Background-Rheumatic heart disease is the most common cause of valvular disease in developing countries. Despite the high prevalence of this disease, the cellular mechanisms are not well known. We hypothesized that rheumatic valve calcification is associated with an osteoblast bone formation and neoangiogenesis. Methods and Results-To test this hypothesis, we examined human rheumatic valves replaced at surgery (nϭ23), normal human valves (nϭ20) removed at cardiac transplantation, and degenerative mitral valve leaflets removed during surgical valve repair (nϭ15). Microcomputed tomography was used to assess mineralization fronts to reconstruct the extents of mineralization. Immunohistochemistry was used to localize osteopontin protein, ␣-actin, osteocalcin, vascular endothelial growth factor, von Willebrand factor, and CD68 (human macrophage). Microcomputed tomography demonstrated complex calcification developing within the heavily calcified rheumatic valves, not in the degenerative mitral valves and control valves. Immunohistochemistry localized osteopontin and osteocalcin to areas of smooth muscle cells within microvessels and proliferating myofibroblasts. Vascular endothelial growth factor was present in areas of inflammation and colocalized with the CD68 stain primarily in the calcified rheumatic valves. Alizarin red, osteopontin, and osteocalcin protein expression was upregulated in the calcified rheumatic valves and was present at low levels in the degenerative mitral valves. Conclusions-These findings support the concept that rheumatic valve calcification is not a random passive process but a regulated, inflammatory cellular process associated with the expression of osteoblast markers and neoangiogenesis. Key Words: angiogenesis Ⅲ calcification Ⅲ cardiovascular diseases Ⅲ rheumatic heart disease Ⅲ valves R heumatic valvular heart disease is the most common cause of valvular heart disease in developing countries. Improvement in living standards and the aggressive treatment of penicillin-sensitive group A ␤-hemolytic Streptococcus are changing the epidemiology of rheumatic valve disease throughout the world. In 1924, Dr Carey Coombs wrote the first systematic textbook on rheumatic heart disease, describing the inflammatory lesion in the rheumatic valve leaflet and the presence of new vessels developing within the valve. 1 Since 1924, a number of studies have demonstrated the histopathology of this disease with correlations of the degree of rheumatic activity, which include the presence of Aschoff bodies, nonspecific edema, and leukocyte infiltration. 2,3 Despite the high prevalence, increased morbidity, and well-described histopathological findings of this disease, little is known about the cellular mechanisms responsible for calcification in these valves. Recently, our laboratory and others have demonstrated that calcification in nonrheumatic, "degenerative" stenotic aortic valves removed at the time of surgical valve replacement is associated with an osteoblast-like phenotype. 4,5 We hypothesized that the i...

Cytokine therapy promises to provide a noninvasive treatment option for ischemic heart disease. Cytokines are thought to influence angiogenesis directly via effects on endothelial cells or indirectly through progenitor cell-based mechanisms or by activating the expression of other angiogenic agents. Several cytokines mobilize progenitor cells from the bone marrow or are involved in the homing of mobilized cells to ischemic tissue. The recruited cells contribute to myocardial regeneration both as a structural component of the regenerating tissue and by secreting angiogenic or antiapoptotic factors, including cytokines. To date, randomized, controlled clinical trials have not reproduced the efficacy observed in pre-clinical and small-scale clinical investigations. Neverthe-less, the list of promising cytokines continues to grow, and combinations of cytokines, with or without concurrent progenitor cell therapy, warrant further investigation.

Objectives We undertook a meta-analysis to assess outcomes for drug-eluting (DES) and bare metal stents (BMS) in percutaneous coronary intervention (PCI) for unprotected left main coronary stenosis (LMCA). Background Uncertainty exits regarding the relative performance of DES versus BMS in unprotected LMCA PCI. Methods Of a total of 838 studies, 44 met inclusion criteria (N=10,342). The co-primary endpoints were mortality, myocardial infarction (MI), target vessel/target lesion revascularization (TVR/TLR), and major adverse cardiac events (MACE: mortality, MI, TVR/TLR). Results Event rates for DES and BMS were calculated at 6–12 months, at 2 years and at 3 years. Crude event rates at 3 years were: mortality (8.8% and 12.7%), MI (4.0% and 3.4%), TVR/TLR (8.0% and 16.4%), and MACE (21.4% and 31.6%). Nine studies were included in a comparative analysis (N=5,081). At 6–12 months the adjusted odds ratio (OR) for DES vs. BMS were: mortality 0.94 (95% confidence interval [CI] 0.06–15.48; p=0.97), MI 0.64 (95% CI 0.19–2.17; p=0.47), TVR/TLR 0.10 (95% CI 0.01–0.84; p=0.01) and MACE 0.34 (95% CI 0.15–0.78; p=0.01). At 2 years the OR were: mortality 0.42 (95% CI 0.28–0.62; p<0.01), MI 0.16 (95% CI 0.01–3.53; p=0.13), and MACE 0.31 (95% CI 0.15–0.66; p<0.01). At 3 years the OR were: mortality 0.70 (95% CI 0.53–0.92; p=0.01), MI 0.49 (95% CI 0.26–0.92; p=0.03), TVR/TLR 0.46 (95% CI 0.30–0.69; p<0.01), and MACE 0.78 (95% CI 0.57–1.07; p=0.12). Conclusion Our meta-analysis suggests that DES is associated with favorable outcomes for mortality, MI, TVR/TLR, and MACE as compared to BMS in unprotected LMCA PCI.