Nikolaos P.E. Kadoglou

The anti-inflammatory effects of exercise training in patients with type 2 diabetes mellitus:

Background Diabetes mellitus (DM) and chronic inflammation are strongly related to increased cardiovascular risk. The purpose of this study was to evaluate whether an aerobic training programme would ameliorate inflammatory and anti-inflammatory markers in patients with type 2 DM. Design Interventional study. Methods A total of 60 overweight individuals with type 2 DM, but without vascular complications, were randomly assigned to either a 6-month aerobic exercise training programme (four times/week, 45-60 min/session), designated as exercise group, or to the control group. All participants were on an oral antidiabetic regimen and none was receiving lipid-lowering medications. Anthropometric parameters, cardiorespiratory fitness, glycaemic and lipid profiles, high sensitivity C-reactive protein (hs CRP), adiponectin, interleukin (IL)-10, IL-18, tumour necrosis factor (TNF)-a, insulin, reciprocal index of homoeostasis model assessment (HOMA-IR), body fat and blood pressure (BP) were measured at baseline and at the end of the study. Results In comparison with baseline and control group, exercise-treated patients improved glucose control, lipid profile, exercise capacity (Vo2 peak) and exhibited decreased insulin resistance and systolic BP considerably (P < 0.05). Plasma adiponectin, TNF-α and body weight changed slightly across treatment (P > 0.05), whereas diastolic BP and fat mass tended to decrease (P = 0.071 and 0.061, respectively). Exercise training reduced hs CRP (from 0.48 ± 0.16 to 0.29 ± 0.2 mg/dl; P = 0.04) and IL-18 (from 315.19 ± 122.76 to 203.77 ± 96.02 pg/ml; P = 0.02). Moreover, exercise provided anti-inflammatory protection through IL-10 increment (P = 0.039) and IL-18/IL-10 ratio downregulation (P = 0.014). In multiple regression analysis, alteration in IL-18 was independently correlated with hs CRP and Vo2 peak changes (P < 0.05). Conclusion Aerobic exercise training without significant weight loss improves metabolic profile and exerts anti-inflammatory effects in patients with type 2 DM. Eur J Cardiovasc Prev Rehabil 14: 837-843

Serum levels of vaspin and visfatin in patients with coronary artery disease—Kozani study

BACKGROUND The association of novel adipokines, vaspin and visfatin, with atherosclerosis is still obscure. The present study aimed to investigate the relationship of those adipokines with the existence as well as the extent of coronary artery disease (CAD), suggesting a link between adiposity and atherosclerosis. METHODS We enrolled a total of 108 patients with angiographically proven stable, asymptomatic CAD and 65 healthy controls (HC) without cardiovascular diseases. The severity of CAD was assessed using coronary angiography by the Gensini score. Clinical parameters, glycemic and lipid profile, high-sensitivity CRP (hsCRP), vaspin and visfatin levels were assayed. RESULTS Serum levels of vaspin were significantly lower in subjects with CAD [0.91 (0.44-1.29) ng/ml] than healthy controls [1.42 (0.96-2.42) ng/ml] (p = 0.009). Inversely, visfatin (p = 0.016) and hsCRP (p < 0.001) levels were considerably up-regulated in CAD vs HC group. Multivariate analysis demonstrated decreased vaspin and increased visfatin levels to correlate with CAD presence, independent of other cardiovascular risk factors (p < 0.05). Standard multiple regression revealed HDL, LDL-C and vaspin to be independent determinants of Gensini score (R² = 0.189, p = 0.019). Notably, statin-free patients had even lower vaspin levels compared to statin users (p = 0.018). CONCLUSIONS Decreased vaspin and increased visfatin serum levels were observed in asymptomatic patients with CAD. Low vaspin concentrations seemed to correlate with CAD severity.

Serum levels of apelin and ghrelin in patients with acute coronary syndromes and established coronary artery disease--KOZANI STUDY.

