Long Term Risk of Recurrence, Morbidity and Mortality in Giant Cell Myocarditis

PAPER OF MAY 2015

Joseph J. Maleszewski, MD a,b,*, Victor M. Orellana, MDc, David O. Hodge, MSd, Uwe Kuhl, MDe, Heinz-Peter Schultheiss, MDe, and Leslie T. Cooper, MDb

Divisions of (a)Anatomic Pathology and (b)Cardiovascular Diseases and (c)Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota; Department of Medicine, Alpert Medical School, Brown University, Providence, Rhode Island; and eDepartment of Cardiology, Charite Hospital, Benjamin Franklin Campus, Berlin, Germany

Am J Cardiol. 2015 Mar 24. pii: S0002-9149(15)00978-9. doi: 10.1016/j.amjcard.2015.03.023.

Presented by Alida LP Caforio, MD, PhD, FESC, Cardiology, Dept of Cardiological Thoracic and Vascular Sciences, University of Padova, Italy. alida.caforio@unipd.it

Summary

Giant cell myocarditis (GCM) is a rare disorder in which survival beyond 1 year without heart transplantation is uncommon. Long-term follow-up data on those with such survival are lacking. Twenty-six patients with biopsy-proved GCM who survived for > 1 year without heart transplantation were identified from a multicenter GCM registry. The incidence of death, transplantation, ventricular assist device placement, and histologically proved disease recurrence was ascertained retrospectively. The rates of recurrent heart failure, ventricular arrhythmias, renal failure, and infectious complications were calculated. The mean age of the cohort was 54.6 ± 13.9 years (65% women). The mean follow-up duration was 5.5 years starting 1 year after diagnosis. There were 3 deaths (12%), 5 heart transplantations (19%), and 1 ventricular assist device placement (4%). Three histologically confirmed recurrences of GCM (12%) occurred between 1.5 and 8 years after diagnosis. Thirteen of 26 patients experienced a total of 30 heart failure episodes ≥1 year after initial diagnosis. There were 23 episodes of elevated creatinine in 12 patients, 41 infectious events in 13 patients, and 19 episodes of ventricular arrhythmias in 6 patients with a total of 144 years of follow-up. Starting 1 year after GCM diagnosis, the combined rate of death, transplantation, ventricular assist device placement, and GCM recurrence was 47% at 5 years. In conclusion, the risk for GCM recurrence continues to ≥ 8 years after diagnosis.

Comments

Giant cell myocarditis (GCM) is a rare but frequently fatal form of autoimmune myocarditis that has been shown to respond to immunosuppressive therapy. In biopsy-proven cases, the most frequent outcome is death or transplantation within the first year after diagnosis. In keeping with its autoimmune pathogenesis, GCM recurrence in the donor heart post-heart transplantation has been reported as high as 20% to 25%. Since patients survive longer without transplantation because of efficacious immunosuppressive therapy, questions of long-term survival and of recurrence risk in the native heart beyond the first year have not been answered. Similarly, the optimal duration and intensity of immunosuppression beyond 1 year are not known, although experts advocate life-long immunosuppression. In addition, extracardiac morbidity in these patients has not been evaluated. Since GCM is a rare condition, no single center has accumulated experience to catalog the long-term risks for disease recurrence and extracardiac morbidity in patients with GCM without heart transplantation. Thus, the study by Maleszewski et al is interesting, because it reports patients from multiple centres in the United States and Germany with biopsy-proved GCM who survived for > 1 year on immunosuppression without cardiac transplantation. This important study shows that contemporary care that includes long-term immunosuppression appears capable of lengthening transplantation-free survival > 19 years beyond initial diagnosis with reasonable safety. Conversely, cessation or sometimes reduction of immunosuppression was associated with GCM recurrence as far as 8 years after diagnosis, again in keeping with the recognized chronic-relapsing course of autoimmune diseases. Eight patients (5 in the first year and 3 in subsequent years) who developed renal failure associated with cyclosporine were switched to a sirolimus-based regimen. However, the study data do not provide more specific insight regarding the optimal protocol or intensity of immunosuppression in this population. Importantly, this study and the recent report by Kandolin et al found that ventricular arrhythmias occur frequently in GCM survivors. Maleszewski et alextend Kandolin’s experience to report that ventricular arrhythmias after the first year occur primarily in patients with GCM who initially present with ventricular arrhythmias, suggesting that arrhythmia risk in GCM may be in relation to the initial clinical presentation. The types of infections affecting chronically immunosuppressed GCM patients were typical of similarly immunosuppressed cohorts and with proper management rarely life threatening, lending support to the recent ESC Task Force indications to extend immunosuppressive therapy to non GCM infection-negative autoimmune forms of biopsy-proven myocarditis. The study data extend the indication for endomyocardial biopsy to include the diagnosis of recurrent GCM in the native heart. Maleszewski et al report for the first time the stepwise, histopathologic improvement of GCM under immunosuppression, whereby giant cells disappear early on, followed by eosinophils, with smoldering lymphocytic myocarditis being the last inflammatory manifestation to disappear. Resolution with replacement type interstitial fibrosis also appears to be common. These observations may suggest that GCM and lymphocytic autoimmune myocarditis are not distinct entities, GCM representing the most severe form of autoimmune reaction to myosin heavy chain, which has been identified as the major autoantigen in both conditions. In conclusion, this study reports that biopsy-proven GCM can be successfully managed in the current era with combined immunosuppression, achieving a better long-term prognosis and even avoiding heart transplantation. Although the study is retrospective, it provides a strong rationale for early diagnosis by endomyocardial biopsy in clinically suspected myocarditis.