Cardiovascular manifestations in idiopathic inflammatory myopathies

Although first described in 1899 by Oppenheim, cardiac involvement in myositis was not a well-recognized manifestation until the 1970s [8, 9]. The understanding and definition of cardiac involvement in myositis have significantly evolved in recent years owing to the advent of more sensitive diagnostic techniques [10]. The prevalence of cardiac manifestations in IIM varies widely, ranging from 6 to 75% depending on the patient inclusion criteria, definition of cardiac involvement, and the imaging modalities used. Importantly, a substantial proportion of cardiac involvement in myositis is subclinical, with fewer than 10% being clinically manifest unless investigated [9]. The EuroMyositis registry, comprising 3067 cases across 11 countries, reported that cardiac involvement occurring due to the IIM disease process was most frequent in the connective tissue diseases-overlap myositis group and was least frequent in patients with IBM [11].

Several independent research groups worldwide have reported an increased risk of cardiovascular mortality in patients with IIM. For instance, a Swedish population-based nationwide cohort study by Dobloug et al. found that cardiac disease was one of the most common causes of mortality among IIM patients [2]. In a retrospective cohort study by Limaye et al., a standardized mortality ratio (SMR) of 1.75 was reported in IIM; the ratio was highest in the DM subtype at 2.40. The study also found that cardiovascular disease accounted for nearly one-third of deaths in the cohort of 364 individuals from South Australasia, followed by infection (22%) and malignancy (11%) [12]. Similarly, a large Korean population-based study of 3014 cases confirmed a high SMR and a high incidence of cardiovascular disease, even in young individuals with IIM (DM: 15.0, PM: 8.1) [14]. Dankó et al. conducted a survival analysis of 162 Hungarian patients and found that lung and cardiac complications were the most frequent causes of death. Death attributable to cardiovascular complications occurred late in the course of the disease (median 59 months). Cardiovascular manifestations were responsible for 8 out of 18 deaths (two cases of arrhythmia, three of heart failure, two of cardiac arrest, and one of myocardial infarction) and were identified as significant adverse prognostic factors [13].

Collectively, these studies suggest cardiac complications are a common cause of mortality among IIM patients.

Accumulating evidence suggests an increased incidence of cardiovascular diseases such as acute coronary syndrome, heart failure, and arrhythmias in patients with IIM. Two meta-analyses (Xiong et al. and Ungprasert et al.) have examined the association between IIM and cardiovascular events in patients with PM and DM. The study by Xiong et al. included 25,433 patients with PM/DM and found a 2.3-fold increase in the risk of cardiovascular events within the first 5 years of IIM diagnosis. Moreover, PM/DM was identified as an independent risk factor for the development of cardiovascular events [15]. The study by Ungprasert et al., which comprised 13,201 patients, reported a 2.24-fold increased risk of cardiovascular disease in patients with IIM. Indeed, cardiovascular disease was identified as the leading cause of mortality in this cohort [16]. Prieto et al. conducted a study in the UK comprising 603 patients with IIM and reported a significantly greater rate of cardiovascular events in patients with IIM than in healthy controls, even after adjustment for traditional cardiovascular risk factors. This finding suggests that the increased risk could not be entirely attributed to traditional cardiovascular risk factors and was partly accounted for by the systemic inflammation present in these patients. The excess risk was most apparent in the first 5 years post IIM diagnosis and then appeared to decline [17]. These results are consistent with a case-control study which reported an increased risk of cardiovascular disease in patients with IIM, even in the absence of traditional risk factors [18]. Overall, the evidence suggests that patients with IIM have an increased risk of developing cardiovascular disease, particularly within the first 5 years of IIM diagnosis. This risk cannot be entirely attributed to traditional cardiovascular risk factors and may be partly due to systemic inflammation.

Diabetes mellitus, hypertension, and dyslipidemia are traditional risk factors for coronary heart disease. Several studies have investigated the prevalence of these risk factors in patients with IIM [12, 19, 21‐27]. For instance, Diederichsen et al. observed a higher prevalence of hypertension (71% versus 42%) and diabetes mellitus (13% versus 0%) in patients with DM and PM compared to age- and sex-matched healthy controls. Patients with IIM also had significantly higher levels of serum triglycerides. Multivariate analysis revealed that smoking and age were associated with accelerated atherosclerosis in this cohort [20].

