The clinical characteristics and outcomes of patients with systemic sclerosis with myocardial involvement

doi:10.21203/rs.3.rs-2226716/v1

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The clinical characteristics and outcomes of patients with systemic sclerosis with myocardial involvement

https://doi.org/10.21203/rs.3.rs-2226716/v1

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published 14 Apr, 2023

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Background: Myocardial involvement (MI) is the primary cause of death in patients with systemic sclerosis (SSc). We analyzed patients with SSc and MI to identify any associations between this complication and their characteristics.

Method: We retrospectively collated 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.

Results: In total, 21 SSc patients (17 females) with MI were enrolled. The mean age at SSc onset was 44.8±15.1 years. Compared with controls, myositis (42.3% vs. 15.4%, P=0.004) were more common in patients with MI; elevations of creatine kinase (CK) (30.8% vs. 6.9%, P=0.006). Of the 7 patients without cardiovascular symptoms, 5 showed elevations in cardiac troponin-I (cTnI), 6 showed elevations of N-terminal brain natriuretic peptide (NT-proBNP). Thirteen patients were followed up for median period of 15.5 months and four patients developed newly occurring left ventricular ejection fraction (LVEF)< 50%.

Conclusion: Almost 50% of SSc patients with MI were subclinical. Regular monitoring of CTnI, NT-proBNP and echocardiography is helpful for the diagnosis of MI during the early stages. Its progress is rapid and prognosis is poor.

Systemic sclerosis

Myocardial involvement

Clinical features

Treatment

Follow-up

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 fibrosis of tissues, skin and the organs [1]. SSc is an orphan disease with an estimated global incidence of 0.1‰ [2] and often involves multiple organ systems, such as gastroesophageal reflux, interstitial lung disease and cardiomyopathy [3]. Myocardial lesions and cardiovascular disease are both significant causes of death in SSc patients [4]. The obvious 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 if we are to reduce irreversible structural changes of the heart and prolong the survival time. The purpose of this study was to use Doppler echocardiography and/or cardiac magnetic resonance imaging (CMR) to investigate SSc patients with myocardial involvement (MI) and identify any association between MI and the clinical and laboratory characteristics of patients, and to evaluate the progression of MI over a specific follow-up period.

Study population

Data were retrospectively collated from SSc patients with myocardial involvement (MI) who had been admitted by 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 [5]. Patients were divided into two groups: diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). dcSSc was defined by 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: (1) evidence of myocardial damage (inflammation or fibrosis) by cardiac magnetic resonance (CMR) imaging; (2) a left ventricular ejection fraction (LVEF) < 50% by echocardiography. Myocarditis and myocardial infarction were excluded by electrocardiograms or CMR. Other causes that induced myocardial lesions were excluded by a doctor, such as coronary atherosclerosis, viral infections, and thyroid dysfunctions. 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.

Data collection

Clinical characteristics, laboratory test results, imaging examinations and treatment data were collected and analyzed. 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.

Statistical analysis

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 or medians (interquartile range, IQR). 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.

General condition and clinical manifestations

In total, 21 SSc patients with MI were included in this study; most were females (17, 81%). The mean age of onset for SSc with MI was 42.3 ± 15.1 years. The mean age of SSc onset in the control group was 38.1 ± 13.6 years. Patients with MI had more diffuse cutaneous SSc (dcSSc) when compared with patients without MI (71.4% vs. 49.2%, P = 0.076) (Table 1). 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).

Table 1

General conditions of SSc patients with and without myocardial involvement
	Myocardial involvement (n = 21)	Non- myocardial involvement (n = 63)	P value
Age at onset (years)	42.3 ± 15.1	38.1 ± 13.6	0.239
Gender/Male (%)	4(19)	12(19)	1
BMI	22.0 ± 5.0	22.0 ± 3.6	0..939
Subset (dcSSc)	15(71.4)	31(49.2)	0.076
Overlap syndrome	1(4.8)	11(17.5)	0.280
Hypertension	3(14.3)	5(7.9)	0.668
Diabetes	1(4.8)	1(1.6)	0.440
Smoking	2(9.5)	3(3.6)	0.790
BMI: body mass index; dcSSc: diffuse cutaneous SSc

