Glucocorticoid ameliorates early cardiac dysfunction after coronary microembolization and suppresses TGF-β1/Smad3 and CTGF expression

Objectives

This study was designed to evidence the protective effect of glucocorticoid therapy on cardiac dysfunction after coronary microembolization (CME), and to clarify its mechanism with the expression of transforming growth factor-beta 1 (TGF-β1)/Smad3 and connective tissue growth factor (CTGF).

Methods

Eighteen mini-pigs were studied, including Sham-operation group (n = 4), CME group (n = 8) and Glucocorticoid therapy group (n = 6, received methylprednisolone 25 mg/kg intravenously 30 min before CME). Magnetic resonance imaging (3.0-T) was performed at baseline, 6th hour and one week after operation to evaluate cardiac function. Serum TGF-β1, CTGF and troponin T were also detected. Myocardial expressions of TGF-β1, CTGF and Smad3 were detected by western blot and immunohistochemistry. Total collagen expression was demonstrated by Masson Trichrome stain.

Results

Compared with Sham-operation group, left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) in CME group were increased at 6th hour after CME, while left ventricular ejection fraction (LVEF) was decreased significantly. Compared with CME group, methylprednisolone greatly improved LVEF after CME (6th hour: 56.0 ± 3.2% vs. 51.8 ± 3.8%, P = 0.030; one week: 57.8 ± 3.2% vs. 54.6 ± 2.6%, P = 0.053). We found that methylprednisolone not only significantly decreased serum TGF-β1, CTGF and troponin T, but also reduced myocardial expressions of TGF-β1, CTGF and Smad3 after CME. In addition, collagen volume fraction in glucocorticoid therapy group was markedly lower than that in CME group.

Conclusions

Glucocorticoid therapy could improve early cardiac function after CME, and its mechanism could be associated with TGF-β1/Smad3 and CTGF suppression.     

Increase in physical activity is associated with lower HbA1c levels in children and adolescents with type 1 diabetes: Results from a cross-sectional study based on the Swedish pediatric diabetes quality registry (SWEDIABKIDS)

Aims

To evaluate the associations between physical activity (PA) and metabolic control, measured by glycated hemoglobin (HbA1c), in a large group of children and adolescents with type 1 diabetes.

Methods

Cross-sectional analysis of data from 4655 patients, comparing HbA1c values with levels of physical activity. The data for the children and adolescents were obtained from the Swedish pediatric diabetes quality registry, SWEDIABKIDS. The patients were 7–18 years of age, had type 1 diabetes and were not in remission. Patients were grouped into five groups by frequency of PA.

Results

Mean HbA1c level was higher in the least physically active groups (PA0: 8.8% ± 1.5 (72 ± 16 mmol/mol)) than in the most physically active groups (PA4: 7.7% ± 1.0 (60 ± 11 mmol/mol)) (p < 0.001). An inverse dose–response association was found between PA and HbA1c (β: −0.30, 95% CI: −0.34 to −0.26, p < 0.001). This association was found in both sexes and all age groups, apart from girls aged 7–10 years. Multiple regression analysis revealed that the relationship remained significant (β: −0.21, 95% CI: −0.25 to −0.18, p < 0.001) when adjusted for possible confounding factors.

Conclusions

Physical activity seems to influence HbA1c levels in children and adolescents with type 1 diabetes. In clinical practice these patients should be recommended daily physical activity as a part of their treatment.     

Plasma osteopontin reveals left ventricular reverse remodelling following cardiac resynchronization therapy in heart failure

Background

Cardiac resynchronization therapy (CRT) promotes left ventricular (LV) reverse remodelling and affects myocardial collagen turnover in heart failure (HF) patients. Osteopontin (OPN) is a matrix glycoprotein required for the activation of fibroblasts upon TGF-β1 stimulation. In humans, plasma OPN and OPN-expressing lymphocytes correlate with the severity of HF. We sought to evaluate whether plasma OPN and TGF-β1 reflect LV reverse remodelling following CRT.

Methods

Eighteen patients (12 men, mean age 65 ± 11 years) undergoing CRT were studied. Patients underwent baseline clinical and echocardiographic evaluation, and assessment of plasma OPN and TGF-β1. The evaluation was repeated 8.5 ± 4 months after device implantation. Eight healthy age- and sex-matched subjects served as controls.

