Primary heart involvement in systemic sclerosis, from conventional to innovative targeted therapeutic strategies

Abstract

Primary heart involvement is frequent in systemic sclerosis, even though often sub-clinical, and includes cardiac abnormalities that are predominantly attributable to systemic sclerosis rather than other causes and/or complications. A timely diagnosis is crucial to promptly start the appropriate therapy and to prevent the potential life-threatening early and late complications. There is little evidence on how to best manage systemic sclerosis-primary heart involvement as no specific treatment recommendations for heart disease are available, and a shared treatment approach is still lacking. The objective of this review is to summarize the state of the art of current literature and the overall management strategies and therapeutic approaches for systemic sclerosis-primary heart involvement. Novel insights into pathogenic mechanisms of systemic sclerosis-primary heart involvement are presented to facilitate the comprehension of therapeutic targets and novel treatment strategies.

Introduction

Systemic sclerosis (SSc) is an immune-mediated multiorgan disease characterized by diffuse vascular damage, aberrant activation of immune system, and fibrosis of the skin and internal organs. ¹ The mortality of SSc is high compared to other rheumatic diseases, and heart involvement is one of the leading causes of SSc-related death. ² Cardiac involvement in SSc occurs in primary and secondary forms. According to a recent definition, primary heart involvement in SSc (SSc-pHI) includes cardiac abnormalities that are predominantly attributable to SSc rather than other causes and/or complications (i.e. interstitial lung disease, pulmonary arterial hypertension, renal involvement, or other non-SSc-specific cardiac condition). SSc-pHI may be sub-clinical and must be confirmed through diagnostic investigations. ³ SSc-pHI is common and, although often asymptomatic, once clinically evident, it is associated with a poor prognosis.^2,4 Therefore, a timely diagnosis is crucial to promptly start the appropriate therapy and to prevent the potential life-threatening early and late complications. SSc-pHI can occur with a broad clinical spectrum, and all cardiac structures may be involved, resulting in pericardial disease, arrhythmias, valve disease, myocardial ischemia, diastolic dysfunction, myocarditis, and heart failure. ⁵ SSc-pHI, chiefly myocarditis and myocardial fibrosis, is increasingly reported,^6–13 likely due to both improved physicians’ awareness and technological advances in noninvasive imaging technologies (i.e. Doppler echocardiography and cardiac magnetic resonance (CMR)). ¹⁴ However, despite the growing interest from the medical community, there is little evidence on how to best manage SSc-pHI as no specific treatment recommendations for heart disease are available ¹⁵ and a shared treatment approach is still lacking. The objective of this narrative review is to summarize the state of the art of current literature and the overall management strategies and therapeutic approaches for SSc-pHI. Novel insights into pathogenic mechanisms of SSc-pHI are preliminarily presented to facilitate the comprehension of therapeutic targets and novel treatment strategies.

Methods

PubMed database was screened from 1964 to November 2021. A combination of Medical Subject Headings (MeSH) terms and keywords pertaining to SSc (“Scleroderma, Systemic” OR “Systemic sclerosis” OR “SSc”), AND cardiology (“primary heart” OR “heart” OR “cardiac” OR “myocardial” OR “myocarditis”) AND “therapy” OR “treatment” were applied to the search strategies. After initial selection based on the title and abstract, selected articles were included for the full-text evaluation, regardless of the article type. Only articles published in English and focusing on SSc-pHI were selected. Review article references were evaluated, and articles were selected according to the title and added to the total references, if not already present.

