Keywords

FormalPara Key Points to Remember

  • Clinically evident heart problems such as symptomatic arrhythmias and congestive heart failure are reported in anywhere from 3% to 10% of patients with IIM, and the incidence of asymptomatic cardiac disease in IIM patients is even higher.

  • Initial evaluation of cardiac status with assessment of traditional CV risk factors as well as echocardiogram and EKG, especially if high cardiovascular risk is recommended in IIM patients.

  • Cardiac MRI and technetium99m-pyrophosphate scintigraphy are noninvasive imaging tools that can be utilized.

  • Comprehensive screening of cardiac function in all IIM patients should be undertaken if patients present with any cardiac or even nonspecific unexplained symptoms.

  • cTnI is more specific for myocardial damage and should be used to evaluate the myocardium in IIM, whereas cTnT and CK-MB are nonspecific and elevated with elevation of CK.

  • Immunosuppressive therapies in conjunction with traditional cardiac medications and risk mitigation can be used for the treatment of cardiac disease in IIM. Severe cases may require pacemaker or defibrillator placement.

Introduction

Cardiac involvement in idiopathic inflammatory myopathies (IIM) was first reported in the late nineteenth century by Oppenheim [1] but until the late 1970s was considered to be a rare disease manifestation. However, with the introduction of sensitive, noninvasive techniques to assess cardiac involvement, heart disease is now a well-recognized clinical manifestation of IIM [2,3,4]. In earlier reports, the cardiac manifestations in IIM were primarily described as being occult or subclinical, mostly manifesting as conduction abnormalities [5]. However, as additional data on various noninvasive testing have accumulated, it has become evident that the heart muscle is frequently affected in patients with IIM, and more importantly, cardiovascular events are one of the major causes of morbidity and mortality [6,7,8,9]. To date, there have been no large epidemiological studies on cardiac involvement in IIM, and thus, the exact frequency of heart involvement is still unknown. In smaller cohort studies, the reported incidence of cardiac involvement varies between 6% and 72% dependent on patient selection, the definition of heart involvement, and the diagnostic modalities used for screening [10,11,12]. Clinically evident heart problems are reported in 3–10% of patients with IIM, of which symptomatic arrhythmias and congestive heart failure constitute a large portion [13].

Pathophysiology

Distinct histopathological features are noted in the skeletal muscle of polymyositis (PM) and dermatomyositis (DM) patients [14]. Similarly, autopsy studies of DM and PM patients demonstrate inflammatory infiltration of the myocardium that resembled the inflammation in the skeletal muscle [15]. Diffuse, severe mononuclear inflammatory infiltrates and fibrosis localized to the endomysium and the perivascular areas were reported with associated degeneration of cardiac myocytes. Such findings were also noted in the conduction system including the SA-AV node and His-Purkinje conduction system, suggesting a mechanistic link to the clinically observed conduction abnormalities including complete heart block [15, 16].

A recent case report compared detailed histopathological findings of both the heart and the skeletal muscle of a DM patient undergoing heart transplantation [17]. A distribution of muscle fiber damage/atrophy in the peripheral areas of the cardiac muscle was noted to be similar to the perifascicular distribution in the DM skeletal muscle. Intense perimysial alkaline phosphatase reactivity was also noted in the cardiac and skeletal muscles. Finally, overexpression of membrane attack complex (MAC) on capillaries, another hallmark finding of DM, was present in both the cardiac and skeletal muscles of the same patient further supporting a similar pathogenesis.

  • Cardiac muscle shows similar histopathological findings as skeletal muscle in DM.

  • Inflammatory infiltrates and fibrosis are seen in the endomysium, perivascular, and perifascicular regions of the cardiac muscle as well as in the conduction system.

Clinical Manifestations

Clinically significant cardiac involvement constitutes a small portion of patients with DM/PM. Table 8.1 represents proportions of clinical symptoms in compiled IIM cohorts in a systematic review. The most commonly reported cardiac problem is congestive heart failure seen in 5–12% of patients [2, 4, 5, 16, 18]. Symptoms such as dyspnea, orthopnea, and palpitations are reported in 5–20% of IIM patients [4, 12, 16], but it is difficult to differentiate between a primary cardiac cause and concurrent respiratory muscle weakness due to skeletal muscle involvement [19].