Results

In HF patients, baseline plasma OPN and TGF-β1 were higher as compared to control subjects (OPN: 99 ± 48 vs 59 ± 22 ng/ml; p < 0.05; TGF-β1: 15.9 ± 8.0 vs 9.3 ± 5.6 ng/ml; p < 0.05). At follow-up, 12 patients responded to CRT and showed LV reverse remodelling, whereas 6 did not. Plasma OPN decreased in CRT responders (108 ± 47 vs 84 ± 37 ng/ml; p = 0.03) and increased in non-responders (79 ± 58 vs 115 ± 63 ng/ml; p < 0.01). TGF-β1 showed a trend towards reduction in responders (17.5 ± 8.7 vs 10.2 ± 8.9 ng/ml; p = 0.08) and was unchanged in non-responders. A significant correlation (r = − 0.56; p = 0.01) was found between relative changes of LVESV and plasma OPN.

Conclusions

CRT-induced LV reverse remodelling is reflected by changes in plasma OPN. Circulating OPN may represent a marker of LV dilation/impairment and an indicator of the response to HF therapies promoting LV reverse remodelling.     

Walnut-enriched diet reduces fasting non-HDL-cholesterol and apolipoprotein B in healthy Caucasian subjects: A randomized controlled cross-over clinical trial

Background

Walnut consumption is associated with reduced risk of coronary heart disease (CHD).

Objective

We assessed the effect of walnuts on lipid and glucose metabolism, adipokines, inflammation and endothelial function in healthy Caucasian men and postmenopausal women ≥ 50 years old.

Design

Forty subjects (mean ± SEM: age 60 ± 1 years, BMI 24.9 ± 0.6 kg/m²; 30 females) were included in a controlled, cross-over study and randomized to receive first a walnut-enriched (43 g/d) and then a Western-type (control) diet or vice-versa, with each lasting 8 weeks and separated by a 2-week wash-out. At the beginning and end of each diet phase, measurements of fasting values, a mixed meal test and an assessment of postprandial endothelial function (determination of microcirculation by peripheral artery tonometry) were conducted. Area under the curve (AUC), incremental AUC (iAUC) and treatment × time interaction (shape of the curve) were evaluated for postprandial triglycerides, VLDL-triglycerides, chylomicron-triglycerides, glucose and insulin.

Results

Compared with the control diet, the walnut diet significantly reduced non-HDL-cholesterol (walnut vs. control: − 10 ± 3 vs. − 3 ± 2 mg/dL; p = 0.025) and apolipoprotein-B (− 5.0 ± 1.3 vs. − 0.2 ± 1.1 mg/dL; p = 0.009) after adjusting for age, gender, BMI and diet sequence. Total cholesterol showed a trend toward reduction (p = 0.073). Fasting VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and glucose, insulin, HOMA-IR, and HbA1c did not change significantly. Similarly, fasting adipokines, C-reactive protein, biomarkers of endothelial dysfunction, postprandial lipid and glucose metabolism and endothelial function were unaffected.

Conclusion

Daily consumption of 43 g of walnuts for 8 weeks significantly reduced non-HDL-cholesterol and apolipoprotein-B, which may explain in part the epidemiological observation that regular walnut consumption decreases CHD risk.     

Differential responses of adiposity,inflammation and autonomic function to aerobic versus resistance training in older adults

Background

Increased body fat, autonomic dysfunction and low-grade chronic inflammation are interrelated risk factors implicated in the etiology of several chronic conditions normally presented by older adults.

Objective

This study aims to assess the effectiveness of different training protocols on reducing body fat, improving autonomic function, and decreasing low-grade systemic inflammation in community-dwelling elderly adults.

Methods

Fifty participants (11 men, 68 ± 5.5 years) were randomly allocated into resistance or aerobic training or control groups. Evaluations were done at baseline and following the 8-month intervention period on their body composition (assessed by DXA), inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], tumor necrosis-alpha [TNF-α], interferon-gamma [IFN-γ], interleukins-6 and -10 [IL-6, IL-10]), lipoproteic profile, fasting glycemia, blood pressure, heart rate variability (HRV; frequency and time domains) and aerobic fitness (assessed by six-minute walk distance [6MWD]). A paired t-test was used to detect changes (%Δ = [(post‐test score − pretest score) / pre‐test score] × 100) within groups, while between-group differences were analyzed using the one-way ANOVA or General Linear Models.

Results

A significant change (Δ%) both in total (− 5.4 ± 6.3% and − 3.3 ± 2.9%, respectively) and central body fat (8.9 ± 11.3% and − 4.8 ± 4.5%) was observed in resistance and aerobic training groups, respectively; along with a change in resting systolic and diastolic blood pressures (− 9.2 ± 9.8% and − 8.5 ± 9.6%), heart rate (− 4.6 ± 6.5%), hs-CRP (− 18.6 ± 60.6%), and 6MWD (9.5 ± 6.9%) in response to aerobic training.

