Cardiac manifestations of systemic sclerosis (scleroderma)

INTRODUCTION — Cardiac involvement is common in systemic sclerosis (SSc) and is often unrecognized until late in the disease course. The myocardium, pericardium, and conduction system can all be affected. Cardiac manifestations in SSc are variable and can be primary (due to the fibrotic and vascular process or inherent cardiomyocyte abnormalities) or secondary (due to pulmonary arterial hypertension [PAH], interstitial lung disease, cardiac inflammation, or scleroderma renal crisis). Certain medications (eg, cyclophosphamide) used to treat SSc can result in cardiac toxicity.

This topic will focus on the pathogenesis, epidemiology, clinical manifestations, diagnosis/screening, and management of cardiac involvement in SSc. Other clinical manifestations of SSc are described in detail separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

EPIDEMIOLOGY, ETIOLOGY AND PATHOGENESIS — Cardiac involvement is clinically overt in approximately 10 to 30 percent of patients with systemic sclerosis (SSc) [1-3]. Subclinical cardiac involvement, however, has been estimated at >70 percent, depending greatly on clinical suspicion and choice of screening and diagnostic tools utilized for its detection [4]. While primary cardiac involvement can occur in both limited and diffuse cutaneous forms of SSc, manifestations are more severe in those with diffuse disease [5]. There is an elevated risk of cardiac involvement in patients with SSc with rapidly progressing skin disease [6], anti-U3-RNP antibody positivity [7,8], and concomitant skeletal myopathies [9].

The pathogenesis of SSc cardiac involvement involves recurrent coronary microvascular ischemia and myocardial inflammation leading to ischemic necrosis, reperfusion damage, and myocardial fibrosis (figure 1). Pathologic changes in small coronary arteries and arterioles of the subendocardium predispose the myocardium to ischemia-reperfusion injury, which causes apoptosis of the cardiomyocytes and replacement fibrosis [4,10,11]. Myocardial perfusion defects inducible by exposure to cold or during exercise may represent cardiac Raynaud phenomenon [12] due to impairment in coronary flow reserve [13,14]. This has been demonstrated by single photon emission computed tomography (SPECT) imaging [13], cardiac magnetic resonance (CMR) [15-18], and positron emission tomography (PET) imaging [19]. However, a causal relationship between impaired coronary flow reserve and myocardial fibrosis has not been established.

Adverse myocardial remodeling and fibrosis lead to increased stiffness and diminished compliance of the heart chambers. Clinically, this manifests as left ventricular (LV) diastolic dysfunction, which is highly prevalent in SSc and is associated with increased mortality [4,20-22]. In addition to coronary microvascular dysfunction and fibrosis, low-grade chronic inflammation can contribute to myocardial dysfunction in SSc. Acute or subacute myocarditis may also occur and, when severe, can be associated with skeletal muscle myositis [2,3,9,23], representing a high-risk disease subset with an SSc and polymyositis overlap syndrome. (See "Neuromuscular manifestations of systemic sclerosis (scleroderma)", section on 'Myopathy'.)

Coronary microvascular dysfunction in SSc leads to focal ischemia and injury mediated via transforming growth factor beta 1, reactive oxygen species, and inflammatory mediators [3]. Inflammation of the myocardium results in fibrosis leading to diastolic and/or systolic dysfunction [4].

Myocardial inflammation significantly contributes to systolic dysfunction in SSc [24]. While endomyocardial biopsy frequently reveals focal replacement fibrosis, CMR studies have demonstrated diffuse subendocardial interstitial fibrosis following a noncoronary distribution [25,26], similar to patterns seen in other inflammatory and infiltrative cardiomyopathies [27]. Myocarditis may occur in patients with SSc with myositis [9,23] and is a significant risk factor for developing LV systolic dysfunction. In one study, patients with SSc with myocarditis had shorter disease duration, cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA)/antiproteinase 3 (PR3) antibody positivity, and concomitant skeletal myositis [24].

SCREENING FOR CARDIAC INVOLVEMENT — Given the high morbidity and mortality of cardiac involvement in systemic sclerosis (SSc), screening for cardiac involvement is essential for early detection. Unlike the guidelines for screening and detecting pulmonary arterial hypertension (PAH) in SSc [28-30], there are limited data to guide the screening recommendations for primary cardiac involvement.

Our screening approach — Given the high prevalence of subclinical cardiac disease in SSc, we suggest initial baseline cardiac screening in all patients with SSc. Our approach to initial baseline screening and ongoing annual screening for patients with SSc for cardiac involvement, which is generally consistent with guidelines developed by professional organizations, is as follows [31,32]:

●Focused history and physical examination.

●12-lead electrocardiogram (ECG).

●Transthoracic echocardiogram (including 2D, Doppler, and tissue Doppler imaging).

●Laboratory testing, including determination of autoantibodies and measurement of natriuretic peptide levels (ie, plasma brain natriuretic peptide [BNP] or N-terminal of the prohormone BNP [NT-proBNP]) and cardiac troponin.

●Additional cardiac testing, which includes ECG monitoring, stress testing, cardiac magnetic resonance (CMR), or cardiac catheterization, should typically be guided by symptoms or other evidence of cardiac involvement.

●Referral to a cardiologist is appropriate if the initial or serial diagnostic evaluations are abnormal or patients have signs or symptoms concerning for cardiac involvement.

Patients with SSc who are at increased risk for cardiac involvement include those with diffuse cutaneous disease, male sex, and/or those with concerning signs such as a drop in diffusing capacity of the lungs for carbon monoxide (DLCO), dyspnea on exertion, or evidence of congestive heart failure. Note that although a reduction in DLCO is often attributable to primary lung disease, it can also be due to heart failure. Patients with any of these signs should have closer monitoring in conjunction with a cardiologist, with whom additional diagnostic testing can be discussed when appropriate.

