Adaptations in mitochondrial function parallel, but fail to rescue, the transition to severe hyperglycemia and hyperinsulinemia: a study in Zucker diabetic fatty rats.

Cross-sectional human studies have associated mitochondrial dysfunction to type 2 diabetes. We chose Zucker diabetic fatty (ZDF) rats as a model of progressive insulin resistance to examine whether intrinsic mitochondrial defects are required for development of type 2 diabetes. Muscle mitochondrial function was examined in 6-, 12-, and 19-week-old ZDF (fa/fa) and fa/+ control rats (n = 8-10 per group) using respirometry with pyruvate, glutamate, and palmitoyl-CoA as substrates. Six-week-old normoglycemic-hyperinsulinemic fa/fa rats had reduced mitochondrial fat oxidative capacity. Adenosine diphosphate (ADP)-driven state 3 and carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated state uncoupled (state u) respiration on palmitoyl-CoA were lower compared to controls (62.3 ± 9.5 vs. 119.1 ± 13.8 and 87.8 ± 13.3 vs. 141.9 ± 14.3 nmol O2/mg/min.). Pyruvate oxidation in 6-week-old fa/fa rats was similar to controls. Remarkably, reduced fat oxidative capacity in 6-week-old fa/fa rats was compensated for by an adaptive increase in intrinsic mitochondrial function at week 12, which could not be maintained toward week 19 (140.9 ± 11.2 and 57.7 ± 9.8 nmol O2/mg/min, weeks 12 and 19, respectively), whereas hyperglycemia had developed (13.5 ± 0.6 and 16.1 ± 0.3 mmol/l, weeks 12 and 19, respectively). This mitochondrial adaptation failed to rescue the progressive development of insulin resistance in fa/fa rats. The transition of prediabetes state toward advanced hyperglycemia and hyperinsulinemia was accompanied by a blunted increase in uncoupling protein-3 (UCP3). Thus, in ZDF rats insulin resistance develops progressively in the absence of mitochondrial dysfunction. In fact, improved mitochondrial capacity in hyperinsulinemic hyperglycemic rats does not rescue the progression toward advanced stages of insulin resistance

Patients with Large Neck Diameter Have a Higher Risk of Type IA Endoleaks and Aneurysm Rupture after Standard Endovascular Aneurysm Repair

Objective: Standard endovascular aneurysm repair (EVAR) is the most common treatment of abdominal aortic aneurysms (AAAs). EVAR has been increasingly used in patients with hostile neck features. This study investigated the outcomes of EVAR in patients with neck diameters ≥30 mm in the prospectively maintained Endurant Stent Graft Natural Selection Global Postmarket Registry (ENGAGE). Methods: This is a retrospective study comparing patients with neck diameters ≥30 mm with patients with neck diameters <30 mm. The primary end point was type IA endoleak (EL1A). Secondary end points included secondary interventions to correct EL1A, aneurysm rupture, and survival. Results: This study included 1257 patients (mean age, 73.1 years; 89.4% male) observed for a median 4.0 years (interquartile range, 2.7-4.8 years). A total of 97 (7.7%) patients had infrarenal neck diameters ≥30 mm and were compared with the remaining 1160 (92.3%) with neck diameters <30 mm. At baseline, there were no differences between groups regarding demographics and comorbidities other than cardiac disease, which was more frequent in the ≥30-mm neck diameter group (P = .037). There were no significant differences between the groups regarding neck length, angulation, thrombus, or calcification. Mean preoperative AAA diameter was 64.6 ± 11.3 mm in the ≥30-mm neck diameter group and 60.0 ± 11.6 mm in the <30-mm neck diameter group (P < .001). Stent graft oversizing was significantly less in the ≥30-mm neck diameter group (12.2% ± 8.9% vs 22.1% ± 11.9%; P <. 001). Five patients (5.2%) in the ≥30-mm neck diameter group and 30 (2.6%) with neck diameters <30 mm developed EL1A, yielding a 4-year freedom from EL1A of 92.4% vs 96.6%, respectively (P = .09). Oversizing was 21.8% ± 13.0% for patients developing EL1A and 21.3% ± 12.4% for the remaining cohort (P = .99). In adjusting for neck length, AAA diameter, and device oversizing, patients with neck diameter ≥30 mm were at greater risk for development of EL1A (hazard ratio, 3.0; 95% confidence interval, 1.0-9.3; P = .05). Secondary interventions due to EL1A did not differ between groups (P = .36). AAA rupture occurred in three patients with neck diameter ≥30 mm (3.1%) and in eight patients with neck diameter <30 mm (0.7%; hazard ratio, 5.1; 95% confidence interval, 1.4-19.2; P = .016); two cases were EL1A related in each group. At 4 years, overall survival was 61.6% for the ≥30-mm neck diameter group and 75.2% for the <30-mm neck diameter group (P = .009), which remained significant on correcting for sex and AAA diameter (P = .016). Conclusions: In this study, patients with infrarenal neck diameter ≥30 mm had a threefold increased risk of EL1A and fivefold risk of aneurysm rupture after EVAR as well as worse overall survival. This may influence the choice of AAA repair and underlines the need for regular computed tomography-based imaging surveillance in this subset of patients. Furthermore, these results can serve as standards with which new, possibly improved technology, such as EndoAnchors (Medtronic, Santa Rosa, Calif), can be compared.info:eu-repo/semantics/publishedVersio

