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The clinical characteristics and outcomes of patients with systemic sclerosis with myocardial involvement
Orphanet Journal of Rare Diseases volume 18, Article number: 83 (2023)
Myocardial involvement (MI) is the primary cause of death in patients with systemic sclerosis (SSc). We analyzed patients with SSc and MI to identify their characteristics and outcome.
We retrospectively collected data from SSc patients with MI admitted to Peking Union Medical College Hospital between January 2012 and May 2021. SSc patients without MI were randomly selected as controls after matching age and gender at a ratio of 1:3.
In total, 21 SSc patients (17 females) with MI were enrolled. The mean age at SSc onset was 42.3 ± 15.1 years old. Compared with controls, myositis (42.9% vs. 14.3%, P = 0.014) and elevation of CK (33.3% vs. 4.8%, P = 0.002) were more common in patients with MI. Of the 7 patients without cardiovascular symptoms, 3 /5 showed elevations in cardiac troponin-I (cTnI), 6 showed elevations of N-terminal brain natriuretic peptide (NT-proBNP). Eleven patients were followed up for a median period of 15.5 months and four patients developed newly occurring left ventricular ejection fraction (LVEF) < 50%.
One third of SSc patients with MI were asymptomatic. Regular monitoring of CTnI, NT-proBNP and echocardiography is helpful for the diagnosis of MI during the early stages. Its prognosis is poor.
Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology that is characterized by abnormal immune activation, neovascularization and vascular remodeling, eventually leading to the tissue fibrosis, affecting the skin and various internal organs . SSc is an orphan disease with an estimated global incidence of 0.1‰  and often involves multiple organ systems, as demonstrated by the frequent occurrence of gastroesophageal reflux, interstitial lung disease and cardiomyopathy . Myocardial lesions and cardiovascular disease are both significant causes of death in SSc patients . Overt clinical symptoms of heart disease consistently indicate irreversible changes in the structure and function of the heart. Therefore, it is important to perform early diagnosis and interventions in SSc patients with cardiac complications, so we could reduce irreversible structural changes of the heart and prolong the survival time.
This study aimed to use doppler echocardiography and/or cardiac magnetic resonance (CMR) to investigate the characteristics and outcomes of SSc patients with myocardial involvement (MI).
Data were retrospectively collected from consecutive SSc patients with myocardial involvement (MI) who had been admitted to Peking Union Medical College Hospital (PUMCH) between January 2012 and May 2021. All patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc . Patients were divided into two groups: diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). DcSSc was defined as skin thickening extending proximally to the elbows and knees or including the trunk. LcSSc involved skin sclerosis that was confined distally to the elbows and knees or face.
MI was defined as one of the following: (1) evidence of myocardial damage (inflammation or fibrosis) by cardiac magnetic resonance (CMR) imaging; or (2) a left ventricular ejection fraction (LVEF) < 50% by echocardiography . Myocarditis and myocardial infarction caused by other diseases were excluded. Other causes of myocardial lesions, such as coronary atherosclerosis, viral infections, and thyroid dysfunctions, were also excluded. SSc patients without MI over the same period were randomly selected as controls after matching for age (± 3 year) and sex at a ratio of 1:3.
Clinical characteristics, laboratory test results, imaging examinations and treatment data were collected when patients were admitted to PUMCH. All patients underwent clinical (i.e., history and physical examination including cardiovascular symptoms and signs) and instrumental evaluations (including routine blood tests, urine examinations, biochemical examination, creatine kinase (CK), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), immunoglobulin (Ig), antinuclear antibody test, 12-lead electrocardiogram (ECG), echocardiography (UCG). Some patients who had abnormal clinical or instrumental cardiac findings were further evaluated by CMR or cardiac radionuclide examinations. Interstitial lung disease (ILD) was defined as ground glass opacification or fibrosis on high-resolution computed tomographic (HRCT) imaging. Pulmonary arterial hypertension (PAH) was defined as a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance (PVR) > 3 Wood units by right heart catheterization (RHC) or an estimated systolic pulmonary artery pressure (SPAP) ≥ 40 mmHg on echocardiography when RHC was unavailable. Leukopenia was defined as a white blood cell (WBC) count < 3.5 × 109/L while thrombocytopenia was defined as a platelet count < 100 × 109/L, excluding other causes, such as drug and infection. We performed a follow-up of SSc patients with MI based on outpatient medical records or admission records.