Table 8.1 Clinically evident cardiac involvement
Full size table

Ischemic heart disease is important in IIM, and angina pectoris has previously been reported in 4–18% of IIM patients [4, 5]. Interestingly, autopsy studies have demonstrated significantly more coronary artery disease than reported clinically as angina, with coronary atherosclerosis including intimal proliferation, medial sclerosis, luminal narrowing, and evidence of remote infarction in up to 44% of patients [5, 15, 18]. In prospective IIM cohorts, MI was seen in 4.6–6.8%, which is similar to the reported age-matched prevalence in the US population [13]. However, a recent large Canadian population study noted an incidence rate of MI being significantly higher than in the general population (22.5 vs. 5.5 events per 1000 person-years) with hazard ratios being the highest within the first year of IIM diagnosis [20]. Vasospastic angina has also been reported to be associated with signs of generalized vasculopathy such as Raynaud phenomenon [21].

Symptoms of arrhythmias and conduction defects such as palpitations, dizziness, and syncope have also been reported in up to 13.8% of IIM patients in prospective cohorts [13]. Such signs may suggest developing fibrosis of the conduction system and should be monitored carefully. Although the mild rhythm disorders do not commonly have clinical significance, there are several reports of patients requiring permanent pacemaker placement and others having fatal arrhythmias [4, 18]. Taken together, this data reinforces the need for increased awareness and monitoring of cardiac involvement in IIM patients. Comprehensive screening of cardiac function in all IIM patients should be undertaken if patients present with any cardiac or even nonspecific unexplained symptoms.

Subclinical Heart Involvement

Subclinical cardiac involvement is reported much more commonly than clinically evident cardiac manifestations, and the reported incidence varies between 13% and 72% of IIM patients depending on the selected noninvasive testing [22]. However, the clinical and prognostic significance of these subclinical cardiac abnormalities are not well known such that routine screening is not recommended beyond initial cardiac evaluation in the asymptomatic patient. Abnormal EKG findings are the most commonly observed findings including atrial or ventricular premature beats, atrial/ventricular tachycardia, atrial fibrillation, A-V conduction block, high-grade heart block, bundle branch block, PR prolongation, abnormal Q waves, nonspecific ST-T wave changes, and left ventricular hypertrophy [4, 18]. Echocardiography is useful in detecting structural heart disease and cardiac function even in the absence of clinical symptoms. In patients with IIM, there are reports of atrial enlargement, ventricular hypertrophy, valvular changes such as thickening and stenosis, global or segmental hypokinesis, reduced systolic or diastolic function, and pericardial involvement [22]. Newer techniques such as tissue Doppler imaging [23] allow detection of earlier manifestations such as left ventricular diastolic dysfunction (LVDD) when conventional measurements may be unremarkable [24]. The incidence of LVDD seems to be significantly higher in IIM patients compared to the general population [25].

  • Initial evaluation of cardiac status with assessment of traditional CV risk factors, echocardiogram, and EKG is recommended in IIM patients.

  • No routine follow-up screening is currently recommended beyond initial cardiac evaluation in an asymptomatic patient.

  • Comprehensive cardiac workup is recommended in a patient with cardiac or nonspecific, unexplained symptoms.

Diagnostic Modalities

Clinically relevant cardiac manifestations may be present even without overt symptoms, which is why noninvasive testing is recommended at the time of diagnosis.

  1. 1.

    Electrocardiogram (EKG)

EKG or Holter abnormalities are detected in 32–72% of IIM patients, which is significantly more frequent than the general population. The most well-described finding is a conduction abnormality, with the most frequently observed being left anterior hemi-block and right bundle branch block [18]. SA or AV nodal dysfunction related to extensive fibrotic damage of the conduction system can be seen and may even result in high-degree heart block, which has been reported in 1–2% of patients. Other rhythm abnormalities include premature atrial or ventricular contractions, atrial dysarrhythmias, ventricular tachyarrhythmias, longer QRS, and supraventricular tachycardia [25]. Nonspecific ST-T wave changes are also seen frequently in 4–15% of patients [22] (Table 8.2).

