Cardiovascular Diabetology - Latest Articles

Intracellular Ca2+ regulating proteins in vascular smooth muscle cells are altered with type 1 diabetes due to the direct effects of hyperglycemia

Yvonne Searls — 2010-02-01T00:00:00Z

Background: Diminished calcium (Ca2+) transients in response to physiological agonists have been reported in vascular smooth muscle cells from diabetic animals. However, the mechanism responsible was unclear.Methodology/Principal Findings: VSMCs from autoimmune type 1 Diabetes Resistant Bio-Breeding (DR-BB) rats and streptozotocin-induced rats were examined for levels and distribution of inositol trisphosphate receptors (IP3R) and the SR Ca2+ pumps (SERCA 2 and 3). Generally, a decrease in IP3R levels and dramatic increase in ryanodine receptor (RyR) levels were noted in the aortic samples from diabetic animals. Redistribution of the specific IP3R subtypes was dependent on the rat model. SERCA 2 was redistributed to a peri-nuclear pattern that was more prominent in the DR-BB diabetic rat aorta than the STZ diabetic rat. The free intracellular Ca2+ in freshly dispersed VSMCs from control and diabetic animals was monitored using ratiometric Ca2+ sensitive fluorophores viewed by confocal microscopy. In control VSMCs, basal fluorescence levels were significantly higher in the nucleus relative to the cytoplasm, while in diabetic VSMCs they were essentially the same. Vasopressin induced a predictable increase in free intracellular Ca2+ in the VSMCs from control rats with a prolonged and significantly blunted response in the diabetic VSMCs. A slow rise in free intracellular Ca2+ in response to thapsigargin, a specific blocker of SERCA was seen in the control VSMCs but was significantly delayed and prolonged in cells from diabetic rats. To determine whether the changes were due to the direct effects of hyperglycemica, experiments were repeated using cultured rat aortic smooth muscle cells (A7r5) grown in hyperglycemic and control conditions. In general, they demonstrated the same changes in protein levels and distribution as well as the blunted Ca2+ responses to vasopressin and thapsigargin as noted in the cells from diabetic animals.Conclusions/Significance: This work demonstrates that the previously-reported reduced Ca2+ signaling in VSMCs from diabetic animals is related to decreases and/or redistribution in the IP3R Ca2+ channels and SERCA proteins. These changes can be duplicated in culture with high glucose levels.

Effect of cardiometabolic risk factors on hypertension management: a cross-sectional study among 28 physician practices in the United States

Daniel Belletti — 2010-02-01T00:00:00Z

ObjectiveThis cross-sectional study sought to determine the prevalence of cardiometabolic risk factor clusters (CMRFCs) and their effect on BP control among hypertensive patients from 28 US physician practices. Methods: Each participating practice identified a random sample of 150-300 adults (>=18 years old) diagnosed with hypertension. The primary outcome variable was BP control (BP <140/90 mmHg for non-diabetic and <130/80 mmHg for diabetic patients). CMRFCs included hypertension in addition to obesity, dyslipidemia, and diabetes. Results: Overall, 6,527 hypertensive patients were identified for study inclusion. More than half (54.3%) were female, and mean age was 64.7 years. Almost half (48.7%) were obese (BMI >30 kg/m2). About 1 in every 4 patients (25.3%) had diabetes, and 60.7% had dyslipidemia. Mean blood pressure was 132.5/77.9 mmHg, and 55.0% of all patients had controlled BP; 62.4% of non-diabetic patients, and 33.3% of diabetic hypertensive patients, had BP controlled to recommended levels. Most (81.7%) hypertensive patients had at least 1 additional cardiometabolic risk factor, and 12.2% had all 3 risk factors. As compared to hypertensive patients without additional risk factors, adjusted odds ratios for BP control were significantly lower for all combinations of CMRFCs (ORs 0.15-0.83, all p<0.04), with the exception of patients who had only dyslipidemia in addition to hypertension (OR=1.09, p=NS). Prescriber adherence to recommended hypertension treatment guidelines for patients with diabetes, heart failure, or prior myocardial infarction was high. Although patients with risk factors were prescribed more antihypertensive medications than those without, hypertensive patients with all 3 risk factors were prescribed a mean of 2.4 antihypertensive medications compared to 1.7 for those with no risk factors; odds of BP control in these patients, however, was 0.23 [95% CI 0.19-0.29] that of patients with no other CMRFCs. Conclusions: Across 28 US practices, only 18% of hypertensive patients did not have any additional cardiometabolic risk factors. The high prevalence of CMRFCs presents a challenge to effective hypertension management.

Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot study

Anne Gill — 2010-01-28T00:00:00Z

Background: Cardiovascular effects of glucose-lowering agents are of increasing interest. Our aim was to assess the effects of the glucagon-like peptide-1 receptor agonist exenatide on heart rate (HR) and blood pressure (BP) in subjects with type 2 diabetes mellitus (T2DM). Methods: In this double-blind, placebo-controlled trial, subjects with T2DM on metformin and/or a thiazolidinedione were randomized to receive exenatide (5mcg for 4 weeks followed by 10mcg) or placebo BID for 12 weeks. Heart rate and BP were assessed with 24-hour ambulatory BP monitoring. The primary measure was change from baseline in mean 24-hour HR. Results: Fifty-four subjects (28 exenatide, 26 placebo) were randomized and comprised the intent-to-treat population. Baseline values (exenatide and placebo) were (mean +/- SE) 74.4 +/- 2.1 and 74.5 +/- 1.9 beats/minute for HR, 126.4 +/- 3.2 and 119.9 +/- 2.8 mm Hg for systolic BP (SBP), and 75.2 +/- 2.1 and 70.5 +/- 2.0 mm Hg for diastolic BP (DBP). At 12 weeks, no significant change from baseline in 24-hour HR was observed with exenatide or placebo (LS mean +/- SE, 2.1+/-1.4 versus -0.7 +/- 1.4 beats/minute, respectively; between treatments, p = 0.16). Exenatide therapy was associated with trends toward lower 24-hour, daytime, and nighttime SBP; changes in DBP were similar between groups. No changes in daytime or nighttime rate pressure product were observed. With exenatide, body weight decreased from baseline by -1.8 +/- 0.4 kg (p <0.0001; treatment difference -1.5 +/- 0.6 kg, p <0.05). The most frequently reported adverse event with exenatide was mild to moderate nausea. Conclusions: Exenatide demonstrated no clinically meaningful effects on HR over 12 weeks of treatment in subjects with T2DM. The observed trends toward lower SBP with exenatide warrant future investigation.Trial registration: NCT00516074

Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat

Erik Vahtola — 2010-01-27T00:00:00Z

Background: Diabetes is associated with changes in myocardial stress-response pathways and is recognized as an independent risk factor for cardiac remodeling. Using spontaneously diabetic Goto Kakizaki rats as a model of type 2 DM we investigated whether post-translational modifications in the Akt - FOXO3a pathway, Sirt1 - p53 pathway and the mitogen activated protein kinase p38 regulator are involved in post-infarct cardiac remodeling Methods: Experimental myocardial infarction (MI) was induced by left anterior descending coronary artery ligation in spontaneously diabetic Goto-Kakizaki rats and non-diabetic Wistar controls. Cardiac function was studied by echocardiography. Myocardial hypertrophy, cardiomyocyte apoptosis and cardiac fibrosis were determined histologically 12 weeks post MI or Sham operation. Western blotting was used to study Caspase-3, Bax, Sirt1, acetylation of p53 and phosphorylation of p38, Akt and FOXO3a. Electrophoretic mobility shift assay was used to assess FOXO3a activity and its nuclear localization. Results: Post-infarct heart failure in diabetic GK rats was associated with pronounced cardiomyocyte hypertrophy, increased interstitial fibrosis and sustained cardiomyocyte apoptosis as compared with their non-diabetic Wistar controls. In the GK rat myocardium, Akt- and FOXO3a -phosphorylation was decreased and nuclear localization of FOXO3a was increased concomitantly with increased PTEN protein expression. Furthermore, increased Sirt1 protein expression was associated with decreased p53 acetylation, and phosphorylation of p38 was increased in diabetic rats with MI. Conclusions: Post-infarct heart failure in diabetic GK rats was associated with more pronounced cardiac hypertrophy, interstitial fibrosis and sustained cardiomyocyte apoptosis as compared to their non-diabetic controls. The present study suggests important roles for Akt-FOXO3a, Sirt1 - p53 and p38 MAPK in the regulation of post-infarct cardiac remodeling in type 2 diabetes.

Outcomes in a diabetic population of south Asians and whites following hospitalization for acute myocardial infarction: a retrospective cohort study

Aman Nijjar — 2010-01-22T00:00:00Z

Background: The aim of this study was to determine whether South Asian patients with diabetes have a worse prognosis following hospitalization for acute myocardial infarction (AMI) compared with their White counterparts. We measured the risk of developing a composite cardiovascular outcome of recurrent AMI, congestive heart failure (CHF) requiring hospitalization, or death, in these two groups. Methods: Using hospital administrative data, we performed a retrospective cohort study of 41,615 patients with an incident AMI in British Columbia and the Calgary Health Region between April 1, 1995, and March 31, 2002. South Asian ethnicity was determined using validated surname analysis. Baseline demographic characteristics and co-morbidities were included in Cox proportional hazard models to compare time to reaching the composite outcome and its individual components. Results: Among the AMI cohort, 29.7% of South Asian patients and 17.6% of White patients were identified as having diabetes (n = 7416). There was no significant difference in risk of developing the composite cardiovascular outcome (Hazard Ratio = 0.90, 95% CI = 0.80-1.01). However, South Asian patients had significantly lower mortality at long term follow-up (HR = 0.62, 95% CI = 0.51-0.74) compared to their White counterparts. Conclusions: Following hospitalization for AMI, South Asian patients with diabetes do not have a significantly different long term risk of a composite cardiovascular outcome compared to White patients with diabetes. While previous research has suggested worse cardiovascular outcomes in the South Asian population, we found lower long-term mortality among South Asians with diabetes following AMI.

