Heart involvement in patients with systemic sclerosis—what have we learned about it in the last 5 years

Systemic sclerosis (SSc) is a connective tissue disease (CTD) with pooled global prevalence of 17.6 per 100,000 individuals [1]. It manifests as an immune-mediated rheumatic disease, characterized by fibrosis of the skin and internal organs with concomitant vasculopathy [2]. Among affected structures, SSc-associated heart involvement (SHI) is one of the most frequent causes of death [3], including primary and secondary cardiac diseases [4]. Recently, two important papers on systemic sclerosis-primary heart involvement (SSc-pHI) emerged, providing both a clear definition of SSc-pHI and a practical guidance on screening, diagnosis and follow-up [5, 6]. A large survey conducted by European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) showed that 12% of SSc deaths are attributed to primary heart disease. However, this determination was made by physicians, and specific SSc-pHI criteria were not provided to investigators during data collection [7]. Additionally, an extensive review uncovered a broad spectrum of estimated clinical prevalence rates for heart involvement in SSc, ranging from 7% to over 39%. This considerable variability underscores the significant heterogeneity in defining heart involvement across studies [8]. SSc-pHI can present clinically through a range of conditions, such as arrhythmias, heart failure, pericardial disease, valvular abnormalities, and myocardial inflammation. The most common forms of SSc-pHI are presented in Fig. 1. Heart involvement may persist subclinical or be misinterpreted as other forms of cardiomyopathy, posing challenges to accurate diagnosis [9, 10]. Detection of myocardial impairment can be achieved through a wide range of tools such as transthoracic echocardiography (TTE) with tissue Doppler echocardiography (TDE) or cardiac magnetic resonance imaging (CMR), offering extensive diagnostic opportunities. However, the prognostic implications of identifying “sub-clinical” fibrosis in this manner remain uncertain [11]. Additionally, the difference in applied diagnostic methods may contribute to epidemiological heterogeneity of SSc-pHI [11]. Moreover, the absence of precise guidelines for SSc-pHI treatment increases the complexity of therapy, making it more challenging and necessitating reliance on empirical procedures [12]. The aim of this study is to summarize recent knowledge about cardiac involvement in SSc, including definitions, screening, diagnostic options and treatment.

A literature search was conducted using the PUBMED, Medline, Web of science, Scopus and DOAJ databases, spanning from Jan 2019 to Aug 2024. The search terms employed were ‘cardiac’ OR ‘cardiovascular’OR 'heart' AND ‘systemic sclerosis’. Only published data were included, encompassing both original studies and reviews written in English. Animal or in vitro studies, case reports, editorial letters, and conference papers were not selected for further review. Abstracts and full articles were thoroughly reviewed and articles with study groups comprising patients with systemic sclerosis were selected for inclusion. Additionally, authors screened the references cited in the selected articles, reviewed the relevant literature and incorporated crucial publications until 2010. Figure 2 shows the screening and selection process.

The pathogenesis of cardiac complications in SSc is not fully understood, due to its complex nature [12, 13]. Small vessel damage, vasoconstriction, chronic ischemia–reperfusion injury, cardiac inflammation and fibrosis are critical mechanisms affecting each of the heart structures [11, 13, 14]. The “vascular hypothesis” (intermittent vascular spasm, ischemic necrosis, and reperfusion injury) is the most well-known mechanism leading to fibrogenesis. Recently, an inflammatory myocardial process resulting in fibrosis has been recognized as a crucial pathomechanism coexisting with vascular injury [15]. Among cytokines, interleukin 1 (IL-1) and interleukin 6 (IL-6) are crucial for cardiac inflammation and subsequent fibrosis, which may lead to the broader application of drugs targeting these points in the inflammatory cascade among patients with SHI [15].