Data were analyzed using SPSS 26.0 (Statistical Package for the Social Sciences, IBM Corp., Armonk, NY, USA). Quantitative variables are presented as mean ± standard deviation on normal distribution or medians (interquartile range, IQR) on non-normal distribution. Qualitative data are presented as the number of cases and percentage. Differences between groups were analyzed by analysis of variance (ANOVA), the Mann-Whitney test or the Chi-squared (χ2) test, depending on the distribution of the variables. P values < 0.05 were considered to be statistically significant.
In total, 21 SSc patients with MI were included in this study; most were females (17, 81%). The mean age of SSc onset and diagnosis were 42.3 ± 15.1 years and 43.6 ± 15.3 years, respectively. The age of MI diagnosis was 46.6 ± 15.8 years (Table 1).
Clinical/laboratory/ imaging features
Patients with MI had more diffuse cutaneous SSc (dcSSc) when compared with patients without MI (71.4% vs. 49.2%, P = 0.076) numerically. Compared with SSc patients without MI, SSc patients with MI had a significantly reduced incidence of puffy fingers (19% vs. 50.8%, P = 0.011), gastroesophageal reflux (23.8% vs. 54%, P = 0.016), but a significantly higher incidence of myositis (42.9% vs. 14.3%, P = 0.014) and hydropericardium (42.9% vs. 11.1%, P = 0.004) (all P < 0.05) (Table 2). Elevated CK (33.3% vs. 4.8%, P = 0.002) and anti-SCL70antibody (71.4% vs. 36.3%, P = 0.005) positivity were statistically higher in SSc patients with MI (Table 3). No significant difference was found in pulmonary function test between two groups (all P>0.05).
Clinical characteristics of myocardial involvement
The mean age at the time of MI diagnosis was 46.6 ± 15.8 years and the median duration from the onset of SSc to MI was 22.0 (3.5, 70.5) months. Of the 21 patients with MI, 14 (66.7%) presented with cardiovascular symptoms, including 9 (42.8%) chest distress, 4 (19%) palpitations, 11 (52.4%) shortness of breath after exercise. The detailed data in each patient are listed in Table 4. No significant differences were found between SSc patients with clinical and subclinical MI. (Table 5). Of the patients with MI, 15 (71.4%) underwent CMR and 12 had myocardial fibrosis; 4 of these 12 patients showed a LVEF < 50% on MRI. The sites of myocardial fibrosis included the left ventricle (10 cases), the right ventricle (2 cases) and the interventricular septum (4 cases); 4 cases had multiple sites of fibrosis simultaneously. Myocardial ischemia was detected in 4 cases. CMR revealed myocardial inflammation in one case.
Treatment and outcomes
Nineteen (90.5%) SSc patients with MI were treated with both corticosteroid and immunosuppressants. 2 patients did not use corticosteroid or immunosuppressants. Four of them (19%) received glucocorticoid pulse therapy due to progressed myocardial involvement. One patient received an increased dose of prednisone (from 0.2 mg/kg/day to 1 mg/kg/day) due to the new occurrence of arrhythmia. The remaining patients continued the former dose of glucocorticoid even if MI was detected. The number of patients who were treated with cyclophosphamide, methotrexate, mycophenolate mofetil, and leflunomide were 18 (85.7%), 2 (9.5%), 1 (4.8%) and 1 (4.8%) respectively. Symptomatic treatments for heart disease, including angiotensin-converting enzyme inhibitors/angiotension II receptor blockers (ACEi/ARB), beta -blockers, diuretic, sacubitril/valsartan were used to control ventricular rate, reduce load and improve ventricular remodeling in 17 (81%) patients.
