Predictive value of abdominal aortic calcification index for mid-term cardiovascular events in patients with acute coronary syndrome.

The utility of abdominal aortic calcification (AAC) for prediction of cardiovascular events (CVEs) in patients with acute coronary syndrome (ACS) remains to be determined. The aim of this prospective study was to determine the predictive value of the abdominal aortic calcification index (ACI), a semi-quantitative measure of AAC, for CVEs in patients with ACS. We evaluated 314 patients with ACS. All patients underwent successful percutaneous coronary intervention to the culprit coronary vessel without in-hospital adverse events. ACI was calculated on non-contrast computed tomography images. CVEs were defined as a composite of cardiovascular death, ACS recurrence, and stroke. During a median follow-up period of 19.1 months, CVEs occurred in 29 patients (9.2%). Multivariable regression analysis after adjustment for age and gender showed a significantly higher baseline ACI in patients with CVEs than in those without [median (interquartile ranges), 42.1 (25.9-60.2) vs. 20.8 (8.8-38.6) %; P = 0.021]. The cutoff value of ACI for prediction of CVEs, estimated by receiver-operating characteristic analysis, was 29.2%, with sensitivity of 76% and specificity of 64% (area under the curve, 0.69). After adjustment for conventional cardiovascular risk factors, Cox analysis showed high ACI (≥29.2%) to be significantly associated with increased risk of CVEs (P = 0.011; hazard ratio, 1.82). Multivariate analysis identified high ACI as an independent predictor of CVEs (P = 0.012; hazard ratio, 1.80). Stepwise forward selection procedure also showed that high ACI was a significant independent determinant of CVEs (P = 0.004; R2, 0.089). Both net reclassification improvement (0.64; P = 0.001) and integrated discrimination improvement (0.04; P < 0.001) improved significantly after the addition of high ACI to conventional risk factors. Evaluation of ACI using CT seems to provide valuable clinical information for proper assessment of mid-term CVEs in patients with ACS after percutaneous coronary intervention.

The association of serum adiponectin level with activities of daily living in hospitalized elderly patients with heart failure.

BACKGROUND: Several studies have reported a relationship between elevated serum adiponectin levels and poor outcomes in patients with heart failure (HF). However, data on the activities of daily living (ADL) in elderly patients with HF are limited. METHODS: We evaluated 218 hospitalized elderly (≥65 years) patients with HF who underwent a comprehensive cardiac rehabilitation (CR) program during hospitalization. Serum adiponectin levels were measured before discharge. The Barthel index (BI) score was evaluated at discharge. Low ADL was defined as a BI score < 85. RESULTS: Serum adiponectin levels were significantly associated with low ADL [p = 0.03; odds ratio (OR), 1.024, per 1.0 µg/mL increase]. In logistic or regression analyses adjusted for age, sex, body mass index, and estimated glomerular filtration rate, high adiponectin levels (≥16.2 µg/mL) were significantly associated with low ADL (p = 0.04; OR, 2.53), malnutrition (p < 0.01; OR, 2.88), and 6-min walk distance (p = 0.04; ß = -17.5). In the multivariate analysis adjusted for conventional risk factors of low ADL, high adiponectin levels were also significantly associated with low ADL (p = 0.03; OR, 2.68). In the stepwise forward selection procedure, a high adiponectin level was an independent determinant of low ADL (p = 0.02; R2 = 0.0262). Both net reclassification improvement (0.53; p < 0.01) and integrated discrimination improvement (0.02; p = 0.01) improved significantly after the addition of high adiponectin level to conventional risk factors. In the regression analysis adjusted for age and sex, serum adiponectin levels were significantly (p < 0.0025) negatively associated with abdominal visceral and subcutaneous adipose tissue areas, body weight, body mass index, and serum triglyceride levels. CONCLUSIONS: High serum adiponectin levels were not only significantly associated with an increased risk of low ADL, but also with an increased risk of malnutrition and low physical activity in elderly patients with HF after the in-hospital CR program.

Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions.