This same study showed that the presence of coronary artery atherosclerosis, as evidenced by calcification on computed tomography scan, was more prevalent in IIM patients. However, this was associated with the presence of traditional cardiovascular risk factors rather than IIM-specific factors [20]. Conversely, Prieto et al. reported an increased risk of cardiovascular diseases in patients with IIM even in the absence of traditional cardiovascular risk factors [17]. A systematic review and meta-analysis by Qin et al. also reported that patients with IIM were 1.44, 1.67, and 1.48 times more likely to have hypertension, diabetes mellitus, and dyslipidemia respectively, when compared with non-IIM individuals [22]. In a case-control study by Wang et al., untreated patients with early PM (n = 60) had dyslipidemia characterized by high triglyceride and low high-density lipoprotein cholesterol levels, suggesting a high risk of atherosclerosis [19]. Similarly, a study by Pakhchanian et al. using the TriNetX database (5578 DM patients) found that 66.82% of patients had hypertension as opposed to 25.05% of the general population. The prevalence of ischemic heart disease (27.18% vs 7.3%) and diabetes mellitus (33.87% vs 12.14%) was also higher in DM patients when compared to the general population [23]. In contrast, a single-centre study (n = 39 patients) conducted by Oreska et al. found no significant differences in the prevalence of traditional risk factors between patients with IIM and healthy controls [24]. While mixed results have been reported, large cohort studies and meta-analyses all suggest an increased risk of cardiovascular risk factors in patients with IIM.

A possible mechanism for accelerated cardiovascular disease in IIM was explored in a study evaluating the antioxidant function of high-density lipoprotein (HDL) particles isolated from patient blood. The protective function of HDL in IIM patients was abnormal compared to healthy controls, with patients with DM and those with higher disease activity having particularly impaired HDL function [21]. Together, these studies underscore the need to determine the relative contribution of conventional risk factors vis-à-vis disease-specific inflammation-induced accelerated atherogenesis in the development of cardiovascular disease.

Various types of conduction system abnormalities have been described in patients with IIM, including supraventricular and ventricular tachycardia, fascicular blocks, bundle branch blocks, and atrioventricular (AV) blocks. In a large retrospective cohort study of 32,085 patients with DM or PM, Naaraayan et al. reported a significantly higher prevalence of atrial fibrillation, atrial flutter, supraventricular tachycardia, and unclassified arrhythmias in patients with IIMs < 70 years old compared with matched controls. The prevalence of arrhythmias was found to be higher in men than in women. Importantly, the diagnosis of arrythmias was associated with significant in-hospital mortality among patients with PM/DM [28]. A cross-sectional study of 112 IIM patients (78 DM and 34 PM) by Deveza et al. reported a higher frequency of arrhythmia in patients with PM when compared with DM. However, there was no significant difference in the occurrence of arrhythmias between IIM patients and the control group [29]. In a retrospective cohort study of 75 patients with IIM by Huang et al., PM and positive serum anti-mitochondrial antibodies (AMA) were strongly associated with ventricular arrhythmia in PM/DM patients with myocardial involvement [30].

Several mechanisms which may predispose to arrhythmias in patients with chronic inflammatory diseases such as IIM have been hypothesized, including infiltration of atria or ventricle by inflammatory cell infiltrate, autonomic dysfunction with resultant reduced heart rate variability and ‘acquired channelopathies’ due to release of cytokines or autoantibodies [31]. In a clinicopathological study of 16 autopsied patients with PM/DM conducted by Haupt et al., direct involvement of the conduction system by myositis and contraction-band necrosis was described [32].

