricular relaxation, a trend towards a reduced LV ejection fraction (64.9 ± 0.6% vs 67.2 ± 0.7%, P = 0.069) and a higher pulmonary artery pressure (33.3 ± 0.6 vs 30.8 ± 1.0 mmHg, P = 0.053). In addition, 15 patients had reduced LV contractility vs 0 in the control group (P = 0.04), 30 had impaired relaxation vs 2 controls (P = 0.022) and 15 patients had reduced RV contractility vs 0 in the control group (P = 0.039). TDE measurements were correlated with each other, though they were not correlated with lung abnormalities or other disease characteristics. These findings support the theory that abnormal LV and RV functions are common in SSc; the low sensitivity of routinely measured LV ejection fraction mandates the systematic implementation of additional echocardiographic modalities, including pulsed TDE, in order to adequately investigate SSc patients. While PAH is a major concern in SSc, meticulous and detailed cardiac investigations are warranted in search of valvular or primary myocardial involvement with the disease [3]. The prognostic implications of these abnormalities and the effects of therapies that lower the likelihood of cardiac involvement are now under investigations in short-term studies.
When considering other forms of cardiac involvement, a controlled study found pericardial effusion in 33/77 (43%) SSc patients vs 2/45 (4%) controls, but only 11/77 (14%) had a significant effusion [8]. In our study, 15/100 (15%) patients compared with 1/26 (4%) (NS) controls had pericardial effusion. An increased prevalence of valvular heart disease in SSc has previously been suggested. Compared with controls, SSc patients had a higher prevalence of aortic regurgitation [18/100 (18%) vs 0/26 (0%); P = 0.02] and a trend towards more prevalent mitral regurgitation was observed (48/100 vs 8/26; NS). However, the mechanism of valvular heart disease was unable to be identified. Valvular regurgitations were associated with age, and most patients had Grade I aortic or mitral regurgitation or both, which is a benign finding and thus no clear conclusion can be drawn [3].
Myocardial fibrosis is thought to follow repeated focal ischaemia. This results from abnormal vasoreactivity, with or without associated structural vascular disease. 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 [1]. Moreover, myocardial infarction has been observed in SSc patients whose epicardial coronary arteries were normal. SPECT, allowing the assessment of myocardial perfusion, has demonstrated evidence of reversible ischaemia together with irreversible lesions. Studies demonstrating the efficacy of vasodilator agents further emphasize the potential implication of coronary vasospasm in heart involvement. The use of SPECT, which is a qualitative or semi-quantitative method, is limited in quantitative studies. However, cardiovascular MRI is an accurate quantitative method developed for the non-invasive assessment of myocardial perfusion. The MRI parameters analysed for myocardial perfusion evaluation are usually determined by analysing the first pass of a contrast agent bolus through the myocardium. High-resolution perfusion MRI techniques can be used to identify small sub-endocardial defects. MRI may also allow non-invasive coronary reserve determination and the evaluation of fibrotic myocardium compared with viable tissue. Furthermore, delayed enhanced MRI may be of value to assess the distribution and burden of myocardial fibrosis [7]. Cardiac MRI also has the capacity to determine localization, extent and regression of myocardial inflammation after therapy. This powerful tool seems of great interest for the diagnosis and monitoring of myocarditis related to acute idiopathic inflammatory myopathy. Cardiac MRI should also be considered for the rare cases of myositis associated with SSc. Indeed, in these latter cases, this technique may guide towards the use of therapies such as immunosuppressors and high dose corticosteroids, whereas vasodilators, in particular calcium channel blockers, are used more for microcirculation impairment [9]. Despite the predominance of vascular abnormalities and documented ischaemia, the frequency of atherosclerotic coronary artery disease seems to be similar to that of the general population. However, coronary arteriogram may be required for some patients with suspected acute coronary syndrome.
Cardiac evaluation has also been improved by the systemic measurement of ventricular (left and right) hormone secretion. The brain natriuretic peptide (BNP) gene encodes a pro-hormone (pro-BNP) that is cleaved upon secretion to generate BNP and N-terminal pro-BNP (NT-pro-BNP). Assays directed against N-terminal pro-BNP have been validated and several studies have shown that the difference between NT-pro-BNP and BNP values, if any, is of limited clinical significance. In SSc patients, elevated serum NT-pro-BNP was found to be a sensitive and specific diagnostic marker of early echocardiographically measured increases in systolic pulmonary arterial pressure, while NT-pro-BNP levels correlated with haemodynamics and prognosis in patients with established PAH. Recently, we have shown that both lung diffusion carbon monoxide capacity and NT-pro-BNP levels can be used to identify SSc patients at high risk for the development of PAH [10]. Besides the diagnosis or prediction of PAH, natriuretic peptides may be useful for the identification of early heart dysfunction and its predictive value should also be investigated for detection of primary heart involvement.
Disorders of rhythm and conduction may also occur in SSc and relate to primary heart involvement [1]. Conduction alterations (sinus node dysfunction, first-degree heart block), supra-ventricular arrhythmias (supra-ventricular tachycardia, atrial fibrillation, premature beats) and ventricular arrhythmias (ventricular tachycardia, premature beats) are observed and should be assessed when suspected by Holter monitoring. Arrhythmias have been reported to be associated with poor patient prognosis [1], and have been shown to be associated with concomitant myositis and thus myocarditis, as such; their detection must also lead to the evaluation of thyroid function which is suspected to be frequently abnormal in SSc.
To conclude, cardiac involvement is frequent in SSc; as a result, clinicians should no longer focus solely on PAH. Thanks to recent innovations, clinicians have a choice of diagnostic tools that are now available in routine practice, in addition to those modern and accurate tools reserved for research purposes only. Indeed, conventional ECG, pulsed TDE and natriuretic peptides may be used for routine assessment. MRI and SR imaging are as yet unavailable for routine use, and radionuclide imaging may only be considered in specific patients or for research purposes.
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Supplement: This paper forms part of the supplement entitled ‘Update in systemic sclerosis’. This supplement was supported by an unrestricted grant from Encysive.
Disclosure statement: Y.A. has received honoraria for participating in meetings orgnanized by Encysive and Actelion as a speaker. A.K. has received consulting fees from Actelion. The other author has declared no conflicts of interest.
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