Apelin and ghrelin have emerged as novel adipokines, but their role in coronary artery disease (CAD) remains obscure. In the present study, we analyzed their serum levels in patients with acute coronary syndromes (ACS) or established asymptomatic CAD. A total of 355 participants were enrolled. Among them were 80 patients with unstable angina (UA) and 115 patients with acute myocardial infarction (AMI) hospitalized in the coronary care unit. We also included 88 asymptomatic patients with established CAD (asymptomatic CAD) and 72 age-and sex-matched healthy controls (HCs). All groups with CAD underwent coronary angiography, and the Gensini score was determined. Clinical parameters, glycemic and lipid profile, high-sensitivity CRP (hsCRP), insulin resistance (HOMA-IR), as well as apelin and ghrelin were assayed. Patients with ACS (UA or AMI) were sampled at hospital admission. All 3 groups with CAD (UA, AMI, or asymptomatic CAD) showed significantly higher levels of hsCRP, HOMA-IR, and white blood cells than controls (P < 0.01). Conversely, apelin and ghrelin concentrations were considerably (P < 0.05) lower in CAD patients with respect to the control group. Most importantly, UA (6.72 +/- 3.51 ng/mL) and AMI (6.02 +/- 4.07 ng/mL) groups had even lower apelin levels on admission compared with the asymptomatic CAD group (13.53 +/- 5.2 ng/mL) (P < 0.05). Logistic regression analysis showed an independent association of low apelin and ghrelin levels with CAD presence. Besides this result, apelin showed an inverse relationship with ACS incidence and a Gensini score independent of other cardiovascular risk factors (P < 0.05). In conclusion, CAD seemed to correlate with low serum apelin and ghrelin levels. Moreover, apelin concentrations inversely were associated with the severity and the acute phase of CAD, which suggests its involvement in the progression and destabilization of coronary atherosclerotic plaques.

Effects of rosiglitazone and metformin treatment on apelin, visfatin, and ghrelin levels in patients with type 2 diabetes mellitus

Visfatin, ghrelin, and apelin are the most recently identified adipocytokines; but their response to insulin-sensitizing agents is poorly clarified. We aimed to assess the differential effects of either rosiglitazone or metformin monotherapy on the aforementioned adipocytokines in patients with type 2 diabetes mellitus (T2DM). One hundred T2DM patients (30 men, 70 women), with poor glycemic control (glycosylated hemoglobin >6.5%) while taking 850 mg of metformin daily, were enrolled. All participants were randomized to receive either adjunctive therapy with rosiglitazone (8 mg/d, n = 50) or the maximum dose (2550 mg/d) of metformin (MET group, n = 50). Anthropometric parameters, glycemic and lipid profile, high-sensitivity CRP (hs-CRP), insulin resistance (homeostasis model assessment of insulin resistance index [HOMA-IR]), visfatin, ghrelin, and apelin were assessed at baseline and after 14 weeks of therapy. Both rosiglitazone and metformin led to similar, significant improvement in glycemic profile and apelin levels, whereas lipid parameters, fat mass, and visfatin remained almost unaffected (P > .05). Insulin resistance was significantly attenuated in both groups, but to a lesser degree in the MET group (P = .045). Rosiglitazone-treated patients experienced a significant decrease in hs-CRP and systolic blood pressure compared with baseline values and those of the MET group (P < .05). Besides, rosiglitazone treatment considerably increased plasma ghrelin (3.74 +/- 1.52 ng/mL) in comparison with either baseline (P = .034) or metformin monotherapy values (-2.23 +/- 1.87 ng/mL, P = .008). On the other hand, the MET group, rather than the rosiglitazone group, had decreased body mass index (-0.79 +/- 0.47 vs 0.56 kg/m(2), P = .009). The aforementioned changes in apelin and ghrelin were independently associated with HOMA-IR changes. Both rosiglitazone and metformin favorably changed glycemic indexes and apelin levels. The addition of rosiglitazone seemed to confer greater benefits in ghrelin, hs-CRP, systolic blood pressure, and HOMA-IR regulation than metformin monotherapy. Although these results reflect improvement in cardiovascular risk profile, the overall clinical importance of insulin sensitizers must be further assessed.

The differential anti-inflammatory effects of exercise modalities and their association with early carotid atherosclerosis progression in patients with type 2 diabetes.

