The heart in dermatomyositis and polymyositis
Rheumatology Unit, Department of Medicine, Karolinska Institutet At Karolinska University Hospital, Solna Stockholm, Sweden.
Correspondence to: I. E. Lundberg, Rheumatology Unit, Karolinska University Hospital, SE-17176 Stockholm, Sweden. E-mail: Ingrid.lundberg{at}ki.se
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Abstract |
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 Top Abstract IntroductionMortality and cardiovascular...Clinically manifest heart...Subclinical heart involvementPathophysiologyDiagnostic investigationsTreatment and prognosisReferences |
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Cardiovascular manifestations constitute a major cause of death in myositis. Despite this, clinically manifest cardiac involvement in polymyositis and dermatomyositis is relatively rare. In contrast, subclinical manifestations are frequently reported and are predominated by conduction abnormalities and arrhythmias detected by ECG. The most frequently reported clinically overt manifestations are congestive heart failure, conduction abnormalities, that may lead to complete heart block, and coronary artery disease. The underlying pathophysiological mechanisms that may cause cardiac manifestations involve myocarditis and coronary artery disease as well as involvement of the small vessels of the myocardium.
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Introduction |
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TopAbstractIntroductionMortality and cardiovascular...Clinically manifest heart...Subclinical heart involvementPathophysiologyDiagnostic investigationsTreatment and prognosisReferences |
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Polymyositis and dermatomyositis are chronic inflammatory muscle diseases characterized clinically by muscle weakness and fatigue, and histopathologically by inflammatory cell infiltrates in skeletal muscle. Extramuscular involvement is common, such as the skin in dermatomyositis, interstitial lung disease (ILD), arthritis, gastrointestinal involvement and Raynaud's phenomenon, suggesting that myositis is a systemic inflammatory connective tissue disease [1]. Autoantibodies are frequently present, some are more specific for myositis, the most frequent of these are the anti-aminoacyl tRNA synthetase antibodies of which the histidyl-tRNA synthetase antibody (anti-Jo-1) is the most common, present in
20% of poly- or dermatomyositis patients [2, 3]. The anti-synthetase autoantibodies are associated with a distinct clinical phenotype, the anti-synthetase syndrome, which is characterized by myositis, ILD, arthritis, Raynaud's phenomenon and skin changes on the hands, named mechanic's hands [2]. Other so-called myositis specific autoantibodies, but less common, are anti-Mi-2 and anti-signal recognition peptide (SRP) autoantibodies. In some studies anti-SRP antibodies were associated with an increased risk cardiac involvement, but this was not confirmed in a more recent study [2, 4, 5]. Presence of autoantibodies together with cellular infiltrates of T cells in muscle tissue suggests that polymyositis and dermatomyositis are autoimmune diseases. Treatment is based on corticosteroids in high doses over a long time in combination with other immunosuppressive drugs such as azathioprine or methotrexate [1]; in addition, recent data have strongly supported a role of exercise in the treatment regimen in combination with the immunosuppressives summarized in [6]. With this treatment most patients improve, but few patients recover their muscle function and persisting muscle fatigue is common. When corticosteroids were introduced the overall survival increased substantially. Before the corticosteroid era more than 50% of myositis patients died within 5 yrs of disease complications. In two recent cohorts followed over 20 yrs, the 5-yr survival was 95% in both and 10-yr survival was 84 or 89%, respectively [7, 8]. Occurrence of extra-muscular organ involvement such as ILD and cardiac involvement is associated with worse prognosis for survival, as reported in one recent, long-term follow-up study, where cardiovascular manifestations were the most common causes of death of myositis patients [8]. These included heart failure, arrhythmia, cardiac arrest and myocardial infarction. The frequency of heart involvement in patients with myositis varies between 6 and 75% depending on whether clinical manifest or subclinical cardiac involvement is considered, and depending on patient selection, definition of heart involvement and methods used to detect cardiac involvement [9, 10]. Despite that, cardiovascular events are common causes of death in polymyositis and dermatomyositis, and despite that the auto-immune inflammation of skeletal muscle could also affect the heart muscle, clinical overt involvement of the heart is seldom evident in patients with myositis. However, the often reported subclinical cardiac manifestations could suggest that the heart muscle is frequently affected but we may overlook this manifestation. Cardiac involvement in polymyositis or dermatomyositis was first reported in 1899 by Oppenheim [11]. Until the 1970s cardiac involvement was considered to be rare in the inflammatory myopathies. During the last decades more sensitive, non-invasive techniques, which are presented subsequently, have been used to detect cardiac involvement and the number of reports on cardiac involvement in myositis have increased. Thus cardiac involvement is now well-recognized as a clinically important manifestation in patients with polymyositis or dermatomyositis, although its actual frequency is still uncertain as large epidemiological studies on cardiac involvement are missing.