Diabetes is associated with impaired myocardial performance in patients without significant coronary artery disease

Charlotte Andersson — 2010-01-18T00:00:00Z

Background: Patients with diabetes mellitus (DM) have high risk of heart failure. Whether some of the risk is directly linked to metabolic derangements in the myocardium or whether the risk is primarily caused by coronary artery disease (CAD) and hypertension is incompletely understood. Echocardiographic tissue Doppler imaging was therefore performed in DM patients without significant CAD to examine whether DM per se influenced cardiac function. Methods: Patients with a left ventricular (LV) ejection fraction (EF) > 35% and without significant CAD, prior myocardial infarction, cardiac pacemaker, atrial fibrillation, or significant valve disease were identified from a tertiary invasive center register. DM patients were matched with controls on age, gender and presence of hypertension. Results: In total 31 patients with diabetes and 31 controls were included. Mean age was 58 ± 12 years, mean LVEF was 51 ± 7%, and 48% were women. No significant differences were found in LVEF, left atrial end systolic volume, or left ventricular dimensions. The global longitudinal strain was significantly reduced in patients with DM (15.9 ± 2.9 vs. 17.7 ± 2.9, p = 0.03), as were peak longitudinal systolic (S') and early diastolic (E') velocities (5.7 ± 1.1 vs. 6.4 ± 1.1 cm/s, p = 0.02 and 6.1 ± 1.7 vs. 7.7 ± 2.0 cm/s, p = 0.002). In multivariable regression analyses, DM remained significantly associated with impairments of S' and E', respectively. Conclusion: In patients without significant CAD, DM is associated with an impaired systolic longitudinal LV function and global diastolic dysfunction. These abnormalities are likely to be markers of adverse prognosis.

Brain natriuretic peptide is related to diastolic dysfunction whereas urinary albumin excretion rate is related to left ventricular mass in asymptomatic type 2 diabetes patients

Martin Magnusson — 2010-01-18T00:00:00Z

Background: The aims of this study were to estimate the prevalence of left ventricular systolic (LVSD) and diastolic (LVDD) dysfunction, and to test if BNP and urinary albumin excretion rate (AER) are related to LVSD, LVD and left ventricular mass (LVM) in asymptomatic type 2 diabetes patients. Methods: Presence of LVSD, LVDD and LVM, determined with echocardiography, was related to levels of BNP and AER in 153 consecutive asymptomatic patients with type 2 diabetes. Results: LVSD was present in 6.1% of patients whereas 49% (29% mild, 19% moderate and 0.7% severe) had LVDD and 9.4% had left ventricular hypertrophy. Increasing age (P < 0.0001) was the only independent variable related to mild LVDD whereas increasing BNP (P = 0.01), systolic blood pressure (P = 0.01), age (P = 0.003) and female gender (P = 0.04) were independent determinants of moderate to severe LVDD. AER (P = 0.003), age (P = 0.01) and male gender (P = 0.006) were directly and independently related to LVM. Conclusion: About half of asymptomatic type 2 diabetes patients have LVDD. Of those, more than one third display moderate LVDD pattern paralleled by increases in BNP, suggesting markedly increased risk of heart failure, especially in females, whereas AER and male sex are related to LVM.

Long-term prognosis of diabetic patients with acute myocardial infarction in the era of acute revascularization

