Cardiac involvement in systemic sclerosis: mechanisms, manifestations and management

Abstract

Cardiovascular disease remains a leading cause of mortality in systemic sclerosis (SSc). This review summarizes key mechanisms in the pathophysiology of SSc primary heart involvement (SSc-PHI), presents the main clinical manifestations and their management and discusses unmet needs in SSc-PHI with potential solutions. The pathophysiology of SSc-PHI involves both vascular and immune-mediated pathways, exacerbated by the NLRP3 inflammasome and pro-fibrotic cytokines, leading to myocardial fibrosis as the main cardiac manifestation. Regular screening is recommended to detect SSc-PHI, incorporating clinical assessments, cardiac biomarkers and transthoracic echocardiography. Cardiovascular magnetic resonance imaging (CMR) enables detection of subclinical cardiac involvement, with certain CMR phenotypes holding prognostic significance. Early identification of subclinical disease is a critical unmet need to enhance risk stratification and improve outcomes. Emerging programs and cardiology-rheumatology collaboration will enhance interdisciplinary care and diagnostic strategies.

Rheumatology key messages.

• Primary heart involvement in systemic sclerosis is difficult to diagnose but has high mortality.

• Subclinical SSc-PHI can be assessed non-invasively on cardiac magnetic resonance imaging with certain prognostic information.

• Reliable diagnostic pathways support the development of targeted therapies for SSc-PHI (which are currently lacking).

Introduction

SSc, or scleroderma, is a rare multi-system autoimmune disorder which causes small vessel vasculopathy, inflammation and progressive fibrosis of the skin and internal organs [1]. Its prevalence ranges from 3.1 to 144.5 per 100 000, influenced by ethnicity, standards in disease recognition and diagnosis, with approximately 5-fold higher prevalence in women [2–4]. SSc is associated with a significant excess mortality with a standardized mortality rate of 3.5 and cumulative survival from diagnosis of 74.9% at 5 years and 62.5% at 10 years in a meta-analysis [5]. Combined cardiac causes accounted for 31% and 27% mortality in a French and EUSTAR cohort, respectively [6]. In the EUSTAR cohort, 12% of deaths were due to systemic sclerosis primary heart involvement (SSc-PHI) alone [6].

SSc-PHI is defined as cardiac abnormalities that are predominantly attributable to SSc rather than other causes and/or complications [7, 8]. It can present as pericarditis, myocarditis, tissue fibrosis with conduction abnormalities, bi-ventricular diastolic and systolic dysfunction [9–12]. SSc-PHI by definition excludes heart involvement that arises secondary to other SSc organ manifestations (such as renal, pulmonary vascular or pulmonary parenchymal disease) or coincidental disease (i.e., ischemic heart disease) [8]. Although conceptually appealing, distinguishing primary from secondary cardiac involvement is challenging in practice, as symptoms and clinical manifestations overlap and non-cardiac involvement in SSc can mask the symptoms of primary and secondary cardiovascular disease. For example, the symptoms of pulmonary arterial hypertension (PAH) and/or interstitial lung disease (ILD) are difficult to distinguish from those of associated right ventricular (RV) systolic dysfunction or SSc-PHI and both can be associated with abnormal cardiac blood biomarkers and abnormalities on imaging tests [8, 13, 14].

The pathological hallmarks of SSc-PHI include microvascular ischaemia and myocardial inflammation, both contributing to perivascular and myocardial fibrosis with an increasing recognition of the role of accelerated macrovascular disease [15, 16]. In this review, we summarize the main mechanisms of SSc-PHI, discuss its most common manifestations and their management and give an overview of the unmet needs in the management of SSc-PHI with potential solutions.

Mechanisms of SSc-PHI

The pathophysiology of SSc-PHI is complex and remains incompletely understood. It is generally thought that SSc-PHI is driven by vascular and immune mediated pathways, exacerbated by the NLRP3 inflammasome and mediated by cytokines, which jointly orchestrate myocardial fibrogenesis (Fig. 1). However, most of the proposed mechanisms discussed below remain hypothetical and are extrapolated from broader studies of SSc fibrosis or systemic vascular dysfunction [17].

Figure 1.

