C Bakogiannis

Reciprocal Effects of Systemic Inflammation and Brain Natriuretic Peptide on Adiponectin Biosynthesis in Adipose Tissue of Patients With Ischemic Heart Disease

Objective— To explore the role of systemic inflammation in the regulation of adiponectin levels in patients with ischemic heart disease. Approach and Results— In a cross-sectional study of 575 subjects, serum adiponectin was compared between healthy subjects, patients with coronary artery disease with no/mild/severe heart failure (HF), and patients with nonischemic HF. Adiponectin expression and release from femoral, subcutaneous and thoracic adipose tissue was determined in 258 additional patients with coronary artery bypass grafting. Responsiveness of the various human adipose tissue depots to interleukin-6, tumor necrosis factor-&agr;, and brain natriuretic peptide (BNP) was examined by using ex vivo models of human fat. The effects of inducible low-grade inflammation were tested by using the model of Salmonella typhi vaccine-induced inflammation in healthy individuals. In the cross-sectional study, HF strikingly increased adiponectin levels. Plasma BNP was the strongest predictor of circulating adiponectin and its release from all adipose tissue depots in patients with coronary artery bypass grafting, even in the absence of HF. Femoral AT was the depot with the least macrophages infiltration and the largest adipocyte cell size and the only responsive to systemic and ex vivo proinflammatory stimulation (effect reversible by BNP). Low-grade inflammation reduced circulating adiponectin levels, while circulating BNP remained unchanged. Conclusions— This study demonstrates the regional variability in the responsiveness of human adipose tissue to systemic inflammation and suggests that BNP (not systemic inflammation) is the main driver of circulating adiponectin in patients with advanced atherosclerosis even in the absence of HF. Any interpretation of circulating adiponectin as a biomarker should take into account the underlying disease state, background inflammation, and BNP levels.

RAPID, DIRECT EFFECTS OF STATIN TREATMENT ON ARTERIAL REDOX STATE AND NITRIC OXIDE BIOAVAILABILITY IN HUMAN ATHEROSCLEROSIS VIA TETRAHYDROBIOPTERIN-MEDIATED ENOS COUPLING

Methods: We recruited 492 patients undergoing CABG. During surgery segments of internal mammary arteries (IMA) were obtained. Arterial O2was determined by lucigenin chemiluminescence (+/-LNAME), while acetylcholine-induced vasorelaxations were assessed ex-vivo. In a 2nd study, IMA segments from 10 patients were incubated ex vivo with atorvastatin, for 6h (+/mevalonate (Mev)). Vascular tetrahydrobiopterin (BH4 was measured by HPLC, while GTP-cyclohydrolase I (GTPCH-I) gene expression was determined by qRT-PCR.

MYOCARDIAL O2-AND ONOO-GENERATION IN CHRONIC ATRIAL FIBRILLATION

Background: Myocardial redox state is a key feature for atrial fibrillation (AF). We examined the mechanisms regulating myocardial superoxide (O2-) and peroxynitrite (ONOO-) generation in patients with chronic AF. Methods: Samples of right atrium appendage were obtained from 113 patients undergoing elective cardiac surgery (98 in sinus rhythm (SR) and 15 with chronic AF). Myocardial O2- generation was determined by lucigenin chemiluminescence, while urate-inhibitable luminol chemiluminescence was used to estimate ONOO- generation. NADPH oxidase activity was estimated by the NADPH-stimulated O2- and its apocynin inhibitable fraction, uncoupled nitric oxide synthase (NOS) by using LNAME and mitochondrial oxidases by using rotenone. Results: Patients with chronic AF had slightly but not significantly higher resting O2- (A). However, NADPH-stimulated (B) and apocynin-inhibitable (C) O2- were significantly greater in AF compared to SR patients. There was no significant difference in rotenone-inhibitable O2- (D). However, LNAME-inhibitable (E) and ONOO- generation (F) were significantly greater in AF compared to SR patients (F). Left atrium diameter was significantly correlated with NADPH-stimulated O2- (r=0.294, p=0.025) and apocynin-inhibitable O2- (r=0.288, p=0.032). Conclusions: Chronic AF is characterized by greater NADPH-oxidase activity, NOS uncoupling and elevated ONOO- generation in atrial myocardium. Targeting these mechanisms provides new therapeutic strategies for AF.