Myocarditis: A Clinical Overview.

PURPOSE OF REVIEW: In this paper we will review the modern diagnostic approach to patients with clinically suspected myocarditis as well as the treatment modalities and strategy in light of up-to-date clinical experience and scientific evidence. RECENT FINDINGS: Rapidly expanding evidence suggests that myocardial inflammation is frequently underdiagnosed or overlooked in clinical practice, although new therapeutic options have been validated. Moreover, the available evidence suggests that subclinical cardiac involvement has negative prognostic impact on morbidity and mortality and should be actively investigated and adequately treated. Myocarditis represents a growing challenge for physicians, due to increased referral of patients for endomyocardial biopsy (EMB) or cardiac magnetic resonance (CMR), and requires a highly integrated management by a team of caring physicians.

Coronary flow reserve by transthoracic echocardiography predicts epicardial intimal thickening in cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) is the leading cause of morbidity and mortality in heart transplantation (HT). We sought to investigate the role of coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) in CAV diagnosis. CAV was defined as maximal intimal thickness (MIT) assessed by intravascular ultrasound (IVUS) > or =0.5 mm. CFR was assessed in the left anterior descending coronary artery in 22 HT recipients at 6 +/- 4 years post-HT. CAV was diagnosed in 10 patients (group A), 12 had normal coronaries (group B). The mean MIT was 0.7 +/- 0.1 mm (range 0.03-1.8). MIT was higher in group A (1.16 +/- 0.3 mm vs. 0.34 +/- 0.07 mm, p < 0.0001). CFR was 3.1 +/- 0.8 in all patients and lower in group A (2.5 +/- 0.6 vs. 3.7 +/- 0.3, p < 0.0001). CFR was inversely related with MIT (r =-0.774, p < 0.0001). A cut point of < or =2.9, identified as optimal by receiver operating characteristics analysis was 100% specific and 80% sensitive (PPV = 100%, NPV = 89%, Accuracy = 91%). CFR assessment by CE-TTE is a novel noninvasive diagnostic tool in the detection of CAV defined as MIT > or =0.5 mm. CFR by CE-TTE may reduce the need for routine IVUS in HT.

Anti-heart and anti-intercalated disk autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis.

BACKGROUND: Idiopathic recurrent acute pericarditis (IRAP) is a rare disease of suspected, yet unproved, immune-mediated origin. The finding of serum heart-specific autoantibodies in IRAP would strengthen the autoimmune hypothesis and provide aetiology-specific non-invasive biomarkers. Objective To assess frequency of serum anti-heart (AHA), anti-intercalated-disk (AIDA) and non-cardiac-specific autoantibodies and their clinical and instrumental correlates in patients with IRAP. Patients 40 consecutive patients with IRAP, 25 male, aged 37+/-16 years, representing a large single-centre cohort collected at a referral centre over a long time period (median 5 years, range 1-22 years). Control groups included patients with non-inflammatory cardiac disease (NICD) (n=160), ischaemic heart failure (n=141) and normal subjects (n=270). METHODS: AHA (organ-specific, cross-reactive 1 and 2 types) and AIDA were detected in serum samples from patients, at last follow-up, and control subjects by indirect immunofluorescence (IIF) on human myocardium and skeletal muscle. Non-cardiac-specific autoantibodies were detected by IIF, and anti-Ro/SSA, anti-La/SSB by ELISA. RESULTS: The frequencies of cross-reactive 1 AHA and of AIDA were higher (50%; 25%) in IRAP than in NICD (4%; 4%), ischaemic (1%; 2%) or normal subjects (3%; 0%) (p=0.0001). AHA and/or AIDA were found in 67.5% patients with IRAP. Of the non-cardiac-specific antibodies, only antinuclear autoantibodies at titre > or =1/160 were more common in IRAP (5%) versus normal (0.5%, p<0.04). AIDA in IRAP were associated with a higher number of recurrences (p=0.01) and hospitalisations (p=0.0001), high titre (1/80 or higher) AHA with a higher number of recurrences (p=0.02). CONCLUSIONS: The detection of AHA and of AIDA supports the involvement of autoimmunity in the majority of patients with IRAP.