Eleven (52.4%) patients were followed-up for a median period of 15.5 (7.8, 29.5) months. Four (36.4%) patients developed new abnormalities in the LVEF (from > 50% to < 50% on echocardiography). Six (54.5%) patients underwent repeated CMR tests but no improvement was found on myocardial involvement (Table 6). In particular, we have also focused on the prognosis of patients who received glucocorticoid pulse therapy. Two patients with pulse therapy were followed up for 13.4 months and 10 months respectively. LVEF by echocardiography did not improve significantly in either of two patients. Levels of CTnI both decreased but still higher than normal in one patient.
Systemic sclerosis is a complex multi-systemic disease. Due to the different definitions used in previous studies, the incidence of myocardial involvement ranges widely from 15 to 66.7% [7, 8] with most cases exhibiting insidious progression. A literature review and meta-analysis on the survival of patients with SSc showed that 19% of deaths were caused by heart disease, and that cardiac involvement significantly increased the risk of death . The pathogenesis of MI in SSc remains unclear although multiple factors have been described previously, including repeated ischemia-reperfusion injury of the heart, vascular microcirculation disorders and inflammatory reactions. Irreversible focal fibrosis is known to lead to heart failure and arrhythmias [10,11,12,13,14]. In some autopsy studies, myocardial fibrosis was found to be very common in SSc patients, with an incidence of up to 81% [10, 15].
Previous studies which focused on SSc with cardiac involvement have shown that SSc patients with heart involvement had an older onset age of SSc , more common in lcSSc , and fibrosis of the heart was correlated with a higher modified Rodnan skin score (mRSS) in subclinical cardiac involvement . But these studies focused more on all kinds of cardiac involvements, including structural cardiac abnormalities, arrhythmia, heart failure and decreased global myocardial perfusion, etc. Our study only focused on existing myocardial involvement which is one part of cardiac alterations, and different study objects may lead to different results. Similar to cardiac involvement, patients with MI were older at the onset of SSc, but dcSSc was more common numerically, and with a higher frequency of anti-Scl70 antibody positivity. A previous study showed myocardial involvement was more common and more severe in dcSSc . Therefore, we should remain vigilant for MI in patients with anti-ScL70 antibody positivity and wide skin sclerosis. Our study showed that patients with MI commonly exhibited CK elevation and myositis. Myositis mainly involves the skeletal muscle but also occasionally affects the myocardium. Aggressive immunosuppressive treatment may control myocardial inflammation and improve cardiac function in patients with inflammatory cardiomyopathy. However, the efficacy of immunosuppressive treatment for MI in SSc patients is still not determined. A recent study found that subclinical cardiac fibrosis in SSc was associated with increase of highly sensitive troponin I (cTNI) and N-terminal brain natriuretic peptide precursor (NT-proBNP) . In the present study, 14/19 patients showed elevated levels of cTnI and 17/21 patients showed elevated levels of NT-proBNP, may be suggesting the importance of these two biomarkers in predicting MI in patients with SSc. Echocardiography is widely used to evaluate cardiac structure but has low sensitivity for detecting myocardial fibrosis in the early stages. Recently, it has been reported that the calculation of stress by the speckle tracking echocardiographic techniques can identify impaired systolic function of both ventricles in patients with no obvious cardiac symptoms and a normal left ventricular ejection fraction . Late gadolinium enhancement (LGE) CMR is considered to be the non-invasive gold standard for imaging macroscopic myocardial fibrosis. A previous study showed that CMR can identify initial cardiac injury in SSc patients earlier than echocardiography and could detect abnormalities prior to the onset of clinical symptoms [21, 22]. In a prospective study of 201 patients with SSc , late gadolinium enhancement (LGE) with negative T2-weighted images was detected in 27.9% patients without known SSc-related cardiac involvement by CMR. However, this technique is not widely used in SSc patients due to limitations imposed by high costs, long appointment times, long scan times, allergies and the deterioration of renal function arising from the use of contrast agents. In conclusion, regular annual monitoring echocardiography is recommended for all patients with SSc while CMR is recommended for those suspected of having myocardial involvement.
