An Overview of Primary Endocardial Fibroelastosis and Chronic Viral Cardiomyopathy

AN OVERVIEW OF PRIMARY ENDOCARDIAL FIBROELASTOSIS AND CHRONIC VIRAL CARDIOMYOPA THY* JOSEPH W. ST. GEME, JR., M.D.,f CATHERINE W. C. DAVIS, Ph.D.,f and GEORGE R. NOREN, M.D. f Our original observations and speculations concerning primary endocardial fibroelastosis provoked understandable disbelief, and we summarize in this paper the efforts to solve a pathogenetic mystery. Although not so apparent at the outset, our researches represented experimental questions about the fundamental cause of an important, broad spectrum of chronic cardiomyopathic disease of man. Primary endocardial fibroelastosis is characterized by the proliferation of fibrous and elastic tissue beneath the left ventricular endocardium. Internally strictured by a jacket of thick connective tissue, the heart loses the resilient contractile force necessary to sustain sufficient cardiac output. Following the preliminary studies of Noren, Adams, and Anderson [1], we undertook extensive clinical and laboratory investigation of the proposed association of intrauterine mumps virus infection and endocardial fibroelastosis. In a substantial number of clinically documented and necropsy-verified cases of primary endocardial fibroelastosis, we found the almost uniform presence of delayed cutaneous hypersensitivity to mumps virus in the absence of circulating neutralizing antibody [2]. Clinically, these children were assessed by careful cardiovascular physical examination, routine thoracic radiography, electrocardiography , cardiac catheterization and angiography, and, when indicated, skeletal muscle biopsy. We attempted to isolate the diagnosis of a chronic cardiomyopathy, which may be a more suitable pathophysiologic label for primary endocardial fibroelastosis, from the *We thank Drs. B. F. Anthony, D. T. Imagawa, T. Yamauchi, G. C. Emmanouilides, A. J. Moss, and F. H. Adams for their constructive discussion of the manuscript and the conceptual issues involved, and Mrs. Judy Liston for her careful preparation of the manuscript . !Department of Pediatrics, Harbor General Hospital, University of California at Los Angeles School of Medicine, Torrance, California 90509. íDepartment of Pediatrics, Hennepin County General Hospital, University of Minnesota Medical School, Minneapolis, Minnesota 55455. Perspectives in Biology and Medicine · Summer 1974 | 495 traditional alternative diagnoses of congenital heart disease, acute myocarditis, anomalous origin of the left coronary artery, disseminated vasculopathy, and glycogen storage disease. At the time, cardiac biopsy was considered too high a price of risk to pay for an absolute pathological diagnosis. Although these children exhibited a cellular immunologic response to mumps virus antigen, suggesting prior exposure to mumps virus, we could not recover the virus from their oropharynges or, on the occasion of untimely death, their heart tissue. This was distressing, since at this time, 1965, intrauterine rubella virus infection was discerned to be a persistent infection, with replication of rubella virus in tissues for as long as 6-12 months after birth [3]. The lack of persistent mumps virus replication in the human necessitated a unique explanation for the presence of delayed hypersensitivity without antibody. We suggested that intrauterine mumps virus infection was perhaps an abbreviated process [2]. In so being, the limited antigenic mass presented to an immature embryonic or fetal host might allow only a partial immunologic response , that of T-cell mediated cellular immunity. There was a precedent for such a hypothesis in the immunologic literature. Salvin and Smith [4] had demonstrated that minimal amounts of antigen evoked only delayed hypersensitivity in the guinea pig, while larger amounts of the same antigen stimulated both cellular and humoral (B-cell) immunity . In many ways, our clinical observations and our immunologic hypothesis were on shaky ground. Perhaps the mumps virus skin test, which was the primary etiologic anchor, was an absolute fluke. Perhaps the cutaneous delayed sensitivity to the inactivated viral antigen bore no relationship to prior mumps virus infection in these patients, whether the infection was transplacental or postnatal. We excluded the possibility of a cell-mediated immune response simply to avian antigens by always skin testing on the opposite arm with a control antigen which contained chicken allantoic fluid proteins without viral proteins. Indeed, if these patients were reacting in such a uniform fashion to only chicken antigens , in sharp contrast to control children, this would be astonishing in itself. However, some epidemiologic and serologic facts supported the relevance of the mumps virus skin test. Many of the mothers of children with endocardial fibroelastosis produced a history of either mumps virus infection...