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CLINICAL STUDY: HYBERNATING MYOCARDIUM

Active interstitial remodeling: an important process in the hibernating human myocardium

Nikolaos G. Frangogiannis, MD^*,,*, Sarah Shimoni, MD^,, SuMin Chang, MD^,, Guofeng Ren, PhD^*,, Oliver Dewald, MD^*,, Christine Gersch, PhD^*,, Kesavan Shan, MD^,, Constandina Aggeli, MD^,, Michael Reardon, MD^,, George V. Letsou, MD^,, Rafael Espada, MD^,, Mahesh Ramchandani, MD^,, Mark L. Entman, MD, FACC^*, and William A. Zoghbi, MD, FACC^,

^* Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, Texas, USA
Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
Department of Surgery, Baylor College of Medicine Houston, Texas, USA
DeBakey Heart Center, Houston, Texas, USA

Manuscript received December 21, 2000; revised manuscript received January 24, 2002, accepted February 6, 2002.

^* Reprint requests and correspondence: Dr. Nikolaos G. Frangogiannis, Section of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, One Baylor Plaza M/S F-602, Houston, Texas 77030, USA.
ngf{at}bcm.tmc.edu

OBJECTIVES: The purpose of this study is to investigate the morphologic characteristics of the cardiac interstitium in the hibernating human myocardium and evaluate whether active remodeling is present and is an important determinant of functional recovery.

BACKGROUND: Myocardial hibernation is associated with structural myocardial changes, which involve both the cardiomyocytes and the cardiac interstitium.

METHODS: We evaluated 15 patients with coronary disease with two-dimensional echocardiography and thallium-201 (²⁰¹Tl) tomography before coronary bypass surgery. During surgery, transmural myocardial biopsies were performed guided by transesophageal echocardiography. Myocardial biopsies were stained immunohistochemically to investigate fibroblast phenotype and examine evidence of active remodeling in the heart.

RESULTS: Among the 29 biopsied segments included in the study, 24 showed evidence of systolic dysfunction. The majority of dysfunctional segments (86.4%) were viable (²⁰¹Tl uptake 60%). After revascularization, 12 dysfunctional segments recovered function as assessed with an echocardiogram three months after bypass surgery. Interstitial fibroblasts expressing the embryonal isoform of smooth muscle myosin heavy chain (SMemb) were noted in dysfunctional segments, predominantly located in border areas adjacent to viable myocardial tissue. Segments with recovery had higher SMemb expression (0.46 ± 0.16% [n = 12] vs. 0.10 ± 0.02% [n = 12]; p < 0.05) and a higher ratio of alpha-smooth muscle actin to collagen (0.14 ± 0.026 [n = 12] vs. 0.07 ± 0.01 [n = 12]; p < 0.05) compared with segments without recovery, indicating fibroblast activation and higher cellularity of the fibrotic areas. In addition, interstitial deposition of the matricellular protein tenascin, a marker of active remodeling, was higher in hibernating segments than in segments with persistent dysfunction (p < 0.05), suggesting an active continuous fibrotic process. Multiple logistic regression demonstrated a significant independent association between SMemb expression and functional recovery (p < 0.01).

CONCLUSIONS: Fibroblast activation and expression of SMemb and tenascin provide evidence of continuous remodeling in the cardiac interstitium of the hibernating myocardium, an important predictor of recovery of function after revascularization.

Abbreviations and Acronyms   -SMAc   alpha-smooth muscle actin   LV   left ventricular   SMemb   embryonal isoform of smooth muscle myosin heavy chain   SPECT   single photon emission tomography   TEE   transesophageal echocardiography   TGF-ß   transforming growth factor-beta   201Tl   thallium-201

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