Dimas Ikeoka

Adipose tissue, inflammation and cardiovascular disease

Obesity has become a very frequent condition with important consequences for the health of affected individuals. Current evidence shows that the excess of adipose tissue as observed in obesity is responsible for secreting inflammatory mediators in a deregulated manner, thus inducing a chronic state of systemic low-grade inflammation that underlies the metabolic and cardiovascular outcomes in these populations. This article reviews the state of the art regarding mediators produced in the adipose tissue, their roles in the pathophysiology of obesity-associated insulin resistance and diabetes, and finally, tries to build a bridge between these mechanistically oriented insights and clinical practice.

Evaluation of the Society of Thoracic Surgeons score system for isolated coronary bypass graft surgery in a Brazilian population

Objective Report the experience with the Society of Thoracic Surgeons scoring system in a Brazilian population submitted to isolated coronary artery bypass graft surgery. Methods Data were collected from January-2010 to December-2011, and analyzed to determine the performance of the Society of Thoracic Surgeons scoring system on the determination of postoperative mortality and morbidity, using the method of the receiver operating characteristic curve as well as the Hosmer-Lemeshow and the Chi-square goodness of fit tests. From the 1083 cardiac surgeries performed during the study period 659 represented coronary artery bypass graft procedures which are included in the present analysis. Mean age was 61.4 years and 77% were men. Results Goodness of fit tests have shown good calibration indexes both for mortality (X2=6.78, P=0.56) and general morbidity (X2=6.69, P=0.57). Analysis of area under the ROC-curve (AUC) demonstrated a good performance to detect the risk of death (AUC 0.76; P<0.001), renal failure (AUC 0.79; P<0.001), prolonged ventilation (AUC 0.80; P<0.001), reoperation (AUC 0.76; P<0.001) and major morbidity (AUC 0.75; P<0.001) which represents the combination of the assessed postoperative complications. STS scoring system did not present comparable results for short term hospital stay, prolonged length of hospital stay and could not be properly tested for stroke and wound infection. Conclusion Society of Thoracic Surgeons scoring system presented a good calibration and discrimination in our population to predict postoperative mortality and the majority of the harmful events following coronary artery bypass graft surgery. Analysis of larger samples might be needed to further validate the use of the score system in Brazilian populations.

Prevalence, characteristics, and predictors of early termination of cardiovascular clinical trials due to low recruitment: Insights from the ClinicalTrials.gov registry

BACKGROUND Early termination of clinical trials due to low recruitment represents an understudied challenge for clinical research. We aimed to describe characteristics of cardiovascular trials terminated because of low recruitment and identify the major predictors of such early termination. METHODS We reviewed all cardiovascular clinical trials (7,042 studies) registered in ClinicalTrials.gov from February 29, 2000, to January 17, 2013, and assessed information about trials that were completed and those that were terminated early. Logistic regression models were developed to identify independent predictors of early termination due to low recruitment. RESULTS Our search strategy identified 6,279 cardiovascular clinical trials, of which 684 (10.9%) were terminated prematurely. Of these halted trials, the main reason for termination was lower than expected recruitment (278 trials; 53.6%). When comparing trials that terminated early because of low recruitment with those that were completed, we found that studies funded by the National Institutes of Health or other US federal agencies (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.14-0.89), studies of behavior/diet intervention (OR 0.35, 95% CI 0.19-0.65), and single-arm design studies (OR 0.57, 95% CI 0.42-0.78) were associated with a lower risk of early termination. University/hospital-funded (OR 1.52, 95% CI 1.10-2.10) and mixed-source-funded studies (OR 2.14, 95% CI 1.52-3.01) were associated with a higher likelihood of early termination due to lower than expected recruitment rates. CONCLUSIONS Low recruitment represents the main cause of early termination of cardiovascular clinical trials. Funding source, type of intervention, and study design are factors associated with early termination due to low recruitment and might be good targets for improving enrollment into cardiovascular clinical trials.

Effects of Bariatric Surgery in Obese Patients With Hypertension: The GATEWAY Randomized Trial (Gastric Bypass to Treat Obese Patients With Steady Hypertension)

