Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome

Abstract

Aims: Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported.

Methods and results: Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients.

Conclusion: Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

Keywords: Autoimmune disease; Myocarditis; Vasculitis; Viral infection.

Graphical abstract

Figure 1

Immune-mediated myocarditis-associated necrotizing coronary vasculitis responding to immunosuppressive therapy. (A–C) Short-axis cardiac magnetic resonance showing remarkably dilated (A, EDV/BSA 124,7 mL/S2) and hypokinetic (B, ejection fraction 23%,) left ventricle with extensive subepicardial late gadolinium enhancement (C) suggesting severe myocarditis. (D) Severe lymphocytic myocarditis with necrotizing vasculitis of an intramural coronary artery (immunohistochemistry with CD45Ro, 200×). (E) Necrotizing coronary vasculitis with overexpression of toll-like receptor 4 in cardiomyocytes and vascular smooth muscle cells suggesting an immune-mediated mechanism of damage (immunoperoxidase for toll-like receptor 4, 200×). (F) Positive anti-heart antibodies (FITC green fluorescence) with autoreactivity for vessel wall, as showed by the co-localization with CD 31 antigen (TRITC red immunostaining), 400×. (G–I) Control cardiac magnetic resonance after immunosuppressive therapy showing normalization of left ventricular end-diastolic dimension (G, EDV/BSA 86,5 mL/S2), contractility (H, ejection fraction rising from 23% to 52%) and reduction with attenuation of late gadolinium enhancement (I). (J–L) Control biopsy after 6-month immunosuppressive therapy showing healed myocarditis with reparative fibrosis of vessel wall (J, arrows, Masson trichrome, 200×), reduction of toll-like receptor 4 immunoreactivity (K, immunoperoxidase for toll-like receptor 4, 200× magnification), and negativity of anti-heart antibodies (L, indirect immunofluorescence).

Figure 2

Anti-heart autoantibodies characterization: evidence for partially organ-specific pattern in patients with Myocarditis-necrotizing coronary vasculitis. (A) Positive partially organ-specific (fine striational) pattern of anti-heart autoantibodies on human heart (FITC green fluorescence, 400×) in the serum of a patient with Myocarditis-necrotizing coronary vasculitis. (B) Weakly positive staining for anti-heart autoantibodies on skeletal muscle (FITC green fluorescence, 400×) in the serum of the same patient of A. (C) Anti-heart autoantibody-negative control serum on human heart; no cardiomyocyte staining is present (FITC green fluorescence, 400×). (D) Anti-heart autoantibody-negative control serum on human skeletal muscle; no myocyte staining is present (FITC green fluorescence, 400×). (E) Positive serum for anti-heart and anti-endothelial cells autoantibodies on human heart (FITC green fluorescence, 400×) in a patient with Myocarditis-necrotizing coronary vasculitis. (F) Positive serum for anti-heart and anti-endothelial cells autoantibodies on skeletal muscle (FITC green fluorescence, 400×) in a patient with Myocarditis-necrotizing coronary vasculitis. (G) Negative control serum for fluoresceinated secondary antibody on human heart (FITC green fluorescence, 400×). (H) Negative control serum for fluoresceinated secondary antibody on skeletal muscle (FITC green fluorescence, 400×). (I) Positive control serum for anti-heart and anti-endothelial cell autoantibodies on human heart (FITC green fluorescence, 400×). (J) Positive control serum for anti-heart and anti-endothelial cell autoantibodies on human skeletal muscle (FITC green fluorescence, 400×).

Figure 3

Post-mortem histologic and molecular study in a 33-year woman died because of infectious myocarditis with necrotizing coronary vasculitis. (A) Massive lymphocytic myocarditis with extensive cell necrosis (H&E 100×). (B) Necrotizing intramural coronary vasculitis with no expression of toll-like receptor 4 suggesting an infectious cause (immunohistochemistry for toll-like receptor 4, 200×). (C) Real-time PCR indicating a myocardial infection by Human Herpes Virus 2.