Table 8.2 ECG abnormalities in IIM patients
Full size table

As rhythm and conduction abnormalities are the most commonly reported cardiac manifestations in IIM patients, experts recommend routine ECG at time of diagnosis. ECG and telemetry monitoring should also be done when patients present with symptoms such as palpitations or syncope. Findings such as high-degree heart block or tachyarrhythmias may require therapeutic intervention such as a permanent pacemaker or defibrillator placement.

  • Baseline EKG should be done in all patients diagnosed with IIM.

  • EKG abnormalities are common in IIM patients, but most are not clinically significant.

  • No association between myositis disease activity and EKG abnormalities has been found in the studies to date.

  • Severe arrhythmias in IIM patients may occur and require telemetry for diagnosis and pacemaker/defibrillator placement.

To date, the degree of systemic disease activity does not seem to correlate with the presence of ECG abnormalities [15, 16]. In a cohort of 77 IIM patients, there was no association between the presence of ECG abnormalities and CK levels, severity of IIM, presence or absence of various clinical phenomenon (i.e., arthritis, Raynaud phenomenon, rash, ILD, malignancy), disease duration, or treatment. Furthermore, ECG findings frequently progressed during clinical remission [18].

  1. 2.

    Echocardiogram

Few prospective, detailed echocardiographic studies are available in the literature, which report echocardiographic abnormalities in 14–62% of myositis patients [4, 11, 23, 26]. Left ventricular diastolic dysfunction (LVDD) by tissue Doppler imaging (TDI) is the most frequently reported abnormality, noted in up to 48% of IIM patients, which is significantly higher than in the general population (30%) [24, 25, 27]. LVDD may be reflective of increased chamber stiffness due to fibrosis and is usually the first sign of systolic and diastolic heart failure. TDI estimates the velocity of contraction and relaxation of myocardial segments during a cardiac cycle. The use of TDI has increased sensitivity and specificity for systolic and diastolic dysfunction when compared to traditional echocardiography [28] and has been shown to be a useful tool to detect preclinical cardiac impairment in several studies [24, 25, 27, 29]. Two prospective controlled studies of echocardiographic measurements on 46 IIM and 51 DM patients with age- and gender-matched healthy controls confirmed a higher frequency and/or severity of LVDD in IIM [24, 27]. In contrast to diastolic dysfunction, compromise of systolic function noted by decreased LV ejection fraction on echocardiogram is rarely noted except when severe cardiac involvement and typical CHF symptoms are present.

Finally, other observed findings noted on echocardiography include mitral valve prolapse (7–23%), hyperdynamic LV function, left atrial and/or left ventricular enlargement, left ventricular hypertrophy, septal hypertrophy, thickened valve leaflet, valve prolapses/stenosis/regurgitation (most frequently in the mitral and aortic valve), pericardial effusions (which were all hemodynamically insignificant), and pulmonary hypertension [30]. However, reported incidences are observational from prospective patient cohorts, and it is unclear if such findings are more common in IIM compared to healthy controls.

  • Left ventricular diastolic dysfunction (LVDD) is reported more frequently in IIM patients compared to matched healthy controls.

  1. 3.

    Cardiac Magnetic Resonance (CMR)

CMR provides not only anatomical imaging but also the ability to detect features of myocardial tissue such as inflammatory edema, irreversible necrosis or scarring, and contractile dysfunction [31]. Contrast-enhanced MRI technique using gadolinium diethylene-triaminepantaacetic (Gd-DTPA) is able to differentiate between myocardial infarction and inflammatory tissue from myocarditis. Early contrast enhancement with high signal intensities detected within the first minutes of injection indicates myocardial hyperemia; however, late gadolinium enhancement (LGE) [32] is highly sensitive for irreversible injury demonstrated as areas with high signal intensity in the equilibrium phase (>10 min post injection) [33]. The pattern and regional distribution of LGE is helpful in distinguishing the etiology of myocardial disease, whereas the severity or extent of LGE is associated with a worse prognosis [34, 35]. Inflammatory myocarditis may have a patchy distribution and can be subepicardial, sparing the subendocardium, which is distinct from ischemic lesions that always involve the subendocardium [36]. As IIM patients have an increased risk of both inflammatory myocarditis and ischemic events, CMR can be considered to differentiate between the two with the differences in regional distribution. This suggests CMR as a useful tool in diagnosis as well as monitoring of myocardial inflammation in IIM [37,38,39].