Prolonged Fasting Identifies Skeletal Muscle Mitochondrial Dysfunction as Consequence Rather Than Cause of Human Insulin Resistance

OBJECTIVE-Type 2 diabetes and insulin resistance have been associated with mitochondrial dysfunction, but it is debated whether this is a primary factor in the pathogenesis of the disease. To test the concept that mitochondrial dysfunction is secondary to the development of insulin resistance, we employed the unique model of prolonged fasting in humans. Prolonged fasting is a physiologic condition in which muscular insulin resistance develops in the presence of increased free fatty acid (FFA) levels, increased fat oxidation and low glucose and insulin levels. It is therefore anticipated that skeletal muscle mitochondrial function is maintained to accommodate increased fat oxidation unless factors secondary to insulin resistance exert negative effects on mitochondrial function. RESEARCH DESIGN AND METHODS-While in a respiration chamber, twelve healthy males were subjected to a 60 h fast and a 60 h normal fed condition in a randomized crossover design. Afterward, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp, and mitochondrial function was quantified ex vivo in permeabilized muscle fibers using high-resolution respirometry. RESULTS-Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity. Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density. CONCLUSIONS-These findings confirm that the insulin-resistant State has secondary negative effects on mitochondrial function. Given the low insulin and glucose levels after prolonged fasting, hyperglycemia and insulin action per se can be excluded as underlying mechanisms, pointing toward elevated plasma FFA and/or intramuscular fat accumulation as possible causes for the observed reduction in mitochondrial capacity. Diabetes 59: 2117-2125, 201

Prognosis of Vascular Surgery Patients Using a Quantitative Assessment of Troponin T Release: Is the Crystal Ball still Clear?

AbstractBackgroundCardiac troponin T (cTnT) assays with increased sensitivity might increase the number of positive tests. Using the area under the curve (AUC) with serial sampling of cTnT an exact quantification of the myocardial damage size can be made. We compared the prognosis of vascular surgery patients with integrated cTnT–AUC values to continuous and standard 12-lead electrocardiography (ECG) changes.Methods513 Patients were monitored. cTnT sampling was performed on postoperative days 1, 3, 7, 30 and/or at discharge or whenever clinically indicated. If cTnT release occurred, daily measurements of cTnT were performed, until baseline was achieved. CTnT–AUC was quantified and divided in tertiles. All-cause mortality and cardiovascular events (cardiac death and myocardial infarction) were noted during follow-up.Results81/513 (16%) Patients had cTnT release. After adjustment for gender, cardiac risk factors, and site and type of surgery, those in the highest cTnT–AUC tertile were associated with a significantly worse cardiovascular outcome and long-term mortality (HR 20.2; 95% CI 10.2–40.0 and HR 4.0; 95% CI 2.0–7.8 respectively). Receiver operator analysis showed that the best cut-off value for cTnT–AUC was <0.01 days*ng m for predicting long-term cardiovascular events and all-cause mortality.ConclusionIn vascular surgery patients quantitative assessment of cTnT strongly predicts long-term outcome

Effect of beta1- and beta2-adrenergic stimulation on energy expenditure, substrate oxidation, and UCP3 expression in humans

