Persistent Prothrombotic State in a Patient With Alström Syndrome

We present the case of a patient with Alström syndrome who was found to have evidence of a prothrombotic state on autopsy after sudden cardiac death. To the best of our knowledge, this case of persistent prothrombotic milieu is the first described in a patient with Alström syndrome

Persistent Prothrombotic State in a Patient With Alström Syndrome

We present the case of a patient with Alström syndrome who was found to have evidence of a prothrombotic state on autopsy after sudden cardiac death. To the best of our knowledge, this case of persistent prothrombotic milieu is the first described in a patient with Alström syndrome

Endothelial Insulin Receptor Restoration Rescues Vascular Function in Male Insulin Receptor Haploinsufficient Mice

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell–specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling

Mechanisms involved in regulation of Systemic Blood Pressure

Regulation of the circulatory system to maintain a constant arterial pressure is critical in ensuring adequate perfusion to meet metabolic requirements of tissues. Blood pressure (BP) can be considered in the context of Ohm’s law, whereby BP (analogous to voltage) is directly proportional to the product of cardiac output (current) and total vascular resistance (TPR). Acute regulatory mechanisms are coordinated in the cardiovascular control centres in the brainstem, which are themselves infl uenced by impulses from other neural centres in addition to sensors both intrinsic and extrinsic to the circulation. However, certain organs such as the heart, kidneys and brain have the ability to coordinate blood flow locally, i.e. autoregulate. This enables alterations in regional perfusion without perturbations of BP. This mini-review provides an exploratory discussion of neural and humoral mechanisms that underpin regulation of systemic BP.</p

Diagnostic yield of a heart failure referral pathway using N-terminal pro-brain natriuretic peptide

Objective To determine the diagnostic yield of a ‘high’ N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with suspected heart failure (HF) referred from primary to secondary care.Methods In this retrospective study, cardiac diagnoses were quantified in consecutive patients with an NT-proBNP&gt;400 ng/L referred from primary care centres to a specialist HF service.Results Among 654 consecutive patients (age: 78.5±9.72 years; 45.9% men; left ventricular ejection fraction (LVEF): 55.4±12.5% (mean±SD)), the primary diagnoses were: valvular disease (39.4%), HF (29.2%; 13.3% with LVEF&lt;40%) and atrial fibrillation (AF; 17.3%). In terms of primary or secondary diagnoses, 68% of patients had valve disease, 46.9% had AF and 29.2% had HF. A cardiac diagnosis was made in 85.9%. In multivariable analyses, NT-proBNP predicted HF with LVEF&lt;40% (OR: 10.2, 95% CI: 5.63 to 18.3) and HF with any LVEF (OR: 6.13, 95% CI: 3.79 to 9.93). In canonical linear discriminant analyses, NT-proBNP correctly identified 54.5% of patients with HF. The remainder were misclassified as valvular disease, AF or no cardiac diagnosis.Conclusion Among patients with an NT-proBNP&gt;400 ng/L referred through a primary care HF pathway, most patients had valve disease or AF rather than HF. NT-proBNP cannot discriminate among HF, valve disease and AF. On this basis, NT-proBNP may be best employed in detecting cardiac disease in general rather than HF per se

Persistent Prothrombotic State in a Patient With Alström Syndrome

We present the case of a patient with Alström syndrome who was found to have evidence of a prothrombotic state on autopsy after sudden cardiac death. To the best of our knowledge, this case of persistent prothrombotic milieu is the first described in a patient with Alström syndrome

Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase–Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance

Shc homology 2-containing inositol 5´ phosphatase-2 (SHIP2) is as lipid phosphatase which inhibits insulin signaling downstream of phosphoinositide-3-kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in EC (ECSHIP2(Δ/+)). Hyperinsulinemic euglycemic clamping studies revealed ECSHIP2(Δ/+) were resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle, compared with littermate controls. EC from ECSHIP2(Δ/+) had increased basal expression and activation of PI3K downstream targets, including Akt and endothelial nitric oxide synthase (eNOS), although incremental activation by insulin and shear stress was impaired. Insulin-mediated vasodilation was blunted in ECSHIP2(Δ/+), as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2(Δ/+), which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2(Δ/+) EC, and was suppressed by PI3K and Nox2 NADPH oxidase inhibitors. These findings were phenocopied in healthy human EC after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction