Virus-Negative Necrotizing Coronary Vasculitis with Aneurysm Formation in Human SARS-CoV-2 Infection

We report a case of myopericarditis associated to SARS-CoV-2 infection with necrotizing coronary vasculitis of intramural vessels, giving rise to biventricular apical microaneurysms and to electrical instability. Negativity of myocardial polymerase chain reaction for the most common cardiotropic viruses and for SARS-CoV-2 suggested an immune-mediated myocardial and pericardial inflammatory disease. High dose (1 mg/Kg daily) prednisone and anti-viral (Remdesivir, IDA Business, Carrigtohill, County Cork, T45 DP77, Ireland) therapy led to resolution of cardiac inflammation and ventricular arrhythmias. Morpho-molecular characterization of endomyocardial tissue may improve the outcome in subjects with SARS-CoV-2-associated myopericarditis and coronary vasculitis.

Coronary Vasculitis

The term coronary “artery vasculitis” is used for a diverse group of diseases with a wide spectrum of manifestations and severity. Clinical manifestations may include pericarditis or myocarditis due to involvement of the coronary microvasculature, stenosis, aneurysm, or spontaneous dissection of large coronaries, or vascular thrombosis. As compared to common atherosclerosis, patients with coronary artery vasculitis are younger and often have a more rapid disease progression. Several clinical entities have been associated with coronary artery vasculitis, including Kawasaki’s disease, Takayasu’s arteritis, polyarteritis nodosa, ANCA-associated vasculitis, giant-cell arteritis, and more recently a Kawasaki-like syndrome associated with SARS-COV-2 infection. This review will provide a short description of these conditions, their diagnosis and therapy for use by the practicing cardiologist.

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

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.

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

Background Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis (M), which incidence, cause and responsiveness to therapy is unreported. Purpose We set out a retrospective study to report our experience in the diagnosis and management of myocarditis-associated necrotizing coronary vasculitis (M-NCV) and patients' outcome. Methods Among 5180 patients undergoing endomyocardial biopsy in our institution, 1916 received a histological diagnosis of myocarditis with associated NCV in 30 (12F, 18M, mean age 47.7 years±15). NVC endomyocardial samples were retrospectively evaluated with, immunohistochemistry for Toll like Receptor 4 (TLR4) and real-time PCR for viral genomes. Serum samples were processed for anti-heart autoantibodies and inflammatory cytokine profile (ELLA assay).Identification of an immunologic pathway (virus-, TLR4+, anti-heart abs +) was followed by immunosuppression including steroids, azathioprine, cyclophosphamide, high dose immunoglobulins and anakinra. M-NCV patients were followed for 6-months with resting ECG, Holter monitoring, 2D-echo and in 45% of cases with cardiac magnetic resonance. Increase of ≥10% in left ventricular EF was classified as response to therapy. M-NCV patients were compared to a control group of 60 consecutive patients with virus + and − lymphocithic myocarditis and a control group of 30 patients with mitral stenosis and normal LV size and function, undergoing surgical repair. Results 26 M-NCV patients presented with heart failure or cardiogenic shock; 3 with electrical instability; 1 with infarct-like symptoms. Cause of M-NCV included infectious agents (PVB19, HHV2, EBV and co-infection of Toxoplasma gondii and PVB19) in 4 patients; chest trauma in 1; drug-hypersensitivity in 2; hypereosinophilic syndrome in 1; primary autoimmune disease in 7; giant cells in 3; while it was idiopathic in the remaining cases. CMR imaging did not detect any qualitative difference between M-NVC and M patients. Anti-heart autoantibodies were positive in immune-mediated M-NCV and virus- M; in M-NCV patients in which anti-heart autoantibodies were positive, we found a cross-reaction with vessel walls. Myocardial expression of TLR4 was high in the immune-mediated forms and negative in the viral. Interleukins 1-beta was more elevated (p<0.001) in patients with M-NCV in comparison with virus-M patients. M-NCV patients presented a more severe clinical profile with 24% in-hospital mortality compared with 1.5% of the M group. Immunosuppression resulted in an improvement of cardiac function in 86% of M-NCV and 88% of virus-M cohort. Conclusion NCV can be histologically detected in up to 1.5% of a large population with myocarditis. Major causes include viral, autoreactive and autoimmune processes. Intra-hospital mortality is high (24%). Presence of an immunologic pathway is associated with a beneficial response to immunosuppression. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): European Project ERA-CVD