History and physical examination — A comprehensive cardiac-focused history should include questions related to heart failure, coronary artery disease, and arrhythmias. Similarly, a cardiac-focused physical examination should assess for findings suggestive of cardiovascular involvement in SSc.

●Heart failure symptoms may include dyspnea at rest or with exertion, orthopnea, paroxysmal nocturnal dyspnea, decreased exercise tolerance, fatigue, and weight gain. Patients should be classified based on New York Heart Association classification (table 1) [2,33].

●Heart failure signs typically include evidence of volume overload (pulmonary congestion with rales/crackles, leg edema, elevated jugular venous pressure, ascites, etc); variable cardiac murmurs (especially systolic murmurs from mitral and/or tricuspid regurgitation) may be heard.

●Coronary artery disease (including coronary microvascular dysfunction) symptoms may include angina (substernal chest discomfort with or without dyspnea associated with exercise or other stressors) and/or decreased exercise tolerance.

●Arrhythmia symptoms may include palpitations, presyncope, syncope, and, in some cases, symptoms of heart failure. Patients with an ongoing arrhythmia may have irregular pulse/heart sounds and be either tachycardic or bradycardic.

Laboratory studies and testing — Baseline and annual screening should include ECG, echocardiogram, and measurement of autoantibodies and circulating levels of natriuretic peptide (ie, plasma BNP or NT-proBNP) and cardiac troponin regardless of symptoms. Additional cardiac testing is typically guided by signs and symptoms or other evidence of cardiac involvement. SSc-specific antibodies obtained during the initial diagnostic workup for SSc may inform the need for closer cardiac monitoring depending on the specific autoantibody profile and other associated risks.

●Electrocardiography – We perform an annual 12-lead ECG in patients with SSc, regardless of symptoms, to screen for conduction system abnormalities. Patients with palpitations or conduction abnormalities on 12-lead ECG require further evaluation, including Holter monitoring. (See "Arrhythmia management for the primary care clinician", section on 'Approach to the patient' and "Etiology of atrioventricular block".)

●Echocardiography – Echocardiography (including 2D, Doppler, and tissue Doppler imaging) is the mainstay in the evaluation for cardiac involvement in SSc, providing crucial information on left ventricular (LV) and right ventricular (RV) size and systolic function, diastolic function, valvular disease, and pericardial disease as well as noninvasive estimates of hemodynamics. Our practice is to perform annual echocardiograms in all patients with SSc to evaluate for emerging cardiopulmonary complications, including pulmonary hypertension (PH) across classifications (eg, Group 1 versus Group 2 versus Group 3 PH). Echocardiography may also distinguish pre-capillary from post-capillary etiologies of PH in SSc. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Echocardiography'.)

●Brain natriuretic peptides – Compared with the general population, levels of BNP >60 pg/mL or NT-proBNP >125 pg/mL signify possible cardiovascular involvement in the patient with SSc [31]. Elevated BNP, however, should be taken in the clinical context and associated with other correlating signs and symptoms of congestive heart failure. Notably, a significant change (ie, increase) in BNP or NT-proBNP from baseline should be considered highly suspicious for underlying cardiac involvement or PAH. (See "Natriuretic peptide measurement in heart failure" and "Natriuretic peptide measurement in non-heart failure settings".)

While BNP and NT-proBNP have lower thresholds for clinical significance in SSc and are known to be disproportionately elevated in SSc-PAH [34], elevated levels of these biomarkers are nonspecific, also increasing in LV systolic dysfunction, LV diastolic dysfunction, and myocardial ischemia [35,36]. In one study, NT-proBNP levels were higher in patients with SSc over 3.5 years of follow-up when compared with age- and sex-matched healthy controls, regardless of other cardiac risk factors and/or the presence of PAH [37]. Long-term survival was worse in patients with an increase of both NT-proBNP and troponin, diffuse subtype, abnormal skin score, diminished LV systolic function, and right bundle branch block (RBBB) on ECG, a known independent predictor of mortality in SSc [38].

●Cardiac troponin – Cardiac troponin T (cTnT) is a sensitive and specific biomarker for cardiac injury; however, it may be nonspecific in patients with concomitant chronic kidney disease (CKD) where troponin clearance is reduced. When elevated in patients with SSc, primary myocardial damage, inflammation, and/or direct cardiac involvement should be suspected [24,35,37,39,40]. cTnT may be a useful clinical tool to detect subclinical cardiac involvement in SSc and, when seen in conjunction with elevated NT-proBNP, LV systolic dysfunction, RBBB by ECG, and in patients with diffuse cutaneous involvement, should prompt thorough evaluation for myocardial disease [31,35,37,39]. Troponin elevation is independently associated with mortality in SSc [41]. Overlap skeletal myositis and inflammatory myocarditis should also be considered with further assessment by CMR [42]. (See "Troponin testing: Clinical use".)

●SSc-specific antibodies – While there are no autoantibodies specific for cardiac involvement in SSc, some autoantibodies are associated with a higher risk for cardiopulmonary complications, and their identification may warrant closer monitoring for cardiac involvement. Autoantibodies in SSc are the strongest predictor of clinical outcomes [7]. Anticentromere antibodies, commonly seen in patients with the limited cutaneous form of SSc, are associated with an increased risk for PAH. Antibodies to topoisomerase I and RNA polymerase III may be related to an increased risk of myocardial involvement. Antibodies to PM-Scl may be associated with myocarditis and antibodies to U1-RNP may be associated with pericarditis. Importantly, autoantibody profiles in SSc remain stable over time, are mutually exclusive, do not vary with disease activity, unlike inflammatory biomarkers, and are associated with distinct clinical phenotypes. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Laboratory testing' and "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Laboratory findings'.)