According to Bissell et al., several factors may be linked to heart involvement in SSc: male gender, diffuse cutaneous SSc (dcSSc), presence of anti-topoisomerase antibodies with rapid progression of skin thickness, anti-Ku, anti-Histone, anti-RNA polymerase, and anti-U3-RNP antibodies, age of onset over 65 years, presence of tendon friction rubs, digital ulcers, lung involvement and myositis [16]. All the above could potentially identify patients of a high risk for cardiac complications that require an exceptional clinical attention. Additionally, Ceribelli et al. determined that patients with anti-Th/To over anticentromere (ACA) antibodies had a greater prevalence of pericarditis [17]. In the study by Höppner et al., patients with SSc who were positive for antimitochondrial antibodies (AMA) M2 subunit, had an increased risk of cardiovascular events, independent of the presence of primary biliary cholangitis (PBC) [18].

In 2022, Bruni et al. published an expert consensus definition for primary heart involvement in systemic sclerosis, being a response to the emerging need in the literature [5, 11]. According to this document “SSc-pHI comprises cardiac abnormalities that are predominantly attributable to SSc rather than other causes and/or complications (such as: non-SSc-specific cardiac conditions and/or SSc non-cardiac conditions). SSc-pHI may manifest as subclinical and requires confirmation through diagnostic investigation.

The pathogenesis of SSc-pHI comprises one or more of inflammation, fibrosis and vasculopathy” [5].

This standardized definition has enhanced our understanding and facilitated focus clinical research efforts on SSc-pHI. Furthermore, establishing clear diagnostic criteria is crucial for determining the prevalence of SSc-pHI, as its frequency remains unknown due to most existing studies not distinguishing between primary and secondary heart involvement [5]. Prior to the publication of SSc-pHI definition, Elhai et al. conducted a large survey through EUSTAR, revealing that 12% of SSc-related deaths were attributed to primary heart disease. However, patients were evaluated by physicians, and their opinions played a key role [7]. Hence, there is an unmet need to assess patients using novel criteria to determine whether SSc-pHI might contribute to varying death rates.

Patients with SSc have an increased risk of conduction and rhythm disorders both at disease onset and over time, in comparison to individuals without SSc [19]. For instance, compared with seemingly healthy non-SSc cohorts, patients with SSc exhibit a 2.5-fold increase in electrocardiogram (ECG) abnormalities, and a twofold increase in conduction blocks [20]. The pathogenesis of arrhythmia remains complex, involving a combination of factors including the direct effects of microvascular injury, subsequent fibrosis development and autonomic dysfunction [9, 14]. A recent study conducted by Ross et al. found a high burden of myocardial fibrosis and arrhythmias among SSc patients without confirmation of evident cardiac disease; however, there was no clear association between focal or diffuse myocardial fibrosis and arrhythmias, indicating that CMR may have limited use as a screening tool to identify SSc patients at risk of future relevant rhythm disorders [21]. In a study conducted by Radwan et al. increasing age and pulmonary arterial hypertension (PAH) were associated with a higher risk of developing any conduction disorder in SSc, while preexisting PAH in addition to current smoking status were associated with higher risk of developing rhythm disorders [19].

Arrhythmias, according to European League Against Rheumatism (EULAR), account for 6% of deaths among patients with SSc [22].The patterns of arrhythmias and conduction disorders are various. Figure 3 shows a wide range of ECG abnormalities in SSc.

A large systematic review and meta-analysis revealed that among patients without known SHI, almost one-third had abnormal resting ECG. Conduction block occurred in 37% of them. Non-specific ST-T wave changes appeared in 10.8%. Right bundle branch block (RBBB) and left bundle branch block (LBBB) were less frequent, occurring in 4.5% and 2.9%, respectively. When heart involvement was reported, the rate of abnormalities was higher [20]. Additionally, in one case–control study, QT corrected for heart rate (QTc) interval in SSc patients was significantly higher than in the control group, with relationship between QTc and skin score of patients [23]. According to ambulatory ECG, non-sustained ventricular tachycardia (NSVT) occurred in 9.6% of SSc patients without known SHI, ventricular arrhythmias in 16.0%, ventricular bigeminy in 13.3%, premature ventricular contractions (PVCs) were detected in 80.1%, paired PVCs in 15.6%, and multiform PVCs in 44.4%. Frequent PVCs (> 1000/24 h) occurred in 5.8%, and > 100 PVCs/24 h in 23.5%. Paroxysmal atrial fibrillation (AF) was detected in 6.8%, combined AF in 8.6%, and paroxysmal supraventricular tachycardia (SVT) in 17.1% [20]. Moreover, in a study of 2519 patients with SSc, a two-fold higher risk of incident AF than controls had been reported [24]. Data from 13,609 individuals assessed an annual incidence of sudden cardiac death (SCD) in SSc cohorts to be between 1.0 and 3.3%. This illustrates at least a tenfold raise compared to general population [20, 25, 26]. Arrhythmias are indeed prevalent in SSc and can lead to increased mortality. However, they are not exclusive to this population and can occur in the general populace as well. Therefore, diagnosing and treating them early and accurately is challenging yet crucial for enhancing patient prognosis.