The pathogenic cascade and novel targets

The pathogenesis of cardiac involvement in SSc is complex and still poorly understood. In fact, several mechanisms are involved (small vessel damage, vasoconstriction and chronic ischemia-reperfusion injury, cardiac inflammation, and fibrosis) and yet their hierarchical role is not elucidated in the pathogenic cascade. ¹⁴ Moreover, despite the fact that myocardial fibrosis traditionally considered the hallmark of SSc heart disease, still some steps in its genesis of cardiac fibrosis are a matter of debate. ¹⁶ The microvascular involvement of epicardial coronaries is frequent, suggesting that myocardial involvement could be related to repeated focal ischemic events due to microcirculation impairment with abnormal vasoreactivity. Repeated ischemia-reperfusion abnormalities may progressively lead first to contraction band necrosis and then to irreversible myocardial fibrosis. ¹⁷ Moreover, using conventional methods, myocardial perfusion impairment has been reported in SSc. ¹⁸ More recently, the role of myocardial inflammation in the pathogenesis of primary SSc heart disease and in the late occurrence of myocardial fibrosis was emphasized, supporting the “inflammation-driven fibrosis” hypothesis that characterizes the disease. ¹⁹ The interleukin 1 (IL-1), an apical pro-inflammatory cytokine, has a cardinal role in both the myocardial inflammation and cardiac dysfunction in several heart diseases. ²⁰ IL-1 is a pivotal cytokine that triggers the inflammatory process, which involves IL-1 itself and downstream mediators, mainly IL-6, that perpetuate heart inflammation and inflammation-driven fibrosis. Both cytokines thus represent a potential therapeutic target that allows to deregulate upstream myocardial inflammation and prevent the development of fibrosis. ²⁰ Most likely, the vascular and the inflammatory hypotheses are closely intertwined. ⁶ Early microvascular injury, such as vasospasm of the small coronary vessels, may be the initial event that leads to ischemia and an activation of the endothelium preceding all pathological changes. Autoimmune and inflammatory responses to the cell damage lead finally to fibroblast activation and their differentiation to myofibroblasts, which are the main source of extracellular matrix protein production leading to myocardial fibrosis.^21,22 Macrophages are increasingly recognized as important players in myocardial fibrosis through interactions with fibroblasts and therefore represent a fascinating therapeutic target in scleroderma heart disease. Macrophages, indeed, are involved in myocardial remodeling and diastolic dysfunction,^23–28 and peripheral blood analysis of SSc patients showed an increased expression of alternatively activated (M2) macrophages. ²⁹ The ischemic, fibrotic, and inflammatory lesions, which develop as a consequence of the aforementioned processes, lead to myocardial remodeling that can result in heart failure and may also affect the conduction system, leading to arrhythmia or, at worst, sudden cardiac death. Inflammatory heart involvement has a central role in the pathogenesis of SSc-pHI and its arrhythmic complications. The high frequency of arrhythmias in SSc patients was historically related to patchy myocardial fibrosis, with subsequent re-entrant circuits by disrupting the normal electrical connectivity of cardiac tissue. ¹⁷ However, an important role in arrhythmogenesis could also be played by the inflammatory burden. ⁹ Thus, in this “bimodal” ischemic-inflammatory pathogenic model, reperfusion products and pro-inflammatory cytokines may jointly orchestrate SSc-HI and provide biologic rationale for targeted therapeutic approaches.

Therapeutic strategies for myocardial inflammation and inflammation-driven fibrosis

Conventional immunosuppression

The SSc-pHI inflammation-driven hypothesis has led to important therapeutic implications. Treatment interventions effectively curbing the acute inflammatory processes at an early stage can prevent late cardiac remodeling and improve patients’ outcome. So far, only few studies have emphasized the crucial importance of treating the underlying inflammatory burden in patients with SSc-pHI, mainly reporting the use of conventional immunosuppressive drugs (steroids, cyclophosphamide, azathioprine, and mycophenolate mofetil (MMF)), rather than targeted treatments. Nonetheless, the mainstay of treatment for SSc-myocarditis, as for myocarditis of other etiologies, remains the symptomatic treatment of heart failure (HF) and of arrhythmias, whereas, in the absence of well-defined guidelines, treatment of cardiac inflammation in SSc is empirically undertaken. ³⁰ The first cases of myocarditis reported in the literature were treated with steroid alone, but with limited therapeutic success. In one report, West et al. ³¹ described three SSc patients with myositis and myocarditis that are treated with 40–100 mg of prednisone daily. However, despite an initial good response to steroids, two developed heart block (one fascicular and one complete). Carette et al. ³² reported a single patient who developed fulminant myocarditis and myositis, which did not respond to either prednisone 60 mg or methylprednisolone 100 mg, but which improved after two 1000 mg pulses of methylprednisolone. In another case, methylprednisolone was used alone in the treatment of acute SSc-myocarditis (1 g intravenously followed by prednisone at 60 mg/day for 1 week, followed by 40 mg/day); however, the patient died from progressive HF. ³³ Kerr and Spiera ³⁴ described six patients with diffuse SSc complicated by myositis and myocarditis. All patients initially received treatment with prednisone for skeletal myositis: the four patients who received high-dose steroids alone as initial therapy died of congestive HF, while the two patients who received azathioprine had preserved left ventricular (LV) function at 7 years and 1 year of follow-up, respectively, thus supporting the central role of myocardial inflammation in SSc-pHI cardiac dysfunction. Similarly, Stack et al. ³⁵ described a case of myocarditis in a rapidly progressive diffuse cutaneous systemic sclerosis (dSSc) treated successfully with pulsed intravenous (IV) cyclophosphamide and methylprednisolone (0.5 mg/kg given for 3 days each month with a maintenance dose of prednisolone 70 mg given once daily between cycles). The steroid dosage was weaned after 3 months to a maintenance dose of prednisolone 20 mg once daily. The treatment strategy consisted of a total of 12 months of pulsed IV cyclophosphamide before reverting to MMF as maintenance therapy. A single case of myocarditis in the setting of SSc was treated with methylprednisolone, cyclophosphamide (IV, six times), and cyclosporine A (50 mg daily) followed by autologous stem cell transplant, with no clinical recurrence after 1 year. ³⁶ Despite the favorable clinical, laboratory, and instrumental response to cyclophosphamide in the treatment of SSc-myocarditis, this drug has a low therapeutic profile and a high toxicity (among which the cardiotoxicity is particularly evident). ³⁷ The TIMIC trial in 2009 changed the therapeutic perspectives in virus negative myocarditis (VNM). This randomized, double-blind, placebo-controlled single-center trial demonstrated that immunosuppression with prednisone (1 mg/kg/day) plus azathioprine (AZA, 2 mg/kg/day) improve patients’ outcome, including 6 months left ventricular ejection fraction (LVEF) and hospitalization rate related to HF. Thus, steroids and azathioprine are now considered the standard first-line therapy to improve heart function in VNM, whether primary or secondary to other rheumatic diseases. ³⁸ Nonetheless, some patients might be intolerant or not responsive to standard first-line immunosuppressive strategy, therefore switching to second-line immunosuppressive agents can be necessary.^6,9,16,39,40 In addition, the concomitant involvement of other organs, such as interstitial lung disease (ILD) or progressive skin fibrosis, requires the addition of a common therapeutic strategy effective on multiple domains. Pieroni et al. ⁶ in their pioneering study treated seven patients with SSc-myocarditis with high-dose IV glucocorticoid (betamethasone 12 mg/day for 3 days, 8 mg/day for 3 days, and 6 mg/day for 3 days), followed by oral steroids (prednisone 0.5 mg/kg/day, gradually tapered to 5 mg/day, decreasing by 5 mg every 10 days). Of these seven patients, four received cyclophosphamide (2 mg/kg/day up to a cumulative dose of 6 g) then followed by azathioprine, while three patients were treated immediately with azathioprine (2 mg/kg/day) for 12 months. Patients who received cyclophosphamide as induction therapy simultaneously had a diffuse skin involvement or evidence of ILD. At 12-month follow-up, all patients showed a significant clinical and laboratory improvement, although only one patient experienced complete recovery of contractile function. Immunosuppressive was shown to be more effective in patients with lower degrees of fibrosis, suggesting that early introduction is crucial for positively impacting on SSc-pHI. A recent study demonstrated the efficacy of MMF used both as first-line agent, in patients with systemic rheumatic disease, such as SSc, and second-line therapy in those with isolated lymphocytic VNM intolerant or resistant to azathioprine, regardless of steroid dosage. ³⁹ MMF is largely used in the management of SSc and represents a beneficial option therapeutic also to curb myocardial inflammation in SSc-pHI. A tremendous body of evidence supports the efficacy of MMF in myocarditis; however, data on SSc-myocarditis are still limited to case series and observational studies^7,9,16,39,40 (Table 1). Prospective randomized controlled trials are needed to confirm its efficacy in this clinical scenario.

Table 1.

Therapeutic strategies for SSc-myocarditis.

