Active interstitial remodeling: an important process in the hibernating human myocardium.
OBJECTIVE
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 ((201)Tl) 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 ((201)Tl uptake > or = 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.
Frangogiannis
Nikolaos G
NG
Section of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. ngf@bcm.tmc.edu
Shimoni
Sarah
S
Chang
Su Min
SM
Ren
Guofeng
G
Dewald
Oliver
O
Gersch
Christine
C
Shan
Kesavan
K
Aggeli
Constandina
C
Reardon
Michael
M
Letsou
George V
GV
Espada
Rafael
R
Ramchandani
Mahesh
M
Entman
Mark L
ML
Zoghbi
William A
WA
D000368:Aged; D005260:Female; D005347:Fibroblasts / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009204:Myocardial Revascularization; D017682:Myocardial Stunning / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000378:metabolism* / Q000648:ultrastructure; D024501:Nonmuscle Myosin Type IIB; D020127:Recovery of Function; D019063:Tenascin / Q000378:metabolism* / Q000648:ultrastructure
D019063:Tenascin; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains