Detection of enterovirus capsid protein VP1 in myocardium from cases of myocarditis or dilated cardiomyopathy by immunohistochemistry: further evidence of enterovirus persistence in myocytes

Abstract

The association of enteroviruses with myocardial disease has been investigated extensively by molecular biological techniques to detect viral RNA, but remains controversial. This retrospective study investigated the involvement of enterovirus in myocarditis or dilated cardiomyopathy (DCM) by detection of viral antigens in myocardial samples from a new patient series using an optimized immunohistochemical technique. Formalin-fixed, paraffin-embedded biopsy, autopsy or explanted myocardial tissue samples were obtained from 136 subjects. These comprised histologically proven cases of acute fatal myocarditis (n=10), DCM (n=89, including 10 patients with healing/borderline myocarditis) and a comparison group of samples from 37 unused donor hearts and cases with other conditions. A monoclonal antibody 5-D8/1 directed against a conserved, non-conformational epitope in capsid protein VP1 was employed for broad detection of different enterovirus serotypes. Investigations were performed blindly. Histological sections from 7 of 10 fatal myocarditis cases, 47 of 89 patients (52.8%) with DCM were positive for the viral capsid protein VP1 by immunohistochemical staining. Consecutive sections of positive samples were negative when the antibody was omitted or replaced with subclass- and concentration-matched normal mouse IgG. In contrast, only 3 of 37 samples (8.1%) in the comparison group were positive (Yates corrected chi(2)=19.99, P<0.001: odds ratio =12.68). VP1 staining was distributed in individual or grouped myofibers and localized in the cytoplasm of myocytes. In some cases, VP1 was detected in only a few myofibers within an entire section. These results provide further evidence of enterovirus involvement in a high proportion of DCM cases and demonstrate that VP1 is present in disease stages from acute myocarditis, healing myocarditis to end-stage DCM requiring cardiac transplantation, indicating translation of viral protein during persistent enterovirus infection.

Mitochondria: A mirror into cellular dysfunction in heart disease

“…In order to maintain normal stroke volume, the heart impaired by DCM alters systolic function in a compensatory fashion, leading to increased end systolic pressure [33]. This, amongst other compensatory mechanism of the heart, is indicative of endstage pathological alterations of more than 50 diseases, including valvular disorders, infectious myocarditis [34], autoimmune mechanisms (including type 1 diabetes) [35] and numerous genetic disorders [36], including Barth syndrome (BTHS) [37]. The X-linked recessive disorder BTHS has been linked to ultrastructural alterations to cardiac mitochondria [38], with associated loss of inner mitochondrial membrane lipid cardiolipin [39].…”

Towards a unifying hypothesis for the pathogenesis of peripartum cardiomyopathy

“…The unified hypothesis (Fig. 1) suggests that a pathway connecting virus as a trigger could be interrelated with other factors mentioned [44][45][46][47][48][49][50][51][52][53]. Whatever the antigen(s) that serve(s) as "trigger," there is strong evidence that eventually a transition occurs to an autoimmune myocarditis and/or cardiomyopathy in which cardiac autoantibodies play an important role [54][55][56][57][58][59].…”

Detection and distribution of culturable Human Enteroviruses through environmental surveillance in Milan, Italy

“…Some HEV infections have a significant impact on public health, being implicated in outbreaks of meningitis, encephalitis, hand-foot-mouth disease and poliomyelitis, one of the most severe diseases in humans (Huang et al 2011;Mirand et al 2012). HEVs have also been associated with other diseases, such as myocarditis, keratoconjunctivitis, and in the development of chronic diseases, such as diabetes mellitus and insulin-dependent dilated cardiomyopathy (Zhang et al 2004;Christen et al 2012). HEVs transmission occurs mostly through the faecal-oral route by direct or indirect contact.…”