Effect of beta1- and beta2-adrenergic stimulation on energy expenditure, substrate oxidation, and UCP3 expression in humans. Hoeks J, van Baak MA, Hesselink MK, Hul GB, Vidal H, Saris WH, Schrauwen P. NUTRIM, Department of Human Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. [email protected] In humans, beta-adrenergic stimulation increases energy and fat metabolism. In the case of beta1-adrenergic stimulation, it is fueled by an increased lipolysis. We examined the effect of beta2-adrenergic stimulation, with and without a blocker of lipolysis, on thermogenesis and substrate oxidation. Furthermore, the effect of beta1-and beta2-adrenergic stimulation on uncoupling protein 3 (UCP3) mRNA expression was studied. Nine lean males received a 3-h infusion of dobutamine (DOB, beta1) or salbutamol (SAL, beta2). Also, we combined SAL with acipimox to block lipolysis (SAL+ACI). Energy and substrate metabolism were measured continuously, blood was sampled every 30 min, and muscle biopsies were taken before and after infusion. Energy expenditure significantly increased approximately 13% in all conditions. Fat oxidation increased 47 +/- 7% in the DOB group and 19 +/- 7% in the SAL group but remained unchanged in the SAL+ACI condition. Glucose oxidation decreased 40 +/- 9% upon DOB, remained unchanged during SAL, and increased 27 +/- 11% upon SAL+ACI. Plasma free fatty acid (FFA) levels were increased by SAL (57 +/- 11%) and DOB (47 +/- 16%), whereas SAL+ACI caused about fourfold lower FFA levels compared with basal levels. No change in UCP3 was found after DOB or SAL, whereas SAL+ACI downregulated skeletal muscle UCP3 mRNA levels 38 +/- 13%. In conclusion, beta2-adrenergic stimulation directly increased energy expenditure independently of plasma FFA levels. Furthermore, this is the first study to demonstrate a downregulation of skeletal muscle UCP3 mRNA expression after the lowering of plasma FFA concentrations in humans, despite an increase in energy expenditure upon beta2-adrenergic stimulation

The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials

Objectives To investigate whether statins reduce all cause mortality and major coronary and cerebrovascular events in people without established cardiovascular disease but with cardiovascular risk factors, and whether these effects are similar in men and women, in young and older (>65 years) people, and in people with diabetes mellitus

Aneurysm Sac Dynamics and its Prognostic Significance Following Fenestrated and Branched Endovascular Aortic Aneurysm Repair

Objective: This study aimed to assess aneurysm sac dynamics and its prognostic significance following fenestrated and branched endovascular aneurysm repair (F/BEVAR). Methods: Patients undergoing F/BEVAR for degenerative complex aortic aneurysm from 2008 to 2020 at two large vascular centres with two imaging examinations (30 day and one year) were included. Patients were categorised as regression and non-regression, determined by the proportional volume change (&gt; 5%) at one year compared with 30 days. All cause mortality and freedom from graft related events were assessed using Kaplan–Meier methods. Factors associated with non-regression at one year and aneurysm sac volume over time were examined for FEVAR and BEVAR independently using multivariable logistic regression and linear mixed effects modelling. Results: One hundred and sixty-five patients were included: 122 FEVAR, of whom 34% did not regress at one year imaging (20% stable, 14% expansion); and 43 BEVAR, of whom 53% failed to regress (26% stable, 28% expansion). Following F/BEVAR, after risk adjusted analysis, non-regression was associated with higher risk of all cause mortality within five years (hazard ratio [HR] 2.56, 95% confidence interval [CI] 1.09 – 5.37; p = .032) and higher risk of graft related events within five years (HR 2.44, 95% CI 1.10 – 5.26; p = .029). Following multivariable logistic regression, previous aortic repair (odds ratio [OR] 2.56, 95% CI 1.11 – 5.96; p = .029) and larger baseline aneurysm diameter (OR/mm 1.04, 95% CI 1.00 – 1.09; p = .037) were associated with non-regression at one year, whereas smoking history was inversely associated with non-regression (OR 0.21, 95% CI 0.04 – 0.96; p = .045). Overall following FEVAR, aneurysm sac volume decreased significantly up to two years (baseline vs. two year, 267 [95% CI 250 – 285] cm 3 vs. 223 [95% CI 197 – 248] cm 3), remaining unchanged thereafter. Overall following BEVAR, aneurysm sac volume remained stable over time. Conclusion: Like infrarenal EVAR, non-regression at one year imaging is associated with higher five year all cause mortality and graft related events risks after F/BEVAR. Following FEVAR for juxtarenal aortic aneurysm, aneurysm sacs generally displayed regression (66% at one year), whereas after BEVAR for thoraco-abdominal aortic aneurysm, aneurysm sacs displayed a concerning proportion of growth at one year (28%), potentially suggesting a persistent risk of rupture and consequently requiring intensified surveillance following BEVAR. Future studies will have to elucidate how to improve sac regression following complex EVAR, and whether the high expansion risk after BEVAR is due to advanced disease extent.</p