Mechanisms of primary heart involvement in systemic sclerosis. In vascular pathway, there is intermittent microvascular spasm, compounded by endothelin-1 (potent vasoconstrictor) and other cytotoxic factors, which leads to repeated myocardial ischaemia and myocardial fibrosis. Autonomic nervous system dysfunction also contributes to intermittent microvascular spasm. In the immune-mediated inflammatory pathway, adhesion molecules facilitate the migration of lymphocytes into the extracellular matrix, where CD4 on T cells and auto-antibodies (found in SSc) activate fibroblasts to become myofibroblasts which secrete collagen, causing myocardial fibrosis. Interleukin IL-1α, released after tissue damage or cell death, induces interleukin IL-6 and platelet-derived growth factor A (PDGFA), both of which activate myofibroblasts to secrete collagen. Increased levels of NLRP3 inflammasome (NOD-, LRR- and pyrin domain-containing protein 3), found in systemic sclerosis (SSc) fibroblasts, activate interleukin IL-1β, which then synergizes with transforming growth factor beta 1 (TGF-1β) to stimulate endothelial to mesenchymal transition (EndMT) and promote fibrogenesis. Created in BioRender. Soo, C. (2025) https://BioRender.com/8z94fux

Vascular pathway

The ‘vascular hypothesis’ of fibrogenesis proposes intermittent vascular spasm or ‘intramyocardial Raynaud’s phenomenon’ as a mechanism leading to myocardial fibrosis. In an autopsy study of 52 SSc patients, 23 (44%) had myocardial lesions (contraction band necrosis to replacement fibrosis), despite morphologically normal intramyocardial and epicardial coronary arteries [18]. More severe histological lesions correlated with clinical ventricular arrhythmias, congestive heart failure, angina and sudden death [18]. In another autopsy study, 31/58 (53%) of SSc patients had patchy myocardial fibrosis without significant atherosclerosis in epicardial coronary arteries [19]. The notion that repeated myocardial ischaemia due to microvascular impairment drives myocardial fibrosis in SSc was further supported by clinical imaging studies [20–24].

Beyond vasospasm, indirect evidence from general SSc cohorts supports the profibrotic role of different vascular mediators and cytotoxic factors [25, 26]. These include endothelin-1(a potent vasoconstrictor) and superoxide anions which inactivate the vasodilator nitric oxide and oxidize circulating low-density lipoproteins (LDLs), increasing vascular susceptibility to free radical damage [25–27]. Cytotoxic factors directly detrimental to endothelial cells have been isolated from SSc sera including anti-endothelial cell antibodies, endothelial cell growth-inhibitory factor and complement membrane attack complex (C5b-C9) [28–30]. They likely synergize to cause intermittent vascular spasm, ischaemic myocardial necrosis, reperfusion injury and eventually fibrogenesis [31].

Immune-mediated inflammatory pathway

Recent studies highlight the prominent role of immune-mediated inflammatory processes in SSc³²-PHI. Increased levels of adhesion molecules facilitate the migration of lymphocytes [T, B cells and natural killers (NK) cells] through the endothelium into the extracellular matrix [33]. Both the vascular cell adhesion molecule-1 (VCAM-1) and endothelial leucocyte adhesion molecule-1 (E-selectin) circulating levels correlate positively with the severity of skin score and renal function in SSc [32]. These mononuclear immune cells adhere so well to the endothelium that their levels are reduced in the peripheral blood in SSc vs healthy controls [34]. In the extracellular matrix, T cells display different markers including CD4, activating fibroblasts to become myofibroblasts which secrete collagen [35, 36]. Approximately 95% of SSc patients have at least one circulating autoantibody [37], which further stimulate fibroblasts to secrete collagen by either upregulating their intercellular adhesion molecule-1 (ICAM-1), promoting secretion of proinflammatory cytokines, activating the platelet-derived growth factor (PDGF) receptors on fibroblasts or binding directly to them [38–40].

Cytokines and inflammasome

Inflammatory cytokines play a cardinal role in the myocardial inflammatory cascade and the development of cardiac dysfunction. The interleukin-1 (IL-1) family of cytokines has 11 individual members which modulate acute phase inflammation by binding to receptors and co-receptors with either pro- or anti-inflammatory function [41]. IL-1α is released following ischaemic endothelial cell death or tissue damage [42]. It induces IL-6 and platelet-derived growth factor A (PDGFA), triggering inflammation, fibroblast proliferation and differentiation into myofibroblasts with increased collagen production [43]. The inactive form of IL-1β is cleaved and activated by inflammasomes, the intracellular multimeric protein complexes involved in the caspase-1 inflammatory response, which modulate apoptosis [44]. Activated IL-1β synergizes with transforming growth factor beta 1 (TGF-1β) to stimulate endothelial to mesenchymal transition (EndMT) and promote fibrogenesis, as seen in the cardiac and pulmonary tissues of mouse models [45, 46]. SSc fibroblasts exhibit increased levels of NLRP3 inflammasome (NOD-, LRR- and pyrin domain-containing protein 3) and micro-RNA (miR)-155 essential for collagen synthesis [47, 48]. Depletion of miR-155 reduced cardiac fibrosis in mice subjected to pressure overload [49].

