Background-In stable coronary artery disease (CAD), exercise training has well-documented positive effects on arterial endothelial function. NO derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. The aim of the present study was to investigate the effects of exercise training on the endothelial function in relation to the expression of eNOS and Akt-dependent eNOS phosphorylation in the left internal mammary artery (LIMA) of patients with stable CAD. Methods and Results-In 17 training patients (T) and 18 control patients (C), endothelium-dependent vasodilation and average peak flow velocity (APV) in response to acetylcholine were measured invasively at study beginning and after 4 weeks in the LIMA. In LIMA tissue sampled during bypass surgery, eNOS expression and content of pospho-eNOSSer 1177 , Akt, and phospho-Akt were determined by Western blot and quantitative reverse transcriptase-polymerase chain reaction. After exercise training, LIMA APV in response to acetylcholine was increased by 56Ϯ8% (from ϩ48Ϯ8% at beginning to ϩ104Ϯ11% after 4 weeks, PϽ0.001). Patients in T had a 2-fold higher eNOS protein expression (T 1.0Ϯ0.7 versus C 0.5Ϯ0.3 arbitrary units, PϽ0.05) and 4-fold higher eNOS Ser 1177 -phosphorylation levels in LIMA-endothelium (1.2Ϯ0.9 versus 0.3Ϯ0.2 arbitrary units, PϽ0.01). A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels (Rϭ0.80, PϽ0.05) and between phospho-eNOS and ⌬ APV (Rϭ0.59, PϽ0.05). Conclusions-Exercise training in stable CAD leads to an improved agonist-mediated endothelium-dependent vasodilatory capacity. The change in acetylcholine-induced vasodilatation was closely related to a shear stress-induced/Aktdependent phosphorylation
Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome.
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