Рабочая группа по диабету, предиабету и сердечно-сосудистым заболеваниям европейского общества кардиологов (ESC) в сотрудничестве с европейской ассоциацией по изучению диабета (EASD).

Abstract-High diastolic stiffness of failing myocardium results from interstitial fibrosis and elevated resting tension (F passive ) of cardiomyocytes. A shift in titin isoform expression from N2BA to N2B isoform, lower overall phosphorylation of titin, and a shift in titin phosphorylation from N2B to N2BA isoform can raise F passive of cardiomyocytes. In left ventricular biopsies of heart failure (HF) patients, aortic stenosis (AS) patients, and controls (CON), we therefore related F passive of isolated cardiomyocytes to expression of titin isoforms and to phosphorylation of titin and titin isoforms. Biopsies were procured by transvascular technique (44 HF, 3 CON), perioperatively (25 AS, 4 CON), or from explanted hearts (4 HF, 8 CON). None had coronary artery disease. Isolated, permeabilized cardiomyocytes were stretched to 2.2-m sarcomere length to measure F passive . Expression and phosphorylation of titin isoforms were analyzed using gel electrophoresis with ProQ Diamond and SYPRO Ruby stains and reported as ratio of titin (N2BA/N2B) or of phosphorylated titin (P-N2BA/P-N2B) isoforms. F passive was higher in HF (6.1Ϯ0.4 kN/m 2 ) than in CON (2.3Ϯ0.3 kN/m 2 ; PϽ0.01) or in AS (2.2Ϯ0.2 kN/m 2 ; PϽ0.001). Titin isoform expression differed between HF (N2BA/N2Bϭ0.73Ϯ0.06) and CON (N2BA/N2Bϭ0.39Ϯ0.05; PϽ0.001) and was comparable in HF and AS (N2BA/N2Bϭ0.59Ϯ0.06). Overall titin phosphorylation was also comparable in HF and AS, but relative phosphorylation of the stiff N2B titin isoform was significantly lower in HF (P-N2BA/P-N2Bϭ0.77Ϯ0.05) than in AS (P-N2BA/P-N2Bϭ0.54Ϯ0.05; PϽ0.01). Relative hypophosphorylation of the stiff N2B titin isoform is a novel mechanism responsible for raised

Background-Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified. Methods and Results-Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; nϭ46) and patients with AS and DM (AS-DM; nϭ16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-m sarcomere length to measure resting tension (F passive ). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21Ϯ1 mm Hg for AS versus 28Ϯ4 mm Hg for AS-DM; Pϭ0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9Ϯ1.1% versus AS-DM, 18.2Ϯ2.

While apelin/APJ myocardial expression decreases, apelin plasma levels increase in LV hypertrophy. Considering apelin's positive inotropic and vasodilator properties, this elevation in apelin plasma levels may represent a compensatory mechanism to maintain inotropism and cardiac output during pressure-overload or diabetic cardiomyopathy.