CMR may also be a useful tool in early detection of subclinical cardiac involvement in IIM by determining the extent of unrecognized myocardial scarring [39]. CMR is also sensitive to changes in the cardiac muscle following treatment. In a study of four patients with IIM and myocarditis, after 6 months of treatment with glucocorticoids, the area of early and delayed contrast enhancement on CMR was substantially reduced and correlated with improvement of cardiac symptoms [38].

  • Cardiac MRI is a useful noninvasive tool for detection of inflammation vs. myocardial damage in IIM.

  1. 4.

    Technetium99m-Pyrophosphate (99mTc-PYP) Scintigraphy

Cardiac uptake of 99mTc-pyrophosphate (99mTc-PYP) in particular has been suggested as a mode of detecting inflammatory activity of the myocardium in IIM patients. A study of 30 DM/PM patients reported abnormal 99mTc-PYP uptake in 57% of patients suggesting that it may assist in early detection of cardiac involvement [40]. Patients with high uptake scores had poor cardiac outcome, and autopsy showed perivascular and interstitial mononuclear infiltrates and degenerative muscle fibers within the myocardium [40]. Smaller studies also have used 99mTc-PYP in the detection of cardiac outcome in IIM and reported uptake in 50–76% of patients [41,42,43]. However, without large comparative studies with a control group, the clinical usefulness of scintigraphy in IIM-related myocarditis is yet to be proven, and further studies are warranted. False-positive results may be seen with hyperparathyroidism, prior myocardial infarction, dystrophic cardiac calcification, and ventricular aneurysms.

  1. 5.

    Endomyocardial Biopsy

Endomyocardial biopsies allow histologic confirmation of inflammatory myocarditis and are the gold standard for diagnosis. However, biopsies are rarely performed in routine clinical practice given the invasive nature and concern for complications such as vascular injury, puncture site complications, or prolonged bleeding [44] and should only be considered at a center where it is performed routinely. A case of endomyocardial biopsy in a patient with abnormal contrast enhancement on Gd-DTPA CMR showed interstitial fibrosis, edema, cellular cluster, and hypertrophy, suggestive of inflammatory damage [45].

  • Endomyocardial biopsy is the gold standard for myocarditis due to connective tissue disease, but is not commonly done due to the risk of complications related to an invasive procedure.

  1. 6.

    Biochemical Markers

Cardiac enzymes in patients with IIM must be interpreted with caution, as elevations may be from damaged or regenerating skeletal muscle. Creatine kinase isoenzymes include the CK-MM form, which is mainly from the skeletal muscle, and the CK-MB isoform, which is thought to be restricted to the myocardium. Although cardiac enzymes are reported to be specific for myocardial damage and ischemia, there have been reports of elevated CK-MB levels and CK-MB/CK ratios in IIM patients even in the absence of cardiac symptoms or ECG changes [46,47,48]. This is also true for cardiac troponins, which are typically thought to be highly specific for myocardial ischemia [49, 50]. It is thought that as regenerating muscle fibers resemble fetal muscles and express similar genes, CK-MB and cTnT isoforms (which are known to be expressed in the skeletal muscle during fetal development) are re-expressed in damaged or regenerating skeletal muscle. Hence, elevated CK-MB and cTnT may be misleading in IIM patients and result in unnecessary investigations for coronary artery disease.

Cardiac troponin isoform I (cTnI) is only expressed in the heart during fetal development and unlikely to be found in a noncardiac muscle [51, 52]. In a study of 49 patients with IIM, CK elevations had a high correlation with cTnT but not with cTnI, suggesting cTnI is the most reliable serum marker to detect myocardial damage in patients with IIM [53, 54]. A study by Erlacher and colleagues also measured various “cardiac” enzymes in IIM patients without clinical evidence of cardiac involvement and showed CKMB elevation in 51%, cTnT in 41%, and cTnI in only 2.5% of patients. CTnT, but not cTnI, was correlated with disease severity scores and skeletal muscle damage markers [55].