Table 2

The clinical manifestations of SSc patients with and without myocardial involvement
	Myocardial involvement (n = 21)	Non- myocardial involvement (n = 63)	P value
Puffy finger	4(19)	32(50.8)	0.011
Raynaud’s phenomenon	19(90.5)	61(96.8)	0.259
Telangiectasia	5(23.8)	24(38.1)	0.233
Loss of finger pad substance	3(14.3)	22(34.9)	0.073
Digital ulcers	9(42.9)	18(28.6)	0.225
Gangrene	3(14.3)	2(3.2)	0.183
Arthritis/ arthralgia	5(23.8)	23(36.5)	0.285
Myositis	9(42.9)	9(14.3)	0.014
Gastroesophageal reflux	5(23.8)	34(54)	0.016
Leukopenia	0(0)	1(1.6)	1
Thrombocytopenia	2(9.5)	5(7.9)	1.000
ILD	15(71.4)	47/58(81)	0.543
PAH	2(9.5)	19(30.2)	0.059
Hydropericardium	9(42.9)	7(11.1)	0.004
Left ventricular diastolic dysfunction	4(19)	7(11.1)	0.575
Scleroderma Renal crisis	1(4.8)	1(1.6)	0.440
Proteinuria	6(23.1)	6/60(8.0)	0.090
Modified Rodnan skin score	10(1.5,33.3)/10	4(2.5,8)/62	0.134
ILD: Interstitial lung disease; PAH: Pulmonary arterial hypertension

Laboratory findings

CK (33.8% vs. 4.8%, P = 0.003) and anti-SCL70antibody (71.4% vs. 36.3%, P = 0.005) positivity were statistically higher in SSc patients with MI (P < 0.05) (Table 3).

Table 3

Laboratory tests and pulmonary function tests between SSc patients with and without myocardial involvement
	Myocardial involvement (n = 21)	Non- myocardial involvement (n = 63)	P value
Elevated IgG	8(38.1)	22(34.9)	0.793
Elevated IgA	1(4.8)	9(14.3)	0.437
Elevated IgM	1(9.5)	6(9.5)	1
Decreased C3	0(0)/20	7(11.3)/72	0.186
Decreased C4	1(5)/20	5(8.1)/62	1
ESR (mm/h)	14.0(10,26.0)	13.5(7,23.5)/62	0.871
Elevated ESR	6(28.6)	23(37.1)/62	0.479
HsCRP (mg/L)	2.9(1.4,9.8)	1.5(0.7,3.7)/61	0.022
Elevated HsCRP	5(23.8)	7(11.5)/61	0.307
Elevated CK	7(33.3)	3(4.8)	0.002
ANA positivity	21(100)	56(88.9)	0.254
Anti-dsDNA antibody positivity	0(0)	4(6.3)	0.568
Anti-RNP antibody positivity	4/20(20)	20(31.7)	0.313
Anti-SSA antibody positivity	4/20(20)	15(23.8)	0.962
Anti-SSB antibody positivity	2/20(10)	3(4.8)	0.750
Anti SCL70 antibody positivity	15(71.4)	23(36.3)	0.005
ACA positivity	2/20(10)	6/59(10.2)	1
Anti PM-Scl antibody positivity	1/19(5.3)	1/56(1.8)	0.445
TCL (%)	84.3(72.7,93.125)/11	80(71,90.5)/56	0.517
FEV1 (%)	84.3(75.6,86)/11	83(65,92.1)/43	0.805
FVC (%)	78.3(79.5,97)/10	84.9(66.9,96)/43	0.420
DLCO (%)	65.4(44,75.5)/11	55.4(44,67.9)/43	0.555
Ig: immunoglobulin; C3/4: Complement 3/4; ESR: erythrocyte sedimentation rate; hsCRP: High-sensitivity C-reactive protein; CK: creatine kinase; ANA: antinuclear antibody; Anti-dsDNA: anti-double-stranded DNA; ACA: anti cardiolipin antibody; anti-SSA and anti-SSB: anti- Sjogren’s-syndrome-related antigen A/B; TCL: total lung capacity; FEV1: Forced expiratory volume in one second; FVC: Forced Vital Capacity; DLCO: carbon monoxide diffusing capacity