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Mortality and cardiovascular involvement |
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TopAbstractIntroductionMortality and cardiovascular...Clinically manifest heart...Subclinical heart involvementPathophysiologyDiagnostic investigationsTreatment and prognosisReferences |
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Cardiac involvement as a cause of death in polymyositis was reported in 10–20% [7, 8, 12, 13]. This figure is uncertain as large epidemiological studies are scarce in which causes of death were registered in patients with polymyositis and dermatomyositis. In one cohort with an average follow-up time of 6 yrs, a nearly four times increased overall mortality for myositis patients compared with the expected in the population was recorded [14]. A 16-times-increased death-rate from myocardial infarction was reported in this myositis population with an even higher risk for females (32 times) than for males (nine times). In two other cohorts, cardiovascular disease was one of the leading causes of death [8, 12].
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Clinically manifest heart involvement |
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TopAbstractIntroductionMortality and cardiovascular...Clinically manifest heart...Subclinical heart involvementPathophysiologyDiagnostic investigationsTreatment and prognosisReferences |
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Clinically manifest heart problems are relatively infrequent in patients with polymyositis and dermatmyositis. The most frequently reported clinically manifest cardiac problem is congestive heart failure, observed in between 3 and 45% of myositis patients [12, 15–18]. Whether this is more than in a matched control population is uncertain due to the lack of controlled studies. However, left ventricular diastolic dysfunction (LVDD) was reported in 12–42% of myositis patients compared with the estimated 30% in the general population, supporting an over risk of at least this type of cardiac manifestation in myositis patients [10, 18]. In some patients heart involvement may have a fatal outcome [12, 15–17]. Coronary heart disease with angina pectoris and myocardial infarction was also reported in patients with myositis, although the frequency is uncertain. In one small Finnish study, clinically manifest heart problems were more frequent. In this study, 16 cases of polymyositis and dermatomyositis were included, and 62% had features of cardiac involvement, most of them were clinically apparent such as congestive heart failure in four and coronary heart disease in six patients [16]. The high frequency of clinically manifest cardiac problem could be a result of a selection of patients, or regional variations of ischaemic heart disease in the population. Also vasospastic angina (Prinzmetal's angina) that accompanied small vessel disease of the heart was reported in one case with dermatomyositis and concomitant Raynaud's pheonomenon [19]. Pericarditis is unusual in patients with inflammatory myopathies, reported with a frequency of
10% [10, 13, 18]. Overt cardiac manifestations may be apparent at time of myositis diagnosis but may also develop and become manifest after the treatment has been initiated. Cardiac failure usually occurs together with active skeletal muscle involvement, but it may also develop despite low inflammatory activity in skeletal muscle disease, during immunosuppressive treatment or even when in remission.
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Subclinical heart involvement |
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TopAbstractIntroductionMortality and cardiovascular...Clinically manifest heart...Subclinical heart involvementPathophysiologyDiagnostic investigationsTreatment and prognosisReferences |
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Subclinical cardiac involvement is much more common than manifest heart problems and the frequency varies depending on the methods used. ECG changes are most common and abnormalities on ECG were observed in 32.5–72% [9, 10, 14, 15, 17, 18]. Whether this is more frequent than in an age and gender matched population is still uncertain in the absence of controlled studies. ECG abnormalities observed in polymyositis and dermatomyositis patients include: atrial and ventricular arrhythmias, bundle branch block, A-V blocks, high-grade heart block, prolongation of PR-intervals, ventricular premature beats, left atrial abnormality, abnormal Q-waves as well as non-specific ST-T wave changes. In one study in which standard populations were referred to as controls, conduction abnormalities in patients with poly- or dermatomyositis including adults and children were observed in 32%, which was significantly more frequent compared with the control populations [17]. A high frequency of bundle branch blocks and A-V blocks were reported. The most frequently observed conduction abnormalities in one study were left anterior hemiblock and right bundle-branch block occurring in 13 and 9%, respectively [17]. There are reports on some patients that required permanent pacemakers and in some cases the conduction abnormalities were reported with fatal out-come [9, 10, 15, 18, 20].
