Heart disease, either clinically apparent or silent, is a frequent complication of systemic sclerosis (SSc, scleroderma) and may affect both patients with diffuse cutaneous and limited cutaneous SSc. The availability of more sensitive modalities has led to an increased awareness of scleroderma heart disease, which often involves the pericardium, myocardium, and cardiac conduction system. This awareness of cardiac involvement requires attention and interventions led by internists, cardiologists, and rheumatologists. Although no specific therapy exists for scleroderma heart disease, early recognition of the presence and type of scleroderma heart disease may lead to more effective management of patients with scleroderma.
Key points
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Although definitive therapy for heart disease related to systemic sclerosis (SSc) has been elusive, novel approaches are being explored.
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It is hoped that hematopoietic stem cell transplantation might demonstrate improvement in heart disease related to SSc, but this has not been investigated to date.
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Cyclophosphamide and imatinib are other potential therapies for patients with SSc, but data regarding efficacy in heart disease associated with SSc are also lacking.
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The cardiac disease associated with scleroderma can present in many forms and is often clinically silent until significant organ dysfunction has ensued.
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As clinical awareness and diagnostic methods have improved, earlier detection and treatment are both feasible and advisable.
Introduction
In 1945, Goetz and Berne characterized scleroderma as a disease with progressive cutaneous and multi-organ involvement, coining the term systemic sclerosis (SSc). Widespread sclerosis of the skin, with other concurrent ailments, had been noted earlier by many scholars and was initially defined by Curzio in the eighteenth century. It was the works by Heine in 1926 and Weiss and Warren in 1943 that laid a foundation for the disease’s involvement of the heart. These investigators described scleroderma in association with cardiac findings and postulated a direct relationship rather than a mere association. SSc has now been recognized as a disease that often has cardiac involvement manifested by multiple processes with potentially serious implications for patients. The myriad of presentations includes involvement of the pericardium, myocardium, conduction system, and vasculature. Weiss, Stead, and Warren’s series in 1943 was a landmark investigation, describing 9 patients with cutaneous findings of scleroderma associated with concurrent cardiac disease. The patients described symptoms of heart failure, and the investigators suspected a direct relationship related to widespread fibrosis of both the skin and heart. Myocardial fibrosis caused directly by SSc, not related to pulmonary or renal complications, was initially debated. A seminal study by Bulkley and colleagues of 52 autopsy cases at The Johns Hopkins Hospital made significant strides to define primary cardiac involvement in SSc. These investigators identified patients with myocardial fibrosis who were noted to have had significant symptoms of heart failure, angina pectoris, and dysrhythmias. At autopsy they were found to have contraction band necrosis and replacement fibrosis without associated coronary disease and without pulmonary, renal, or systemic vascular disease that would offer a secondary explanation. It was postulated that the myocardial fibrosis was related to a Raynaudlike phenomenon of the microvasculature, leading to ischemia-reperfusion injury with multiple small areas of necrosis and eventual fibrosis. Through extensive study, patchy myocardial fibrosis has been recognized as a hallmark of scleroderma heart disease.
Symptoms of heart failure and underlying myocardial fibrosis are by no means the sole finding of cardiac disease in SSc ( Table 1 ). As more investigation has been undertaken, pericardial disease and conduction abnormalities have become more apparent. Both acute pericarditis and chronic pericardial effusion have been described, rarely with effusions causing cardiac tamponade. In a series described by McWhorter and LeRoy in 1974, pericardial involvement was more common than significant myocardial fibrosis at autopsy (62% vs 30%). However, pericardial involvement may often be limited to asymptomatic effusions; clinically significant disease is less common. A wide spectrum of dysrhythmias and conduction abnormalities may be seen in scleroderma, varying from premature ventricular contractions to heart block or potentially fatal ventricular dysrhythmias. James published an autopsy analysis in 1974 of 8 patients with scleroderma and cardiac symptoms that revealed abnormalities in the sinus node, atrioventricular node, His bundle, and small coronary arteries. Widespread narrowing of these small coronary arteries (less than 1 mm diameter) caused by mural fibrosis, endothelial proliferation, and platelet-fibrin clots were thought to be the basis for myocardial fibrosis and also structural abnormalities in the conduction tissue they supplied. These microvascular abnormalities have established a plausible nidus for varying degrees of heart block and dysrhythmias.
| Pericardial | Acute pericarditis, chronic pericarditis, pericardial fibrosis, pericardial effusion, tamponade |
| Myocardial | Myocardial fibrosis, ventricular diastolic dysfunction, ventricular systolic dysfunction, myocarditis |
| Conduction system disease | Autonomic dysfunction, heart block, supraventricular dysrhythmia, ventricular dysrhythmia |
| Vascular | Mural fibrosis, intimal proliferation, platelet-fibrin clotting |
The various cardiovascular diseases in scleroderma represent a wide spectrum of clinical entities, varying from asymptomatic processes to those associated with much morbidity and mortality. Although disease-modifying therapy is lacking at this time, early consideration of organ involvement (eg, scleroderma heart disease) may allow treatment of secondary processes and more aggressive management of symptoms. This recognition of cardiac involvement requires attention and interventions led by internists, cardiologists, and rheumatologists.