Clinical characteristics of heart

The mean age of MI was 46.0 ± 3.4 years and the median duration from the onset of SSc to MI was 220.0 (3.5, 70.5) months. Of the 21 patients with MI, 14 (66.7%) presented with cardiovascular symptoms, including chest distress, chest pain, reduced activity endurance and shortness of breath after exercise. Of the 7 patients (33.3%) without cardiovascular symptoms, 5 patients (71.4% vs. 75%, P = 1.000) exhibited elevated levels of CTnI, 6 (85.7% vs. 78.6%, P = 1.000) showed elevations of N-terminal brain natriuretic peptide (NT-proBNP).

Arrhythmia was detected in 7 cases (33.3%) by electrocardiogram or 24-hour Holter monitoring. Ten patients (47.6%) developed heart failure. Elevated levels of CTnI were detected in 14 (73.7%) patients while echocardiography detected a reduction in LVEF (< 50%) in 7 (50%) patients.

Of the patients with MI, 15 (71.4%) underwent CMR and 11 had myocardial fibrosis; 4 of these 11 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

Four patients received glucocorticoid pulse therapy due to myocardial involvement. In two cases, CTnI was continually elevated even after treatment with a moderate dose of glucocorticoid. Further cardiac radionuclide examinations for octreotate (TATE) detected diffuse myocardial radionuclide uptake; therefore, glucocorticoid pulse therapies were used in these two patients. Two of the four cases with pulse therapy were followed up; the second patient was followed up for 10.0 months. Levels of CTnI decreased but were still higher than normal. The first case (case number 1) was followed up for 13.4 months. LVEF by echocardiography did not improve significantly in either of these two patients. In one patient, the dose of glucocorticoid was increased to 60mg per day due to the new occurrence of arrhythmia. The remaining patients were maintained on the former dose of glucocorticoid even if MI was detected Twenty-four patients were treated with immunosuppressive drugs. Treatment for heart disease was mainly used to control ventricular rate, reduce cardinal load and improve ventricular remodeling.

Eleven patients were followed-up for a median period of 15.5 (7.8, 29.5) months. Four patients developed new abnormalities in the LVEF. Six patients underwent repeated CMR tests but showed no improvement (Table 4).

Table 4

CMR of the patients during follow-up
No.	Follow-up time (months)	Before					After
No.	Follow-up time (months)	LV EF (%)	RV EF (%)	Hypoperfusion/location	Gadolinium-enhanced /location	Hp	LV EF (%)	RV EF (%)	Hypoperfusion/location	Gadolinium-enhanced /location	Hp
1	5.7	51.2	42.9	Inferolateral and inferior	LV and RV diffuse subendocardial	Y	38.6	19.9	Ventricle septal LV	LV and RV diffuse subendocardial	Y
2	16.2	51.8	35.5		LV apical	Y	44.4	30.5		LV apical	Y
3	6.3	31.5	22.8		LV and RV subendocardial	N	26.4	22.5		LV and RV subendocardial	N
4	5.9	77.7	68.2		Ventricular septal LV	Y	67.6	62.4		Ventricular septal LV	N
5	32.9	57	60.6		Ventricular septal	Y	56.3	47.7		Ventricular septal	Y
6	26.4	42.4	50.6	Lateral	Ventricular septal LV	Y	43.7	48.4	LV lateral	Ventricular septal LV	N
HP: Hydropericardium; LV: left ventricular; RV: right ventricular; EF: Ejection fraction

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 15–66.7% [6, 7] 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, thus significantly increasing the risk of death [8]. 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 (referred to as the "myocardial Raynaud's phenomenon") and inflammatory reactions. Irreversible focal fibrosis is known to lead to heart failure and arrhythmias [8–13]. Myocardial involvement is more common and more severe in dcSSc [14]. In some autopsy studies, myocardial fibrosis was found to be very common in SSc patients, with an incidence of up to 81% [8, 15]. Focal injury of the myocardium, necrosis of the myocardial contractile zone and fibrous scarring have all been reported but unrelated to the corresponding area supplied by the coronary artery [8, 16, 17].