CARDIAC MANIFESTATIONS — The spectrum of clinical cardiac manifestations in systemic sclerosis (SSc), shown in the figure (figure 1), includes vascular disease, conduction disease/arrhythmia, pericardial disease, and myocardial disease. The optimal evaluation and management of cardiac involvement in patients with SSc requires an integrated multidisciplinary approach involving rheumatologists, pulmonologists, and cardiologists.

Microvascular coronary artery disease — Vascular involvement in SSc predominately affects the small arteries and arterioles rather than major epicardial arteries [4]. The prevalence of coronary microvascular dysfunction in SSc is unknown and associated with Raynaud phenomenon activity [43]. Coronary arteriolar vasospasm and coronary microvascular dysfunction are likely more prevalent than previously recognized and may represent an early preclinical phase of myocardial involvement. Microvascular dysfunction underlies fibrosis commonly seen on autopsy studies of patients with SSc (figure 1) [4,44]. (See "Microvascular angina: Angina pectoris with normal coronary arteries".)

By contrast, the frequency of large-vessel atherosclerotic coronary disease in SSc appears similar to that of the general population and related to traditional risk factors such as diabetes, hypertension, and hyperlipidemia [11]. (See "Overview of established risk factors for cardiovascular disease".)

Clinical manifestations — Some patients with SSc experience anginal-type chest pain (ie, substernal chest discomfort triggered by exercise or another stressor such as exposure to cold) in the absence of macrovascular obstructive disease due to pathologic changes in small coronary arteries and arterioles. However, there is likely a preclinical asymptomatic phase of coronary microvascular dysfunction [11,12,45]. For example, a small observational study demonstrated that impaired coronary flow reserve was more common in asymptomatic patients with SSc than in healthy controls [11]. Another study utilizing radionuclide myocardial perfusion imaging showed that regardless of symptoms, 60 percent of patients with SSc with both limited and diffuse cutaneous subtypes showed reversible myocardial perfusion defects [14].

Anginal symptoms are associated with a higher incidence of fixed or reversible defects on radionuclide myocardial perfusion imaging [46]. (See 'Diagnostic evaluation' below.)

Diagnostic evaluation — Patients with symptoms suggestive of myocardial ischemia should be evaluated for coronary artery disease. In patients with high-pretest probability for coronary artery disease, a referral to cardiology is indicated and may result in symptom-limited stress testing, typically with cardiac imaging, as exercise is generally the preferred form of stress for patients who can exercise and achieve an adequate cardiac workload and heart rate. Pharmacologic stress testing is typically performed when a patient is unable to exercise. The choice of concurrent imaging (eg, radionuclide myocardial perfusion or echocardiographic imaging) will vary depending on local availability and expertise.

The evaluation of patients with chest pain of suspected cardiac etiology, as well as our approach to selecting the optimal diagnostic modality, are discussed in detail separately. (See "Approach to the patient with suspected angina pectoris" and "Stress testing for the diagnosis of obstructive coronary heart disease" and "Selecting the optimal cardiac stress test".)

Treatment — There are no SSc-specific therapies for the treatment of microvascular angina. Similar to the general population of patients with coronary artery disease, patients with SSc should be optimized for anti-anginal treatment, which may include calcium channel blockers, nitrates, statins, and aspirin. (See "Chronic coronary syndrome: Overview of care", section on 'Antianginal therapy'.)

Although beta blockers are frequently used for microvascular angina, in patients with SSc, beta blockers potentially exacerbate Raynaud’s phenomenon due to unopposed alpha-receptor activity. Carvedilol (a nonselective beta blocker with alpha blockade and dihydropyridine calcium channel blocker properties) might be used in patients with SSc-associated cardiac involvement and is generally well tolerated, even in combination with long-acting dihydropyridines. Limitations with both medications are related to bradycardia, significant conduction abnormalities, and/or low blood pressure.

Long-acting dihydropyridine calcium channel blockers might be used as anti-anginal therapy in patients with SSc, partly because of their additional benefit for treating Raynaud phenomenon. There are limited data regarding the use of calcium channel blockers for managing microvascular angina in patients with SSc, and the rationale for their use is primarily based on clinical experience and extrapolation from experience for vasospastic angina and microvascular angina. A large cohort study with 601 unselected patients with SSc found that using vasodilator therapy or low-dose acetylsalicylic acid was associated with a lower incidence of cardiac events at follow-up [47]. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Calcium channel blocker' and "Vasospastic angina", section on 'Initial therapy' and "Microvascular angina: Angina pectoris with normal coronary arteries", section on 'Management' and "Microvascular angina: Angina pectoris with normal coronary arteries", section on 'Initial therapy for rest or mixed angina'.)

Conduction defects and tachyarrhythmias — Estimates of conduction defects in SSc range from 4 to 51 percent depending on whether resting electrocardiogram (ECG) or 24-hour ambulatory ECG monitoring is used [48]. Conduction system disease, such as bundle branch blocks (BBB) and/or atrioventricular (AV) blocks, is likely due to fibrosis of the conduction system from recurrent microvascular ischemic insult and autonomic dysfunction [39,48].

Symptomatic supraventricular tachyarrhythmias tend to be more common than bradyarrhythmias [2,3,48]. Ventricular arrhythmias are less common but are associated with an increased risk of sudden death and mortality, especially when concurrent with skeletal myopathies and systolic dysfunction [2,49].

Clinical manifestations — The clinical presentation of patients with conduction defects or tachyarrhythmias can vary significantly depending upon the resulting bradycardia or tachycardia and the impact on hemodynamic status. However, most patients are generally asymptomatic or develop relatively mild symptoms.

●Conduction defects – Ambulatory ECG monitoring (for 24 hours or longer) should be performed in symptomatic patients with a nondiagnostic 12-lead ECG, as this allows for longer-term assessment of average heart rates at rest and while active and will be more sensitive in detecting conduction defects and arrhythmia [48,50,51]. Patients with severe conduction system disease (eg, Mobitz type II second-degree AV block or third-degree [complete] AV block) are usually symptomatic with presyncope or syncope, exercise intolerance, and/or generalized fatigue. (See "Second-degree atrioventricular block: Mobitz type II" and "Third-degree (complete) atrioventricular block".)