BACKGROUND: The inhibition of dipeptidyl peptidase-4 (DPP4) protects the heart from acute myocardial ischemia. However, the role of DPP4 in chronic heart failure independent of coronary artery disease remains unclear. METHODS AND RESULTS: We first localized the membrane-bound form of DPP4 to the capillary endothelia of rat and human heart tissue. Diabetes mellitus promoted the activation of the membrane-bound form of DPP4, leading to reduced myocardial stromal cell-derived factor-1α concentrations and resultant angiogenic impairment in rats. The diabetic rats exhibited diastolic left ventricular dysfunction (DHF) with enhanced interstitial fibrosis caused partly by the increased ratio of matrix metalloproteinase-2 to tissue inhibitor of metalloproteinase-2 in a DPP4-dependent fashion. Both genetic and pharmacological DPP4 suppression reversed the stromal cell-derived factor-1α-dependent microvasculopathy and DHF associated with diabetes mellitus. Pressure overload induced DHF, which was reversed by DPP4 inhibition via a glucagon-like peptide-1/cAMP-dependent mechanism distinct from that for diabetic heart. In patients with DHF, the circulating DPP4 activity in peripheral veins was associated with that in coronary sinus and with E/e', an echocardiographic parameter representing DHF. Comorbid diabetes mellitus increased the circulating DPP4 activities in both peripheral veins and coronary sinus. CONCLUSIONS: DPP4 inhibition reverses DHF via membrane-bound DPP4/stromal cell-derived factor-1α-dependent local actions on angiogenesis and circulating DPP4/glucagon-like peptide-1-mediated inotropic actions. Myocardium-derived DPP4 activity in coronary sinus can be monitored by peripheral vein sampling, which partly correlates with DHF index; thus, circulating DPP4 may potentially serve as a biomarker for monitoring DHF.

Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes.

Glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) is a remedy for type 2 diabetes mellitus (T2DM). Ex-4 ameliorates cardiac dysfunction induced by myocardial infarction in preclinical and clinical settings. However, it remains unclear whether Ex-4 may modulate diabetic cardiomyopathy. We tested the impact of Ex-4 on two types of diabetic cardiomyopathy models, genetic (KK) and acquired T2DM induced by high-fat diet [diet-induced obesity (DIO)], to clarify whether Ex-4 may combat independently of etiology. Each type of mice was divided into Ex-4 (24 nmol·kg(-1)·day(-1) for 40 days; KK-ex4 and DIO-ex4) and vehicle (KK-v and DIO-v) groups. Ex-4 ameliorated systemic and cardiac insulin resistance and dyslipidemia in both T2DM models. T2DM mice exhibited systolic (DIO-v) and diastolic (DIO-v and KK-v) left ventricular dysfunctions, which were restored by Ex-4 with reduction in left ventricular hypertrophy. DIO-v and KK-v exhibited increased myocardial fibrosis and steatosis (lipid accumulation), in which were observed cardiac mitochondrial remodeling and enhanced mitochondrial oxidative damage. Ex-4 treatment reversed these cardiac remodeling and oxidative stress. Cytokine array revealed that Ex-4-sensitive inflammatory cytokines were ICAM-1 and macrophage colony-stimulating factor. Ex-4 ameliorated myocardial oxidative stress via suppression of NADPH oxidase 4 with concomitant elevation of antioxidants (SOD-1 and glutathione peroxidase). In conclusion, GLP-1R agonism reverses cardiac remodeling and dysfunction observed in T2DM via normalizing imbalance of lipid metabolism and related inflammation/oxidative stress.

Atorvastatin prevents ischemic limb loss in type 2 diabetes: role of p53.

AIM: Diabetic peripheral artery disease (PAD) is prone to be aggressive and recent reports have demonstrated that p53 accumulation may be responsible for impaired wound healing in diabetes. Statins has been demonstrated to facilitate p53 degradation by activating its specific ubiquitin ligase, MDM2. The aim of this study was to determine whether atorvastatin (ATR) improves the outcome of diabetic PAD through MDM2-mediated reduction of p53. METHODS: Male KK/Ay mice (9 weeks old) were treated with ATR (2 mg/kg/day p.o.) or vehicle for 2 weeks and subjected to ischemic hindlimb operation to generate a diabetic PAD model. Incidences of amputation and changes of p53/MDM2 signaling in each ischemic limb were assessed 2 weeks after the operation (at 13 weeks of age). Effects of ATR on the insulin resistance of age-matched (13-week-old) and unoperated KK/Ay mice were assessed by the glucose tolerance test, circulating adiponectin concentration, and changes in insulin signaling (IRS-1/Akt phosphorylation). RESULTS: In intact KK/Ay, ATR treatment mitigated insulin resistance without affecting cholesterol levels. All diabetic PAD models exhibited autoamputation (100%); however, ATR treatment partially restored the limb loss (41.7%). The p53 expression level in the ischemic limb of ATR-treated KK/Ay was significantly decreased and MDM2 phosphorylation level was markedly increased in tandem with the activation of Akt. Hypoxia mimetic iron chelator deferroxamine promoted p53 accumulation in H9c2 myoblast cells by suppressing the Akt/MDM2 pathway, which was restored by ATR. CONCLUSIONS: ATR was found to restore ischemic limb loss in diabetes by augmenting p53 degradation through direct activation of the Akt/MDM2 pathway in skeletal muscle.