A previous retrospective study carried out in a single center in Spain showed that SSc patients with heart involvement had an older onset age for SSc [18]; lcSSc patients were more common [19]. Our study only focused on MI, and showed that, similar to cardiac involvement, patients with MI seem were older at the onset of SSc, but in contrast, dcSSc (71.4% vs. 49.2%, P = 0.076) was more common. In a study evaluating SSc subclinical cardiac involvement [20], fibrosis of the heart was correlated with a higher modified rodnan skin score (mRSS). On the other hand, our study also showed a greater extent of positivity to anti-scl70 antibody, consistent with the fact that dcSSc is more common. Therefore, we should remain vigilant for MI in patients with positivity to anti-SCL70 antibody and wide skin sclerosis. The correlation between scleroderma renal crisis (SRC) and cardiac or myocardial involvement has been reported in previous studies [21, 22]; severe myocardial damage resulted in reduced blood supply to the kidneys, thus aggravating renal ischemia.

Familiarity with key clinical features (including the established risk factors of MI) may prove useful in raising our awareness to the possibility of SSc-MI in relevant patients. Our study showed that patients with MI commonly exhibited CK elevation and myositis. Myositis mainly involves the skeletal muscle but can occasionally involve the myocardium. SSc patients with myositis were more likely to develop issues with the. Aggressive immunosuppressive treatment may control myocardial inflammation and improve cardiac function in patients with inflammatory cardiomyopathy. Therefore, it is very important to identify myocardial inflammation as early as possible if we are to improve outcomes. A recent study found that subclinical cardiac fibrosis in SSc was associated with highly sensitive troponin I (cTNI) and N-terminal brain natriuretic peptide precursor (NT-proBNP) [20]. In the present study, 14/19 patients showed elevated levels of cTnI and 17/21 patients showed elevated levels of NT-proBNP, thus suggesting the importance of these two biomarkers in predicting MI in patients with SSc. However, 10.5% of patients with MI had normal levels of cTNI and NT-proBNP; thus, it would be difficult to identify MI in such patients in the early stages.

Echocardiography is used widely to evaluate cardiac structure but is associated with low sensitivity for detecting myocardial fibrosis in the early stages. Recently, it has been reported that the calculation of stress by the echocardiographic spot tracking method can identify impaired systolic function of both ventricles in patients with no obvious cardiac symptoms and a normal left ventricular ejection fraction, as indicated by conventional echocardiography [23]. However, this method is not routinely used in clinical practice; our patients did not receive this diagnostic test. 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 early cardiac injury in SSc patients earlier than echocardiography and could identify abnormalities prior to the onset of clinical symptoms [24, 25]. In a prospective study of 201 patients with SSc [26], 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. Positron emission tomography (PET) testing of the heart is now being investigated as a potential diagnostic option. One patient in our study underwent both CMR and PET examination (including fibroblast activation protein inhibitor (FAPI) and TATE); CMR suggested myocardial fibrosis while PET (FAPI) did not. FAPI labels fibroblast activating protein, which appears in the early stages of myocardial fibrosis. Thus, FAPI is not a sensitive test for myocardial fibrosis during the middle and late stages; thus, this test may generate negative result in these populations. On the other hand, it was also possible that subendocardial fibrosis was not extensive enough to be recognized by PET. Similarly, it was still not known whether inflammation presented with an increased uptake of TATE or had the same clinical meanings as that presented with positive T2-weighted images in CMR. The true clinical value of FAPI and TATE examinations still need to be validated in larger studies. In conclusion, echocardiography is recommended for all patients with SSc for diagnosis and regular annual monitoring while CMR is recommended for those suspected of having myocardial involvement. Our data indicate that SSc patients with elevated CTnI or NT-proBNP should be examined for myocardial involvement.