Drug	Type of study	No. of patients	Diagnosis	Results
Cyclophosphamide	Case report, 35 2009	1	Myocarditis (clinical) in SSc	Resolution of symptoms, normalization of cardiac enzyme, and improvement of LV function.
	Observational cohort study, 6 2014	7 (4 treated with cyclophosphamide)	EMB-proven myocarditis in SSc	At 12-month follow-up significant clinical and laboratory improvement.
Azathioprine	Observational cohort study, 6 2014	7 (3 treated immediately with AZA)	EMB-proven myocarditis in SSc	At 12-month follow-up significant clinical and laboratory improvement.
	Observational cohort study, 16 2020	12 (7 received AZA)	EMB-proven myocarditis in SSc	–
	Case reports9,30	2	Myocarditis (clinical) in SSc	Clinical and hemodynamic status improvement, normalization of cardiac enzyme.
Mycophenolate	Prospective cohort study, 39 2020	2	EMB-proven myocarditis in SSc	6 months improvement of clinical status, LVEF on echocardiography, LV volumes, and wall motion abnormalities.
	Case reports7,9	2	EMB-proven myocarditis in SSc	Clinical and biochemical improvement.
	Case series, 40 2019	4 (3 patients treated with MMF and 1 patient was started on azathioprine)	Myocarditis in SSc	Two patients were achieved an optimal disease control.
	Observational cohort study, 16 2020	12 (5 received MMF)	EMB-proven myocarditis in SSc
Rituximab	Case series, 40 2019	4 (only 1 patient treated with RTX as rescue therapy)	Myocarditis (clinical) in SSc	Only partial benefit.
Tocilizumab	Case series 41	1	CMR	Normalization of cardiac biomarkers and complete reversal of cardiac inflammation on CMR.

SSc: systemic sclerosis; EMB: endomyocardial biopsy; AZA: azathioprine; LVEF: left ventricular ejection fraction; LV: left ventricle; MMF: mycophenolate mofetil; RTX: rituximab; CMR: cardiac magnetic resonance.

Targeted anti-cytokine therapy

IL-1

Recent experimental and clinical data support the pivotal role of IL-1 and inflammasome activation in heart inflammation and cardiac dysfunction in several heart diseases (including SSc), and its potential role in inflammation-driven heart fibrosis.^19,20

Moreover, IL-1 directly causes impaired contractile function by inducing multiple downstream events, including uncoupling of the b-adrenergic receptor from the adenylyl cyclase, inhibition of L-type calcium channels. ²⁰

Despite extensive experimental evidence pointing at a central role for IL-1 in the pathogenesis of heart inflammation, systolic dysfunction, and fibrosis, the use of available IL-1 blocking agents in SSc has only anecdotally been reported. ¹⁹

Rilonacept, a fusion protein consisting of the human IL-1 receptor (IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP) which binds and neutralizes both IL-1a and IL-1b, was evaluated in single phase I/II randomized, double-blind, placebo-controlled trial on 19 SSc patients. Both the primary and the secondary endpoints were not met, as no changes in gene expression or in the modified Rodnan skin score (mRSS) between treated and placebo patients were observed after 6 weeks. ⁴² However, this trial had several limitations, including the small sample size and the short duration of therapy, even more important in the context of a chronic fibrotic disease. Moreover, no exploratory secondary endpoints to evaluate SSc-pHI were considered.

It is important to note that recent evidences support IL-1 therapeutic blockade in HF and myocarditis. Indeed, in patients with myocardial inflammation and HF, a short-term treatment regimen (14 days) with anakinra improved exercise capability, as determined by oxygen consumption (VO₂).^43,44 Prolonged administration (12 weeks) reduced hospitalizations and further improved VO₂, NT-proBNP, and the quality of life in a randomized clinical trial (RCT). ⁴⁵ Similarly, treatment with the anti–IL-1β monoclonal-antibody canakinumab significantly reduced cardiovascular events in 10,061 patients with previous myocardial infarction and C-reactive protein > 2 mg/L in the CANTOS trial. ⁴⁶ Moreover, our group has recently described the dramatic clinical improvement after IL-1 suppression with anakinra in a patient with dilated cardiomyopathy. Improvement began soon after anakinra administration with the reduction of the arrhythmic outburst, decrease in cardiac biomarkers, and normalized echocardiography and CMR imaging—including those that measured LVEF. ⁴⁷ Anakinra treatment was also beneficial in patients with fulminant myocarditis.^48–51 Taken together, these observations suggest that IL-1 inhibition could be effective in curbing heart inflammation while ameliorating myocardial contractility. Thus, IL-1 inhibition may reduce disease progression and fibrotic evolution in patients with myocarditis and other inflammatory cardiomyopathies (Figure 1).

Figure 1.

