👤 Wolfgang A Linke

We investigated the relationship between heart failure etiology and lipoprotein subfractions, and to explore their associations with left ventricular dimension and function in heart failure with reduced ejection fraction (HFrEF) patients. Cross-sectional investigation of serum lipoprotein subfractions from 205 HFrEF patients in the SMARTEX heart failure study. Serum levels of triglycerides, cholesterol, free cholesterol, phospholipids, lipoproteins (Apolipoproteins; A-1, A-2, and B), very-low-density (VLDL), intermediate-density (IDL), low-density (LDL), and high-density lipoprotein (HDL) were determined using Stable HFrEF patients [left ventricular ejection fraction (LVEF) ≤ 35%, NYHA class II-III], with ischemic (ICM, n = 119) or non-ischemic (NICM, n = 86) cardiomyopathy were studied. NICM patients had higher levels of 48 lipoproteins compared to ICM patients, including 29 LDL, 13 VLDL, and 6 HDL subfractions [p <0.05]. NICM patients had 22% higher cholesterol and 27% higher remnant cholesterol levels, with 24% more atherogenic ApoB containing subfractions (VLDL, IDL, LDL) (p <0.05). Heart failure etiology and statin treatment explained 23-24% of the variability in cholesterol, free cholesterol, and ApoB (p <0.001). Triglyceride content in some VLDL and LDL subfractions was weakly associated with left ventricular end-diastolic volume, end-diastolic diameter, ejection fraction, and S'. NICM patients had the highest atherosclerotic lipoprotein burden, attributed to elevated ApoB particles and partly due to less statin treatment. The triglyceride content of some VLDL and LDL subfractions was weakly associated with left ventricular structure and function. However, further research is needed to determine their prognostic significance before implementation into strategies for prevention and treatment. Show less

Atherosclerosis, the leading cause of heart attack and stroke, involves plaque formation driven by various cell types, including endothelial cells, immune cells and vascular smooth muscle cells (VSMCs). VSMCs undergo a phenotypic switch from a contractile to a synthetic state, contributing to disease progression. The Eph/ephrin signaling pathway, particularly ephrin-A1 and its receptor EphA2, has been implicated in this phenotypic modulation. Its role in atherosclerosis was explored using in vitro and in vivo models. In plaque-containing arteries, both ephrin-A1 and EphA2 were upregulated compared to plaque-free regions. The phenotypic transition of VSMCs from a contractile to a synthetic state is associated with reduced ephrin-A1 levels, elevated EphA2 expression, and increased cellular proliferation. A consistent expression pattern with low ephrin-A1 and high EphA2 was observed in proliferating cells. Additionally, under pro-proliferative conditions, the non-canonical phosphorylation site S897/898 of EphA2 is phosphorylated in a MEK/ERK/RSK-dependent manner, while the canonical site Y588/589 undergoes autophosphorylation at higher ephrin-A1 levels. These in vitro findings suggest an anti-proliferative, potentially anti-atherogenic role for ephrin-A1 in VSMCs. This hypothesis was further examined in ApoE-KO mice using a conditional VSMC-specific ephrin-A1 knockout. Surprisingly, neither high-fat diet-induced atherosclerosis nor wire injury-induced stenosis differed between ephrin-A1-deficient and wild-type mice, implying functional compensation by other ephrin ligands. The present findings highlight significant roles for the Eph/ephrin system in VSMC biology and plaque development. However, its effects appear to be multimodal, influenced by the interplay between various cell types and distinct members of the Eph/ephrin family. Show less

Obesity and Type 2 diabetes mellitus (DM) induce left ventricular (LV) diastolic dysfunction, which contributes to an increasing prevalence of heart failure with a preserved LV ejection fraction. We investigated the effects of sitagliptin (SITA), an inhibitor of dipeptidylpeptidase-4 (DPP-4) and anti-diabetic drug, on LV structure and function of obese mice with Type 2 DM. Obese Type 2 diabetic mice (Lepr(db/db), BKS.Cg-Dock7(m)+/+ Lepr(db)/J), displaying increased cardiomyocyte and LV stiffness at the age of 16 weeks, were treated with SITA (300 mg/kg/day) or vehicle for 8 weeks. SITA severely impaired serum DPP-4 activity, but had no effect on glycaemia. Invasive haemodynamic recordings showed that SITA reduced LV passive stiffness and increased LV stroke volume; LV end-systolic elastance remained unchanged. In addition, SITA reduced resting tension of isolated single cardiomyocytes and intensified phosphorylation of the sarcomeric protein titin. SITA also increased LV concentrations of cGMP and increased activity of protein kinase G (PKG). In vitro activation of PKG decreased resting tension of cardiomyocytes from vehicle-treated mice, but had no effect on resting tension of cardiomyocytes from SITA-treated mice. In obese Type 2 diabetic mice, in the absence of hypoglycaemic effects, inhibition of DPP-4 decreases LV passive stiffness and improves global LV performance. These effects seem at least partially mediated by stimulatory effects on the myocardial cGMP-PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus. Show less