In experimental studies, IL-1 directly depressed left ventricular (LV) function in mice injected with serum from patients with heart failure or septic shock [50–53]. Additionally, IL-17, secreted by T helper cells (TH17), contributed to post-myocarditis cardiac fibrosis and dilated cardiomyopathy, in synergy with IL-1 [54, 55].

Cardiac autonomic nervous system dysfunction

Cardiac autonomic nervous system dysfunction occurs early in SSc [56, 57]. In practice, it can be detected by reduced heart rate variability (HRV) on 24-h Holter monitor and abnormal responses to Ewing’s autonomic tests [56]. In a prospective study, 13/26 (50%) SSc without cardiovascular (CV) symptoms had cardiac autonomic nervous system dysfunction which correlated with an active pattern on nailfold video-capillaroscopy [58]. Another study showed independent association between reduced HRV and subclinical cardiac impairment (reduced global longitudinal strain, GLS and global circumferential strain, GCS on echocardiography) [59]. These observations suggest that autonomic nervous system dysfunction may contribute to SSc-PHI by promoting vasospasm and subsequent microvascular injury.

Manifestations of SSc-PHI

The prevalence of primary cardiac involvement in SSc varies between 15% and 35%, with subclinical SSc-PHI thought to be much more common [5]. Predictors for cardiac involvement include demographic factors (male gender, Black/Eastern European ethnicity, onset ≥65 years old), diffuse subtype of SSc, certain physical signs (rapidly progressing skin disease, digital ulcers, tendon friction rubs), positive serum auto-antibodies (especially anti-U3-RNP and anti-SCL70), pulmonary involvement, peripheral myositis and late pattern on nailfold video-capillaroscopy [8, 21, 60–63]. The most common manifestations of SSc-PHI are myocarditis, pericarditis, conduction abnormalities, micro- and macrovascular coronary artery disease, and the final pathway of LV and RV contractile dysfunction (Table 1, Fig. 2).

Table 1.

Manifestations, symptoms, diagnostic approach and management of SSc-PHI.

Manifestation	Symptoms	Diagnosis	Management
Myocarditis	Often subclinical Chest pain dyspnoea Fatigue Palpitations	Serum high sensitive troponin Serum NT-proBNP ECG Echocardiogram CMR	Immunosuppressants Corticosteroids (cave scleroderma renal crisis) Management of complications
Pericardial disease	Pleuritic chest pain, dyspnoea, peripheral swelling	ECG Chest X-ray Serial echocardiograms CMR Cardiac CT	Acute pericarditis:  Anti-inflammatory medication Colchicine for up to 3 months Recurrent pericarditis:  Corticosteroids Longer-term immunosuppressants Intravenous immunoglobulin Anakinra Azathioprine Large effusion with haemodynamic compromise:  Cardiology review Pericardiocentesis Pericardial window as last resort
Heart failure	Exertional dyspnoea Paroxysmal nocturnal dyspnoea, Peripheral oedema	Serum NT-proBNP Serum high-sensitive troponin ECG Chest X-ray Echocardiogram Consider CMR	Acute presentation:  Cardiology admission Intravenous diuretics Chronic presentation:  ARNI/ARB/ACEI BBs with caution MRA, SGLT-2 inhibitors Diastolic HF:  SGLT-2 inhibitor MRA
Conduction system disease (brady-arrhythmias)	Syncope Pre-syncope Light-headedness	Serum electrolytes Thyroid function tests ECG Ambulatory ECG Loop recorder	Cardiology review Medication review (consider stopping BB or CCB) Pacemaker for high degree AV block
Tachy-arrhythmias	Palpitations Syncope	Serum electrolytes Thyroid function tests ECG Ambulatory ECG Loop recorder	Cardiology review Electro-physiological studies BB other anti-arrhythmic drugs Ablation Defibrillator
Microvascular coronary artery disease	Angina-like chest pain	Serum high sensitive troponin ECG Echocardiogram CMR or PET with (quantitative) stress perfusion Cardiac CT angiogram to rule out epicardial CAD	Cardiology review Calcium channel blockers Beta blockers Nitrates Ranolazine Consider combining BB with CCB to reduce Raynaud’s phenomenon

ACEI, angiotensin-converting enzyme inhibitor; ARNI, angiotensin receptor-neprilysin inhibitor; ARB, angiotensin receptor blocker; AV, atrioventricular; BBs, beta-blockers; CAD, coronary artery disease; CCB, calcium channel blocker; CMR, cardiac magnetic resonance; CT, computed tomography; ECG, electrocardiogram; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PET, positron emission tomography; SGLT-2, sodium-glucose cotransporter-2 inhibitor.

Figure 2.

