Abstract-In ventricular cardiac myocytes, T-tubule density is an important determinant of the synchrony of sarcoplasmic reticulum (SR) Ca 2ϩ release and could be involved in the reduced SR Ca 2ϩ release in ischemic cardiomyopathy. We therefore investigated T-tubule density and properties of SR Ca 2ϩ release in pigs, 6 weeks after inducing severe stenosis of the circumflex coronary artery (91Ϯ3%, Nϭ13) with myocardial infarction (8.8Ϯ2.0% of total left ventricular mass). Severe dysfunction in the infarct and adjacent myocardium was documented by magnetic resonance and Doppler myocardial velocity imaging. Myocytes isolated from the adjacent myocardium were compared with myocytes from the same region in weight-matched control pigs. T-tubule density quantified from the di-8-ANEPPS (di-8-butyl-aminonaphthyl-ethylene-pyridinium-propyl-sulfonate) sarcolemmal staining was decreased by 27Ϯ7% (PϽ0.05). Synchrony of SR Ca 2ϩ release (confocal line scan images during whole-cell voltage clamp) was reduced in myocardium myocytes. Delayed release (ie, ] i occurring later than 20 ms) occurred at 35.5Ϯ6.4% of the scan line in myocardial infarction versus 22.7Ϯ2.5% in control pigs (PϽ0.05), prolonging the time to peak of the line-averaged [Ca 2ϩ ] i transient (121Ϯ9 versus 102Ϯ5 ms in control pigs, PϽ0.05). Delayed release colocalized with regions of T-tubule rarefaction and could not be suppressed by activation of protein kinase A. The whole-cell averaged [Ca 2ϩ ] i transient amplitude was reduced, whereas L-type Ca 2ϩ current density was unchanged and SR content was increased, indicating a reduction in the gain of Ca 2ϩ -induced Ca 2ϩ release. In conclusion, reduced T-tubule density during ischemic remodeling is associated with reduced synchrony of Ca 2ϩ release and reduced efficiency of coupling Ca 2ϩ influx to Ca Key Words: myocardial infarction Ⅲ contractility Ⅲ myocytes Ⅲ calcium A lthough new therapeutic approaches have decreased the mortality associated with myocardial infarction (MI) over the past decades, 1 many patients nevertheless sustain a regional loss of myocardial contractile tissue following an ischemic event. The resulting increased hemodynamic burden on the left ventricle leads to structural and functional changes in the remaining viable myocardium, which further reduces ventricular performance, a process referred to as myocardial remodeling. 2 Sustained regional chronic and/or intermittent ischemia further contributes to this process, and the resulting ischemic cardiomyopathy is currently among the major causes of heart failure. 3 Contractile dysfunction of the ventricle is partly related to the abnormal loading in vivo 4 and partly to the intrinsic properties of the cardiomyocytes. Myocytes isolated from patients with ischemic cardiomyopathy at the time of heart transplantation have a reduced contractile function resulting from abnormal Ca 2ϩ handling. [5][6][7] Animal models have examined the mechanisms of cellular dysfunction in ischemic cardiomyopathy in more detail. Myocytes from the infarct border...
Background Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction (MI) in transgenic mice with cardiomyocyte-specific over-expression of PDE5 (PDE5-TG). Methods and Results Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening and calcium handling in isolated cardiomyocytes, and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates (WT). Ten days after MI, LV cGMP levels increased to a greater extent in WT than PDE5-TG (P<0.05). Ten weeks after MI, LV end-systolic and -diastolic volumes were larger in PDE5-TG than in WT (57±5 vs 39±4 and 65±6 vs 48±4 µL, respectively, P<0.01 for both). LV systolic and diastolic dysfunction was more marked in PDE5-TG than WT associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium. Conclusions Increased PDE5 expression predisposes mice to adverse LV remodeling after MI. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.
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