[Recurrent acute idiopathic pericarditis: rheumatologic therapy, autoantibodies and long term outcome]. / Pericardite acuta idiopatica recidivante: terapia reumatologica, autoanticorpi e long term outcome.

OBJECTIVE: To evaluate therapy and rheumatologic aspects of recurrent acute idiopathic pericarditis (RAIP). METHODS: We studied 46 patients. We used non-steroidal anti-inflammatory drugs (NSAIDs) at high dosage. We did not start corticosteroid: if already started, we planned a very slow tapering; 37 patients (80.4%) were treated with colchicine. We also assessed the frequency of ANA, anti-SSA and Rheumatoid factor. RESULTS: With our protocol recurrences dropped from 0.46 to 0.03 attacks/patient/month (p<0.00001) within 12 months and remained at the same level (0.024) till the end of the follow-up (mean 8 years). In the 37 patients treated with colchicine recurrences dropped from 0.5 to 0.03 (p<0.0001) within 12 months, and in 9 patients not given colchicine from 0.27 to 0.045 (p<0.005). When colchicine was used the decrease was significantly higher (0.47 vs 0.23) (p<0.001). In 27 (58.7%) patients ANA were positive at a titre >1/80, in 7 (15.2%) >1/160. Rheumatoid factor was positive in 7 (15.2%) and anti-SSA in 4 (8.7%). During the follow-up 4 (8.7%) new diagnosis of Sjogren and 1 (2.2%) of Rheumatoid Arthritis were made. CONCLUSION: NSAIDs at high dosage, slow tapering of corticosteroid and colchicine are very effective in RAIP. The improvement is more dramatic in colchicine treated patients, but also other patients can achieve good control of the disease. The finding of ANA, anti-SSA and the new rheumatological diagnoses support the involvement of autoimmunity.

Coronary flow reserve by contrast-enhanced echocardiography: a new noninvasive diagnostic tool for cardiac allograft vasculopathy.

Noninvasive tests have proven unsatisfactory in cardiac allograft vasculopathy (CAV) diagnosis. We assessed coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) in heart transplantation (HT). CFR was assessed in the left anterior descending coronary artery in 73 HT recipients (59 male, aged 50+/-12 years at HT), at 8+/-4.5 years post-HT. CFR measurements were taken blindly from coronary angiographies. CFR cut points were the standard value of

Clinical implications of anti-cardiac immunity in dilated cardiomyopathy.

Criteria of organ-specific autoimmunity are fulfilled in a subset of patients with myocarditis/dilated cardiomyopathy (DCM). In particular, circulating heart-reactive autoantibodies are found in such patients and symptom-free relatives. These autoantibodies are directed against multiple antigens, some of which are expressed in the heart (organ-specific), others in heart and some skeletal muscle fibres (partially heart-specific) or in heart and skeletal muscle (muscle-specific). Distinct autoantibodies have different frequency in disease and normal controls. Different techniques detect one or more antibodies, thus they cannot be used interchangeably for screening. It is unknown whether the same patients produce more antibodies or different patient groups develop autoimmunity to distinct antigens. IgG antibodies, shown to be cardiac- and disease-specific for myocarditis/DCM, can be used as autoimmune markers for relatives at risk as well as for identifying patients in whom immunosuppression may be beneficial. Some autoantibodies may also have a functional role, but further work is needed.

Characterization of anti-myosin monoclonal antibodies.