Introduction
In 1945, Goetz and Berne characterized scleroderma as a disease with progressive cutaneous and multi-organ involvement, coining the term systemic sclerosis (SSc). Widespread sclerosis of the skin, with other concurrent ailments, had been noted earlier by many scholars and was initially defined by Curzio in the eighteenth century. It was the works by Heine in 1926 and Weiss and Warren in 1943 that laid a foundation for the disease’s involvement of the heart. These investigators described scleroderma in association with cardiac findings and postulated a direct relationship rather than a mere association. SSc has now been recognized as a disease that often has cardiac involvement manifested by multiple processes with potentially serious implications for patients. The myriad of presentations includes involvement of the pericardium, myocardium, conduction system, and vasculature. Weiss, Stead, and Warren’s series in 1943 was a landmark investigation, describing 9 patients with cutaneous findings of scleroderma associated with concurrent cardiac disease. The patients described symptoms of heart failure, and the investigators suspected a direct relationship related to widespread fibrosis of both the skin and heart. Myocardial fibrosis caused directly by SSc, not related to pulmonary or renal complications, was initially debated. A seminal study by Bulkley and colleagues of 52 autopsy cases at The Johns Hopkins Hospital made significant strides to define primary cardiac involvement in SSc. These investigators identified patients with myocardial fibrosis who were noted to have had significant symptoms of heart failure, angina pectoris, and dysrhythmias. At autopsy they were found to have contraction band necrosis and replacement fibrosis without associated coronary disease and without pulmonary, renal, or systemic vascular disease that would offer a secondary explanation. It was postulated that the myocardial fibrosis was related to a Raynaudlike phenomenon of the microvasculature, leading to ischemia-reperfusion injury with multiple small areas of necrosis and eventual fibrosis. Through extensive study, patchy myocardial fibrosis has been recognized as a hallmark of scleroderma heart disease.
Symptoms of heart failure and underlying myocardial fibrosis are by no means the sole finding of cardiac disease in SSc ( Table 1 ). As more investigation has been undertaken, pericardial disease and conduction abnormalities have become more apparent. Both acute pericarditis and chronic pericardial effusion have been described, rarely with effusions causing cardiac tamponade. In a series described by McWhorter and LeRoy in 1974, pericardial involvement was more common than significant myocardial fibrosis at autopsy (62% vs 30%). However, pericardial involvement may often be limited to asymptomatic effusions; clinically significant disease is less common. A wide spectrum of dysrhythmias and conduction abnormalities may be seen in scleroderma, varying from premature ventricular contractions to heart block or potentially fatal ventricular dysrhythmias. James published an autopsy analysis in 1974 of 8 patients with scleroderma and cardiac symptoms that revealed abnormalities in the sinus node, atrioventricular node, His bundle, and small coronary arteries. Widespread narrowing of these small coronary arteries (less than 1 mm diameter) caused by mural fibrosis, endothelial proliferation, and platelet-fibrin clots were thought to be the basis for myocardial fibrosis and also structural abnormalities in the conduction tissue they supplied. These microvascular abnormalities have established a plausible nidus for varying degrees of heart block and dysrhythmias.
| Pericardial | Acute pericarditis, chronic pericarditis, pericardial fibrosis, pericardial effusion, tamponade |
| Myocardial | Myocardial fibrosis, ventricular diastolic dysfunction, ventricular systolic dysfunction, myocarditis |
| Conduction system disease | Autonomic dysfunction, heart block, supraventricular dysrhythmia, ventricular dysrhythmia |
| Vascular | Mural fibrosis, intimal proliferation, platelet-fibrin clotting |
The various cardiovascular diseases in scleroderma represent a wide spectrum of clinical entities, varying from asymptomatic processes to those associated with much morbidity and mortality. Although disease-modifying therapy is lacking at this time, early consideration of organ involvement (eg, scleroderma heart disease) may allow treatment of secondary processes and more aggressive management of symptoms. This recognition of cardiac involvement requires attention and interventions led by internists, cardiologists, and rheumatologists.