●Tachyarrhythmias – Patients with tachyarrhythmias may present with palpitations or, more frequently, asymptomatic, presenting with nonspecific symptoms such as dyspnea on exertion, generalized fatigue, or exercise intolerance. On rare occasions, patients may present with sudden cardiac arrest due to sustained ventricular tachyarrhythmia.

Diagnostic evaluation — All patients with suspected conduction system disease or a tachyarrhythmia should have a resting 12-lead ECG. Additional evaluation will vary depending on the ECG findings and underlying symptoms (if any).

●Conduction defects – Ambulatory ECG monitoring (for 24 hours or longer) should be performed in symptomatic patients with a nondiagnostic 12-lead ECG, as this allows for longer-term assessment of average heart rates at rest and while active and will be more sensitive in detecting conduction defects and arrhythmia [31]. In patients with exercise intolerance and resting bradycardia without evidence of conduction defects, an exercise stress test may help detect inappropriate heart rate response or chronotropic incompetence as the cause of symptoms.

●Tachyarrhythmias – Patients with palpitations suggesting a tachyarrhythmia should undergo ambulatory ECG monitoring for at least 24 hours. Extended ECG monitoring may be indicated when symptoms are less frequent and/or are associated with cardiogenic syncope. In cases with significant symptoms (eg, unexplained syncope) where noninvasive monitoring for up to 30 days is unrevealing, insertable cardiac monitors (ICMs; also sometimes referred to as implantable cardiac monitors or implantable loop recorders) may extend the ability to detect arrhythmias over a longer period. (See "Ambulatory ECG monitoring".)

Given its potential pathogenic impact, further evaluation of coronary microvascular dysfunction is often warranted in patients with SSc with documented tachyarrhythmias. (See 'Diagnostic evaluation' above.)

Treatment

●Conduction defects – If there is evidence of a significant conduction defect, medications that slow AV node conduction (eg, beta-blockers, nondihydropyridine calcium channel blockers, digoxin) should be avoided. Patients with evidence of high-grade AV block, symptomatic bradycardia, or symptomatic sinus node dysfunction (formerly called sick sinus syndrome) should be treated with a permanent pacemaker. Patients with early conduction system disease generally do not require treatment. (See "Permanent cardiac pacing: Overview of devices and indications".)

●Tachyarrhythmias – There are limited data on the use of antiarrhythmic therapy, ablation therapy, or intracardiac devices such as pacemakers or defibrillators specifically in the SSc population [48]. Therapy should follow general treatment guidelines from professional societies and is discussed in detail separately [52,53]. (See "Overview of the acute management of tachyarrhythmias".)

Beta-1 selective blockers should generally be avoided or used with caution given the possibility of exacerbating Raynaud phenomenon. Carvedilol, a nonselective beta blocker with additional blockades of alpha(1)-adrenoceptors, has less direct nodal effects and is not typically utilized for treating tachyarrhythmias. (See 'Treatment' above.)

Autonomic insufficiency — Autonomic insufficiency is frequent in SSc, occurs at early stages of the disease process, and might precede the development of myocardial fibrosis [54]. Lack of heart rate variability and resting tachycardia predict increased mortality in SSc [48].

Clinical manifestation — Patients with SSc and autonomic insufficiency present similarly to that of the general population, with symptoms of positional dizziness or orthostatic hypotension, inappropriate heart rate response to exertion or exercise intolerance, and inappropriate sweating or sensation of warmth. These symptoms may sometimes be associated with reflex (neurocardiogenic) syncope. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Autonomic dysfunction'.)

Diagnostic evaluation — If patients have clinical evidence of autonomic dysfunction, the first step is typically assessment of heart rate and blood pressure in supine, sitting, and standing positions. In some cases, tilt-table testing may be helpful to elucidate whether symptoms of inappropriate blood pressure and heart rate response are due to autonomic neuropathy. (See "Upright tilt table testing in the evaluation of syncope".)

Treatment — Depending on the severity of symptoms, autonomic dysfunction is typically treated with conservative measures such as elevating the head of the bed, adequate hydration, liberation of salt intake, wearing compression stockings, and modification of changes in positioning. In some cases, medications such as fludrocortisone may be indicated. Midodrine, often used for autonomic and orthostatic dysfunction, is relatively contraindicated in SSc due to its vasoconstrictive effects, which can exacerbate Raynaud phenomenon. (See "Treatment of orthostatic and postprandial hypotension".)

Treatment of a concomitant disease that may also contribute to autonomic dysfunction, such as diabetes, is also beneficial. Unfortunately, in many cases, no apparent underlying cause of autonomic dysfunction may be found.

Pericardial involvement

Clinical manifestations — Pericardial involvement in SSc varies from 33 to 72 percent, most commonly asymptomatic pericardial effusions [55]. SSc-associated pericardial disease is symptomatic in 5 to 16 percent of patients and can be associated with considerable morbidity [2,3,25,56].

Pericardial involvement can present in the following ways:

●Pericardial effusion (asymptomatic or associated with cardiac tamponade)

●Acute pericarditis

●Constrictive pericarditis

Most patients with SSc and pericardial involvement are found to have an asymptomatic pericardial effusion. In such cases, the effusion has accumulated slowly and does not impact cardiac function. Patients who develop symptoms of increased intrapericardial pressure typically present with dyspnea, chest discomfort or fullness, peripheral edema, fatigue, or other symptoms related to increased filling pressures and limited cardiac output. Findings on physical examination (hypotension, tachycardia, dilated neck veins, and muffled heart sounds) are not highly sensitive or specific for the diagnosis. Pericardial effusions are typically small to moderate in size and rarely complicated by cardiac tamponade [57]. However, new-onset or worsening pericardial effusions should prompt evaluation for scleroderma renal involvement [58]. (See "Cardiac tamponade".)