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Pathophysiology |
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TopAbstractIntroductionMortality and cardiovascular...Clinically manifest heart...Subclinical heart involvementPathophysiologyDiagnostic investigationsTreatment and prognosisReferences |
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Polymyositis and dermatomyositis are both characterized by chronic inflammation of skeletal muscle [21]. The inflammatory cellular infiltrates are typically composed of T cells and macrophages, although infiltrates with B cells have been observed in occasional patients, often with dermatomyositis. There seems to be two patterns of the localization and cellular composition of the inflammatory infiltrates in the skeletal muscle. In patients with typical skin rash of dermatomyositis, the inflammatory cellular infiltrates are predominantly localized to areas surrounding blood vessels, perivascularly and mainly observed in the perimysium surrounding the muscle fascicles. These perivascular infiltrates are predominated by CD4+ T cells and by macrophages and dendritic cells. B cells were detected in occasional patients. In patients without skin rash, polymyositis, the inflammatory infiltrates are typically localized within the muscle fascicles, in the endomysium, surrounding muscle fibres. These endomysial infiltrates are predominated by CD8+ T cells and macrophages. Other characteristic histopathological features are muscle fibres changes, such as fiber degeneration or necrosis and regenerating fibres. These observations suggest that there may be two different pathways that are involved in the chronic muscle inflammation in skeletal muscle.
As the heart is a muscle it could be assumed that the muscle inflammation could also involve the cardiac muscle. This assumption is supported by reports of myocarditis and cardiomyopathy in patients with polymyositis and dermatomyositis. The histopathology of the myocarditis resembles the inflammation in the skeletal muscle with mononuclear inflammatory cell infiltrates localized to the endomysium and to the perivascular areas and with degeneration of cardiac myocytes [15, 20]. However, more detailed characterization of the cellular phenotype or localization of inflammation is lacking. Histopathological changes similar to those in the myocardium were also observed in the conducting system including lymphocytic infiltration, fibrosis of the sinoatrial node and contraction band necrosis at autopsy of myositis patients [20, 22]. Some of these cases developed complete heart block.
One of the most frequently reported clinical cardiac manifestations in polymyositis and dermatomyositis is congestive heart failure that could be caused by myocarditis. The myocarditis could also lead to impaired left ventricular dysfunction and restrictive cardiomyopathy. Other pathophysiological mechanisms that may cause LVDD include increased chamber stiffness due to fibrosis, but LVDD may also reflect disturbances in calcium regulation [10].
The most often reported cardiac problems in patients with poly- and dermatomyositis, impaired left ventricular function and arrhythmias, could also be secondary to vascular changes in the heart. Vascular alterations in coronary arteries have also been reported such as vasculitis, intima proliferation, media sclerosis and microvessel disease of the heart with vasospasm angina [16, 17, 20]. In one autopsy study, 44% of the patients had coronary atherosclerosis [20], but this was less frequently observed in other studies [15, 17]. Small vessel disease characterized by narrowing of vessel lumen by smooth muscle hyperplasia with little or no intimal proliferation was also observed, this may cause clinical symptoms like arrhythmia and angina pectoris [15].
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Diagnostic investigations |
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TopAbstractIntroductionMortality and cardiovascular...Clinically manifest heart...Subclinical heart involvementPathophysiologyDiagnostic investigationsTreatment and prognosisReferences |
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Clinical assessment including history and signs of cardiac involvement is important at time of diagnosis as well as during follow-up of myositis patients. Even clinically relevant cardiac manifestations, although silent, may be present, which is why some minimal procedures are recommended to check for cardiac involvement. As arrhythmias and conduction abnormalities are common manifestations in myositis patients, an electrocardiogram (ECG) is recommended at the time of diagnosis. Other investigations are indicated when clinically relevant both at the time of diagnosis and during follow-up.
Electrocardiography (ECG) is the basic method to detect arrhythmias, conduction defects and ST-T changes and should be included in the evaluation of all patients with inflammatory myopathies, as ECG changes are frequent and may demand treatment [17].
Echocardiography. The frequency of echocardiographic abnormalities in patients with poly- and dermatomyositis varies between 14 and 62% [9, 10, 18, 23]. The frequency of cardiac abnormalities in myositis patients may vary due to several factors such as patient selection and different echocardiography techniques. The most frequently observed abnormalities were LVDD, hyperdynamic heart and mitral valve prolapse [9, 10].
Technetium 99m-pyrophosphate scintigraphy permits detection of left ventricular global and regional wall abnormalities and both decreased function and hyperkinetic left ventricular contraction systolic function can be detected [18]. No control group was included in any of the reports that used technetium 99m-pyrophosphate to determine cardiac involvement that makes it difficult to draw conclusion from the results, and the clinical usefulness of this technique needs to be determined.