Management of primary heart involvement in systemic sclerosis. Clinical manifestations of primary heart involvement in systemic sclerosis (SSc) include: myocardial fibrosis [red arrow pointing to mid-wall fibrosis (white) in the basal infero-lateral segment on cardiac magnetic resonance imaging (CMR) with gadolinium]; myocarditis (red arrow on CMR image pointing to mid-wall late gadolinium hyperenhancement in the basal infero-septum, inferior and lateral segments); Pericarditis [red arrow pointing to pericardial hyperenhancement (white) on CMR]; microvascular disease (quantitative perfusion on CMR showing circumferentially reduced subendocardial myocardial blood flow with adenosine stress); arrhythmia (electrocardiogram rhythm strip showing complete heart block on background of atrial fibrillation). ACEI, angiotensin-converting enzyme inhibitor; ARNI, angiotensin receptor-neprilysin inhibitor; DMARDs, disease-modifying anti-rheumatic drugs; EP studies, electrophysiological studies; ICD, implantable cardioverter-defibrillator; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter-2 inhibitor. Created in BioRender. Soo, C. (2025) https://BioRender.com/6z7snix

Myocarditis

Myocardial inflammation as a manifestation of SSc-PHI is common and often subclinical. Symptoms of myocarditis are highly variable, ranging from chest discomfort and lethargy in mild instances to symptoms of overt heart failure (dyspnoea, leg swelling), syncope or even death (from arrhythmias or ventricular failure) in fulminant myocarditis [64]. Acute SSc myocarditis is typically more severe than other forms of myocarditis. A retrospective study involving three Italian centres analysed endomyocardial biopsy-proven non-viral myocarditis, satisfying the Dallas criteria, in three cohorts of patients: SSc, other autoimmune diseases and isolated non-viral myocarditis [65]. SSc myocarditis was significantly more likely to present with dyspnoea, clinical cardiac failure, had higher frequency of ventricular ectopics on 24-h electrocardiogram (ECG) and more severe myocardial fibrosis on histological analysis [65]. The latter correlated positively with the modified Rodnan skin score and mortality between 12 and 60 months post-myocarditis [65]. At the cellular level, the release of IL-1α from injured myocytes, precipitated by tissue damage, sets in motion a downstream inflammatory cascade involving other mediators including IL-6, TGF-β and inflammasome, leading to myocardial inflammation, potentially apoptosis, fibrosis and eventually cardiac dysfunction [31, 66].

Pericardial disease

Pericardial involvement is common in SSc and can be a manifestation of primary heart involvement, often concomitant with myocarditis as a myopericardial inflammatory syndrome, or secondary to other SSc organ manifestations, including PAH and renal disease [67]. Acute pericarditis usually presents with positional pleuritic chest pain, pyrexia or dyspnoea, with or without pericardial effusion [68]. Chronic pericarditis may lead to pericardial constriction, where the diastolic expansion of the cardiac chambers becomes restricted by fibrosed pericardium, causing features of right heart failure [69]. Features of focal, diffuse fibrous or fibrinous pericarditis were evident in 33–78% of SSc patients in two autopsy studies [18, 67]. A prospective echocardiography study detected pericardial effusion in 41% (22/54) SSc patients without correlation to PAH [70]. Most pericardial effusions (82%) were small to moderate (<200 mL) and asymptomatic [70]. Another prospective study showed asymptomatic pericardial effusion in 15% (15/100) of SSc patients without PAH [71]. An SSc autopsy series identified higher prevalence of pericardial disease (fibrinous adhesions or effusion >50 mL) in 19/34 (56%) without correlation to PAH [72]. In a 10-year retrospective study, 6.9% (32/462) of SSc patients were admitted with symptomatic pericardial effusion, of whom 47% and 74% had concurrent RV failure and PAH, respectively [73]. Severe pericardial effusion (very large >1 litre or rapidly accumulating) can cause cardiac tamponade, a medical emergency with high mortality, when increased intrapericardial pressure exceeds the elastic limit of the pericardium, compressing the heart chambers [74]. A review of 25 SSc patients, without PAH, diagnosed with cardiac tamponade at presentation recorded significant mortality (12.5%) despite treatment [75]. In a prospective study of 335 SSc patients with concurrent PAH, persistent pericardial effusion was associated with reduced survival compared with those who never had pericardial effusion [76].