The pathogenic cascade and novel therapeutic targets for systemic sclerosis primary heart involvement. Heart inflammation, together with endothelial dysfunction and microvascular damage, results in myocardial injury. As a consequence, IL-1α and other inflammatory mediators are released from dying myocardiocytes; these in turn activate a molecular complex known as the “inflammasome” inside macrophages which processes and releases active IL-1β. Once induced, inflammation escalates into a redundant process, involving T and B lymphocytes, neutrophils and macrophages; hence, other pro-inflammatory cytokines, mainly IL-6, are produced and they perpetuate heart inflammation and inflammation-driven fibrosis. IL-1 and IL-6 also promote Th17 differentiation, and in post-myocarditis, the role of IL-17A emerged in cardiac remodeling, thus contributing to both myocardial fibrosis and progression to dilated cardiomyopathy. IL-1 and other pro-inflammatory and pro-fibrotic mediators also stimulate fibroblast to myofibroblast differentiation and collagen production, thus leading to myocardial fibrosis. Here are represented the novel targets and the therapeutic options to treat the multiple pathogenic events involved in the mechanisms of SSc primary heart disease.

Considering its unprecedented safety profile, mainly due to short half-life, IL-1 inhibition with anakinra, even in combination with MMF or other conventional immunosuppressants, may be a fascinating therapeutic strategy in SSc-myocarditis.

IL-6

Once induced, inflammation escalates into a redundant process; hence, other pro-inflammatory cytokines may also play a key role in heart inflammation and inflammation-driven fibrosis (Figure 1). The IL-1 biological activity sustains an inflammatory process which involves IL-1 itself and downstream mediators. IL-6 is induced by IL-1 and acts as a downstream mediator of several inflammatory effects. ¹⁹ It is thereby not surprising that IL-6 concentrations are elevated in the serum and myocardium of patients with HF and myocarditis, while also being predictive of adverse outcomes. ⁵² In myocarditis, the primary sources of IL-6 are likely cardiomyocytes and cardiac fibroblasts.^41,53 Overexpression of IL-6 in experimental animals subjected to viral myocarditis results in extensive myocardial inflammation, whereas IL-6 inhibition with tocilizumab (TCZ) reduced heart inflammation and infiltration with CD3+ T cells and CD68+ macrophages. ⁵⁴

Recently, TCZ was used to effectively treat SSc-related myocarditis, and improvement of myocardial inflammation was revealed as a reduction in myocardial edema at CMR, and by the improvement of cardiac function, clinical status, and cardiac enzymes.^41,54

Moreover, IL-6 plays a major role in heart fibrosis induced by Ang-II, through TGF-b/Smad activation. Consistently, IL-6 deficiency reduces cardiac inflammation, and contractile dysfunction and interstitial fibrosis, without affecting blood pressure in Ang-II-high salt-induced hypertension in IL-6 knockout (IL-6^−/−) mice. ⁵⁵ Furthermore, deletion of IL-6 alleviates interstitial fibrosis also in experimental diabetic cardiomyopathy in IL-6^−/− mice. ⁵⁶ The deletion or inhibition of miR155 yielded the same protective effects,^57,58 and recent studies revealed that the soluble IL-6 receptor (IL6R) is a target of miR155. ⁵⁹ In summary, these studies delineate a miR-155/IL-1/IL-6 loop sustaining inflammation-driven fibrosis: overexpression of miR-155 in SSc fibroblasts induces inflammasome-mediated release of IL-1b, which in turn stimulates IL-6 production and collagen synthesis during fibrosis.

An IL-6-rich inflammatory milieu, as expected in patients affected by SSc, ¹ could also negatively affect heart function and feed a detrimental inflammatory cycle. In this context, selective cytokine inhibition represents an intriguing therapeutic opportunity in SSc-pHI. Although larger studies are warranted to confirm these preliminary data, IL-6 inhibition may be considered in the portfolio of therapeutic options to treat SSc-pHI, even considering its efficacy in SSc-ILD.

IL-17

Another important signaling axis which potentially contributes to inflammation and fibrosis in SSc is the IL-1/IL-17 axis (Figure 1). Many inflammatory cytokines that are involved in the SSc pathogenesis, (i.e. IL-1, IL-6, and TGF-b), also promote Th17 differentiation. This strongly suggests their potential role in skewing CD4+ T cells toward Th17 differentiation in SSc. ¹⁹ A recent in vivo study showed that IL-17 is involved in fibrosis and inflammation in bleomycin (BLM)-induced SSc. The authors also used another murine model of SSc, chronic graft-versus-host disease (cGVHD), to show that blocking IL-17 activity was able to attenuate disease severity. IL-1 and IL-17 synergically induce the expression of pro-fibrotic and inflammatory mediators, both in human and murine dermal fibroblasts. Subsequent animal studies in vivo confirmed the anti-fibrotic and anti-inflammatory potential of IL-1Ra. ⁶⁰ Hence, IL-17 inhibition, either directly or by blocking IL-1, has therapeutic rationale for tissue inflammation-driven fibrosis in SSc.