Adipokines, visfatin, apelin, vaspin and ghrelin have emerged as novel cardiovascular risk factors. We aimed to evaluate the effects of different exercise modalities on the aforementioned novel adipokines and carotid intima‐media thickness in patients with Type 2 diabetes mellitus.

The impact of aerobic exercise training on novel adipokines, apelin and ghrelin, in patients with type 2 diabetes

Summary Background Accumulating data support the atheroprotective role of the novel adipokines, apelin and ghrelin. The aim of the present randomized study was to investigate the effects of aerobic exercise training on these adipokines in patients with type 2 diabetes mellitus (T2DM). Material/Methods Fifty-four overweight (BMI >25 kg/m2) patients with T2DM, but without vascular complications, were randomized to either the aerobic exercise training group (EG, N=27), 4 times/week, 45–60 min/session; or to the control group (CG, N=27), orally instructed to increase physical activity. Clinical glycemic and lipid parameters, exercise capacity (VO2peak), insulin, HOMA-IR, and serum levels of apelin and ghrelin were assessed at baseline and after 12 weeks. Results Aerobic exercise significantly improved lipid and glycemic profile and insulin sensitivity compared to CG (p<0.05). Furthermore, between-groups comparison showed a considerable exercise-induced upregulation in apelin (p=0.007) and VO2peak (p<0.001) levels. Negligible changes in body-weight, waist-hip ratio and ghrelin concentrations were detected within and between groups after the completion of the study (p>0.05). However, subgroup analysis revealed a considerable increment in ghrelin levels only in the exercise-treated women compared to their control counterparts (p=0.038). LDL and HOMA-IR reduction were found to be independent predictors of apelin increment in multiple regression analysis (R2=0.391, p=0.011). Conclusions In patients with T2DM, systemic, long-term, aerobic exercise exerts positive effects on apelin and ghrelin (only in women), even in the absence of significant weight loss, suggesting its pleiotropic effects.

Exercise ameliorates serum MMP-9 and TIMP-2 levels in patients with type 2 diabetes.

AIM This study assessed the impact of regular exercise on inflammatory markers (high-sensitivity C-reactive protein [hsCRP], fibrinogen), and matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), in patients with type 2 diabetes mellitus (T2DM). PATIENTS Fifty overweight patients with T2DM were randomly assigned to two groups: (A) an exercise group (EXG, n=25), with self-controlled exercise for at least 150 min/week and one additional supervised exercise session/week; and (B) a control group (COG, n=25), with no exercise instructions. All participants were taking oral antidiabetic drugs, and none had diabetic complications. Clinical parameters, exercise capacity (VO(2 peak)), ventilatory threshold (VT), insulin resistance indices (fasting insulin, HOMA-IR, HOMA%S), hsCRP, fibrinogen, MMP-2, MMP-9, TIMP-1 and TIMP-2 were assessed at baseline and after 16 weeks. RESULTS No significant changes were found in body mass index, waist/hip ratio, insulin-resistance indices, MMP-2 and TIMP-1 throughout the study in either group (P>0.05). Compared with controls, the EXG showed a significant decrease in systolic and mean blood pressure, total and LDL cholesterol, and HbA(1c) (P<0.05). Also, exercise significantly suppressed levels of fibrinogen (P=0.047), hsCRP (P=0.041) and MMP-9 (P=0.028), and the MMP-9-to-TIMP-1 ratio (P=0.038), whereas VO(2 peak) (P=0.011), VT (P=0.008) and plasma TIMP-2 levels (P=0.022) were considerably upregulated in the EXG vs. COG. Standard multiple-regression analyses revealed that MMP-9 changes were independently associated with fibrinogen and HbA(1c) changes, while fibrinogen changes independently predicted TIMP-2 alterations with exercise. CONCLUSION Mostly self-controlled exercise of moderate intensity ameliorated serum levels of pro- and anti-atherogenic markers in patients with T2DM, with no effects on body weight. These data offer further insight into the cardioprotective mechanisms of exercise in patients with T2DM.