There is still no effective treatment for MI in SSc patients. Furthermore, it is unknown as to whether immunosuppressive therapy could prevent or cure myocardial lesions in this population. Four patients in our study were treated with steroid pulse therapy; no significant improvement in LVEF was observed on follow-up in these patients. The follow-up of 6 patients by CMR found no evidence of an improvement in fibrosis or EF following treatment. These results suggested that immunotherapy did not improve myocardial fibrosis although further studies are needed to confirm whether this treatment could prevent the progression of myocardial fibrosis. Theoretically, immunotherapy should help to control myocardial inflammation although it is still difficult to accurately determine the presence of myocardial inflammation. The role and consistency of CMR, TATE or myocardial biopsy for the evaluation of myocardial inflammation still need to be confirmed in larger studies. Considering the inflammatory process of the myocardium before the progression of myocardial fibrosis and the key role of IL-1 in the process of myocardial inflammation, De Luca et al. proposed the concept of targeted treatment with an interleukin-1 antagonist; however, this strategy has not been described further in the existing literature [27]. In addition to immunotherapy, symptomatic treatment of the heart is also very important, including controlling the ventricular rate to reduce cardiac load, diuresis, vasodilation and improving ventricular remodeling. A previous study showed that some drugs with potent vasodilator activity on small coronary arteries, such as dipyridamole, may be beneficial in the treatment of SSc patients with myocardial perfusion abnormalities [28]. One patient in our study showed a gradual decrease of LVEF (58% down to 47%) 4 months after the discontinuation of Sakobactral valsartan although this improved again (60%) in 2 months after re-treatment with Sakobactral valsartan without the adjustment of other treatments. The results of the DeSScipher cohort study also showed that vasodilators 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 [29].

In summary, myocardial involvement in SSc is not uncommon. Almost half of the patients with MI wee subclinical and likely to have myositis and SRC. Regular monitoring of CTnI and NT-proBNP levels, along with echocardiography, can facilitate the early diagnosis of myocardial involvement. For SSc patients with a high suspicion of MI, further CMR testing will be helpful in confirming the diagnosis and assessing myocardial inflammation and fibrosis in order to identify therapeutic options.

Myocardial involvement is common in systemic sclerosis, and always insidious in early stage. Effect of immunotherapy is still unknown for myocardial involvement in systemic sclerosis. Regular monitoring of CTnI, NT-proBNP and echocardiography is helpful for earlier diagnosis of MI.

Systemic sclerosis (SSc); cardiac magnetic resonance imaging (CMR); myocardial involvement (MI); diffuse cutaneous SSc (dcSSc); limited cutaneous SSc (lcSSc); left ventricular ejection fraction (LVEF); Interstitial lung disease (ILD); high-resolution computed tomographic (HRCT) ;Pulmonary arterial hypertension (PAH) ; pulmonary arterial pressure (mPAP); pulmonary artery wedge pressure (PAWP); pulmonary vascular resistance (PVR); right heart catheterization (RHC) ; systolic pulmonary artery pressure (SPAP) ; scleroderma renal crisis (SRC); late gadolinium enhancement (LGE); octreotate (TATE); fibroblast activation protein inhibitor (FAPI); troponin I (cTNI); N-terminal brain natriuretic peptide precursor (NT-proBNP); calcium channel blocker (CCB); angiotensin-converting enzyme inhibitors (ACEi); angiotension II receptor blockers (ARB)

Ethics approval and consent to participate

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.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Competing interests

The authors have no conflicts of interest to declare.

Funding

This study was supported from Mengtao and Xiaofeng Zeng 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).

Authors’ Contributions

HH.: consult literature, data collection and collation, statistical analysis, make charts, thesis writing. JL.: consult literature, data entry, data collation and article revision. JZ.: data entry and data collation. YH: data entry and data collation. DX: Data entry, research guidance and article revision. ML.: data entry, research guidance, technical support. XZ.: data entry, research guidance, technical support. All authors read and approved the final manuscript.

Acknowledgements

The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.

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published 14 Apr, 2023

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15 Nov, 2022
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First submitted to journal
03 Nov, 2022

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The clinical characteristics and outcomes of patients with systemic sclerosis with myocardial involvement

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Journal Publication

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Abstract

Introduction

Methods

Study population

Data collection

Statistical analysis

Results

General condition and clinical manifestations

Laboratory findings

Clinical characteristics of heart

Treatment and outcomes

Discussion

Conclusion

Abbreviations

Declarations

References

Status:

Journal Publication

Version 1