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

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 ((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.

Evidence for an active inflammatory process in the hibernating human myocardium.

Myocardial hibernation refers to a state of prolonged impairment of left ventricular function in the presence of coronary artery disease, which may be reversed by revascularization. In this study we present evidence for a local inflammatory reaction in hibernating myocardial segments from patients undergoing coronary revascularization. We obtained transmural myocardial biopsies guided by transesophageal echocardiography from patients with ischemic ventricular dysfunction undergoing bypass surgery. Among the 28 biopsied segments included in the study, 23 showed evidence of systolic dysfunction. The majority of dysfunctional segments (85.7%) were viable ((201)Tl uptake >/= 60%). The samples were stained with markers for mast cells, mature resident macrophages, and the monoclonal antibody Mac387 that labels newly recruited myeloid cells. Dysfunctional segments showed more extensive fibrosis and higher macrophage density than normal segments. Among the 23 dysfunctional segments, 12 recovered function as assessed with echocardiograms 3 months after revascularization. Segments with postoperative functional recovery had comparable macrophage and mast cell density with those showing persistent dysfunction. However, biopsied segments that subsequently recovered function contained significantly higher numbers of newly recruited Mac387-positive leukocytes (18.7 +/- 3.1 cells/mm(2), n = 12 versus 8.6 +/- 0.9 cells/mm(2), n = 11; P = 0.009). In addition, monocyte chemotactic protein-1, a potent mononuclear cell chemoattractant, was predominantly expressed in segments with recovery of function. Myocardial hibernation is associated with an inflammatory response leading to active leukocyte recruitment. Dysfunctional myocardial segments that show an active inflammatory reaction have a greater potential for recovery of function after revascularization. We postulate that revascularization may promote resolution of the ongoing inflammation, preventing further tissue injury and fibrosis.