Conclusions

The present findings provide further evidence for the benefits of aerobic and resistance training on reducing body fat. Aerobic training was demonstrated to reduce hs-CRP and blood pressure in community-dwelling elderly participants with no serious medical conditions.     

Effects of direct infusion of bone marrow-derived progenitor cells and indirect mobilization of hematopoietic progenitor cells on atherosclerotic plaque and inflammatory process in atherosclerosis

Background

We sought to investigate the effects of lin −/sca + cells, endothelial progenitor cells (EPCs) and granulocyte colony-stimulating factor (G-CSF) administration on atherosclerotic plaque progression.

Methods

Apolipoprotein E-deficient (apoE^−/−) mice were splenectomized and treated with high-cholesterol diet for 6 weeks in order to induce atherosclerotic plaque development. Bone marrow-derived Lin −/sca-1 + cells were isolated and further cultured to early growth endothelial progenitor cells (EPCs). Mice were divided in four groups (n = 10/group) and received two intravenous injections of 5 × 10⁵ cells (lin −/sca-1 + or EPCs), or granulocyte colony-stimulating factor (G-CSF 100 μg/kg/day) for 7 days or normal saline. The same interventions were administered to animals, which had undergone unilateral hind-limb ischemia. Effects on inflammatory parameters, lesion severity, and atherosclerotic plaque area size were assessed.

Results

The administration of both G-CSF and progenitor cells significantly decreased the levels of IL-6, 6 weeks after the initiation of treatment. Atherosclerotic lesion area was reduced by G-CSF (atherosclerotic plaque area percentage 22.94% ± 3.68, p = 0.001), by lin −/sca-1 + (23.27% ± 5.98, p = 0.002) and cultured EPCs (23.16 ± 4.86%, p = 0.002) compared to control (32.75% ± 7.05). In the atherosclerotic mice that underwent limb ischemia, the atherosclerotic plaque area, was not significantly different between the treatment groups cultured EPCs-treated mice and the control group (p = NS, for all).

Conclusions

Direct infusion of progenitor cells and indirect mobilization of hematopoietic progenitor cells decreased plaque progression and levels of inflammatory molecules in a murine model of atherosclerosis. Treatment with G-CSF, lin −/sca-1 +, or EPCs may exert beneficial effects on vascular inflammation and atherosclerotic plaque progression. However, the effects are diminished in an ischemic setting.     

Insulin detemir in the management of type 2 diabetes in non-Western countries: Safety and effectiveness data from the A1chieve observational study

Aims

This subgroup analysis of the A₁chieve study examined data from 15,545 people who started treatment with insulin detemir ± oral glucose-lowering drugs in routine clinical care.

Methods

A₁chieve was a 24-week, international, prospective, non-interventional study of people with type 2 diabetes from non-Western nations starting treatment with basal insulin detemir, bolus insulin aspart or biphasic insulin aspart 30, alone or in combination, to evaluate their safety and effectiveness in routine clinical practice.

Results

HbA_1c for the global cohort improved after 24 weeks from 9.5 ± 1.6% by −2.0 ± 1.6% [80 ± 17 by −22 ± 17 mmol/mol] (−2.1 ± 1.6% [−23 ± 17 mmol/mol] for insulin-naïve participants; −1.6 ± 1.7% [−17 ± 19 mmol/mol] for prior insulin users). Fasting plasma glucose and postprandial plasma glucose were also significantly reduced (p < 0.001), irrespective of prior therapy or geographical region. The incidence of major hypoglycaemia decreased significantly over 24 weeks in both the insulin-naïve and insulin-experienced groups (p < 0.0001). Mean body weight decreased overall by −0.4 ± 4.0 kg and blood pressure, lipid profiles, and self-reported quality of life improved over 24 weeks for all people starting treatment with insulin detemir.

Conclusion

People with type 2 diabetes in poor glycaemic control starting treatment with insulin detemir reported significant improvements in glycaemic control with improved treatment tolerability, irrespective of prior treatment and geographical region, after 24 weeks.     

20-Hour preprocedural hydration is not superior to 5-hour preprocedural hydration in the prevention of contrast-induced increases in serum creatinine and cystatin C

Background

Although intravenous hydration with isotonic saline is the standard therapy for the prevention of contrast-induced nephropathy (CIN), there is still insufficient evidence concerning the optimal timing to initiate preprocedural intravenous hydration with isotonic saline.