  • CK-MB and cTnT may be elevated in myositis without cardiac involvement

  • cTnI is more specific for myocardial damage and should be used to evaluate the myocardium in IIM

Management

  1. 1.

    Glucocorticoids and Immunomodulatory Agents

There are no randomized trials to evaluate the treatment effects for DM/PM-specific heart disease. Glucocorticoids and immunosuppressive therapy are used to control the underlying disease process as active disease is thought to be driving the cardiac disease. However, reports of response in the cardiac manifestations to immunosuppressive therapy are conflicting. In a study of four patients with IIM-related myocarditis, two of four (50%) patients who presented with symptoms of heart failure had resolution of their symptoms after 2 months of immunosuppressive therapy, and cardiac MRI normalized in all four patients after 6 months, suggesting a beneficial role for systemic immunosuppression [38]. In contrast, other studies assessing abnormal EKGs, complete heart block, and abnormalities on autopsy in IIM cohorts suggested that cardiac involvement was independent of skeletal muscle disease activity or treatment [16, 18, 56].

Systemic immunosuppressive agents other than glucocorticoids that have been used in treating cardiac disease in IIM include cyclophosphamide, cyclosporine, methotrexate and azathioprine, but the impact of individual agents remains unknown. Intravenous immunoglobulin (IVIG) has shown good immunomodulatory effects in IIM and is frequently used for cutaneous and skeletal disease. There are no studies of its use in IIM cardiac disease, but in pediatric acute myocarditis, IVIG was shown to improve LV function and survival in the first year after treatment [57]. When considering IVIG in patients with IIM cardiac involvement, it is important to consider co-management with cardiology and close monitoring of their volume status with appropriate adjustments in their diuretics given the risk of volume overload with IVIG. Subcutaneous immunoglobulin also may be of benefit with lower risk of volume overload in such cases [58].

  1. 2.

    Traditional Cardiac Medications

For clinically evident cardiac involvement, patients are managed similarly to non-IIM patients in regard to their cardiac manifestations. Antiarrhythmics, antianginals, and heart failure medications are considered depending on the clinical presentation. When there is myocardial involvement with clinically significant CHF, pharmacological treatment includes beta-blockers, aspirin, diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin-II receptor blockers (ARBs) [59]. IIM patients also have a higher risk of vascular involvement leading to ischemic episodes in which case anti-anginals such as calcium channel blockers and nitrates may be used.

  1. 3.

    Pacemaker and Cardiac Implantable Cardiac Defibrillator

Conduction abnormalities including high-degree heart block are seen in IIM patients with cardiac involvement, and there are several reports of patients requiring a temporary or permanent pacemaker placement (PPM) with variable outcomes [18, 56, 60]. In the general population, PPM success rates are reported between 88% and 92%, but success rates in IIM patients are yet to be determined [59]. Some reports have shown a successful outcome, whereas others have noted mortality from progressive conduction abnormalities resulting in sudden cardiac death (SCD) despite PPM placement. Most cases that require PPM placement were below the AV node with SA node dysfunction noted infrequently [60].

Cardiac resynchronization therapy with an implantable cardiac defibrillator (ICD) may be considered in patients with symptomatic ventricular tachycardia or ventricular fibrillation which can be fatal. In non-IIM patients, cardiac resynchronization therapy with ICD is indicated for patients with impaired LV function (LV ejection fraction <35%) and left bundle branch block in NYHA functional classes II to IV [61]. There are no studies regarding ICD placement in patients with IIM-related myocarditis, and further investigation is needed to address the benefits and timing of ICD placement in IIM-related cardiomyopathy.

  1. 4.

    Management of Traditional Cardiovascular Risk Factors

There is increasing evidence of a higher prevalence of traditional cardiovascular risk factors (obesity, hypertension, dyslipidemia) in patients with IIM [62,63,64,65]. One retrospective study of 344 patients with IIM reported a high prevalence of hypertension (62%) and diabetes (49%) [62], and other cross-sectional studies have shown an increased frequency of dyslipidemia, glucose intolerance, and obesity [63,64,65]. A Canadian population study showed an increased myocardial infarction frequency but not ischemic stroke in DM and PM patients compared to age-/gender-matched control group selected from the general population [66]. Age/sex/entry time-matched hazard ratios (HR) for MI among PM and DM patients compared with the control cohort were 5.2 and 3.5, respectively. For stroke, the HR for PM was 2.46 and for DM was 1.81 (not statistically significant). The incidence of MI and stroke were highest in the first year of diagnosis.