Less commonly, patients may manifest acute or chronic pericarditis, which has similar SSc presentation to the general population. Acute pericarditis is typically associated with pleuritic-type chest discomfort with or without a pericardial friction rub. Most patients with acute pericarditis do not have a significant pericardial effusion. Rarely, patients may present with evidence of constrictive pericarditis, a late occurrence following extended periods of pericardial inflammation [57]. Constrictive pericarditis may be challenging to diagnose in SSc until symptoms of right-sided heart failure such as abdominal distension, fatigue, dyspnea, and cardiac cachexia develop. (See "Overview of pericardial disease".)

Diagnostic evaluation — The diagnostic approach for pericardial effusion, acute pericarditis, and constrictive pericarditis is the same as for patients without an underlying diagnosis of SSc. (See "Pericardial effusion: Approach to diagnosis", section on 'Cardiac imaging' and "Acute pericarditis: Clinical presentation and diagnosis", section on 'Diagnostic evaluation' and "Constrictive pericarditis: Diagnostic evaluation", section on 'Initial tests'.)

All patients with suspected pericardial involvement should have a 12-lead ECG and a transthoracic echocardiogram. Findings on ECG and echocardiography include:

●ECG findings – None (possible in pericardial effusion and constrictive pericarditis), diffuse ST elevation and PR depression (acute pericarditis), QRS alternans (in patients with large pericardial effusion). (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Electrocardiogram' and "Constrictive pericarditis: Diagnostic evaluation", section on 'Electrocardiogram' and "Pericardial effusion: Approach to diagnosis", section on 'ECG findings'.)

●Echocardiographic findings – Echocardiographic findings can be entirely normal but may also include pericardial effusion or other evidence of constrictive pericarditis (increased respiratory variation in mitral and tricuspid inflow, hepatic vein diastolic flow reversal during expiration, etc). (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Echocardiogram' and "Constrictive pericarditis: Diagnostic evaluation", section on 'Echocardiography' and "Pericardial effusion: Approach to diagnosis", section on 'Echocardiography'.)

Cardiac magnetic resonance (CMR) can also help assess pericardial disease in patients with SSc, especially when initial echocardiographic images are unclear or suboptimal or if localized pericardial disease may be suspected [59]. CMR allows for quantification of pericardial involvement and morphologic assessment, with high spatial resolution to demonstrate the involvement of adjacent structures. Further, due to excellent tissue characterization, CMR enables delineation of inflamed versus fibrotic tissue as well as functional imaging distinguishing between restrictive versus constrictive physiology (eg, dynamic increase in interventricular septal flattening at peak inspiration on deep breathing cine images is indicative of constrictive physiology). Respiratory flow variation of the mitral inflow velocities >25 percent by CMR is sensitive and specific, similar to echocardiography, in identifying constrictive pericarditis [59,60].

Treatment — Pericardial involvement in patients with SSc is typically managed like other forms of pericarditis. Treatment varies according to the manifestation:

●Observation (asymptomatic small to moderate-size pericardial effusions).

●Pericardial fluid drainage (large or symptomatic effusions, or for diagnostic purposes). SSc-PAH can also be associated with pericardial effusion, and in those patients pericardiocentesis should only be used in the setting of cardiac tamponade given the possibility of cardiovascular compromise with drainage of the pericardial effusion.

●Nonsteroidal antiinflammatory drugs (NSAIDs) and colchicine (acute pericarditis).

●Pericardiectomy (rarely required for constrictive pericarditis).

Treatment of the specific entities is discussed in detail separately. (See "Acute pericarditis: Treatment and prognosis" and "Cardiac tamponade" and "Constrictive pericarditis: Management and prognosis", section on 'Management of constrictive pericarditis' and "Pericardial effusion: Approach to management".)

Heart failure — Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. It is characterized by dyspnea and fatigue, and signs of fluid retention. Many asymptomatic patients with diffuse cutaneous SSc who undergo CMR are found to have myocardial inflammation and/or diminished myocardial perfusion reserve index with evidence of diffuse fibrosis despite normal routine cardiac evaluation [42]. These findings suggest that early myocardial involvement in SSc can occur without cardiac symptoms. Clinically active myocarditis, while uncommon, is associated with significant morbidity and mortality and is typically associated with myositis and overlap syndromes. (See "Neuromuscular manifestations of systemic sclerosis (scleroderma)", section on 'Myopathy'.)

Clinical manifestations — Heart failure signs and symptoms may include dyspnea at rest or with exertion, orthopnea, paroxysmal nocturnal dyspnea, decreased exercise tolerance, fatigue, weight gain, and volume overload (pulmonary congestion with rales/crackles, leg edema, jugular venous distension, ascites, etc). Patients with symptomatic heart failure can be divided into two groups based upon their left ventricular (LV) ejection fraction: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Right-sided heart failure and right ventricular (RV) dysfunction can result from HFpEF or HFrEF. Occasionally, patients with SSc may present with acute myocarditis and clinical decompensation, which should prompt urgent hospitalization and attempts to confirm the diagnosis using cardiac MRI or endomyocardial biopsy. (See 'Diagnostic evaluation' below and 'Treatment' below.)

Diastolic dysfunction is a key pathophysiologic factor underlying the clinical syndrome of HFpEF, the most common presentation of heart failure in patients with SSc. Diastolic dysfunction reflecting impaired ventricular filling represents a stiff ventricle, which may lead to upstream effects such as atrial enlargement, associated arrhythmias, and pulmonary venous congestion and edema.