Therapeutic strategies for myocardial fibrosis

At present, there is no therapy specifically designed to target myocardial fibrosis.

Nintedanib, an anti-fibrotic drug, has recently been approved for use in the treatment of SSc-ILD. ⁶¹ Nintedanib is a potent tyrosine kinase inhibitor (TK-i) that primarily targets receptor tyrosine kinases (RTKs), such as vascular endothelial growth factor receptor (VEGFR)-1-2-3, platelet-derived growth factor receptor (PDGFR) α and β, and fibroblast growth factor receptor (FGFR)-1-2-3. Pre-clinical studies have demonstrated that nintedanib has anti-fibrotic effects in disease models of different organs, including the lung, liver, skin, and kidney.^61–64 Given the common background underlying fibrotic changes in SSc, it is conceivable that nintedanib could also prevent the adverse fibrotic remodeling implicated in heart disease involvement. ⁶⁵ Based on this notion, nintedanib might fit in a proof-of-concept rationale for anti-fibrotic therapeutic strategy in SSc-pHI. Besides, considering that myocardial fibrosis is often, at least partially, the outcome of an inflammatory process, early immunosuppressive treatment introduction might be necessary to stop the inflammatory pathways leading to irreversible fibrosis. In a recent study, nintedanib showed to inhibit macrophage activation and to ameliorate both vascular and fibrotic manifestations in the Fra2 mouse model of SSc. ⁶⁶ The anti-fibrotic effects of nintedanib were associated with impaired M2 polarization of monocytes and reduced numbers of M2 macrophages. ⁶⁶ Based on the notion that SSc patients show increased peripheral blood expression of M2 macrophages, ²⁹ and given the cardinal role of macrophages in pathogenic mechanisms of myocardial remodeling and HF,^23–28 nintedanib may therefore represent a fascinating therapeutic option to curb the inflammation-driven fibrosis in SSc heart disease.

Furthermore, one case report emphasized the role of TCZ, an IgG1 subclass humanized anti-human IL-6 receptor antibody, in improving myocardial fibrosis in SSc. ⁶⁷ The use of TCZ in SSc has been recently investigated in a randomized double-blind study in which TCZ was shown to significantly reduce the rate of lung deterioration in SSc patients. ⁶⁸ Moreover, these patients had a lower incidence of adverse effects related to cardiac lesions; seven serious cardiac events were reported in 6 (5.7%) of 106 participants in the placebo group compared with two serious adverse events in 2 (1.8%) of 104 participants in the TCZ group. ⁶⁸ Based on these preliminary results and the aforementioned biologic rationale, TCZ represents a fascinating therapeutic strategy for SSc-pHI. Combining anti-cytokine agents with conventional immunosuppressants and anti-fibrotic agents as nintedanib could be a potential therapeutic strategy in the near future. The safety profile of such a combination therapy needs to be confirmed in real-life scenarios.

Hematopoietic stem cell transplantation

Finally, despite severe cardiac involvement is generally considered a contraindication for hematopoietic stem cell transplantation, there are case reports of the beneficial effects of this procedure for the treatment of SSc-related myocarditis and pSHI, ³⁶ in particular with the use of less cardiotoxic protocols. ⁶⁹

Therapeutic strategies for vasculopathy

Endothelial dysfunction and vascular abnormalities are thought to be early pathogenic events in SSc ¹ (Figure 1). Historically, scleroderma heart disease has been considered the results of ischemia-reperfusion damage following intermittent vasospasm (the so-called “cardiac Raynaud’s phenomenon”). ¹⁷ Apart from ischemia-reperfusion damage, vascular damage represents a central pathogenic event in SSc heart disease and myocardial dysfunction.^17,18 Based on this notion, vasodilators may therefore be potentially useful in the treatment of cardiac dysfunction in patients with SSc. One study analyzed the effect of captopril therapy, showing a statistical difference in ventricular function and an improvement of markers of diastolic function with captopril use. ⁷⁰ Another study demonstrated that regional contractility and diastolic function improved in patient treated with nifedipine. ⁷¹