There is still no effective treatment for MI in SSc patients. It is unknown whether immunosuppressive therapy could prevent or cure myocardial lesions in this population. Theoretically, immunotherapy should be helpful to control myocardial inflammation although it is still difficult to accurately determine the presence of myocardial inflammation. De Luca proposed the concept of targeted treatment with an interleukin-1 antagonist; however, this strategy has not been described further in the existing literature . In addition to immunotherapy, a previous study showed that some treatments with potent vasodilator activity on small coronary arteries, such as dipyridamole, may be beneficial in the treatment of SSc patients with myocardial perfusion abnormalities . One patient in our study showed a gradual decrease of LVEF (58% down to 47%) 4 months after the discontinuation of sacubitril/valsartan, but it improved again (60%) in 2 months after re-treatment with sacubitril/valsartan without the adjustment of other treatments. The results of the DeSScipher cohort study also showed that vasodilators, in particular calcium channel blocker (CCB), and/or angiotensin-converting enzyme inhibitors (ACEi), and/or angiotension II receptor blockers (ARB) and low-dose acetylsalicylic acid reduced the occurrence of different types of myocardial involvement .
There are some limitations in this study. Firstly, due to the lack of literature consensus on the definition of MI [6, 27, 28], we defined MI based on imaging (UCG or CMR). Due to the retrospective nature of our study, all patients underwent echocardiography, which is not sensitive enough for identification of early stage MI, while only part of patients with abnormal heart manifestations underwent further CMR evaluation. Thus, subclinical myocardial damage may have been missed in some patients. Secondly, this is a single-center study with only a small number of patients, and some patients did not have follow-up. We did not analyze the long-term prognosis in patients with different immunotherapy. The efficacy of immunosuppressive treatment for MI in SSc patients is still not determined. Future prospective study with larger sample size should be done.
Myocardial involvement is common in systemic sclerosis. Effect of immunotherapy is still unknown for myocardial involvement in systemic sclerosis. Regular monitoring of CTnI, NT-proBNP and echocardiography may be helpful for earlier diagnosis of MI. For SSc patients with a high suspicion of MI, CMR should be considered especially in patients with normal UCG.
cardiac magnetic resonance
diffuse cutaneous SSc
limited cutaneous SSc
left ventricular ejection fraction
Interstitial lung disease
high-resolution computed tomographic
Pulmonary arterial hypertension
pulmonary arterial pressure
pulmonary artery wedge pressure
pulmonary vascular resistance
right heart catheterization
systolic pulmonary artery pressure
late gadolinium enhancement
fibroblast activation protein inhibitor
Erythrocyte sedimentation rate
cardiac troponin I
N-terminal pro-B-type natriuretic peptide
calcium channel blocker
angiotensin-converting enzyme inhibitors
angiotension II receptor blockers
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This study was supported by the Chinese National Key Technology R&D Program Ministry of Science and Technology (Reference:2021YFC2501301-6), Beijing Municipal Science& Technology Commission (Reference: Z201100005520025), CAMS Innovation Fund for Medical Sciences (CIFMS) (Reference: 2021-I2M-1-005).
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The study was approved by the Medical Ethics Committee of PUMCH (Beijing, China) (IRB reference: S-191). Informed consent was not relevant as this was a retrospective study.
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He, H., Lai, J., Zhou, J. et al. The clinical characteristics and outcomes of patients with systemic sclerosis with myocardial involvement. Orphanet J Rare Dis 18, 83 (2023). https://doi.org/10.1186/s13023-023-02699-1
- Systemic sclerosis
- Myocardial involvement
- Clinical features