Predictors of death, heart transplantation and relapse in clinically suspected and biopsy-proven myocarditis in the pre-immunosuppression era

Abstract

Abstract Background Myocarditis is an infectious or autoimmune inflammatory disease of the myocardium; diagnosis relies on the exclusion of an acute coronary syndrome, and is confirmed by endomyocardial biopsy (EMB). Prognosis is highly variable, outcome predictors are not well defined. Purpose To identify clinical, imaging and immunological predictors of death, heart transplantation (HTx) and relapse in patients with myocarditis in the pre-immunosuppression era. Methods From 1993 to 2012 we consecutively enrolled 466 patients (68% male, mean age 37±17 years), 216 with clinically suspected and 250 with EMB-proven myocarditis. All patients underwent coronary angiogram and transthoracic echocardiogram, 44% of patients underwent cardiac magnetic resonance (CMR). Circulating auto-antibodies were measured in patients' sera by indirect immunofluorescence. All patients were prospectively followed-up at the local Cardio-immunology outpatient clinic. Results After a median follow-up of 50 months (IQR 25–75), 366 patients (79%) were alive, while 42 (9%) were dead or underwent HTx; 58 were lost to follow-up. Ten-year survival free from death or HTx was overall 83%, but was lower in patients with EMB-proven myocarditis (76% vs 94% in patients with clinically suspected myocarditis, p<0.001). On univariate analysis, predictors of death and HTx were female gender (p=0.003), previous myocarditis (p=0.03), heart failure on presentation and advanced NYHA class (p<0.001, respectively), histological diagnosis of giant-cell myocarditis (p=0.002), positivity for anti-heart antibodies (AHA, p=0.04), anti-cardiac endothelial cell (AECA, p=0.002) and anti-nucleus antibodies (ANA, p=0.003). On multivariate analysis, female gender (HR 2.69, p=0.02), lower left ventricular ejection fraction on echocardiogram (p<0.001), positivity for high-titre organ-specific AHA (HR 4.1, p=0.02) and for ANA (HR 5.1, p<0.001) were independent predictors of death and HTx. Seventy-seven patients had relapsing myocarditis; on univariate analysis, young age (p<0.001), previous myocarditis (p<0.001), symptoms preceding diagnosis (p=0.004), positivity for anti-intercalated disk autoantibody (AIDA, p=0.02), and presence of diffuse late gadolinium enhancement (LGE) on CMR (p<0.001) were predictors of relapse. On multivariate analysis young age (p=0.02) and previous myocarditis (HR 8.4, p<0.001) were independent predictors of relapse. Predictors of death, HTx and relapse, respectively, did not differ when considering separately patients with EMB-proven myocarditis and those with clinically suspected myocarditis. Conclusions In the pre-immunosuppressive era, young age and a previous episode of myocarditis were independent predictors of relapse, female gender, left ventricular dysfunction at presentation and high-titre organ-specific AHA and ANA were independent predictors of death and HTx, suggesting that autoimmune features in myocarditis predict worse prognosis. Funding Acknowledgement Type of funding source: None