Conduction system disease

Microvascular ischaemic injury and subsequent fibrosis in the cardiac conduction system provides substrate for a range of cardiac arrhythmias [77]. The annual incidence of sudden cardiac death (SCD) in SSc of 1.0–3.3% is >10 times higher than in the general population (0.05–0.1%) [78, 79]. The most common arrhythmias in SSc are ventricular ectopic beats (VEBs, 70%), non-sustained ventricular tachycardia (NSVT, 18%) and atrial fibrillation (AF, 8%) [78]. Increased replacement myocardial fibrosis (detected as mid-wall late gadolinium enhancement, LGE), diffuse myocardial fibrosis (measured as increased extracellular volume, ECV) and increased T1 value on CMR correlated with abnormal arrhythmias on both Holter and implantable loop recorders [65, 80–83]. In a prospective study, a threshold of >1190 VEBs in 24 h predicted sudden cardiac death or need for implantable cardiac defibrillator (ICD) in SSc without PAH [84]. Right bundle branch block (RBBB) and severe ventricular arrhythmias were independently associated with increased risk of SCD [77, 78]. The risk of SCD was even higher (n = 12/25) in SSc patients who had concomitant skeletal myopathy.

Ventricular impairment

Primary LV diastolic dysfunction in SSc had a prevalence of 18–23% in echocardiography studies, which either excluded patients with PAH or adjusted for PAH and ILD, and was independently associated with mortality [85, 86]. LV diastolic dysfunction is thought to be the result of progressive myocardial fibrosis which causes LV stiffness with impaired relaxation, ultimately leading to clinical heart failure as restrictive cardiomyopathy [87]. The risk factors independently associated with LV diastolic dysfunction were SSc disease duration, age, systemic hypertension and co-existing coronary artery disease, hence the importance of managing modifiable traditional CV risks [85].

Overt LV systolic dysfunction is less common (5.3% in EUSTAR database) in SSc, but is independently associated with male gender, age, digital ulcerations, myositis and non-use of calcium channel blockers [63, 88]. In a retrospective study of SSc patients without CV symptoms or PAH, CMR identified sub-clinical reduction in LV GLS, despite normal bi-ventricular ejection fractions (EFs) [89]. Reduced LV GLS was independently predictive of mortality, affirming its role as a more sensitive marker of subtle cardiac dysfunction in SSc [89]. When SSc patients with PAH and ILD were included in a broader retrospective cohort, both increased native T1 value and reduced RVEF independently predicted mortality [90]. When adjusted for PAH, three phenotypic clusters on CMR that were predictive of mortality were RV failure, bi-ventricular failure and dilated cardiac chambers despite normal contractile function [90].

RV systolic dysfunction can be caused by primary RV disease or occur secondary to PAH. The concept of primary RV involvement in SSc is supported by several prospective studies which demonstrated subclinical RV systolic and diastolic impairment in cohorts without PAH [13, 91, 92]. An ex vivo biopsy study showed abnormal RV sarcomere function in SSc without PAH, suggesting that primary RV dysfunction in SSc can occur irrespective of PAH [93]. While impairment in RV systolic dysfunction in the absence of PAH is commonly subclinical, clinically relevant and more severe RV disease is seen in SSc with PAH [13].

PAH from ILD may lead to reduced RV systolic function (cor pulmonale) associated with 3-year survival of 52% from diagnosis of PAH in a meta-analysis [94, 95]. In addition, both cyclophosphamide (at myeloablative dose) and anthracycline (at cumulative dose of >300 mg/m²), used in haematological stem cell transplantation for SSc can also cause reduced LVEF [96–98].

Microvascular and epicardial coronary artery disease

In SSc, the coronary micro-circulation is particularly vulnerable to insults from vascular mediators, cytotoxic factors and vasospasm [99]. Inadequate blood flow through the micro-circulation to meet cardiac metabolic demands causes CMD or microvascular angina with symptoms almost indistinguishable from epicardial coronary artery disease [100].

Transient myocardial ischaemia due to peripheral cold exposure (cardiac Raynaud’s phenomenon) was identified on thallium-201 single photon emission computed tomography (SPECT) in SSc patients without clinical PHI [101, 102]. In a prospective study using cold provocation test and contrast echocardiography, 29.4% (n = 15) of SSc patients without clinical PHI had severe cardiac Raynaud’s phenomenon, which predicted deterioration in LVEF over 7 years of follow-up [103].

Unlike microvascular disease, most previous studies have shown similar prevalence of epicardial coronary artery disease in SSc vs the general population [104]. However, a recent systematic review found that the risk of myocardial infarction in SSc was nearly double compared with a control group, suggesting combined cumulative risks over time from vascular injury, chronic inflammation and autoimmunity [16].

Accelerated atherosclerosis

Whilst microvasculopathy is the hallmark of SSc-PHI, it is increasingly being recognized that the prevalence of macrovascular disease is also increased in SSc, involving peripheral arteries, cerebrovascular vessels, carotid arteries and epicardial coronary arteries, implicating accelerated atherosclerosis [15]. This, along with SSc-PHI, adds to the overall CV burden in SSc [15, 16]. Although there is no prospectively validated risk score for CV disease specific for SSc to account for this excess risk, when the systemic lupus erythematosus (SLE) option in QRISK3 was applied as a surrogate for SSc, it estimated a higher proportion of patients at high risk of cardiovascular disease (CVD) compared with Framingham Risk Score [105]. Modifiable risk factors accounted for 79.6% of global CVD burden, reinforcing the need for aggressive control of traditional CV risk factors, alongside SSc-specific management [106].