Arterial stiffness and novel biomarkers in patients with abdominal aortic aneurysms

OBJECTIVES Pulse wave velocity (PWV) constitutes a valid index of arterial stiffness osteoprotegerin (OPG) and osteopontin (OPN) which are well-established vascular calcification inhibitors, highly correlated with inflammation, and cardiovascular events incidence. We investigated the association of PWV with the aforementioned novel biomarkers in patients with abdominal aortic aneurysm (AAA). METHODS We enrolled 108 men with AAA (AAA group) candidates for endovascular repair. We excluded patients with Marfan syndrome or other collagen-related disorders. Forty-one age-matched men, with stable coronary artery disease (CAD), but without AAA, served as controls (CO group). PWV, clinical parameters and serum levels of osteoprotegerin (OPG), osteopontin (OPN), interleukin-6 (IL-6) and IL-10 were determined. RESULTS With the exception of higher smoking rate and the lower statins usage in the AAA group, there were non-significant differences in the rest of demographic and clinical parameters (p>0.05). We found significantly higher levels of PWV in AAA than CO group (12.99±3.75 m/s vs 10.03±1.57 m/s, p<0.001). In parallel, serum OPG, OPN, IL-6 levels were considerably increased, while IL-10 levels were downregulated (p<0.001) in AAA group. PWV positively correlated with mean blood pressure, OPG concentrations and AAA diameter in univariate and multivariate analysis (R(2)=0.498, p=0.008). Finally, age and OPG remained independent determinants of AAA presence in the whole study cohort. CONCLUSIONS Arterial stiffness, circulating vascular calcification inhibitors and inflammatory mediators seem to be significantly upregulated in patients with AAA. An independent association of PWV with mean blood pressure, OPG and AAA diameter is of clinical importance which requires further investigation.

Insulin and the heart.

The main role of insulin in the heart under physiological conditions is obviously the regulation of substrate utilization. Indeed, insulin promotes glucose uptake and its utilization via glycolysis. Insulin, promoting glucose as the main cardiac energy substrate, reduces myocardial O(2) consumption and increases cardiac efficiency. Moreover, insulin seems to augment cardiomyocyte contraction, while it affects favorably myocardial relaxation, increases ribosomal biogenesis and protein synthesis, stimulates vascular endothelial growth factor (VEGF) and thereby angiogenesis, suppresses apoptosis, promotes cell survival and finally ameliorates both myocardial microcirculation and coronary artery resistance, leading to increased blood perfusion of myocardium. Thus, insulin acts directly on heart muscle, and this action is mediated principally through PKB/Akt signal pathway. Under pathological conditions, such as type 2 diabetes, myocardial ischaemia, and cardiac hypertrophy, insulin signal transduction pathways and action are clearly modified. In this review we summarize the evidence that the heart is an important target of insulin action and that elimination of these actions is important in disease states.

The Pathophysiology of HIV-/HAART-Related Metabolic Syndrome Leading to Cardiovascular Disorders: The Emerging Role of Adipokines

Individuals infected with human immunodeficiency virus (HIV) frequently demonstrate metabolic syndrome (MS) associated with increased incidence of cardiovascular disorders. Characteristics of HIV infection, such as immunodeficiency, viral load, and duration of the disease, in addition to the highly active antiretroviral therapy (HAART) have been suggested to induce MS in these patients. It is well documented that MS involves a number of traditional cardiovascular risk factors, like glucose, lipids, and arterial blood pressure abnormalities, leading to extensive atherogenic arterial wall changes. Nevertheless, the above traditional cardiovascular risk factors merely explain the exacerbated cardiovascular risk in MS. Nowadays, the adipose-tissue derivatives, known as adipokines, have been suggested to contribute to chronic inflammation and the MS-related cardiovascular disease. In view of a novel understanding on how adipokines affect the pathogenesis of HIV/HAART-related MS and cardiovascular complications, this paper focuses on the interaction of the metabolic pathways and the potential cardiovascular consequences. Based on the current literature, we suggest adipokines to have a role in the pathogenesis of the HIV/HAART-related MS. It is crucial to understand the pathophysiology of the HIV/HAART-related MS and apply therapeutic strategies in order to reduce cardiovascular risk in HIV patients.