Background: Recent research efforts on bariatric surgery have focused on metabolic and diabetes mellitus resolution. Randomized trials designed to assess the impact of bariatric surgery in patients with obesity and hypertension are needed. Methods: In this randomized, single-center, nonblinded trial, we included patients with hypertension (using ≥2 medications at maximum doses or >2 at moderate doses) and a body mass index between 30.0 and 39.9 kg/m2. Patients were randomized to Roux-en-Y gastric bypass plus medical therapy or medical therapy alone. The primary end point was reduction of ≥30% of the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure <140 mm Hg and 90 mm Hg, respectively, at 12 months. Results: We included 100 patients (70% female, mean age 43.8±9.2 years, mean body mass index 36.9±2.7 kg/m2), and 96% completed follow-up. Reduction of ≥30% of the total number of antihypertensive medications while maintaining controlled blood pressure occurred in 41 of 49 patients from the gastric bypass group (83.7%) compared with 6 of 47 patients (12.8%) from the control group with a rate ratio of 6.6 (95% confidence interval, 3.1–14.0; P<0.001). Remission of hypertension was present in 25 of 49 (51%) and 22 of 48 (45.8%) patients randomized to gastric bypass, considering office and 24-hour ambulatory blood pressure monitoring, respectively, whereas no patient submitted to medical therapy was free of antihypertensive drugs at 12 months. A post hoc analysis for the primary end point considering the SPRINT (Systolic Blood Pressure Intervention Trial) target reached consistent results, with a rate ratio of 3.8 (95% confidence interval, 1.4–10.6; P=0.005). Eleven patients (22.4%) from the gastric bypass group and none in the control group were able to achieve SPRINT levels without antihypertensives. Waist circumference, body mass index, fasting plasma glucose, glycohemoglobin, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and 10-year Framingham risk score were lower in the gastric bypass than in the control group. Conclusions: Bariatric surgery represents an effective strategy for blood pressure control in a broad population of patients with obesity and hypertension. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT01784848.

Interleukin-6 produced in subcutaneous adipose tissue is linked to blood pressure control in septic patients

Cytokines are inflammatory mediators of major relevance during sepsis. Recent evidence shows that adipose tissue can produce many distinct cytokines under physiological and pathological conditions, but the role of cytokines produced in adipose tissue was not addressed in sepsis. In the present study the open-flow microperfusion (OFM) technique was used to investigate whether the cytokines produced in subcutaneous adipose tissue (SAT) of patients with severe sepsis correlate with clinical variables. Interstitial fluid effluent samples were collected using an OFM catheter inserted in the abdominal SAT of nine patients with severe sepsis. Blood samples were withdrawn concomitantly and interleukin-1beta (IL-1beta), IL-8, IL-6 and tumor necrosis factor alpha (TNF-alpha) were measured both in SAT effluent and serum samples. Different time profiles were registered for each cytokine. IL-1beta increased in a time-dependent manner, indicating a localized response against the catheter insertion. Interleukin-1beta, 6 and 8 were higher in SAT than in serum suggesting they were locally produced. Diastolic blood pressure (DBP) negatively correlated with IL-1beta, IL-6 and IL-8 in SAT indicating a possible interaction between adipose tissue inflammation and vascular tone regulation. A multiple regression analysis disclosed that mean DBP was significantly related to IL-6 concentrations in SAT (B=-43.9; R-square=0.82; P=0.002).

Physiological Hyperinsulinemia Has No Detectable Effect on Access of Macromolecules to Insulin-Sensitive Tissues in Healthy Humans

OBJECTIVE—Physiologically elevated insulin concentrations promote access of macromolecules to skeletal muscle in dogs. We investigated whether insulin has a stimulating effect on the access of macromolecules to insulin-sensitive tissues in humans as well. RESEARCH DESIGN AND METHODS—In a randomized, controlled trial, euglycemic-hyperinsulinemic clamp (1.2 mU · kg−1 · min−1 insulin) and saline control experiments were performed in 10 healthy volunteers (aged 27.5 ± 4 years, BMI 22.6 ± 1.6 kg/m2). Distribution and clearance parameters of inulin were determined in a whole-body approach, combining primed intravenous infusion of inulin with compartment modeling. Inulin kinetics were measured in serum using open-flow microperfusion in interstitial fluid of femoral skeletal muscle and subcutaneous adipose tissue. RESULTS—Inulin kinetics in serum were best described using a three-compartment model incorporating a serum and a fast and a slow equilibrating compartment. Inulin kinetics in interstitial fluid of peripheral insulin-sensitive tissues were best represented by the slow equilibrating compartment. Serum and interstitial fluid inulin kinetics were comparable between the insulin and saline groups. Qualitative analysis of inulin kinetics was confirmed by model-derived distribution and clearance parameters of inulin. Physiological hyperinsulinemia (473 ± 6 vs. 18 ± 2 pmol/l for the insulin and saline group, respectively; P < 0.001) indicated no effect on distribution volume (98.2 ± 6.2 vs. 102.5 ± 5.7 ml/kg; NS) or exchange parameter (217.6 ± 34.2 vs. 243.1 ± 28.6 ml/min; NS) of inulin to peripheral insulin-sensitive tissues. All other parameters identified by the model were also comparable between the groups. CONCLUSIONS—Our data suggest that in contrast to studies performed in dogs, insulin at physiological concentrations does not augment recruitment of insulin-sensitive tissues in healthy humans.