Methods

This study prospectively compared the contrast-induced increases in serum creatinine and cystatin C between 5-hour preprocedural intravenous hydration with isotonic saline (5 h-HS) and 20-hour preprocedural intravenous hydration with isotonic saline (20 h-HS) in 122 patients with renal insufficiency (estimated glomerular filtration rate of 15–60 ml/min/1.73 m²) undergoing an elective coronary procedure. The patients were randomly assigned to receive either 5 h-HS (n = 60) or 20 h-HS (n = 62). Serum creatinine and cystatin C were measured at baseline, immediately before contrast exposure, and 24 hours and 48 hours after contrast exposure. The primary end points were the maximal absolute and percent changes in serum creatinine and cystatin C from the baseline up to 48 hours after contrast exposure.

Results

The maximal absolute and percent changes in serum creatinine (0.01 ± 0.13 mg/dl vs. − 0.03 ± 0.16 mg/dl, p = 0.16; 0.87 ± 10.05% vs. − 1.50 ± 12.92%, p = 0.26; respectively) and cystatin C (− 0.05 ± 0.17 mg/l vs. − 0.06 ± 0.17 mg/l, p = 0.59; − 2.94 ± 9.29% vs. − 3.46 ± 9.21%, p = 0.75; respectively) did not differ between the 2 regimens.

Conclusions

20 h-HS is not superior to 5 h-HS in the prevention of the contrast-induced increases in serum creatinine and cystatin C in patients with renal insufficiency undergoing an elective coronary procedure.     

Time course of markers of tissue repair after ablation of atrial fibrillation and their relation to left atrial structural changes and clinical ablation outcome

Background

Radiofrequency ablation of atrial fibrillation (AF) creates left atrial (LA) tissue damage with a subsequent healing process. We sought to prospectively assess the time course of biomarkers of tissue repair after ablation and to evaluate their association with clinical variables.

Methods

30 consecutive patients (57.9 ± 1.7 yrs, 63% males) with paroxysmal AF underwent a CARTO-guided LA circumferential ablation, Lasso-guided segmental pulmonary vein isolation and ablation of complex fractionated atrial electrograms. Matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β1 (TGF-β1), both key regulators of tissue repair, and the aminoterminal propeptide of type III procollagen (PIIINP), reflecting collagen synthesis, were determined in blood samples before and 6 h, 1, 2, 7, 30, 90 and 180 days post-ablation.

Results

All markers showed a significant ablation-induced up-regulation (MMP-9: 1.8 ± 0.1-fold, TGF-β1: 2.4 ± 0.4-fold, PIIINP: 1.3 ± 0.1-fold). MMP-9 was significantly up-regulated until day 90, TGF-β1 only on day 2. PIIINP increased from day 2 to 7. The area under the curve (AUC) of MMP-9 and TGF-β1 correlated with the ablation-induced reduction of LA volume (both p < 0.05). The AUC of MMP-9 was additionally associated with the amount of radiofrequency energy delivered during ablation (p < 0.05). At 12 months of follow-up 57% of patients were free of AF off antiarrhythmic drugs. The AUC of PIIINP independently predicted recurrent AF (p < 0.05).

Conclusions

Markers of healing showed a significant up-regulation after AF ablation detectable for up to 90 days. A more pronounced up-regulation of MMP-9 or TGF-β1 is associated with a greater reduction of LA size. High PIIINP levels after ablation predict a poor ablation outcome.     

Relationship between whole-body macronutrient oxidative partitioning and pancreatic insulin secretion/β-cell function in non-diabetic humans

Background

Glucose-stimulated insulin secretion correlates inversely with the degree of whole-body insulin sensitivity suggesting a crosstalk between peripheral organs and pancreas. Such sensing mechanism could be mediated by changes in glucose flux (uptake, oxidation or storage) in peripheral tissues that may drive insulin secretion.

Aim

To relate whole-body non-protein respiratory quotient (npRQ), an index of macronutrient oxidative partitioning, with insulin secretion and β-cell function in non-diabetic individuals.

Methods

Macronutrient oxidation was measured after an overnight fast and for 4 h after a 75-g oral glucose tolerance test (OGTT) in 30 participants (15/15 males/females; 35 ± 12 y; 27 ± 4 kg/m²). Furthermore, npRQ was assessed for 24 h in a metabolic chamber. Insulin secretion was estimated by deconvolution of serum C-peptide concentration (fasting and 4-h OGTT) and from 24-h urinary C-peptide excretion corrected for energy intake (metabolic chamber). β-Cell function parameters were obtained by mathematical modeling, while insulin sensitivity was determined by a euglycemic–hyperinsulinemic clamp (120 mU · m^− 2 · min^− 1).