Inflammation is known to play a role in promoting thrombosis by upregulating procoagulant pathways, downregulating natural anticoagulant factors and suppressing fibrinolysis [33]. An increased incidence of thrombosis in patients with chronic inflammatory diseases and autoimmune diseases is well described [34‐38]. Patients with IIM are no exception, with several studies having reported a significantly increased risk of venous thromboembolism in patients with DM/PM [34, 39‐42]. An enhanced in vitro thrombin generation profile in patients with DM/PM has been demonstrated, which may correlate to an increased risk of thromboembolic events [43]. Carruthers et al. reported an eight- and six-fold higher risk of developing venous thromboembolism in patients with DM and PM respectively. Notably, this risk was highest during the first year for patients with PM and during the initial 2 years after diagnosis in patients with DM, potentially attributable to uncontrolled inflammatory activity [44]. Similarly, in a retrospective analysis of 1144 Chinese patients with IIM, over half of IIM patients with thromboembolic events developed this complication in the 6 months before or after diagnosis of IIM. Increased myositis disease activity, malignancy, infection, and duration of steroid use were significant risk factors for thrombosis in this study [45]. A Swedish population-based cohort study (Antovic et al.), found that the risk of thromboembolic events was eight times higher in patients with IIM than in the general population, with the highest observed in patients with DM and a history of cancer. In line with other reports, the incidence rates were maximum in the first year post diagnosis and decreased thereafter [46]. Conversely, another retrospective cohort study found that age at diagnosis was the only independent risk factor for thrombotic events in patients with IIM. For each year of age, there was a 3.5% increased chance of experiencing a thrombotic event in patients with IIM. In their cohort of 253 patients with IIM, only 6% had anti-phospholipid antibodies, with no significant difference between the patients and comparators [47].

Pregnant women with autoimmune disease, including IIM, are also at an increased risk of thromboembolism. Indeed, Bleau et al. studied 43,523 pregnant women with autoimmune disease and observed that the risk of thromboembolism was particularly high for patients with DM comparted to other autoimmune diseases [48].

Numerous studies have investigated the relationship between IIM and cardiovascular events. In a case-control analysis of 10,156 patients with DM conducted in the USA, researchers found that 20% of all DM hospitalizations were associated with an atherosclerotic cardiovascular diagnosis. Patients with DM and atherosclerotic heart disease were twice as likely to die during their hospital stay compared to DM patients who did not suffer from atherosclerotic heart disease (odds ratio (OR) 2.0, 95% confidence interval (CI) 1.7–2.5, p < 0.0001). Furthermore, among patients with both DM and cardiovascular disease, the odds ratio for death was 1.98 when compared to controls with only cardiovascular disease [49]. This suggests an additive effect of DM and cardiovascular disease on risk of death. Similarly, other studies have reported an increased risk of coronary heart disease in IIM patients when compared to controls [50, 56].

Patients with IIM are at a significantly increased risk of experiencing an acute coronary syndrome (ACS) when compared to the general population as evidenced by several studies [51‐54]. A study by Lin et al. reported a greater incidence of ACS in men than in women, and in those with hypertension and end stage renal disease. However, the authors also noticed an higher risk of ACS [Hazard ratio (HR) 1.75] in DM/PM patients without comorbidities when compared to the non-DM/PM cohort, leading them to postulate that mechanisms other than traditional cardiovascular risk factors may contribute to the increased ACS risk in these patients [53]. In line with previously mentioned study, Lai et al. reported an adjusted HR (3.37) for acute myocardial infarction close to the crude hazard ratio (3.96) in 907 patients of DM, implying that DM plays an independent role in increased cardiovascular events [54]. Finally, a nested case-control analysis by Tisseverasinghe et al. reported an association between the incidence of myocardial infarction and stroke, hypertension and lipid abnormalities. On the other hand immunomodulators such as methotrexate, azathioprine, antimalarial agents, cyclophosphamide were negatively associated with these arterial events [55].

Thus, factors besides traditional cardiovascular risk factors might contribute to the increased risk of cardiovascular disorders in patients with IIM; a finding which needs to be explored further.

Heart failure is the most frequently reported clinically apparent cardiovascular manifestation in patients with IIM [9, 57]. In a retrospective cohort study in Taiwan, patients with PM/DM showed a significantly increased risk of heart failure as compared to those without PM/DM (HR 2.06, 95%CI 1.36–3.12). The risk of heart failure was found to be highest within first 10 years following diagnosis of PM/DM [58]. In a cross-sectional multicenter study of 108 patients with IIM and with myocardial involvement, 62% of patients presented with heart failure, 56.5% with clinically significant arrhythmia, and 18.5% of patients presented with both. Anti-mitochondrial antibodies and pulmonary hypertension were significant associated factors [59]. In a single center retrospective study of 32 Chinese patients with IIM and heart failure, 13 of the 17 recorded deaths were attributed to cardiogenic shock [60].

