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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

View larger version (117K): [in a new window]   Figure 1 Structural alterations of the myocytes and the cardiac interstitium in dysfunctional myocardial segments. (A) Segment with preserved function showing relatively few morphologic abnormalities. (B) Segment with reversible dysfunction demonstrating a widened interstitial space (arrows), with a relatively high cellular content, and myocyte degeneration with significant loss of contractile material (arrowheads). (C) Segments with persistent dysfunction after revascularization show more extensive pathologic changes, severe sarcomeric loss and significant extracellular matrix accumulation in the cardiac interstitium. All slides were stained with hematoxylin-eosin (400x).

View larger version (149K): [in a new window]   Figure 2 Smooth muscle cells and myofibroblasts in the dysfunctional human myocardium. Immunostaining of serial sections for SM1 (A), SM2 (B), markers of mature smooth muscle cells, the embryonic isoform of smooth muscle myosin heavy chain (SMemb) (C), and alpha-smooth muscle actin (-SMAc) (D). Note that the myocardial arteriole (arrows) expresses SM1 (A), SM2 (B) and -SMAc (D) but not SMemb (C). Expression of SMemb is noted in interstitial myofibroblasts (C), which are also positive for -SMAc. Counterstained with eosin (100x).

View larger version (101K): [in a new window]   Figure 3 The embryonic isoform of smooth muscle myosin heavy chain (SMemb) positive cells are predominantly localized in border zone areas adjacent to viable myocytes. Serial sections from a hibernating myocardial segment were stained for SM1 (A), SM2 (B), SMemb (C) and collagen (D). Arteriolar smooth muscle cells (arrows) express SM1 and SM2 but not SMemb. In contrast, the interstitial SMemb positive cells (C) are negative for SM1 and SM2 and are predominantly located in border areas adjacent to viable myocytes. Areas with extensive collagen deposition show lower SMemb expression (100x). (E) High magnification image of an area from a hibernating myocardial segment stained for SMemb. Note that SMemb expression is localized in spindle-shaped interstitial cells (1,000x).

View larger version (95K): [in a new window]   Figure 4 Immunohistochemistry for tenascin (A), alpha-smooth muscle actin (-SMAc) (B) and vinculin (C) in the dysfunctional human myocardium from a segment with recovery of function after revascularization. Marked deposition of tenascin is noted in the cardiac interstitial space, suggesting an active continuous remodeling process. Interstitial myofibroblasts demonstrate expression of the focal adhesion protein vinculin (C), a factor promoting their attachment to the matrix. Note that vinculin immunoreactivity is also noted in the sarcolemma and the intercalated discs (200x). Counterstained with eosin.

View larger version (90K): [in a new window]   Figure 5 Immunohistochemistry for tenascin (A), alpha-smooth muscle actin (-SMAc) (B) and vinculin (C) in the dysfunctional human myocardium from a segment with persistent dysfunction after revascularization. Tenascin immunoreactivity is present in the cardiac interstitium; however, its expression is low in comparison with the extent of fibrosis. In addition, vinculin-positive, -SMAc expressing myofibroblasts are found in the fibrotic area (arrow). Note the presence of myocytes with extensive degenerative changes, demonstrating disorganized cytoplasmic expression of vinculin (arrowheads). Counterstained with eosin (200x).