In SSc, both left and right ventricles may be affected, leading to their dysfunction and failure. Heart failure (HF) is defined as a clinical syndrome with increasing prevalence that imposes a huge burden on health care systems worldwide. The pathomechanism of HF in SSc is still unclear, regarding myocardial fibrosis. Ongoing theories include vessel obliteration and arteriolar endothelial injury resulting in fibrosis [9]. Patients with SSc, compared with non-SSc individuals, have an increased risk of HF [27]. A study conducted among 1,830 SSc patients and 27,981 controls revealed that the cumulative HF rates at 1, 3, 5, and 10 years among patients with SSc were 1.3%, 3.5%, 5.3%, and 9.7%, respectively. In contrast, the cumulative incidence of HF at 1, 3, 5, and 10 years in the control group were 0.2%, 0.7%, 1.4%, and 3.1%, respectively [27]. Moreover, Sherif et al. in a recent study confirmed that among patients hospitalized due to HF, those with SSc had a higher likelihood of in-hospital mortality compared to those without SSc [28]. PAH and resulting right‐sided HF are a significant cause of morbidity and mortality in SSc [29‐31]. The prevalence of left ventricle diastolic dysfunction (LVDD) varies, ranging from 17–21% at baseline to 29% after median 3.4 years follow-up [32, 33]. In a study conducted by Tennøe et al. the presence of LVDD among patients with SSc was associated with high mortality; however, assessing causality between diastolic dysfunction and death was not possible due to study design [32]. Although the occurrence of left ventricle systolic dysfunction (LVSD) appears to be rare, the data on its actual frequency within the SSc population is limited [34]. In a large cohort of 1141 participants with SSc without non-SSc cardiac disease or PAH, only 2.4% had a left ventricular ejection fraction (LVEF) < 50%, and 0.6% a LVEF < 40%. Survival and functional capacity were significantly worse in SSc patients with reduced LVEF, even after its improvement. However, reduced LVEF alone may underestimate the true frequency of systolic dysfunction in SSc [34]. In a study by Tennøe et al., with significantly smaller SSc patient group, LVEF was reduced in SSc patients compared with control individuals. A LVEF from 40 to 49% was observed in 8% of the entire cohort, while 3% had LVEF < 40% [32]. Based on the LVSD risk factors identified in the study by Werakiat et al., high mRSS, steroid use, and elevated creatine kinase (CK) level were associated with unimproved LVSD. In contrast, treatment with mycophenolate mofetil (MMF) might help prevent the progression of LVSD [35]. The abovementioned data highlight the urgent need for appropriate and early diagnosis and treatment of patients with SSc suspected or diagnosed with HF in order to prevent complications and death.

Myocarditis has been recognized as a potentially life-threatening aspect of myocardial involvement in SSc. However, the limited data hinders its diagnosis and treatment [36, 37]. In a study by De Luca et al. it was noted that SSc-associated myocarditis frequently presents with heart failure and severe dyspnea. Additionally, the extent of myocardial fibrosis on endomyocardial biopsy (EMB) was found to be higher compared to other forms of EMB-proven myocarditis and was linked to a poorer cardiac prognosis [37]. Currently, CMR is increasingly utilized to assess heart involvement in SSc, offering non-invasive and non-irradiating methods to identify cardiac disease through specific indexes and measurements [38]. A recent study has indicated that CMR can differentiate between reversible inflammatory or fibrotic lesions and irreversible fibrotic lesions among SSc patients with active myocarditis [39]. This underscores the role of CMR in myocarditis assessment, although guidelines regarding the use of CMR in monitoring treatment for SSc-associated myocarditis are lacking. Further research is necessary to establish appropriate diagnostic methods and treatment strategies in SSc myocarditis.

Pericardial effusion in SSc can manifest as either acute or chronic, with or without accompanying clinical symptoms. The prevalence of pericardial involvement varies, influenced by the criteria used for assessment. Autopsy studies often report a high occurrence, whereas echocardiography examinations commonly reveal lower frequencies [40]. In research conducted at a single tertiary center, clinically symptomatic pericardial effusions were observed in 6.9% of patients [40]. Cardiac tamponade was less common, occurring in 0.2% of patients with pericardial effusion, with a higher incidence among those with a history of atrial fibrillation. Patients with SSc might also develop constrictive pericarditis, however it is mainly described in the literature as case reports. Nonetheless, the true prevalence of pericardial involvement among SSc individuals may be higher [41‐43]. Patients with pericardial effusion often present with pulmonary circulatory diseases, PAH, congestive heart failure, and end-stage renal disease. The presence of pericardial effusion and tamponade is associated with increased morbidity and mortality in SSc patients. Persistent pericardial effusion in SSc-PAH patients is linked to poorer survival outcomes [40, 43]. Various diagnostic tools are available to assess pericardial involvement, with echocardiography being a commonly used initial approach, however advancements in imaging modalities have provided additional diagnostic capabilities in recent years [44]. Considering the substantial mortality linked to these conditions, early identification and diagnosis of patients with comorbidities could be crucial in averting the advancement of pericardial effusion or pericardial tamponade. Nonetheless, additional research is required to determine the precise roles of the aforementioned characteristics and to establish diagnostic and treatment guidelines.

Valvular heart disease (VHD) manifests as one of the SSc-associated cardiovascular complications, and its prevalence may be underestimated [45]. Traditionally, it was primarily linked with tricuspid regurgitation secondary to PAH. However, emerging literature suggests a broader spectrum of VHD presentations, encompassing all valves [45, 46]. The pathogenesis of VHD in SSc has not yet been extensively studied, however endocarditis-like changes on the mitral, tricuspid, or aortic valve in autopsy cases have been described [47].

According to a Danish nationwide cohort study, the relative risk of aortic stenosis (AS) is three times higher, aortic regurgitation (AR) four times higher, and mitral regurgitation (MR) five times higher in patients with SSc compared to the general population [30]. Although mild valve dysfunctions are common, particularly in the elderly, two studies focused on moderate and severe dysfunction degree. Kurmann et al. found a fourfold increase in the prevalence of moderate/severe VHD at SSc diagnosis compared to non-SSc patients, with a similar risk of developing moderate/severe VHD after SSc diagnosis. Moreover, SSc patients seemed to develop VHD prematurely [47, 48]. In another study by Narváez et al., the most prevalent moderate or severe valvular dysfunction was MR, observed in 5.2% of patients, followed by AS in 3.5% and AR in 1.7%. The prevalence of moderate to severe mitroaortic valve dysfunction was significantly higher in SSc patients compared to controls [46]. It's noteworthy that systematic echocardiography screening is recommended for SSc patients, which may facilitate early VHD detection. However, further studies are needed to establish this correlation definitively.

For many years, efforts have been made to establish a consensus on the assessment of patients with SSc-pHI. Various algorithms have been developed to help in the detection, monitoring, and treatment of SSc-pHI patients [6, 16]. Among these, the UK Systemic Sclerosis Study Group was the first to offer guidance for physicians [16]. Recently, consensus-based guidelines have emerged, focusing on screening, diagnosis, and follow-up of SSc-pHI, with an emphasis on the role of multidisciplinary teams (MDT), that comprises cardiologists (with necessary subspecialist expertise as indicated) and rheumatologists with SSc expertise, moreover the importance of patient-doctor cooperation has been highlighted. It has been emphasized that both acute and chronic coronary syndromes (ACS and CCS) should be excluded when there is suspicion of SSc-pHI. In the event of their occurrence, they should be treated in accordance with current guidelines [6]. These guidelines facilitate clinicians' approaches to managing SSc-pHI patients and standardize the type and timing of procedures used to prevent or detect cardiac involvement early. Table 1 presents key consensus recommendations for clinical practice [6].