Atorvastatin for high-risk statin-naïve patients undergoing noncardiac surgery: The Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD) randomized trial

Background Preliminary evidence suggests that statins may prevent major perioperative vascular complications. Methods We randomized 648 statin‐naïve patients who were scheduled for noncardiac surgery and were at risk for a major vascular complication. Patients were randomized to a loading dose of atorvastatin or placebo (80 mg anytime within 18 hours before surgery), followed by a maintenance dose of 40 mg (or placebo), started at least 12 hours after the surgery, and then 40 mg/d (or placebo) for 7 days. The primary outcome was a composite of all‐cause mortality, nonfatal myocardial injury after noncardiac surgery, and stroke at 30 days. Results The primary outcome was observed in 54 (16.6%) of 326 patients in the atorvastatin group and 59 (18.7%) of 316 patients in the placebo group (hazard ratio [HR] 0.87, 95% CI 0.60‐1.26, P = .46). No significant effect was observed on the 30‐day secondary outcomes of all‐cause mortality (4.3% vs 4.1%, respectively; HR 1.14, 95% CI 0.53‐2.47, P = .74), nonfatal myocardial infarction (3.4% vs 4.4%, respectively; HR 0.76, 95% CI 0.35‐1.68, P = .50), myocardial injury after noncardiac surgery (13.2% vs 16.5%; HR 0.79, 95% CI 0.53‐1.19, P = .26), and stroke (0.9% vs 0%, P = .25). Conclusion In contrast to the prior observational and trial data, the LOAD trial has neutral results and did not demonstrate a reduction in major cardiovascular complications after a short‐term perioperative course of statin in statin‐naïve patients undergoing noncardiac surgery. We demonstrated, however, that a large multicenter blinded perioperative statin trial for high‐risk statin‐naïve patients is feasible and should be done to definitely establish the efficacy and safety of statin in this patient population.

Lipid‐Heparin Infusion Suppresses the IL‐10 Response to Trauma in Subcutaneous Adipose Tissue in Humans

An imbalance between pro‐ and anti‐inflammatory cytokine productions in adipose tissue is thought to contribute to chronic, systemic, low‐grade inflammation and consequently to an increased risk of cardiovascular complications in obese and type 2 diabetic patients. Nonesterified fatty acids (NEFA), whose serum levels are elevated in such patients, have been shown to interfere with cytokine production in vitro. In order to evaluate the effects of elevated NEFA levels on cytokine production in adipose tissue in vivo we used an 18‐gauge open‐flow microperfusion (OFM) catheter to induce local inflammation in the subcutaneous adipose tissue (SAT) of healthy volunteers and to sample interstitial fluid (IF) specifically from the inflamed tissue. In two crossover studies, nine subjects received either an intravenous lipid‐heparin infusion to elevate circulating NEFA levels or saline over a period of 28 h. The former increased the circulating levels of triglycerides (TGs), NEFA, glucose, and insulin over the study period. NEFA effects on locally induced inflammation were estimated by measuring the levels of a panel adipokines in the OFM probe effluent. Interleukin‐6 (IL‐6), IL‐8, tumor necrosis factor‐α (TNF‐α) and monocyte chemoattractant protein‐1 (MCP‐1) levels increased during the study period but were not affected by lipid‐heparin infusion. In contrast, the level of IL‐10, an anti‐inflammatory cytokine, was significantly reduced during the final hour of lipid‐heparin infusion (saline: 449.2 ± 105.9 vs. lipid‐heparin: 65.4 ± 15.4 pg/ml; P = 0.02). These data provide the first in vivo evidence that elevated NEFA can modulate cytokine production by adipose tissue.

Assessment of different techniques for subcutaneous glucose monitoring in Type 1 diabetic patients during 'real-life' glucose excursions.

Diabet. Med. 27, 332–338 (2010)

The Role of Metabolic Surgery on Blood Pressure Control

Obesity and hypertension are growing epidemics in the modern world. Lifestyle changes and medical treatment for obesity have disappointing long-term results and albeit drugs for hypertension are usually very effective, the necessity of multiple pills and frequent side effects make the adherence to treatment a huge challenge for healthcare systems. Bariatric/metabolic surgery is a very effective treatment and an exponential number of studies have been showing its positive impact beyond weight loss, mainly on type 2 diabetes. There is also growing evidence suggesting that bariatric/metabolic surgery is associated with reduced incidence of cardiovascular events, but the impact on hypertension and other components of metabolic syndrome usually derive from trials’ secondary end points. Taking this limitation in mind, bariatric/metabolic surgery action on blood pressure is reaching a significant proportion of hypertension resolution or improvement. In this review, we discussed the current evidence on the impact of bariatric/metabolic surgery on blood pressure control and pointed out perspectives in this research area.