Results

Insulin secretion (from 24-h urinary C-peptide) correlated inversely with 24-h npRQ (r = − 0.61; p = 0.001), even after controlling for insulin sensitivity, energy balance, age and body mass index (r = − 0.52; p = 0.01). In turn, insulin secretion (from serum C-peptide) was not associated with fasting or OGTT npRQ. However, fasting npRQ was positively correlated with rate sensitivity (r = 0.40; p < 0.05) and marginally with glucose sensitivity (r = 0.34; p = 0.08).

Conclusion

Macronutrient oxidative partitioning, specifically glucose oxidation, might play a role on the regulation of insulin secretion. Further studies should aim at identifying the signals linking these processes.     

The effect of a diabetes education programme (PRIMAS) for people with type 1 diabetes: Results of a randomized trial

Objective

In a randomized, multi-centre trial, the efficacy of a self-management-oriented education programme (PRIMAS) for people with type 1 diabetes was compared with an established education programme as control group (CG). Primary outcome was the effect on glycaemic control in a 6-month follow-up. Secondary outcomes were the impact on emotional aspects, self-management related aspects and hypoglycaemia problems.

Methods

The study was conducted in an outpatient setting. 160 participants were randomized. Baseline characteristics in PRIMAS and CG were similar (age 45.1 ± 13.5 vs. 45.9 ± 13.1 years, p = .716; diabetes duration 18.8 ± 12.3 vs. 19.8 ± 13.4 years, p = .615; BMI 26.5 ± 4.6 vs. 27.5 ± 5.0 kg/m², p = .236; HbA1c 8.3 ± 1.1 vs. 8.1 ± 1.0%, p = .236).

Results

At follow-up there was a significant 0.4 percentage points greater reduction of HbA1c in PRIMAS compared to CG (Δ −0.4 ± 1.0% vs. Δ 0.0 ± 0.6%; p = .012). Also, diabetes-related distress (Δ −0.3 ± 0.7 vs. −0.1 ± 0.4, p = .032) and dissatisfaction with diabetes treatment (Δ −3.3 ± 6.9 vs. −1.9 ± 5.6, p = .024) decreased more in PRIMAS. Diabetes empowerment (Δ 2.6 ± 5.9 vs. 0.8 ± 5.1, p = .037) and diabetes self-efficacy (Δ 1.4 ± 3.6 vs. 0.2 ± 4.0, p = .013) increased in PRIMAS. Incidence of severe hypoglycemia, hypoglycemia awareness, diabetes knowledge, and self-care behaviour improved in both groups with no significant differences between groups.

Conclusion

PRIMAS is more effective in lowering HbA1c than a previously established education programmes and also showed superiority in reducing diabetes-related distress and increasing diabetes empowerment, diabetes self-efficacy and satisfaction with insulin therapy.     

Beneficial effects of liraglutide on adipocytokines,insulin sensitivity parameters and cardiovascular risk biomarkers in patients with Type 2 diabetes: A prospective study

Aims

To evaluate the effects of liraglutide after 14 weeks of treatment on serum adipokines, insulin resistance index and cardiovascular risk biomarkers in overweight or obese T2DM patients unable to achieve glycemic control with metformin alone or in association with a sulfonylurea in daily clinical practice.

Methods

Prospective study in 59 consecutive overweight or obese (BMI ≥ 25 kg/m²) T2DM patients unable to achieve glycemic control (HbA1c > 7%, 53 mmol/mol) with metformin alone or in association with sulfonylurea that require initiation of liraglutide in progressive dose increase up to 1.8 mg/day subcutaneously. Weight, body composition, blood pressure, glucose, HbA1c, C-peptide, insulin, plasma lipids, adipokines (leptin, adiponectin, resistin and visfatin) as well as cardiovascular biomarkers (IL-6 and TNF-a) levels were measured fasting at baseline and 14 weeks after liraglutide initiation.

Results

14 weeks of liraglutide treatment significantly reduced HbA1c, BMI and total body fat mass by 0.9%, 1.4 kg/m² and 0.5% respectively. Statistically significant lower insulin resistance and higher insulin secretion was found by HOMA-IR 8.4 (1.6) vs 4.6 (0.9) mol m IU/L² and HOMA-B 48.2 (9.0) vs 87.6 (16.3) μIU/mmol. Statistically significantly higher levels of visfatin 6.3 (2.1) vs 6.8 (2.1) ng/ml and resistin 3.6 (2.0) vs 4.3 (2.3) ng/ml were also observed after treatment. Baseline visfatin was negatively correlated with basal fasting plasma glucose r = −0.360 (p < 0.05).

Conclusions

Liraglutide treatment for 14 weeks in daily clinical practice led to reduction of BMI and improvement of glucose control and insulin sensitivity and resistance parameters. Additionally, circulating levels of adipokines and pro-inflammatory factors could play an important role in GLP-1 treatment response.     