●Left ventricular diastolic dysfunction – LV dysfunction in SSc is thought to be due to focal ischemia from microvascular disease, leading to inflammation and myocardial fibrosis [4], and ultimately to a stiff LV. Reduced LV compliance may also be due to primary stiffening of cardiomyocytes due to abnormalities in titin phosphorylation, which can also be induced by coronary microvascular dysfunction and reduced nitric oxide bioavailability. Diastolic dysfunction may occur early in diffuse SSc independent of comorbid cardiac abnormalities such as essential hypertension [20]. Studies suggest that diastolic dysfunction is highly prevalent in SSc, with estimates ranging between 20 to 60 percent [20,22,61]. Diastolic dysfunction typically appears before clinical symptoms of heart failure, regardless of SSc disease subtype, and is associated with increased mortality [21,61]. Risk factors for diastolic dysfunction in SSc include older age, longer disease duration, diffuse cutaneous involvement, and presence of cardiovascular risk factors such as essential hypertension and ischemic heart disease [20].

The clinical manifestations of HFpEF are discussed in detail separately. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

●Left ventricular systolic dysfunction – LV systolic dysfunction is far less common in SSc than diastolic dysfunction, with an estimated incidence of 11 to 15 percent depending on diagnostic technique [2]. Overt LV systolic dysfunction is uncommon but, when present, is thought to be due to coronary artery disease [62]. LV systolic dysfunction may also result from myocarditis, a critical potential sequelae in patients with SSc and myositis [9,23,63]. Observational data suggest that patients with SSc with systolic dysfunction are more likely to be older males with digital ulcerations, concomitant myositis, and lung involvement who have not received medical treatment with calcium channel blockers [20,22,64].

●Right ventricular systolic dysfunction – RV dysfunction in SSc may result from HFpEF or HFrEF involving the LV, from primary abnormalities of the RV, or secondary to pulmonary arterial hypertension (PAH). Clinical manifestations of right-sided heart failure, such as peripheral volume overload (fatigue, dyspnea, dependent edema, ascites, jugular venous distension, etc) are described separately (see "Clinical manifestations and diagnosis of advanced heart failure"). Translational studies suggest that intrinsic cardiomyocyte abnormalities (depressed sarcomere function) [65] may predispose SSc patients to right heart failure and poor clinical outcomes [66,67] when compared with other subtypes of PAH.

Despite routine clinical and echocardiographic monitoring, RV involvement and PAH prediction in SSc remain imprecise [68]. Although two-dimensional echocardiography is a useful screening tool in PAH [29], RV dysfunction is often undetected or underestimated [69]. Speckle-tracking echocardiography (STE) has several advantages and can be used with conventional two-dimensional echocardiography to optimize RV imaging [70]. STE-based studies have demonstrated that SSc patients have unique patterns of RV contractility [71] that precede the development of PH, and alone [72] and when coupled with exercise, may provide important insights into emerging PH and poor clinical outcomes [73,74]. Echocardiographic metrics can also detect clinical improvement in SSc [75] and improve with upfront therapies in PAH [76]. Newer echocardiographic variables that incorporate measures of RV function to pulmonary pressure [77] have been shown to predict incident PH in SSc [78] and may improve upon existing screening algorithms [79].

Diagnostic evaluation — The initial diagnostic evaluation in patients with SSc and suspected heart failure symptoms is the same as for those without SSc. The assessment typically includes laboratory testing for brain natriuretic peptide (BNP) levels and cardiac troponin T (cTnT), echocardiography, and, in select cases (eg, suspected myocarditis, nondiagnostic echocardiographic images) cardiac magnetic resonance (CMR). Serum cTnT and creatine kinase MB fraction (CK-MB) are not typically elevated in SSc-associated cardiomyopathy and, if elevated, should raise suspicion for myopericarditis, acute coronary syndrome, or pulmonary embolism [2,80]. Novel approaches to right heart and pulmonary vasculature imaging is an important area of active investigation in SSc and systemic inflammatory diseases [81]. Right heart catheterization (RHC) with or without endomyocardial biopsy may also be a part of the evaluation in selected patients. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults", section on 'Diagnostic evaluation'.)

Echocardiography is at the forefront of screening and early detection of cardiac manifestations in SSc, including diastolic dysfunction, and emerging PH across subtypes. We perform yearly screening with echocardiography. In some cases, additional provocative testing may be helpful when there are borderline pulmonary pressures and/or signs of emerging right heart dysfunction from resting echocardiography [73]. Both resting and exercise stress echo may also reveal whether pulmonary pressures are elevated due to Group 1 PH versus primarily being driven by left heart disease (Group 2 PH) [82].

Currently, no evidence supports using CMR as a screening tool for detecting SSc cardiac involvement in asymptomatic patients. It is our clinical practice to refer patients with SSc for CMR in the following instances:

●If echocardiographic findings suggest global LV systolic dysfunction in the absence of ischemic etiologies

●If there is a concern for overlapping inflammatory processes

●If there is a persistent elevation in cardiac enzymes of unexplained etiology

●If myocarditis or constrictive pericarditis is suspected

CMR is the gold standard for evaluating cardiac structure and function due to excellent spatial resolution, especially when assessing the RV [16-18,25,42,83,84]. In addition, stress CMR can detect coronary microvascular dysfunction. In a cross-sectional study utilizing CMR, RV ejection fraction was reduced in patients with SSc compared with controls and was even lower in those with diffuse cutaneous SSc [83]. CMR is also beneficial for tissue characterization and can reliably detect myocardial inflammation versus fibrosis in addition to early perfusion defects [42]. The detection of fibrosis due to myocardial scar is based on the differential uptake of gadolinium in scarred fibrotic and adjacent non-fibrotic myocardial tissue [42]. Patients with late gadolinium enhancement (LGE), indicative of focal myocardial fibrosis, are at risk for arrhythmia and LV dysfunction [42]. Patients with SSc show a unique patchy mid-wall pattern of LGE of the basal and mid-LV segments that differs from regional subendocardial or transmural LGE pattern that typically characterizes prior myocardial infarction [42].