The characterization of monoclonal antibodies (MAbs) with regard to reactivity and specificity is important for the successful application as a molecular probe and/or diagnostic reagent. Furthermore, it is recognized that some monoclonal reagents perform well in some assay systems but not others. In this study, the reactivity profiles of two anti-myosin MAbs (H1 and DH2, raised against human cardiac myosin) were evaluated in enzyme-linked immunosorbent assay (ELISA), slot-blotting, and immunocytochemistry. Both antibodies performed well in slot-blotting against myosin heavy chain preparations from cardiac and skeletal muscle and from non-human sources. In general, MAb H1 demonstrated strong to moderate reactivity in all assay systems, whilst MAb DH2 faired poorly in ELISA. MAb H1 also showed reactivity to synthetic peptides of myosin, one of which possessed a motif (ERRDA, single amino acid code) that was found in other human and nonhuman myosin protein sequences that could explain its cross-reactive profile. Intriguingly, this motif was found on viral and other pathogenic agents associated with myocarditis. Hence, it is speculated that this region could give some credence to the mechanism of molecular mimicry associated with some cardiac diseases. Overall, MAb H1 may serve as a useful probe of myosin structure.

Autoimmune myocarditis and dilated cardiomyopathy: focus on cardiac autoantibodies.

Criteria of organ-specific autoimmunity are fulfilled in a subset of patients with myocarditis/dilated cardiomyopathy (DCM). In particular, circulating heart-reactive autoantibodies are found in patients and symptom-free relatives. These autoantibodies are directed against multiple antigens, some of which are expressed in the heart (organ-specific), others in heart and some skeletal muscle fibres (partially-heart specific) or in heart and skeletal muscle (muscle-specific). Distinct autoantibodies have different frequency in disease and normal controls. Different techniques detect one or more antibodies, thus they cannot be used interchangeably for screening. It is unknown whether the same patients produce more antibodies or different patient groups develop autoimmunity to distinct antigens. IgG antibodies, shown to be cardiac and disease-specific for myocarditis/DCM, can be used as autoimmune markers for identifying patients in whom immunosuppression may be beneficial and relatives at risk. Some autoantibodies may also have a functional role, but further work is needed.

Idiopathic recurrent acute pericarditis: familial Mediterranean fever mutations and disease evolution in a large cohort of Caucasian patients.

Idiopathic recurrent acute pericarditis (IRAP) is suspected to be an autoimmune phenomenon. We studied 46 consecutive patients. We looked for: 1) the occurrence of new diagnoses of autoimmune diseases during our follow up; 2) HLA typing; and 3) the presence of the most frequent mutations linked to familial Mediterranean fever (FMF gene or MEFV). HLA typing was done in 21 patients at loci B, DRB1, DQA1 and DQB1. MEFV gene was looked in 23 patients using specific primers. During the follow-up we made a new diagnosis of primary Sjögren's syndrome in four patients (8.7%) and of rheumatoid arthritis in one patient (2.2%). HLA B14, DRB1*01 and DQB1*0202 were significantly more prevalent, but we did not find a typical HLA typing. MEFV gene was searched: exon 10 was checked by sequence and the E148Q mutation by restriction site analysis. No mutations were found. In conclusion, the prevalence of definite immunorheumatological diseases and the absence of the mutations linked to FMF reinforce the notion that idiopathic acute recurrent pericarditis is an autoimmune condition.

Elevated serum levels of soluble interleukin-2 receptor, neopterin and beta-2-microglobulin in idiopathic dilated cardiomyopathy: relation to disease severity and autoimmune pathogenesis.