Contractility of myofibrils from the heart and diaphragm muscles measured with atomic force cantilevers: Effects of heart-specific deletion of arginyl-tRNA–protein transferase

Background

Contractile properties of myofibrils from the myocardium and diaphragm in chronic heart failure are not well understood. We investigated myofibrils in a knockout (KO) mouse model with cardiac-specific deletion of arginyl-tRNA–protein transferase (α-MHCAte1), which presents dilated cardiomyopathy and heart failure.

Objective

The aim of this study was to test the hypothesis that chronic heart failure in α-MHCAte1 mice is associated with abnormal contractile properties of the heart and diaphragm.

Methods

We used a newly developed system of atomic force cantilevers (AFC) to compare myofibrils from α-MHCAte1 and age-matched wild type mice (WT). Myofibrils from the myocardium and the diaphragm were attached to the AFC used for force measurements during activation/deactivation cycles at different sarcomere lengths.

Results

In the heart, α-MHCAte1 myofibrils presented a reduced force during full activation (89 ± 9 nN/μm²) when compared to WT (132 ± 11 nN/μm²), and the decrease was not influenced by sarcomere length. These myofibrils presented similar kinetics of force development (K_act), redevelopment (K_tr), and relaxation (K_rel). In the diaphragm, α-MHCAte1 myofibrils presented an increased force during full activation (209 ± 31 nN/μm²) when compared to WT (123 ± 20 nN/μm²). Diaphragm myofibrils of α-MHCAte1 and WT presented similar K_act, but α-MHCAte1 myofibrils presented a faster K_rel (6.11 ± 0.41 s^− 1 vs 4.63 ± 0.41 s^− 1).

Conclusion

Contrary to our working hypothesis, diaphragm myofibrils from α-MHCAte1 mice produced an increased force compared to myofibrils from WT. These results suggest a potential compensatory mechanism by which the diaphragm works under loading conditions in the α-MHCAte1 chronic heart failure model.     

Direct implantation versus platelet-rich fibrin-embedded adipose-derived mesenchymal stem cells in treating rat acute myocardial infarction

Background

This study tested whether adipose-derived mesenchymal stem cells (ADMSC) embedded in platelet-rich fibrin (PRF) scaffold is superior to direct ADMSC implantation in improving left ventricular (LV) performance and reducing LV remodeling in a rat acute myocardial infarction (AMI) model of left anterior descending coronary artery (LAD) ligation.

Methods

Twenty-eight male adult Sprague Dawley rats equally divided into group 1 [sham control], group 2 (AMI only), group 3 (AMI + direct ADMSC implantation), and group 4 (AMI + PRF-embedded autologous ADMSC) were sacrificed on day 42 after AMI.

Results

LV systolic and diastolic dimensions and volumes, and infarct/fibrotic areas were highest in group 2, lowest in group 1 and significantly higher in group 3 than in group 4, whereas LV performance and LV fractional shortening exhibited a reversed pattern (p < 0.005). Protein expressions of inflammation (oxidative stress, IL-1β, MMP-9), apoptosis (mitochondrial Bax, cleaved PARP), fibrosis (Smad3, TGF-β), and pressure-overload biomarkers (BNP, MHC-β) displayed a pattern similar to that of LV dimensions, whereas anti-inflammatory (IL-10), anti-apoptotic (Bcl-2), and anti-fibrotic (Smad1/5, BMP-2) indices showed a pattern similar to that of LV performance among the four groups (all p < 0.05). Angiogenesis biomarkers at protein (CXCR4, SDF-1α, VEGF), cellular (CD31 +, CXCR4 +, SDF-1α +), and immunohistochemical (small vessels) levels, and cardiac stem cell markers (C-kit +, Sca-1 +) in infarct myocardium were highest in group 4, lowest in group 1, and significantly higher in group 3 than in group 2 (all p < 0.005).

Conclusion

PRF-embedded ADMSC is superior to direct ADMSC implantation in preserving LV function and attenuating LV remodeling.     

Recovery of respiratory gas exchange after exercise in adults with congenital heart disease

Background

Delayed gas exchange kinetics in the early recovery period after exercise testing has been reported in children and adults with congenital heart disease (ACHD). Our objective was to compare early and late phase recovery kinetics in three groups of ACHD-patients.

Methods

Sixty-seven adults with complex ACHD (33 repaired tetralogy of Fallot, 19 Fontan operations, and 15 transposition complexes) and 10 healthy controls underwent symptom-limited cardiopulmonary exercise testing measuring gas-exchange kinetics over a 10 minute recovery period. Changes within the first minute of recovery and late changes, characterized as the time to reach 50% of peak values (T_1/2), were compared between groups.

