Toko Mitsui

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-1&agr; 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-1&agr;–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-1&agr;–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.

Impact of night-time blood pressure on cerebral white matter hyperintensity in elderly hypertensive patients.

Cerebral white matter hyperintensity (WMH) is highly prevalent in the elderly population, and increases the risk of dementia and stroke. We investigated the relationship between ambulatory blood pressure monitoring levels and quantitatively measured WMH volumes among elderly hypertensive patients with well‐controlled blood pressure (BP) to re‐evaluated effective hypertension management methods to prevent the progression of WMH.

Left ventricular diastolic dysfunction is directly associated with cerebral white matter lesions in elderly patients.

Cerebral white matter lesions (WML) have been established to increase with age, and are associated with heightened risks of stroke, cognitive decline and depressive disorder. We previously reported that the severity of left ventricular (LV) diastolic dysfunction is associated with the volume of cerebral WML. However, the analysis could not be carried out by removing the effect of the common or specific risk factors that are known to be involved in the progression of LV diastolic dysfunction and/or cerebral WML, such as age, hypertension, diabetes mellitus, hyperlipidemia, smoking, obesity and so on. Consequently, whether LV diastolic dysfunction is directly associated with cerebral WML remained unclear. Therefore, to clarify this, we carried out a cross-sectional study by conducting further in-depth examination of these risk factors and also by increasing the study population. The study registration period was from April 2010 to October 2013. Participants comprised 133 outpatients between aged 65 and 75 years with normal LV contraction (ejection fraction >50%) and no signs or history of symptomatic heart failure, ischemic heart diseases, atrial fibrillation, stroke, or cognitive dysfunction. We also excluded those patients with ≥50% stenosis in the carotid arteries on ultrasonography with 2-D and Doppler analysis. The volume of cerebral WML was quantified on brain magnetic resonance imaging using a fully automatic segmentation program developed in the Department of Radiology at Leiden University Medical Center (Leiden, the Netherlands), and early diastolic mitral inflow and early diastolic mitral annular tissue velocity (E/E’) ratio, a parameter that indicates the severity of LV diastolic dysfunction, was measured by tissue Doppler echocardiography. A total of 20 4-h systolic and diastolic blood pressure were obtained by ambulatory blood pressure monitoring. In addition, LV ejection fraction, body mass index, estimated glomerular filtration rate, carotid intimal media thickness, and levels of plasma B-type natriuretic peptide, hemoglobin A1c and low density lipoprotein cholesterol were also determined. Values are shown as mean ± standard deviation unless otherwise stated. Data were analyzed using SPSS version 17.0 software (SPSS, Chicago, IL, USA). The study protocol was approved by the ethics/conflict of interest committee at the National Center for Geriatrics and Gerontology. Written informed consent was obtained from all participants before participation. Table A shows the patient characteristics. The results of linear regression analysis between cerebral WML volume and estimated factors are shown in Table B. These results showed that four factors (age, systolic blood pressure, plasma B-type natriuretic peptide and E/E’) had a significant correlation (P < 0.05) with cerebral WML volume. Based on the results, multivariate analysis was carried out in order to clarify the principal factors involved in the increase of the cerebral WML. As a result, E/E’ and age had been shown to be significantly correlated with cerebral WML volume (P < 0.01), with the correlation greater for E/E’ (P = 0.003) than for age (P = 0.03; Table C). The present study clarified the direct association between the severity of LV diastolic dysfunction and the volume of WML in elderly patients even after removing the effects of risk factors that were involved in the progression of LV diastolic dysfunction and/or cerebral WML. The results can be interpreted in two ways. The first interpretation is that a common, but unknown, factor exacerbates both cerebral WML and LV diastolic dysfunction, with this complicating factor being profoundly involved in the onset and progression of both diseases. The second interpretation involves chronic low cardiac output and chronic cerebral ischemia. Some reports in recent years have suggested that cerebral perfusion is impaired in patients with chronic low cardiac output. Thus, considering that cardiac output decreases with the decrease in blood flow into the LV from the left atrium as a result of the progression in LV diastolic dysfunction, and also considering that a chronic decrease in cerebral blood flow is thought to be the primary mechanism underlying cerebral WML formation, the present results can also be interpreted as suggesting that decreased cardiac output elicits chronic cerebral ischemia. Further investigation is necessary to clarify these points. Correspondence: Dr. Manabu Kokubo MD PhD, Department of Cardiology, National Center for Geriatrics and Gerontology, 7-430, Morioka-cho, Obu, Aichi 474-8511, Japan. Email: mkokubo@ncgg.go.jp Geriatr Gerontol Int 2015; 15 (Suppl. 1): 81–85 bs_bs_banner