The definitive diagnosis of PH requires invasive cardiac hemodynamic assessment with RHC [29]. It is our clinical practice to refer patients with SSc for RHC if there is elevated pulmonary artery systolic pressure ≥35 mmHg on resting echocardiogram or moderate to severe right-sided chamber dilatation or RV dysfunction. Clinical judgment is based on symptoms and abnormal echocardiographic findings, pulmonary function testing, and laboratory data. A common diagnostic challenge is the distinction between PAH and PH due to left-sided heart disease. PH is defined as mean PAP >20 mmHg at rest, assessed by RHC [29]. Endomyocardial biopsy performed during RHC may be indicated in SSc if infiltrative cardiac disease, drug toxicity [85], or overlap myocarditis [86] is suspected. Left heart catheterization includes coronary angiography, the gold standard for assessing and managing obstructive coronary artery disease, coronary flow reserve testing, and invasive measurements of LV end-diastolic pressure and/or transaortic gradients. Simultaneous LV and RV end-diastolic pressure measurements allow for the differentiation between constrictive and restrictive cardiomyopathies.

Treatment — Generally, the management of cardiomyopathy associated with SSc is the same as for patients without SSc. The goals of therapy include:

●Management of symptoms

●Management of volume overload

●Control of underlying risk factors (eg, hypertension) or provoking factors (eg, myocardial ischemia)

●Optimization of long-term outcomes

Treatment varies depending on whether the patient has HFpEF or HFrEF. The approach to heart failure therapy is discussed in detail separately (see "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults"). Guideline-directed treatment of HFpEF and HFrEF must be individualized to the SSc patient because trials of these medications have not been conducted specifically in SSc. Patients with HFpEF and HFrEF will most likely tolerate mineralocorticoid receptor antagonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors. Patients with HFpEF should not be treated with beta blockers unless there are other indications for these drugs. Patients with HFrEF should be treated with a nonselective beta blocker such as carvedilol. The choice of angiotensin receptor-neprilysin inhibitors (ARNIs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) should be used in SSc according to their heart failure indications (eg, left ventricular ejection fraction <55 to 60 percent for ARNIs) and other potential SSc-related indications (eg, ACE inhibitors for scleroderma renal crisis).

Acute myocarditis or myopericarditis may respond to the addition of immunosuppressive therapy. We suggest treatment with immunosuppressive therapy and the typical treatment of cardiomyopathy for biopsy-proven or high clinical suspicion for SSc-associated myocarditis. We usually use low-dose glucocorticoids (less than 10 to 20 mg daily of prednisone or equivalent) in combination with cyclophosphamide. Mycophenolate may be a reasonable alternative to cyclophosphamide, given the coexistence of other disease manifestations for which mycophenolate is used. This approach to therapy is based mainly on clinical experience, observational data, and extrapolation from immunosuppressive trials for other manifestations of SSc. Since high doses of glucocorticoids are recognized as a risk factor for scleroderma renal crisis, we use only low-dose glucocorticoid therapy with close monitoring for new onset of hypertension. Cyclophosphamide is typically given for three to six months and then replaced by a medication with a lower risk of toxicity, such as azathioprine or mycophenolate [24,31]. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases".)

Limited observational data suggests that treatment with glucocorticoids and cyclophosphamide results in clinical improvement and normalization of cardiac enzymes [24,87]. In a case series of six patients with diffuse cutaneous SSc and myocarditis, the two patients treated with glucocorticoids died due to progressive LV failure despite apparent clinical improvement [23]. Clinical improvement following the use of combination therapy including intravenous immune globulin (IVIG) has been reported in myocarditis and, as such, IVIG might also be an appropriate add-on treatment option in some patients with SSc-associated myocarditis [88].

Cardiotoxicity from systemic sclerosis therapies — Unfortunately, some treatments used to treat SSc may have adverse cardiovascular side effects. These include cyclophosphamide [89] and autologous stem cell transplantation [90]. Although stem cell transplantation likely does not cause cardiotoxicity, myeloablative doses of cyclophosphamide can. Patients with SSc and preexisting cardiac dysfunction are at increased risk for morbidity and mortality with stem cell transplantation [91]. High-dose cyclophosphamide therapy can be complicated by LV or RV systolic dysfunction, especially in those patients with SSc who are older or have abnormal cardiac function. Rarely, cyclophosphamide has resulted in early hemorrhagic myopericarditis [92], which may be associated with pericardial effusion and cardiac tamponade. Non-myeloablative doses of cyclophosphamide are uncommonly associated with cardiac toxicity (see "General toxicity of cyclophosphamide in rheumatic diseases"). Therefore, screening with echocardiography or CMR prior to stem cell transplantation is crucial to exclude cardiac dysfunction.

PROGNOSIS — Cardiac involvement in systemic sclerosis (SSc) is a harbinger of aggressive systemic disease [1,3,93,94]. A meta-analysis with 11,526 person-years of follow-up found that clinically overt cardiac involvement was associated with a 2.8-fold increased risk of death and was the strongest predictor of mortality [93,94]. In another study of 5860 patients with SSc, 26 percent of deaths were attributable to cardiac involvement. Cardiac involvement, the third leading cause of death following interstitial lung disease and pulmonary arterial hypertension (PAH), was primarily due to heart failure and arrhythmias [1]. Studies demonstrate that while mortality from SSc-associated PAH has improved, there has been minimal change in survival rates from SSc pulmonary hypertension (PH) resulting from Group 2 [94,95] and Group 3 disease [96].

