👤 Walter Paulus

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

The Restless Legs Syndrome (RLS) is a heterogeneous disease. Symptomatic or secondary forms encompass iron deficiency, uremia, pregnancy, polyneuropathy, and other causes. The so-called idiopathic RLS syndrome preferentially affects patients with a younger onset before the age of 30. Here we summarize pathophysiological results along the anatomical route, beginning at the cortex and followed by the basal ganglia, thalamus, A11 neurones, substantia nigra, brainstem nuclei, and spinal cord. Genetic risk variants for RLS have recently been identified in two genes, one of them the homeobox gene MEIS1, known to be involved in embryonic development and variants in a second locus containing the genes encoding mitogen-activated protein kinase MAP2K5, and the transcription factor LBXCOR1. A third one, the BTBD9 gene with unknown function encodes a BTB(POZ) domain. Accordingly, new concepts on pathophysiology have to bridge conventional knowledge with possible consequences deriving from these findings. Furthermore, this may create a framework to help understand why dopamine, opioid, and some anticonvulsant therapies are effective in RLS patients. Show less

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder. Show less