Incidence and prognosis
Cardiovascular involvement in scleroderma is often unrecognized, making it difficult to estimate the true frequency. Depending on the diagnostic technique used, contemporary reviews suggest a clinical incidence of cardiac involvement in 15% to 35% of patients with SSc. Postmortem study was the initial methodology allowing for the first identification of cardiac disease in scleroderma. Analysis at autopsy likely biases toward those with the most severe systemic processes but allows definitive identification of even occult pathophysiology. Noninvasive studies, such as electrocardiography (ECG), echocardiography, thallium scintigraphy, single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), can identify less clinically apparent processes. Echocardiography and other imaging modalities may also recognize sequelae of other organ system involvement, such as elevated right ventricular pressures secondary to pulmonary hypertension. These modalities may identify patients without symptoms earlier in the disease course, optimizing the opportunity for intervention.
Significant cardiac involvement in SSc portends a poor prognosis. A study by Medsger and Masi in 1973 reported that patients with SSc with clinically apparent cardiac disease had an estimated 5-year mortality as high as 70%. Further analyses propose a lower mortality rate. Although not all of the deaths were related to primary cardiac causes, the findings indicate that cardiac involvement is a harbinger of more aggressive systemic disease. Larger analyses have shown that cardiac-related causes of death account for 14% to 36% of all-cause mortality. A recent meta-analysis of 2691 patients with SSc reported an overall mortality rate of 27% at a mean follow-up period of 7.3 years; 29% of deaths were defined as related to cardiac causes.
The skin-thickness-progression rate has also been identified as a method of predicting significant organ involvement, including cardiac disease. Domsic and colleagues demonstrated that severe cardiac involvement was statistically more common in patients with rapid skin thickness progression. Rapid cutaneous progression was associated with severe cardiac disease in 3% of patients versus 1% of patients with a slow skin-thickness-progression rate ( P = .03). These findings may suggest that patients with rapid skin thickness progression should be monitored more closely for signs or symptoms of cardiac disease.
Although pathologic cardiac involvement has traditionally been associated with diffuse cutaneous SSc (dcSSc), there has been increasing recognition that patients with limited cutaneous SSc (lcSSc) may also have significant cardiac abnormalities. As noninvasive imaging techniques have become more advanced, the identification of cardiac abnormalities in lcSSc has shown to be equal to the incidence in dcSSc. Registry analyses using MRI or echocardiography have demonstrated that the presence of cardiac abnormality is statistically equal in patients with dcSSc and lcSSc. However, there is a higher prevalence of symptomatic disease associated with dcSSc.
Myocardial disease
Myocardial disease is a prominent feature in patients with scleroderma with cardiovascular involvement, with a wide range of manifestations and varying underlying pathophysiology. Microvascular alterations, collagen overproduction, and complex immune system dysregulation lead to ischemic, fibrotic, and inflammatory lesions involving the myocardium ( Fig. 1 ). These processes may ultimately manifest as ventricular fibrosis (principally recognized as diastolic dysfunction), ventricular systolic dysfunction, myositis, or myocarditis. Although other imaging modalities have been developed, echocardiography remains the standard method for the assessment of the myocardium largely because of its relative accuracy, reproducibility, sensitivity, and widespread availability. However, innovations in imaging have added new modalities to aid clinicians and may be useful in conjunction with standard techniques ( Box 1 ).
ECG
Chest radiography
Doppler echocardiography
Tissue Doppler echocardiography
Echo-derived myocardial strain rate
Thallium perfusion scanning with SPECT
Six-minute walk test
Cardiopulmonary exercise testing
Calcium scoring by computed tomography
MRI
Cardiac catheterization
Myocardial Fibrosis and Ventricular Diastolic Dysfunction
The pathologic hallmark of SSc cardiac involvement is patchy myocardial fibrosis with a characteristically haphazard distribution of lesions in the myocardium. The fibrosis of the myocardium of SSc differs from that observed in atherosclerotic coronary artery disease in that it does not correspond to the regional distribution of a single coronary artery. Ventricular diastolic function is thought to be one of the principal noninvasive measures of myocardial fibrosis. Impaired ventricular filling, synonymous with diastolic dysfunction, has traditionally been identified by means of Doppler echocardiography. Impaired filling may involve either or both ventricles, and multiple studies have demonstrated diastolic dysfunction in patients with SSc. Impaired ventricular filling represents a stiff or fibrotic ventricle, which may eventually lead to upstream effects, such as atrial enlargement and associated dysrhythmias, pulmonary venous congestion and pulmonary edema, or ventricular systolic dysfunction.