Ayako Takara — 2010-01-04T00:00:00Z

Background: The long-term prognosis of diabetic patients with acute myocardial infarction (AMI) treated by acute revascularization is uncertain, and the optimal pharmacotherapy for such cases has not been fully evaluated. Methods: To elucidate the long-term prognosis and prognostic factors in diabetic patients with AMI, a prospective, cohort study involving 3021 consecutive AMI patients was conducted. All patients discharged alive from hospital were followed to monitor their prognosis every year. The primary endpoint of the study was all-cause mortality, and the secondary endpoint was the occurrence of major cardiovascular events. To elucidate the effect of various factors on the long-term prognosis of AMI patients with diabetes, the patients were divided into two groups matched by propensity scores and analyzed retrospectively. Results: Diabetes was diagnosed in 1102 patients (36.5%). During the index hospitalization, coronary angioplasty and coronary thrombolysis were performed in 58.1% and 16.3% of patients, respectively. In-hospital mortality of diabetic patients with AMI was comparable to that of non-diabetic AMI patients (9.2% and 9.3%, respectively). In total, 2736 patients (90.6%) were discharged alive and followed for a median of 4.2 years (follow-up rate, 96.0%). The long-term survival rate was worse in the diabetic group than in the non-diabetic group, but not significantly different (hazard ratio, 1.20 [0.97-1.49], p = 0.09). On the other hand, AMI patients with diabetes showed a significantly higher incidence of cardiovascular events than the non-diabetic group (1.40 [1.20-1.64], p < 0.0001). Multivariate analysis revealed that three factors were significantly associated with favorable late outcomes in diabetic AMI patients: acute revascularization (HR, 0.62); prescribing aspirin (HR, 0.27); and prescribing renin-angiotensin system (RAS) inhibitors (HR, 0.53). There was no significant correlation between late outcome and prescription of beta-blockers (HR, 0.97) or calcium channel blockers (HR, 1.27). Although standard Japanese-approved doses of statins were associated with favorable outcome in AMI patients with diabetes, this was not statistically significant (0.67 [0.39-1.06], p = 0.11). Conclusions: Although diabetic patients with AMI have more frequent adverse events than non-diabetic patients with AMI, the present results suggest that acute revascularization and standard therapy with aspirin and RAS inhibitors may improve their prognosis.

Aminoguanidine inhibits aortic hydrogen peroxide production, VSMC NOX activity and hypercontractility in diabetic mice

Jeong-Ho Oak — 2009-12-30T00:00:00Z

Background: Dysfunctionally uncoupled endothelial nitric oxide synthase (eNOS) is involved in producing reactive oxygen species (ROS) in the diabetic endothelium. The present study investigated whether anti-diabetes drug Aminoguanidine (AG) has any effect on eNOS function and vascular oxidant stress.Methods and ResultsBlood glucose levels were increased to 452.0 ± 15.1 mg/dl in STZ-treated male C57BL/6J mice (148.4 ± 3.2 mg/dl in untreated controls). Aortic productions of NO• and O2 •- were measured specifically and sensitively using electron spin resonance. Diabetic mice had a marked increase in aortic O2 •- production. Aortic hydrogen peroxide (H2O2) production was also increased in diabetic aortas and significantly attenuated by AG. AG however had only a marginal effect in reducing aortic O2 •- production, which corresponded to a minimal effect in improving aortic nitric oxide (NO•) bioavailability. The endothelium-dependent vasodilatation however was modestly but significantly improved by AG, likely consequent to AG-induced reduction in hyper-contractility. NAD(P)H oxidase (NOX)-dependent O2 •- production was completely attenuated by AG in endothelium-denuded diabetic aortas. Conclusion: In summary, despite that AG is not an effective eNOS recoupling agent presumably consequent to its ineffectiveness in preventing endothelial NOX activation, it is inhibitory of aortic H2O2 production, VSMC NOX activity, and hypercontractility in diabetes.

Lipogenesis in arterial wall and vascular smooth muscular cells: regulation and abnormalities in insulin-resistance

Nadjiba Hamlat — 2009-12-23T00:00:00Z

Background: Vascular smooth muscular cells (VSMC) express lipogenic genes. Therefore in situ lipogenesis could provide fatty acids for triglycerides synthesis and cholesterol esterification and contribute to lipid accumulation in arterial wall with aging and during atheroma. Methods: We investigated expression of lipogenic genes in human and rat arterial walls, its regulation in cultured VSMC and determined if it is modified during insulin-resistance and diabetes, situations with increased risk for atheroma. Results: Zucker obese (ZO) and diabetic (ZDF) rats accumulated more triglycerides in their aortas than their respective control rats, and this triglycerides content increased with age in ZDF and control rats. However the expression in aortas of lipogenic genes, or of genes involved in fatty acids uptake, was not higher in ZDF and ZO rats and did not increase with age. Expression of lipogenesis-related genes was not increased in human arterial wall (carotid endarterectomy) of diabetic compared to non-diabetic patients. In vitro, glucose and adipogenic medium (ADM) stimulated moderately the expression and activity of lipogenesis in VSMC from control rats. LXR agonists, but not PXR agonist, stimulated also lipogenesis in VSMC but not in arterial wall in vivo. Lipogenic genes expression was lower in VSMC from ZO rats and not stimulated by glucose or ADM. Conclusion: Lipogenic genes are expressed in arterial wall and VSMC; this expression is stimulated (VSMC) by glucose, ADM and LXR agonists. During insulin-resistance and diabetes, this expression is not increased and resists to the actions of glucose and ADM. It is unlikely that this metabolic pathway contribute to lipid accumulation of arterial wall during insulin-resistance and diabetes and thus to the increased risk of atheroma observed in these situations.