BACKGROUND: It has not been assessed whether high levels of soluble interleukin 2 receptor (sIL-2R), neopterin and beta-2 microglobulin in idiopathic dilated cardiomyopathy reflect heart failure severity and/or an active autoimmune process. The aim of this study was to relate serum levels of these markers to clinical and autoimmune features. METHODS: We studied 60 patients with idiopathic dilated cardiomyopathy, 67 controls with ischemic heart failure and 34 normals. RESULTS: Abnormal levels of sIL-2R, but not of neopterin and beta-2 microglobulin, were more frequent in idiopathic dilated cardiomyopathy than in ischemic patients (35% vs. 16%; P=0.02) or in normals (35% vs. 12%, P=0.01); mean sIL-2R levels were, however, similar in idiopathic dilated cardiomyopathy and ischemic heart failure (842+/-75 vs. 762+/-93 U/ml, P=NS). In idiopathic dilated cardiomyopathy abnormal levels of sIL-2R were associated with lower peak oxygen consumption (P=0.008), higher neopterin and HLA class II expression in the myocardium (P=0.02), but were unrelated to cardiac autoantibody status or titer. In addition, abnormal levels of neopterin were associated with adverse prognosis and higher beta-2 microglobulin; abnormal levels of beta-2 microglobulin with lower echocardiographic percent fractional shortening, higher sIL-2R and higher neopterin. CONCLUSIONS: There is no convincing evidence that abnormal sIL-2R, neopterin and/or beta-2 microglobulin are disease-specific markers of idiopathic dilated cardiomyopathy. The lack of association with cardiac autoantibodies suggests that these abnormalities are mainly related to heart failure severity rather than autoimmune pathogenesis. In keeping with this view, high levels of sIL-2R, neopterin and/or beta-2 microglobulin identified a subset of idiopathic dilated cardiomyopathy patients with advanced disease and poor prognosis.

Cardiac autoantibodies to myosin and other heart-specific autoantigens in myocarditis and dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is characterized by dilation and impaired contraction of the left ventricle or both; it is a relevant cause of heart failure and a common indication for heart transplantation. It may be idiopathic, familial/genetic, viral, autoimmune or immune-mediated, associated with a viral infection. Myocarditis is an inflammatory disease of the myocardium; it may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Thus, in a patient subset, myocarditis and DCM are thought to represent the acute and chronic stages of an organ-specific autoimmune disease of the myocardium. In keeping with this hypothesis, autoimmune features in patients with myocarditis/DCM include: familial aggregation, a weak association with HLA-DR4, abnormal expression of HLA class II on cardiac endothelium on endomyocardial biopsy, detection of organ- and disease-specific cardiac autoantibodies in the sera of affected patients and of symptom-free relatives. The organ-specific cardiac autoantibodies detected by immunofluorescence are directed against multiple antigens. One of these, first identified using immunoblotting and confirmed by ELISA, is the cardiac-specific alpha-myosin isoform. Myosin fulfils the expected criteria for organ-specific autoimmunity, in that immunization with cardiac but not skeletal myosin reproduces, in susceptible mouse strains, the human disease phenotype of myocarditis/DCM; in addition, alpha-myosin is entirely cardiac-specific. The organ-specific cardiac autoantibodies detected by immunofluorescence in symptom-free relatives were associated with echocardiographic features suggestive of early disease. Short-term follow-up is in keeping with this interpretation, although extended follow-up is necessary to define better the role of the antibody as predictor of disease susceptibility in healthy subjects at risk of myocarditis/DCM, such as first-degree relatives.

Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients.

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.

Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection.

Post-transplant lymphoproliferative disorders (PTLD) are a well known complication after orthotopic heart transplantation (OHT). Although Epstein-Barr virus (EBV) infection has long been implicated in the pathogenesis of such disorders, other factors may play a part. Because of its lymphotropic properties, hepatitis C virus (HCV) may induce clonal expansion of B-lymphocytes and lead to PTLD. The aim of this study was to evaluate the potential association between HCV and EBV infection and PTLD in OHT patients. The retrospective study considered 404 adult patients screened for HCV. EBV serology, histology, and molecular analysis on tissue biopsies were performed in the PTLD patients (10/404, 2.5%). HCV positivity was found in 36/404 (8.9%) patients. The EBV genome was expressed on all neoplastic tissue samples analyzed. A higher proportion of HCV-positive patients developed PTLD than the HCV-negative cases (8% vs 2%, P = 0.017). EBV has a demonstrated role in the onset of PTLD, but HCV infection probably has to be considered as well.