Diagnosing cardiac involvement in SSc

Many patients with SSc-PHI are asymptomatic. The World Scleroderma Foundation/Heart Failure Association consensus statement for SSc-PHI therefore advocates regular screening for PHI in all SSc patients, emphasizing prompt cardiology input, where indicated [7, 31]. The standard diagnostic work-up at new SSc diagnosis thence annually, including in asymptomatic patients, should include history, examination, 12-lead ECG, serial serum biomarkers of cardiac involvement (hs-troponin, NT-proBNP) and a transthoracic echocardiogram [7].

SSc patients may present with a range of CV symptoms including angina-like chest pain (precipitated by physical exertion or exposure to cold weather), palpitations, syncope or pre-syncope, exertional dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea (PND), postural hypotension, pleuritic chest pain, peripheral swelling or abdominal distension [107]. The severity of SSc-PHI can be graded using a scoring system (Table 2). CV symptoms should prompt repeat ECG or Holter monitor (24 h or longer) and blood biomarkers [107]. Transthoracic echocardiography is generally the first-line imaging tool. However, the quality of echocardiography, particularly for RV imaging, may be variable, and is more dependent on body habitus than with cross-sectional imaging techniques [108].

Table 2.

Modified Medsger severity score for cardiac involvement in SSc.

Score	Criteria
0 (normal)	Normal ECG; LVEF ≥50%
1 (mild)	Conduction defects on ECG; LVEF 45–49%
2 (moderate)	Arrhythmia on ECG; LVEF 40–44%
3 (severe)	Arrhythmia requiring treatment; LVEF 30–40%
4 (end-stage)	Congestive heart failure; LVEF <30%

Adapted from Medsger et al. [61].

ECG, electrocardiogram; LVEF, left-ventricular ejection fraction.

CMR is now recommended when SSc-PHI is suspected following initial assessment [7]. CMR allows accurate assessment of structure and function of all cardiac chambers, including the RV, pericardium and detailed myocardial tissue characterization including oedema, diffuse and focal fibrosis and ischemia [108]. CMR is particularly useful in suspected immune-mediated myocarditis, to accurately assess bi-ventricular function and quantify myocardial fibrosis. The decision to refer for CMR may be supported by ‘red flags’ of elevated blood CRP and troponin levels, as well as the presence of ILD and arrhythmias on 24 h Holter according to a recent retrospective study in which these clinical findings were independently associated with abnormal CMR in patients with SSc-PHI [81].

Where available, PET CT can also be used to detect myocardial and vascular inflammation and ischaemia. 18F FDG PET has been used to track inflammation in SSc myocarditis [65] and the new PET tracer 68Ga Fibroblast Activation Protein Inhibitor (FAPI) may track fibrogenesis in the heart [109].

It is, however, important to note that findings on CMR and PET/CT are generally non-specific, and no imaging biomarkers exist to definitively identify SSc-related CV disease. In particular, in the absence of specific diagnostic criteria for immune-mediated myocarditis, in practice diagnosis is based on guidance developed for viral myocarditis, which may lack sensitivity and specificity in SSc [110]. Furthermore, widely accepted standards for imaging acquisition and interpretation in SSc and other immune-mediated inflammatory diseases (IMIDs) are lacking.

Endomyocardial biopsy may be used to evaluate cases of myocarditis and cardiomyopathy where the aetiologies remain unclear despite non-invasive investigations [111]. When occasionally used, biopsy provides insights into the cellular mechanisms of SSc-PHI [65].

Management of cardiac involvement in SSc

Treatments are guided by the nature of cardiac involvement and best overseen by a multi-disciplinary team comprising rheumatologists and cardiologists experienced in the management of SSc and its CV manifestations (Fig. 2). However, there is a limited evidence base for the management of SSc-PHI with data derived from small case series or cohort studies (summarized by Batani et al.). [112] Controlling SSc disease activity in general is paramount in patients with cardiac manifestations, combined with supportive therapies and interventions in line with other, non-immune mediated cardiovascular diseases [107]. Based on the current literature, among the available immunosuppressants, mycophenolate (MMF) will often be the first choice to treat suspected SSc-PHI, with biologics such as tocilizumab and rituximab potential alternatives [112]. In addition, calcium channel blockers or vasodilators are commonly added [112].

