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CLINICAL RESEARCH: MYOCARDITIS

Myocardial Expression of Fas and Recovery of Left Ventricular Function in Patients With Recent-Onset Cardiomyopathy

Richard Sheppard, MD^_*, Maninder Bedi, MD, Toru Kubota, MD, PhD, Marc J. Semigran, MD, William Dec, MD, Richard Holubkov, PhD^||, Arthur M. Feldman, MD, PhD^¶, Warren D. Rosenblum, MD^#, Charles F. McTiernan, PhD, Dennis M. McNamara, MD^,_* for the IMAC Investigators

^_* McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada
Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Cardiovascular Medicine, Kyushu University, Fukuoka, Japan
Massachusetts General Hospital, Boston, Massachusetts
^|| Department of Family and Preventive Medicine, School of Medicine, University of Utah, Salt Lake City, Utah
^¶ Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania
^# New York Medical College, Valhalla, New York

Manuscript received March 4, 2005; revised manuscript received April 27, 2005, accepted May 3, 2005.

^_* Reprint requests and correspondence: Dr. Dennis M. McNamara, Heart Failure/Transplantation Program, Cardiovascular Institute, University of Pittsburgh Medical Center, 566 Scaife Hall, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213 (Email: mcnamaradm{at}upmc.edu).

OBJECTIVES: This study aimed to evaluate the role of gene expression for predicting myocardial recovery in recent-onset cardiomyopathy.

BACKGROUND: Apoptosis may limit ventricular recovery. We examined the myocardial expression of Fas, Fas ligand (FasL), tumor necrosis factor (TNF)-alpha, and TNF receptor 1 (TNFR1), and myocardial recovery in patients from the multicenter Intervention in Myocarditis and Acute Cardiomyopathy (IMAC) study.

METHODS: Endomyocardial biopsy samples were obtained in 20 patients with recent-onset (<6 months) idiopathic dilated cardiomyopathy (left ventricular ejection fraction [LVEF] 0.40). The LVEF was assessed at baseline and at 6 and 12 months by nuclear scans. Myocardial expression was assessed by ribonuclease (RNase) protection, normalized to a constitutively active gene (glyceraldehydes 3-phosphate dehydrogenase [GAPDH]) and reported as percent GAPDH expression. The change in LVEF at 6 and 12 months was compared by tertiles of expression.

RESULTS: For all patients (14 men, 6 women; age 46.5 ± 10.7 years), the mean LVEF was 0.28 ± 0.05 at baseline and 0.40 ± 0.14 at six months. Patients in the highest tertile of Fas expression had minimal improvement at six months (EF = 0.03 ± 0.05) when compared with the intermediate (EF = 0.10 ± 0.13) and lowest tertiles (EF = 0.21 ± 0.11, change in LVEF by tertile, p = 0.006). A similar relationship was seen with TNFR1 expression (highest tertile, EF = 0.06 ± 0.07; lowest tertile, EF = 0.21 ± 0.11, p = 0.02). In contrast with Fas and TNFR1, expression of TNF-alpha and FasL did not predict recovery of LV function.

CONCLUSIONS: In cardiomyopathy of recent onset, increased expression of Fas and TNFR1 was associated with minimal recovery of LV function. Apoptosis limits myocardial recovery, and represents a potential target for therapeutic intervention.

Abbreviations and Acronyms   ACEI = angiotensin-converting enzyme inhibitor   FasL = Fas ligand   FLICE = Fas-associated death domain-like interleukin-1ß-converting enzyme   GAPDH = glyceraldehydes 3-phosphate dehydrogenase   IMAC = Intervention in Myocarditis and Acute Cardiomyopathy study   LVEF = left ventricular ejection fraction   NYHA = New York Heart Association   RNA = ribonucleic acid   TNF = tumor necrosis factor   TNFR = tumor necrosis factor receptor

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