Impaired ventricular filling is more pronounced in patients with SSc with predisposing conditions, such as systemic hypertension, but is often one of the first markers of primary scleroderma heart disease. Diastolic dysfunction is not limited to the left ventricle; a surprisingly high prevalence of right-sided diastolic abnormalities has been reported in patients regardless of SSc subset. Right ventricular diastolic dysfunction correlates independently with both pulmonary hypertension and left ventricular diastolic dysfunction. Giunta and colleagues assessed diastolic function by echocardiography in 77 patients with SSc compared with 33 controls; an abnormal right ventricular filling pattern was found in 40% of patients with SSc but not in controls ( P <.001). These abnormal filling patterns reflect elevated pulmonary pressures, either secondary to left ventricular diastolic dysfunction or pulmonary arterial hypertension. It was concluded that patchy fibrosis impairs the diastolic function of both ventricles, but right ventricular diastolic dysfunction may also represent elevated pulmonary afterload. These studies confirm the frequent occurrence of diastolic dysfunction in patients with SSc regardless of concomitant systemic hypertension or atherosclerotic coronary artery disease.
Ventricular diastolic dysfunction is readily identified using tissue Doppler echocardiography (TDE), which is a relatively new ultrasound technique. TDE allows direct determination of myocardial tissue velocities, patterns of tissue movement, and myocardial strain rate (SR). Data obtained from the mitral or tricuspid valve inflow pattern, valve annulus Doppler velocities, and pulmonary venous flow Doppler patterns allows for the identification and staging of diastolic dysfunction. TDE has emerged as a robust indicator of both left and right ventricular contractility and stiffness. Early ventricular diastolic filling velocities gauge ventricular stiffness, which likely correlates with myocardial fibrosis. Ventricular filling velocities have emerged as another useful echo technique for recognizing dysfunction. In the specific context of SSc, combining conventional echocardiography with mitral and tricuspid annular velocity measurements results in greater detection of cardiac complications. Considering the availability of pulsed TDE, it should be considered for routine evaluation of patients with SSc. Because of its usefulness, tissue Doppler study is now commonly a standard component of echocardiography in many centers.
SPECT imaging of thallium perfusion was identified as a modality to demonstrate stress-induced perfusion defects thought to represent fibrotic or microvasculature changes associated with SSc cardiac involvement. The prevalence of cardiac abnormalities identified using exercise or cold provocation SPECT has widely varied, as high as 82% of patients. In comparison, Nakajima and colleagues compared 34 patients with SSc to 16 controls using exercise nongated and rest-gated SPECT and identified minimal perfusion abnormalities in 9 patients, whereas diastolic dysfunction was confirmed in more than half the patients with SSc using echocardiography. Although SPECT seems sensitive to identify potential cardiac abnormalities, the clinical significance of these abnormalities remains uncertain.
Cardiac MRI has emerged as a sensitive technique for identifying cardiac disease in SSc. Imaging techniques include gadolinium-delayed contrast enhancement to evaluate for myocardial fibrosis, T2-weighted imaging to identify inflammatory lesions, and accurate measurements of chamber dimensions and volumes to asses ejection fraction or chamber sizing. Cardiac MRI has identified a high incidence of disease that correlates with previous autopsy studies, which may imply a sensitivity advantage over echocardiography. An MRI study of 52 patients from a French center reported some form of cardiac disease in 75%, with equal incidence in dcSSc compared with lcSSc. Although not confirmed with histologic specimens, MRI demonstrated linear midmyocardial delayed contrast enhancement thought to correlate with myocardial fibrosis. Increased uptake with T2-weighted images may suggest myocardial edema and acute inflammation. Ventricular diastolic function and kinetic patterns may be examined with MRI, and right ventricular dysfunction may be more readily identified with MRI compared with echocardiography.
Although conventional echocardiography has been the standard diagnostic modality, echo-derived myocardial SR has been recognized recently as a sensitive method for identifying diastolic dysfunction. SR is a powerful correlate of myocardial contraction and is independent of myocardial translational motion. SR may provide a method for identifying myocardial fibrosis at an earlier stage. In one study examining SR, patients with SSc with a normal cardiac examination, pulmonary artery pressure, and radionuclide left ventricular ejection fraction (LVEF) were compared with matched controls ; patients with SSc had lower systolic SR and lower diastolic SR than controls. SR may detect reduced left ventricular contractility in the setting of a normal LVEF, allowing for early identification of depressed myocardial contractility.