Myocarditis

There is a very limited evidence base for the use of immunosuppressants in the management of SSc myocarditis. In one small study (n = 18) symptomatic SSc-myocarditis was treated with immunosuppressants (cyclophosphamide/rituximab, MMF, tocilizumab or methotrexate), corticosteroids alone or autologous stem cell transplantation [113]. In response to treatment, myocardial oedema on CMR reduced and cardiac function improved, while native T1 and ECV remained unchanged. Another study of 35 SSc-PHI patients from two centres showed reduction in myocardial T1 and T2 on CMR, indicative of reduced myocardial inflammation in response to 12 month treatment with a range of immunosuppressants (including MMF, cyclophosphamide and biologics) [114]. These changes were paralleled by a reduction in cardiac biomarkers (NT-proBNP, hsTnI) and CRP. And in a small study of asymptomatic SSc patients (n = 9) with subclinical myocarditis, CMR showed resolution of myocardial oedema and ECV at 6 months using prednisolone 20 mg and azathioprine 100 mg once daily [115]. Despite these initial studies suggesting improvement in myocardial oedema/inflammation in response to immunosuppressive therapy, larger randomized controlled trials are required to clarify optimal management of SSc myocarditis.

Both IL-1 and IL-6 play pivotal roles in immune-mediated myocarditis and could represent potential therapeutic targets [51]. A case report showed resolution of myocardial oedema with IL-6 inhibitor tocilizumab in SSc myocarditis [116]. Other agents including rilanocept, anakinra and rituximab have theoretical benefits in treating immune-mediated myocarditis but currently lack specific evidence [117–119].

Corticosteroids (>15 mg/day) can precipitate scleroderma renal crisis especially in diffuse SSc and those with positive anti-RNA polymerase III antibodies [120]. Cyclophosphamide at high doses (in haematopoietic stem cell transplantation) risks cardiotoxicity [96–98]. Therefore, their use necessitates extreme caution and close monitoring of renal and cardiac functions, respectively.

Pericardial disease

Asymptomatic mild (<10 mm) to moderate pericardial effusion (10–20 mm) without imaging markers of haemodynamic compromise may be monitored with transthoracic echocardiogram regularly [118]. Pericardiocentesis is recommended for larger or symptomatic pericardial effusion or for diagnostic purposes to assess for concurrent bacterial or neoplastic aetiology [118]. Surgical pericardial windows can be considered as a last resort for recurrent large pericardial effusion with haemodynamic compromise but it carries high risks of mortality in the presence of PAH [121, 122].

Acute pericarditis can be treated with oral aspirin or ibuprofen for 1–2 weeks and colchicine for up to 3 months [118]. However, evidence for their efficacy in SSc is lacking. Chronic or recurrent pericarditis, without obvious aetiology, is generally considered immune-mediated [118, 123]. It is treated with a longer course of aspirin, ibuprofen or indomethacin, and colchicine with gradual withdrawal [118]. Corticosteroids may be used at low doses (0.2–0.5 mg/kg/day) in the absence of bacterial infections, especially tuberculosis, and with very slow decrements of 1–2.5 mg every 2–6 weeks [118]. Exercise restrictions should be considered until symptoms and CRP have resolved [118]. Intravenous immunoglobulin (IVIG), rilonacept or anakinra (interleukin-1 receptor antagonists) or azathioprine may be used in recurrent pericarditis not responsive to colchicine [118].

Pericarditis of any cause may lead to constrictive pericarditis which often requires pericardiectomy [118]. However, there were reports of transient constriction which had resolved with empiric anti-inflammatory drugs [124, 125].

Conduction defects and tachyarrhythmias

There is no specific guideline for management of SSc arrhythmias and general cardiology guidelines apply which are well-evidenced. In bradyarrhythmias, medications should be withheld which slow the atrio-ventricular (AV) node conduction including beta-blockers, non-dihydropyridine calcium channel blockers or other anti-arrhythmic agents. Persistent higher degree AV node block, symptomatic bradycardia, sinus node disease or chronotropic incompetence may need treatment with permanent pacemaker implantation [126]. Tachy-arrhythmias may require interrogation by electro-physiological studies and are managed according to their mechanisms and risk-stratification [127, 128]. Treatments include beta-blockers – with caution due to their potential vasospastic effects – other anti-arrhythmic drugs, ablation therapy or implantation of a defibrillator [127, 128]. The CHA2DS2-VASc score is used to assess stroke risk in non-valvular atrial fibrillation to guide decision on anticoagulation [129]. In a non-randomized observational study, low-dose aspirin (≤325 mg daily) was associated with lower incidence of heart block or eventual pacemaker implantation [130]. However, its use needs to be balanced against bleeding risks, especially in SSc with gastrointestinal involvement.

