Background -Disintegrin metalloproteinases(ADAMs) may contribute to structural cardiac remodeling by altering cell-surface matrix receptors(integrins) and activating potent biomolecules. We compared expression of ADAM...Background -Disintegrin metalloproteinases(ADAMs) may contribute to structural cardiac remodeling by altering cell-surface matrix receptors(integrins) and activating potent biomolecules. We compared expression of ADAMs, their endogenous inhibitor tissue inhibitor of metalloproteinases(TIMP)-3, and integrins in human heart tissue with varied patterns of structural remodeling. Methods and Results -Myocardium was obtained from patients with dilated cardiomyopathy(n=20), hypertrophic obstructive cardiomyopathy(n=5), and nonfailing donor hearts(n=7). Paired samples(n=10) were obtained before left ventricular assist device insertion and at transplantation. The expressions of ADAM10, ADAM12, ADAM15, and ADAM17, TIMP-3, and integrin receptors β1D and β3 were determined by quantitative immunoblotting. Integrin shedding was assessed by the ratio of integrin cleavage products to intact protein abundance. Confocal microscopy was performed. Dilated cardiomyopathy was characterized by increased ADAM10 and ADAM15 expression and reduced TIMP-3 expression. The integrin β1D cleavage ratio was elevated, indicating receptor shedding. ADAM10 and ADAM15 expressions correlated with the cleavage ratio. ADAM10 colocalized with integrin β1D by confocal microscopy. ADAM10 expression correlated with clinical indices of chamber dilatation and systolic dysfunction. Hemodynamic unloading reduced ADAM10 and ADAM12 expressions and increased integrin β1D expression. ADAM12 and integrin β1D expressions were increased in HOCM. ADAM17 was increased in both dilated cardiomyopathy and hypertrophic obstructive cardiomyopathy. Conclusions -Disintegrin metalloproteinases are differentially expressed in human myocardium, reflecting the underlying pattern of structural remodeling. ADAM10 and ADAM15 may contribute to cardiac dilatation by reducing cell-matrix interactions via integrin shedding. Targeting disintegrin metalloproteinases, perhaps by restoring deficient TIMP-3 levels with gene or cell-based therapies, may prevent progressive chamber dilatation in human dilated cardiomyopathy.展开更多
Background -The clinical value of revascularization and other procedures in patients with severe systolic heart failure is unclear. It has been suggested that assessing ischemia and viability by positron emission tomo...Background -The clinical value of revascularization and other procedures in patients with severe systolic heart failure is unclear. It has been suggested that assessing ischemia and viability by positron emission tomography(PET) with fluorodeoxyglucose(FDG) imaging may identify patients for whom revascularization may lead to improved survival. We performed a propensity analysis to determine whether there might be a survival advantage from revascularization. Methods and Results -We analyzed the survival of 765 consecutive patients(age 64±11 years, 80%men) with advanced left ventricular systolic dysfunction(ejection fraction ≤35%) and without significant valvular heart disease who underwent PET/FDG study at the Cleveland Clinic between 1997 and 2002. Early intervention was defined as any cardiac intervention(surgical or percutaneous) within the first 6 months of the PET/FDG study. In the entire cohort, 230 patients(30%) underwent early intervention(188[25%] had open heart surgery, most commonly coronary artery bypass grafting, and 42[5%] had percutaneous revascularization); 535(70%) were treated medically. Using 39 demographic, clinical and PET/FDG variables, we were able to propensity-match 153 of the 230 patients with 153 patients who did not undergo early intervention. Among the propensity-matched group, there were 84 deaths during a median of 3 years follow-up. Early intervention was associated with a markedly lower risk of death(3-year mortality rate of 15%versus 35%, propensity adjusted hazard ratio 0.52, 95%CI 0.33 to 0.81, P=0.0004). Conclusions -Among systolic heart failure patients referred for PET/FDG, early intervention may be associated with improved survival irrespective of the degree of viability.展开更多
文摘Background -Disintegrin metalloproteinases(ADAMs) may contribute to structural cardiac remodeling by altering cell-surface matrix receptors(integrins) and activating potent biomolecules. We compared expression of ADAMs, their endogenous inhibitor tissue inhibitor of metalloproteinases(TIMP)-3, and integrins in human heart tissue with varied patterns of structural remodeling. Methods and Results -Myocardium was obtained from patients with dilated cardiomyopathy(n=20), hypertrophic obstructive cardiomyopathy(n=5), and nonfailing donor hearts(n=7). Paired samples(n=10) were obtained before left ventricular assist device insertion and at transplantation. The expressions of ADAM10, ADAM12, ADAM15, and ADAM17, TIMP-3, and integrin receptors β1D and β3 were determined by quantitative immunoblotting. Integrin shedding was assessed by the ratio of integrin cleavage products to intact protein abundance. Confocal microscopy was performed. Dilated cardiomyopathy was characterized by increased ADAM10 and ADAM15 expression and reduced TIMP-3 expression. The integrin β1D cleavage ratio was elevated, indicating receptor shedding. ADAM10 and ADAM15 expressions correlated with the cleavage ratio. ADAM10 colocalized with integrin β1D by confocal microscopy. ADAM10 expression correlated with clinical indices of chamber dilatation and systolic dysfunction. Hemodynamic unloading reduced ADAM10 and ADAM12 expressions and increased integrin β1D expression. ADAM12 and integrin β1D expressions were increased in HOCM. ADAM17 was increased in both dilated cardiomyopathy and hypertrophic obstructive cardiomyopathy. Conclusions -Disintegrin metalloproteinases are differentially expressed in human myocardium, reflecting the underlying pattern of structural remodeling. ADAM10 and ADAM15 may contribute to cardiac dilatation by reducing cell-matrix interactions via integrin shedding. Targeting disintegrin metalloproteinases, perhaps by restoring deficient TIMP-3 levels with gene or cell-based therapies, may prevent progressive chamber dilatation in human dilated cardiomyopathy.
文摘Background -The clinical value of revascularization and other procedures in patients with severe systolic heart failure is unclear. It has been suggested that assessing ischemia and viability by positron emission tomography(PET) with fluorodeoxyglucose(FDG) imaging may identify patients for whom revascularization may lead to improved survival. We performed a propensity analysis to determine whether there might be a survival advantage from revascularization. Methods and Results -We analyzed the survival of 765 consecutive patients(age 64±11 years, 80%men) with advanced left ventricular systolic dysfunction(ejection fraction ≤35%) and without significant valvular heart disease who underwent PET/FDG study at the Cleveland Clinic between 1997 and 2002. Early intervention was defined as any cardiac intervention(surgical or percutaneous) within the first 6 months of the PET/FDG study. In the entire cohort, 230 patients(30%) underwent early intervention(188[25%] had open heart surgery, most commonly coronary artery bypass grafting, and 42[5%] had percutaneous revascularization); 535(70%) were treated medically. Using 39 demographic, clinical and PET/FDG variables, we were able to propensity-match 153 of the 230 patients with 153 patients who did not undergo early intervention. Among the propensity-matched group, there were 84 deaths during a median of 3 years follow-up. Early intervention was associated with a markedly lower risk of death(3-year mortality rate of 15%versus 35%, propensity adjusted hazard ratio 0.52, 95%CI 0.33 to 0.81, P=0.0004). Conclusions -Among systolic heart failure patients referred for PET/FDG, early intervention may be associated with improved survival irrespective of the degree of viability.