There are limited data on therapy for diastolic dysfunction or myocardial fibrosis in SSc. Conventional wisdom suggests that afterload reduction may be beneficial because this is the primary therapeutic strategy in other forms of diastolic dysfunction. However, studies have provided mixed results. One small investigation of ventricular function before and after enalapril therapy found no statistical difference in either patients with SSc or control subjects after 3 months of therapy. In contrast, another study examining the effects of captopril therapy (after at least 11 months) revealed a statistical difference in ventricular function with captopril use. LVEF and markers of diastolic function were statistically improved.
Another target of vasodilator therapy has been the so-called Raynaud phenomena of the microvasculature. In a study using nifedipine (60 mg/d for 14 days), posterior wall systolic SR and diastolic SR increased significantly. Because peak systolic and early diastolic SR are respective indicators of regional contractility and diastolic function, nifedipine is thought to improve myocardial contraction. This conclusion is thought to have significant merit because SR determined by Doppler echocardiography is less load-dependent than other methods. However, the afterload estimated by the systolic blood pressure/heart rate product did not change significantly after nifedipine. It may be concluded that there is some effect with afterload reduction or vasodilator therapy. However, it should be noted that these results lack large study populations or hard outcomes data. Thus, large-scale evidence-based therapy has not been established.
Ventricular Systolic Dysfunction
Systolic or diastolic dysfunction may occur early in SSc heart disease, years before becoming clinically evident. This finding is particularly true in the case of patients with SSc with left ventricular diastolic dysfunction, whereas systolic dysfunction is less common and occurs mainly because of concomitant coronary artery disease or hypertensive heart disease. Systolic dysfunction is much less common than diastolic dysfunction, with recent studies reporting an incidence between 11% and 15%.
Radionuclide ventriculography has been used to assess LVEF and right ventricular ejection fraction (RVEF) and peak filling rate. Several studies reported a decreased global LVEF in a minority of patients, although segmental dysfunction or exercise-induced dysfunction was more prevalent. In one study of 26 patients with dcSSc, 4 had reduced LVEF and 7 had reduced RVEF, including the 4 patients with reduced LVEF. In another study, 42 consecutive patients with SSc with normal pulmonary arterial pressure and less than 5 years of disease duration were compared with 20 matched controls. Sixteen patients had reduced RVEF, 3 had reduced LVEF, and 10 had reduced peak filling rate (an indicator of early right systolic and left diastolic dysfunction). RVEF correlated with LVEF and the peak filling rate, whereas no correlation was found with either pulmonary function impairment or pulmonary arterial pressure, implying intrinsic myocardial involvement in these patients rather than a secondary effect.
The association of myocardial perfusion abnormalities with myocardial dysfunction suggests a common mechanism for myocardial involvement. Myocardial perfusion, as examined by thallium perfusion scans, is likely a marker of microvascular ischemia. Thallium perfusion defect scores more than the median were associated with a significantly lower mean LVEF, and all patients with abnormal resting LVEF had thallium scores more than the median. Nicardipine was shown to acutely improve global LVEF and segmental abnormalities and to improve LVEF and RVEF. These results provide further evidence for a similar pathogenic pathway with reversible vasospastic small coronary artery disease inducing segmental and global heart dysfunction.
Allanore and colleagues evaluated 129 patients with SSc and LVEF less than 55% compared with 256 patients with SSc with normal LVEF. They demonstrated that male sex, age, digital ulcerations, myositis, and lack of treatment with calcium-channel blockers were independent factors associated with left ventricular dysfunction. However, typical cardiovascular risk factors were not associated with reduced LVEF, suggesting that indicators of severity of SSc as well as markers of microvascular lesions, such as digital ulcerations, are associated with reduced LVEF.
There are no long-term outcome studies of the treatment of systolic dysfunction associated with scleroderma. Traditional therapy for heart failure is implemented, including diuretics, angiotensin-converting enzyme inhibitors (or angiotensin-receptor blockers), and aldosterone antagonists. Calcium-channel blockers may also be used because the pathophysiology for systolic dysfunction is similar to that of diastolic dysfunction.
Myositis and Myocarditis
Inflammatory myocarditis has been recognized as a possible complication of scleroderma and is usually associated with skeletal muscle myositis. Cardiac MRI allows for the identification of myocarditis and may assist in the morphologic evaluation of affected myocardium compared with viable tissue. Serum creatinine kinase MB isoenzyme elevation in conjunction with echocardiography has also been used to diagnose and monitor myocarditis.
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