Diagnosing myocarditis in patients with inflammatory myopathies poses a challenge due to its subclinical nature in the majority of cases [9]. The prevalence of myocarditis in IIM has been reported to be 38% on cardiac pathology [61]. Conversely, Dieval et al. reported that the prevalence of clinically apparent was 3.4% in patients with ASSD. Myocarditis was the initial presenting feature in 42% of the ASSD patients with myocarditis in this study. Myocarditis was reported to be associated with active disease but not with any particular antibody specificity [62]. Liu et al. reported a shorter disease duration, more manifestations of heart failure and symptoms of IIMs and increased frequency of AMA-M2 antibody positivity in patients of IIM with myocarditis [63].

Emerging data indicate an association between cardiovascular disease and certain myositis-specific antibodies, myositis-associated antibodies and anti-mitochondrial antibodies [64‐66]. In a longitudinal cohort study comprising 619 adult and 371 juvenile patients with IIM, 31 adult patients were diagnosed with cardiomyopathy. While only 5% of adult patients in this cohort were AMA-positive, the presence of this antibody was associated with the development of cardiomyopathy and persistent muscle weakness. Notably, this association was not seen in the pediatric population [67]. Additionally, a retrospective case review reported cardiac involvement in five of seven patients with positive anti-mitochondrial antibodies. The authors noted that cardiac function in patients with cardiomyopathy or myocarditis could improve with immunosuppression [68]. In another study of 63 patients with IIM (DM, PM, CADM), those who were anti-MDA5 (melanoma differentiation-associated protein 5) positive (N = 21) showed significantly lower T waves amplitude on the electrocardiogram (ECG) than anti-MDA-5 negative patients. Nonetheless, there were no differences in the contractile function of the heart between the two groups. These low amplitudes were restored during the remission phase, suggesting a possible role for aberrant immune responses associated with active anti-MDA5+ DM [69].

JDM, although rare, is the most common childhood inflammatory myopathy. There are several similarities between the clinical features of JDM and those of adult DM [78].

Cardiovascular risk factors and metabolic syndrome appear prevalent among patients with JDM. For instance, several studies have observed a high frequency of hypertension [70, 71], dyslipidemia [70‐73] and elevated body fat percentage [70, 74] in JDM patients versus controls. In several studies, metabolic abnormalities were found to be correlated with JDM disease activity [70, 72]. Importantly, increased rates of cardiovascular involvement have been observed even in the absence of traditional cardiovascular risk factors, suggesting that such risk factors may not completely account for the increased rates of cardiovascular disease in JDM [71].

Potential cardiac manifestations in JDM include pericarditis, systolic or diastolic dysfunction and electrocardiographic abnormalities [75, 76, 79]. In a cross-sectional study of 57 patients with JDM, 18% of the patients had cardiac involvement- defined as left ventricular systolic or diastolic dysfunction on echocardiography, which was mostly subclinical. Patients with cardiac involvement showed higher disease activity 1 year after diagnosis and an unfavorable lipid profile [73]. In a cross-sectional study of 59 patients with JDM examined at a median of 16.8 years after disease onset, both systolic and diastolic dysfunction were reported to be linked to longer disease duration and high disease activity score of skin but not muscle at 1 year. The cumulative prednisolone dose was also a predictor of diastolic dysfunction. Thus, sustained early skin activity could predict cardiac dysfunction in the long term [76].

A low heart rate variability (HRV) is a strong predictor of cardiac arrest [80]. Barth et al. demonstrated a lower HRV in patients with active JDM than in those with inactive JDM, indicating the presence of autonomic nervous system dysregulation in JDM. This reduced HRV was found to be associated with elevated inflammatory markers, reduced myocardial function, and active disease [77].

Abnormal nailfold capillary density (NCD) is an indicator of systemic vasculopathy and thus may have utility in the evaluation of JDM. Barth et al. did not find any significant differences in the electrocardiography, heart rate variability, and systolic or diastolic function between patients with low and normal NCD. However, these authors reported an association between lung involvement and low NCD. A plausible explanation for the lack of association between NCD and cardiac dysfunction could be the small sample size of the study, making the study underpowered to demonstrate this association [75].

Given that cardiovascular involvement is one of the most common causes of increased morbidity and mortality in patients with IIM, screening of patients for cardiac involvement is of paramount importance. As most patients have subclinical cardiac involvement, the need for highly sensitive and noninvasive testing methods is gaining importance.