Several contributing factors have been proposed to explain the increased atherosclerosis in patients with IIM. Long-term use of glucocorticoids is known to increase glucose intolerance and dyslipidemia and accelerate the development of atherosclerosis. The Danish study demonstrated that present use of glucocorticoids correlated with severe coronary artery calcification [65]. Physical inactivity caused by the disease itself as well as the constant low-grade inflammation may also lead to increased development of atherosclerosis and metabolic syndrome, as suggested in patients with RA and SLE [67, 68].

Such results support increased vigilance in cardiovascular prevention and aggressive treatment of modifiable CV risk factors in IIM. Structured exercise programs have been well established as beneficial to skeletal muscle disease in IIM [69, 70], but the increased physical activity and improvement in aerobic capacity may also be beneficial in improving cardiovascular outcomes. Statins are completely contraindicated in patients with immune-mediated necrotizing myopathy related to the anti-HMGCR antibodies [71, 72]. Approximately 10% of patients developed some worsening muscle symptoms associated with statin use with the majority of symptoms improving after holding therapy, suggesting that particular attention should be paid to statin use in some myositis patients.

  1. 5.

    Cardiac Transplantation

Severe cardiac involvement in IIM requiring cardiac transplantation is rare, and only a few cases of cardiac transplant in IIM have been reported. Successful cardiac transplantation was first reported in 1999 in a patient with dilated cardiomyopathy related to polymyositis [73]. A recent report described a case of a patient with treatment refractory DM with severe cardiomyopathy with cardiogenic shock who underwent a successful orthotropic heart transplant doing well at 25 months post-transplant [17].

Cardiac Management

  • Immunosuppressive/immunomodulatory therapies

    • Glucocorticoids

    • Other immunosuppressive agents including cyclophosphamide, cyclosporine, methotrexate, azathioprine, etc.

    • IVIG or SQIG

  • Traditional cardiac medications

    • Beta-blockers, aspirin, diuretics, ACE inhibitors, or ARBs

    • Antiarrhythmic drugs

  • Risk factor modification

    • Smoking

    • Obesity

    • Diabetes/insulin resistance

    • Hypertension

    • Dyslipidemia

    • Steroids

  • Pacemaker and cardiac implantable cardiac defibrillator

  • Cardiac ablation

  • Cardiac transplantation

Footnote 1

Prognosis

Patients with DM/PM have increased mortality compared to the general population with cardiopulmonary disease as the leading cause of death, ranging between 5% and 20% [8, 10, 12, 75]. Congestive heart failure and/or myocarditis, myocardial infarction, and complete heart block were most frequently noted in a systematic review including 33 retrospective and prospective IIM cohorts (30%, 18%, and 10%, respectively) (Table 8.3) [13]. Unlike viral myocarditis, which leads to spontaneous recovery with minimal or no sequelae, cardiac involvement in IIM portends an overall poor prognosis of the disease [59]. Prospective studies are needed to evaluate the effect of various cardiac and immunomodulatory therapies/strategies on survival in IIM patients.

Table 8.3 Causes of cardiac mortality
Full size table

Conclusions and Recommendations

Cardiac involvement is increasingly recognized in patients with IIM as a poor prognostic factor as well as a major cause of morbidity and mortality. When clinically evident, patients may present with congestive heart failure, arrhythmias, or coronary artery disease, but most patients will have subclinical involvement that is only evident on further testing. Experts recommend that all patients with a diagnosis of IIM undergo a detailed cardiac history and a screening EKG and echocardiogram on initial evaluation. Tailored cardiac therapy should be used in conjunction with immunosuppression, and patients require continued monitoring even when the skeletal disease is in remission (Fig. 8.1.).

Fig. 8.1
figure 1

Evaluation of cardiac involvement in IIM. * Co-management by Cardiology and Rheumatology for all IIM patients with cardiovascular disease

Full size image