There are numerous diagnostic methods employed in SHI, ranging from laboratory tests, resting ECG, and ambulatory ECG to TTE with TDE, speckle tracking echocardiography (STE) and CMR. These methods are incorporated into various algorithms, encompassing recent screening, diagnosis, and follow-up recommendations [6, 16, 49].

Evaluating the risk of heart complications in patients with autoimmune diseases, such as SSc is essential for identifying individuals at high cardiovascular (CV) risk and applying preventive measures [50]. Various tools, including the Framingham risk score (FRS) and QRISK3, have been utilized for this purpose [51].

The effectiveness of these scales in assessing CV risk in SSc patients was examined, with the study by Battista et al. suggesting that employing the QRISK3 algorithm among SSc patients could offer benefits by identifying individuals at high CV risk early, potentially capturing cases overlooked by conventional assessment scales [51].

Assessing serum biomarkers offers a valuable, non-invasive method for screening SSc patients for cardiac involvement. Literature data suggests that NT-proBNP and high-sensitivity cardiac troponin (hs-Troponin) hold significant diagnostic and monitoring value for SHI, both pHI and secondary [6, 74, 75]. The abovementioned biomarkers could be useful in detecting subclinical cardiac involvement as well as predicting worse survival among SSc patients, exhibiting elevations in both NT-proBNP and hs-Troponin [74, 76]. However, considering hs-Troponin, it is worth mentioning that cardiac troponin I is regarded as specific to myocardial tissue, whereas troponin T (hs-cTnT) has been observed in regenerating skeletal muscle tissue as well [75]. Bosello et al. study noted a higher incidence of impaired systolic function, ECG abnormalities, and worse outcomes in SSc patients with elevated cardiac enzymes (hs-cTnT and NT-proBNP) [74]. Paik et al. similarly found that SSc patients with elevated troponin I face approximately double the risk of death compared to those without [75]. Wang et al. study demonstrated that NT-proBNP and C-reactive protein (CRP) independently predict death in SSc individuals [77]. The role of serum organ-specific anti-heart (AHA) and anti-intercalated disk autoantibodies (AIDA) as markers for autoimmune myocarditis in SHI was recently evaluated in a multicenter study. AHA and AIDA were more prevalent in SSc patients than in controls, with AHA positivity alone linked to their worse survival and increased mortality [78]. Moreover, novel biomarkers like angiopoietin 2 (ANGPT2), osteopontin (OPN), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) appear to be associated with both left ventricular (LV) and right ventricular (RV) dysfunction in SSc [79]. However, despite their potential, anti-heart antibodies and these novel biomarkers have yet to feature in recent screening algorithms due to insufficient data on their clinical utility and limited clinical availability. [78, 80] In addition to typical cardiac biomarkers, CRP, Erythrocyte Sedimentation Rate (ESR), and CK have been proposed for annual assessment in SSc-pHI screening among unselected, stable/asymptomatic patients, serving as a non-specific workup that may indicate underlying cardiac disease [6].

In recent years more data on treatment options among patients with SHI is available and algorithms are evolving. The role of MDT, involving cardiologists, is highlighted. Table 2 summarizes the current approach to the treatment options. It is crucial to note that no randomized controlled trials have been conducted for SHI [81]. Moreover, in the absence of well-defined guidelines, the treatment of cardiac inflammation, fibrosis, and vasculopathy is carried out empirically [82].

Myocardial involvement is common in SSc and worsens the prognosis, being one of the leading causes of death among SSc patients [22]. Its management requires exceptional attention in clinical practice with timely and accurate diagnosis. Recently, comprehensive definition of SSc-pHI has emerged, providing structure to knowledge and advancing understanding of this manifestation. The new consensus on the assessment of SSc-pHI facilitated clinicians in their daily management of this patient subgroup. This visible progress in diagnostic approaches is promising for patient care, however continued research efforts are necessary to elucidate all potential pathogenetic mechanisms and identify biomarkers crucial for targeted treatment strategies. Additionally, the development of specific recommendations for SHI patients, encompassing therapeutic options, is essential to enhance their outcomes.