Results

Recovery of VO₂ in early and late recoveries was significantly delayed in all ACHD-patients compared to controls without significant differences between patient groups. VO₂-recovery at 1 min compared between patients and controls was − 7.2 ± 4.0 versus − 17.0 ± 4.5 ml·kg·min^− 1 and T_1/2 VO₂ was 147 ± 62 versus 66 ± 23 s (p < 0.0001 for both comparisons). Similar changes were observed for VCO₂-recovery. Peak VO₂ (ml·kg·min^− 1) demonstrated strong correlation with VO₂-recovery at 1 min (ml·kg·min^− 1, r = 0.90) and moderate correlation with T_1/2 VO₂ (r = − 0.70).

Conclusion

Gas exchange recovery after exercise testing is prolonged in ACHD-patients, independent of the congenital heart lesion but related to peak aerobic capacity, particularly recovery kinetics within the first minute. Recovery kinetics at 1 min is a useful and easily obtained clinical measure that warrants further study as a prognostic measure.     

Abdominal subcutaneous and omental adipocyte morphology and its relation to gene expression,lipolysis and adipocytokine levels in women

Objective

We tested the hypothesis that women with adipocyte hypertrophy in either omental (OM) or subcutaneous (SC) adipose tissue are characterized by alterations in adipocyte lipolysis and adipose tissue expression of genes coding for proteins involved in adipocyte metabolism or inflammation, independent of overall adiposity and fat distribution.

Methods

OM and SC fat samples were obtained surgically in 44 women (age: 47.1 ± 5.0 years, BMI: 27.7 ± 5.3 kg/m²). In a given depot, women with larger adipocytes than predicted by the regression of adipocyte size vs. total and regional adiposity measurements were considered as having adipocyte hypertrophy, whereas women with smaller adipocytes than predicted were considered as having adipocyte hyperplasia.

Results

Women with OM adipocyte hypertrophy had significantly lower SC GLUT4 mRNA abundance (p ≤ 0.05), higher SC CEBPB mRNA expression (p ≤ 0.05) as well as higher mRNA expression of OM PLIN (p ≤ 0.05), CD68 (p ≤ 0.10), CD14 (p ≤ 0.10), CD31 (p ≤ 0.05) and vWF (p ≤ 0.05) compared to women with OM adipocyte hyperplasia. OM adipocyte isoproterenol- (10^− 10 to 10^− 5 mol/L), forskolin- (10^− 5 mol/L) and dibutyryl cAMP- (10^− 3 mol/L) stimulated lipolysis was higher in women with hypertrophic OM adipocytes (p ≤ 0.05, for all). Women with SC adipocyte hypertrophy had lower SC mRNA expression of GLUT4 (p ≤ 0.10), higher SC mRNA expression of CEBPB (p ≤ 0.05), lower plasma adiponectin concentrations (p ≤ 0.05) and higher SC adipocyte isoproterenol- (10^− 9 to 10^− 5 mol/L) stimulated lipolysis (p ≤ 0.05) compared to women with SC adipocyte hyperplasia.

Conclusion

Hypertrophic adipocytes in both fat compartments are characterized by alterations in adipocyte lipolysis and adipose tissue expression of genes coding for proteins involved in adipocyte metabolism or inflammation.     

Effects of high dose aleglitazar on renal function in patients with type 2 diabetes

Background

Aleglitazar is a new, balanced dual peroxisome proliferator-activated receptor (PPAR)α/γ agonist designed to optimize lipid and glycemic benefits and minimize PPAR-related adverse effects.

Methods

SESTA R was a 26-week, randomized, double-blind, multicenter study comparing the effects of a supratherapeutic dosage of aleglitazar (600 μg/day) with pioglitazone (45 mg/day) on change in measured GFR (mGFR) in 174 patients with type 2 diabetes and normal to mildly impaired renal function (estimated GFR [eGFR] 60 to 120 ml/min/1.73 m²).

Results

In 118 patients with evaluable GFR measurements, baseline mean (± SD) mGFR was 97.6 ± 17.5 ml/min/1.73 m² in the aleglitazar group and 101.9 ± 21.6 ml/min/1.73 m² in the pioglitazone group. Mean percent change from baseline mGFR was −16.9% (90% confidence interval −22.0 to −11.5) with aleglitazar and −4.6% (−10.15 to 1.35) with pioglitazone, a mean treatment difference of −13.0% (−19.0 to −6.5). The 17% decrease from baseline in mGFR was consistent with the 19% decrease in eGFR Modification of Diet in Renal Disease (MDRD) observed with aleglitazar, which reached a plateau after 4 weeks, with no further progression until treatment discontinuation. Following aleglitazar withdrawal, eGFR values returned to pretreatment levels within the 4-8-week follow-up, which suggests reversible hemodynamic changes in renal function.