Heart failure (HF)

As in non-SSc patients, the priorities in treating heart failure in patients with SSc are the management of symptoms, alleviating volume overload, mitigating precipitating causes and improving patient outcomes. Acute decompensated heart failure requires hospitalization and monitored diuresis with intravenous diuretics [131]. In chronic heart failure with reduced LVEF, European Society of Cardiology guidelines advocate four pillars of medical treatments (Class I indication): angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor neprilysin inhibitor (ARNI) with angiotensin II receptor blocker (sacubitril/valsartan), beta-blocker (B blocker), mineralocorticoid receptor antagonists (MRA), sodium-glucose cotransporter 2 (SGLT-2) inhibitor, which independently improve prognosis [131]. Cardiac re-synchronization therapy (CRT) is recommended for symptomatic HF patients with LVEF ≤ 35%, QRS duration ≥150 ms and left bundle branch block (LBBB) morphology on ECG, despite optimal medial therapy, to reduce morbidity or mortality [131]. Implantation of a cardioverter-defibrillator in HF patients, fulfilling certain criteria, is recommended for primary or secondary prevention of SCD [131]. Challenging decisions on these treatments are evaluated by local heart multi-disciplinary teams.

SGLT-2 inhibitors (Class I recommendation) reduce hospitalizations and improve prognosis in heart failure with preserved EF (diastolic dysfunction) [132]. The non-steroidal MRA inhibitor, finerenone, was recently found to improve prognosis and reduce hospitalizations in heart failure with either mildly reduced or preserved EF (LVEF ≥50%) [133]. There are no specific prognostic data of these agents in SSc-specific cohorts.

There are no established treatments for myocardial fibrosis, which is thought to be the precursor to heart failure. Nintedanib is an anti-fibrotic agent which competitively inhibits the tyrosine kinase domains on vascular endothelial growth factor (VEGF), PDGF and fibroblast growth factor (FGF) [134]. These growth factors are indispensable to fibrogenesis in SSc and ILD [135]. In a small study of 20 patients with SSc-ILD, nintedanib significantly reduced myocardial ECV on CMR, indicative of reduced diffuse myocardial fibrosis, suggesting a possible anti-fibrotic effect in the heart [136].

Microvascular angina

Microvascular angina can be treated with calcium channel blockers, beta blockers, nitrates or ranolazine [137]. Oral nifedipine 60 mg once daily improved myocardial perfusion reserve on CMR over a 14-day period [138]. In a multicentre observational study, vasodilator therapy (nifedipine up to 60 mg, or captopril up to 100 mg, once daily) correlated with lower incidence of ventricular arrhythmias (P= 0.03) over 4 years of follow-up [130]. Potential adverse effects of beta-blockers on Raynaud’s phenomenon may be ameliorated with concurrent administration of beta blockers with dihydropyridine calcium channel blockers [139]. The latter primarily act on vascular smooth muscles rather than cardiac receptors to minimize risks of bradycardia [140].

Unmet needs and potential solutions in SSc-PHI

Despite much progress in the management of SSc in general, SSc-PHI remains under-researched and CV mortality in SSc remains high. There is an unmet need to better understand the vascular, inflammatory and immune-mediated mechanisms that drive PHI in SSc. How existing and emerging biologic therapeutics impact CV involvement in SSc is largely unknown. Additionally, the advancement of multi-omic platforms which reveal intricate correlations between genetic predispositions, immune dysregulation and environmental triggers in the pathogenesis of SSc, offers opportunities for new therapeutic targets and more personalized treatments. Early detection of subclinical CV disease in SSc is perhaps the most important unmet need to improve risk stratification and CV outcome. Developing reliable diagnostic pathways, including the appropriate use of current and new humoral and imaging biomarkers for SSc-PHI is timely. This is also a prerequisite for the development and testing of specific therapies targeting SSc-PHI, which currently are lacking. Most importantly, multicentre studies and registries with larger number of SSc patients are warranted to validate the findings of studies with smaller number of patients to better understand the prognostic implications of subclinical disease detected on imaging.

Conclusions

SSc-PHI is common and is associated with significantly adverse outcomes. The underlying mechanisms of SSc-PHI are complex and incompletely understood. As an evidence base for the prevention and management of SSc is largely lacking, patient care is inconsistent and undoubtedly suboptimal in many cases. Several programmes are in development to address this limitation, including the CARDIO-IMID network in the UK, that will provide critical data for the best use of screening and advanced diagnostic tools in the coming years. The increasingly close collaboration of cardiologists and rheumatologists in many healthcare systems will aid in providing inter-disciplinary care for patients with SSc.

Data availability

No new scientific data were generated or analysed in support of this review. All information discussed is drawn from previously published studies cited in the article. The interpretations and views presented are those of the authors.

Funding

No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: F.D.G. holds the position of Associate Editor of Rheumatology and has not peer reviewed or made any editorial decisions for this article. The remaining authors have declared no conflicts of interest.