Gadolinium diethylenetriaminepantaacetic enhanced magnetic resonance imaging (Gd-DTPA-MRI) has been used to detect myocarditis with viral infections and in sarcoidosis and in ischaemic myocardial damage [24, 25]. Enhanced transmural contrast with Gd-DTPA-MRI was observed in the left ventricle of the heart and myocardial inflammation, and interstitial fibrosis was confirmed by endomyocardial biopsy from the same area in a patient with polymyositis and congestive heart failure [25]. Gd-DTPA-MRI had a higher sensitivity to detect myocardial inflammatory areas compatible with myocarditis in three cases with inflammatory myopathies than conventional laboratory tests such as ECG and echocardiography [26]. Two of these patients did not have any clinical cardiac symptoms. Gd-DTPA-MRI was also sensitive to changes when myositis patients with myocarditis were treated for 6 months with corticosteroids and other immunosuppressors [26]. Thus Gd-DTPA-MRI could be a helpful technique to detect myocardial inflammation and possibly to evaluate effects of treatment but its sensitivity and specificity in patients with inflammatory myopathies need to be determined.
Endomyocardial biopsies have been used to confirm myocardial inflammation in patients with poly- or dermatomyositis; however, this invasive method has rarely been used in clinical practices [19, 25].
Biochemistry/autoantibodies
The cardiac isoform troponin-I (cTnI) has the highest specificity to detect myocardial involvement and is the most reliable serum marker to detect myocardial damage in patients with inflammatory muscle disease [27]. The other cardiac troponin isoforms, troponin C (cTnC) and troponin T (cTnT), are less specific and are also expressed in adult skeletal muscle, and increased serum levels have been reported in various muscle disorders.
Creatine kinases (CK) are enzymes in muscle cells, which may be released into the blood stream upon damage of myocytes. CK consists of three isoenzymes designated MM, MB and BB. Adult skeletal muscle contains mainly CK-MM, cardiac muscle CK-MB and smooth muscle CK-BB [28]. In regenerating skeletal muscle fibres, the subunit CK-B is upregulated, which may lead to increased release of CK-MB and CK-BB into the circulation. Notably, in inflammatory muscle disease, without cardiac involvement, the CK-MB/total CK ratio may be more than 3%, which is a threshold that is commonly used to determine myocardial damage [27].
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Treatment and prognosis |
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TopAbstractIntroductionMortality and cardiovascular...Clinically manifest heart...Subclinical heart involvementPathophysiologyDiagnostic investigationsTreatment and prognosisReferences |
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The effects of corticosteroid treatment and other immunosuppressives on cardiac manifestations in patients with poly- or dermatomyositis are conflicting. In some cases congestive heart failure improved during corticosteroid treatment but progressed in other individuals [16, 17, 26]. In a longitudinal study conduction abnormalities progressed and new disturbances developed despite corticosteroid treatment and remission of the polymyositis [17]. In the autopsy study by Denbow et al. [15], the occurrence of myocarditis appeared to be independent of steroid therapy [17]. There are several reports of development of cardiac involvement during follow-up such as conduction abnormalities including complete heart block independent of signs of active disease in skeletal muscle activity [17].
Besides the immunosuppressive therapy, patients with congestive heart failure have been treated with traditional heart medication. Vasospastic angina (Prinzmetal's angina) should be considered in patients with poly- or dermatomyositis, in particular, in those who have Raynaud's phenomenon [19]. Vasospastic angina could be provoked by acetylcholine and successfully treated with high doses of calcium channel blockers [19]. There are a few reports of patients with atrioventricular block who have been treated with pacemaker, in some with successful outcome, but in others the outcome has still been fatal [16, 17, 29]. Recently there was one report of successful heart transplant for dilated cardiomyopathy in a woman with polymyositis, with a 14-month post-operative observation period [29].
The correlation of cardiac manifestations in polymyositis with overall severity of the disease is also controversial. No correlation was observed between presence of conduction abnormalities on ECG and disease activity (CK levels or skeletal muscle inflammation) or disease severity (function) or corticosteroid dosages in one of the studies [10, 17, 18].
In conclusion, clinically significant cardiac involvement is infrequent in polymyositis and dermatomyositis, but cardiovascular manifestations constitute a major cause of death. This could indicate that significant cardiac involvement in patients with myositis is underestimated or that cardiac involvement is a late complication of the inflammatory muscle disease or a consequence of the treatment. Available data suggests that inflammation of the heart muscle could contribute to the pathophysiological mechanisms that could lead to myocarditis and congestive heart failure or conduction disturbances in patients with myositis. The prevalence of these problems in myositis is unknown. Furthermore, whether cardiac involvement is more prevalent in polymyositis or dermatomyositis or is restricted to a certain subtype of myositis is still unclear. To address these questions controlled studies with carefully characterized patients are needed.
The author has declared no conflicts of interest.
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References |
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TopAbstractIntroductionMortality and cardiovascular...Clinically manifest heart...Subclinical heart involvementPathophysiologyDiagnostic investigationsTreatment and prognosisReferences |
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