Data from EUSTAR cohort showed that a reduced use of calcium-channel blockers could be associated with a greater occurrence of LV systolic dysfunction. ⁷²

In the DeSScipher study, Valentini et al. ⁷³ evaluated the impact of aspirin and vasodilator therapy on SSc-pHI. Vasodilator therapy was associated with lower incidence of ventricular arrhythmias on multivariate analysis. In addition, low-dose aspirin was associated with lower incidence of Q waves, conduction blocks, and/or pacemaker implantation in univariate and multivariate analysis.

However, the occurrence of SSc-pHI despite the fact that the vast majority of SSc patients is routinely treated with calcium-channel blockers and/or other vasodilator, indirectly suggest that vascular damage is not the solely event implicated in SSc heart disease. The preventive or therapeutic role of aspirin in myocardial inflammation and fibrosis, moreover, needs to be further elucidated. Indeed, aspirin could negatively impact on SSc-related gastro-intestinal manifestations, and its usefulness in SSc should therefore be carefully evaluated.

Conventional cardiologic therapy and anti-arrhythmic drugs

Conventional cardiologic therapy of SSc-pHI is based on the treatment of HF and arrhythmias.^74,75 Likewise, a close monitoring of heart disease with traditional and novel techniques, including echocardiography with tissue Doppler imaging and speckle-tracking,^76–79 CMR with mapping techniques, ⁸⁰ and 24-h-ECG Holter monitoring,^8,76,81 is of cardinal importance.

Myocardial fibrosis is often the cause of diastolic dysfunction which is one of the first markers of SSc-pHI. ⁷⁶ There are limited evidences on the therapeutic options for the management of diastolic dysfunction or myocardial fibrosis in SSc. As in other forms of diastolic dysfunction, afterload reduction can be helpful to improve cardiac function.^70,76

In SSc, systolic dysfunction is less common than diastolic dysfunction and it is more frequently the result of myocarditis rather than myocardial fibrosis. The standard therapy for systolic dysfunction includes diuretics, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and calcium-channel blockers.^74,76 Arrhythmias are frequent in SSc and portend a bad prognosis, accounting alone for 6% of total deaths.^2,76,81 It is therefore important to identify patients at high risk for arrhythmias with a complete cardiologic assessment. No RCT has been performed specifically in SSc patients; therefore, the choice of therapy should be comparable to that of patients without SSc. ⁸¹ It is important to consider the negative effect of β-blockers on Raynaud’s phenomenon (RP). However, a recent study demonstrated that metoprolol, when co-administered with calcium-channel blockers, reduces the symptoms in SSc suffering from RP. ⁸²

Prevention of life-threatening arrhythmias and sudden cardiac death is a major goal in SSc. To support this important issue, in a recent study, it was shown that the use of an implantable cardioverter defibrillator (ICD) in high-risk SSc patients was effective in reverting several episodes of ventricular tachycardia (VT) in 3 out of 10 implanted patients. ⁸³ Another study reported the efficacy of catheter ablation in a SSc patient with VT originating from right ventricular scar, suggesting that ablation could be a potential therapeutic strategy for treating ventricular arrhythmias. ⁸⁴ These studies, together with others,^8,13 underlie again the prognostic importance of Holter abnormalities (and electrophysiology studies in selected cases) and the clinical significance of primary prevention of sudden death in selected SSc populations.

The recent Scleroderma Arrhythmia Clinical Utility Study (SAnCtUS) study demonstrated that T2 ratio and percent of late gadolinium enhancement (LGE) at CMR have the greatest utility as independent predictors of rhythm disturbances at 24-h-ECG Holter in SSc patients. ⁸⁵ CMR can thus potentially translate Holter findings to distinguishable structural myocardial abnormalities functioning as arrhythmogenic foci, and represents a useful tool to risk stratify the SSc patients with arrhythmic burden.

Conclusion

Primary heart involvement is common in SSc and associated with a poor prognosis. A timely diagnosis is therefore crucial. Ischemic, inflammatory, and fibrotic pathogenic events all represent therapeutic targets. Novel insights into pathogenic mechanisms of SSc-pHI, together with specific recommendations, including management strategies and therapeutic approaches for SSc-pHI, are the key to improve patients’ outcomes.