Conclusions

Despite the increased incidence of expected, dose-dependent PPAR class side effects (e.g., peripheral edema, weight gain, and congestive heart failure) limiting further development of this supratherapeutic dosage of aleglitazar (600 μg/day), these data, together with the data from the dose-ranging SYNCHRONY study, suggest aleglitazar may be a potential new treatment for cardiovascular risk reduction in post-acute coronary syndrome patients at the therapeutic 150 μg daily dose.     

Effects of continuous positive airway pressure on endothelial function and circulating progenitor cells in obstructive sleep apnoea: A randomised sham-controlled study

Objective

Obstructive sleep apnoea (OSA) is characterised by reoccurring apnoeas and hypopneas, causing repetitive hypoxia and reoxygenation, and is associated with endothelial dysfunction and reduced levels of circulating progenitor cells (CPCs). The potential to improve endothelial function and CPC levels in people with OSA by preventing hypoxic episodes with Continuous Positive Airway Pressure (CPAP) was investigated in a sham-controlled CPAP study.

Methods

Men with moderate-to-severe OSA (mean ± SD: age = 49 ± 12 y, apnoea hypopnea index (AHI) = 37.6 ± 16.4 events/h, body mass index = 31.5 ± 5.7 kg/m²) who were CPAP naïve without diabetes mellitus were randomised in a 12-week double-blind sham-controlled parallel group study to receive either active (n = 25) or sham (n = 21) CPAP. CPCs, isolated from blood, were measured by flow cytometry and by co-staining cultured cells (7 days) with acetylated low-density lipoprotein (acLDL) and lectin. Endothelial function was assessed by peripheral arterial tonometry (PAT).

Results

Compared to sham, CPAP significantly decreased AHI (mean between-group difference − 36.0 events/h; 95%CI, − 49.7 to − 22.3, p < 0.0001) after 12 weeks. Despite this improvement in AHI, CPAP had no effect on change in CPC levels (including CD34⁺/KDR⁺ (565 cells/mL; − 977 to 2106, p = 0.45), CD34⁺/KDR⁺/CD45⁻ (37.0 cells/mL; − 17.7 to 85.7, p = 0.13), acLDL⁺/lectin⁺ (− 43.1 cells/field, − 247 to 161, p = 0.67)) or change in endothelial function (0.27; − 0.14 to 0.67, p = 0.19) compared to sham therapy.

Conclusions

Despite the improvement in OSA parameters and ablation of apnoeic events by CPAP, CPC counts and endothelial function in men with moderate-to-severe OSA were not significantly improved after 12 weeks of therapeutic CPAP when compared to sham control.     

Calreticulin overexpression correlates with integrin-α5 and transforming growth factor-β1 expression in the atria of patients with rheumatic valvular disease and atrial fibrillation

Objectives

The aim of this study was to determine whether altered calreticulin expression and distribution contribute to the pathogenesis of atrial fibrillation (AF) associated with valvular heart disease (VHD).

Background

AF affects electrophysiological and structural changes that exacerbate AF. Atrial remodeling reportedly underlies AF generation, but the precise mechanism of atrial remodeling in AF remains unclear.

Methods

Right and left atrial specimens were obtained from 68 patients undergoing valve replacement surgery. The patients were divided into sinus rhythm (SR; n = 25), paroxysmal AF (PaAF; n = 11), and persistent AF (PeAF; AF lasting > 6 months; n = 32) groups. Calreticulin, integrin-α5, and transforming growth factor-β1 (TGF-β1) mRNA and protein expression were measured. We also performed immunoprecipitation for calreticulin with either calcineurin B or integrin-α5.

Results

Calreticulin, integrin-α5, and TGF-β1 mRNA and protein expression were increased in the AF groups, especially in the left atrium in patients with mitral valve disease. Calreticulin interacted with both calcineurin B and integrin-α5. Integrin-α5 expression correlated with TGF-β1 expression, while calreticulin expression correlated with integrin-α5 and TGF-β1 expression. Despite similar cardiac function classifications, calreticulin expression was greater in the PeAF group than in the SR group.

Conclusions

Calreticulin, integrin-α5, and TGF-β1 expression was increased in atrial tissue in patients with AF and was related to AF type, suggesting that calreticulin is involved in the pathogenesis of AF in VHD patients.