Clinically overt cardiac involvement is also a significant factor in SSc deaths due to other causes. For instance, in a retrospective review, 60 percent of SSc-related deaths over 30 years were attributable to PAH or pulmonary fibrosis [93,94]. PAH has the strongest correlation with increased mortality, affecting approximately 10 to 12 percent of patients with SSc, with a median survival of four years after diagnosis [93,94]. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Prognosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic sclerosis (scleroderma)".)

SUMMARY AND RECOMMENDATIONS

●Overview – Cardiac involvement is common in systemic sclerosis (SSc) but frequently remains unrecognized until late in the disease. SSc-associated cardiac disease is associated with marked increases in morbidity and mortality; therefore, screening with appropriate diagnostic tools is essential. (See 'Introduction' above and 'Epidemiology, etiology and pathogenesis' above.)

●Etiology – The broad categories of cardiac manifestations of SSc include vascular disease; conduction disease/arrhythmia and conduction disease; pericardial disease, including pericardial effusion and constrictive pericarditis; and myocardial disease, including left heart failure with preserved or reduced ejection fraction, right heart failure, restrictive cardiomyopathy, and myocarditis. (See 'Epidemiology, etiology and pathogenesis' above.)

●Screening – Given the high prevalence of subclinical cardiac disease in SSc, we suggest initial baseline and annual cardiac screening in all patients. The evaluation includes a focused history and physical examination, with electrocardiogram (ECG), echocardiogram, and measurement of natriuretic peptides (brain natriuretic peptide [BNP] or N-terminal of the prohormone BNP [NT-proBNP]) and cardiac troponin regardless of symptoms. Additional cardiac testing, including stress testing, cardiac magnetic resonance (CMR) imaging, or cardiac catheterization, should be guided by symptoms or other evidence of cardiac involvement. Prompt referral to a cardiologist is appropriate if baseline or follow-up diagnostic evaluations are abnormal or signs or symptoms concerning for cardiac involvement are noted. (See 'Screening for cardiac involvement' above.)

●Microvascular coronary artery disease – Vascular involvement in the heart in SSc predominately affects the small arteries and arterioles rather than major epicardial arteries. Some patients with SSc may experience anginal-type chest pain (ie, substernal chest discomfort triggered by exercise or another stressor) without obstructive disease due to pathologic changes in small coronary arteries and arterioles. Patients with symptoms suggestive of myocardial ischemia should be evaluated for large-vessel coronary artery disease. (See 'Microvascular coronary artery disease' above and 'Clinical manifestations' above and 'Diagnostic evaluation' above.)

●Treatment of angina – There are no SSc-specific therapies for the treatment of microvascular angina. Similar to the general population of patients with coronary artery disease, patients with SSc should be optimized on anti-anginal medications, including calcium channel blockers, nitrates, statins, and aspirin. Long-acting dihydropyridine calcium channel blockers are among the preferred anti-anginal medications for patients with SSc partly because of their additional benefit for treating Raynaud phenomenon. Unlike other forms of coronary artery disease, beta blockers are typically avoided in SSc due to the possibility of exacerbating Raynaud phenomenon. (See 'Microvascular coronary artery disease' above and 'Treatment' above.)

●Conduction system defects – Conduction system defects and arrhythmias are likely due to fibrosis of the conduction system from recurrent microvascular ischemic insult and autonomic dysfunction. Symptomatic supraventricular tachyarrhythmias are more common than bradyarrhythmias. The evaluation and treatment of patients with SSc with conduction system defects and/or arrhythmias is generally the same as for patients without SSc. (See 'Conduction defects and tachyarrhythmias' above.)

●Autonomic insufficiency – Autonomic insufficiency is frequently seen in SSc, occurs early in the disease, and can precede the development of myocardial fibrosis. Patients with SSc with autonomic insufficiency present similar to the general population, with symptoms of positional dizziness or orthostatic hypotension, inappropriate heart rate response to exertion or exercise intolerance, and inappropriate sweating or sensation of warmth. The evaluation and treatment of patients with SSc and autonomic dysfunction is generally the same as for patients without SSc. (See 'Autonomic insufficiency' above.)

●Pericardial disease – Pericardial involvement in patients with SSc can include pericardial effusions (asymptomatic or associated with cardiac tamponade), acute pericarditis, or constrictive pericarditis. The diagnostic approach and treatment of patients with SSc complicated by pericardial involvement is typically managed the same was as patients without SSc. (See 'Pericardial involvement' above.)

●Heart failure – Cardiac manifestations of SSc include left ventricular (LV) diastolic and systolic dysfunction and right ventricular (RV) systolic dysfunction. LV diastolic dysfunction, the most common manifestation, typically precedes clinical heart failure. Overt LV systolic dysfunction is uncommon and may be due to coronary artery disease or, less commonly, myocarditis. RV systolic dysfunction in SSc may be the result of heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) involving the left ventricle, the development of primary abnormalities of the right ventricle, or secondary to pulmonary arterial hypertension (PAH). The evaluation and management of cardiomyopathy associated with SSc is the same as for patients without SSc. (See 'Heart failure' above.)

●Myocarditis – For patients with biopsy-proven or high clinical suspicion for SSc-associated myocarditis, we suggest immunosuppressive therapy and the typical treatment of cardiomyopathy (Grade 2C). We usually give low-dose glucocorticoids (less than 10 to 20 mg daily of prednisone or equivalent) in combination with cyclophosphamide. Mycophenolate may be a reasonable alternative to cyclophosphamide given the coexistence of other disease manifestations for which mycophenolate is used. This approach is largely based on clinical experience, limited observational data, and extrapolation of trials of immunosuppressive agents used for other manifestations of SSc. Since high doses of glucocorticoids are a known risk factor for scleroderma renal crisis, we use only low-dose glucocorticoids with close monitoring for new onset of hypertension. When cyclophosphamide is used, it is typically given for three to six months and then replaced by a medication with a lower risk of toxicity. (See 'Heart failure' above and 'Treatment' above.)