心力衰竭心力衰竭 -糖尿病患者急性心肌梗死后无法回避的难题 吴永健中国医学科学院 中国协和医科大学心血管病研究所 阜外心血管病医院糖尿病患者急性心肌梗死后心力衰竭糖尿病患者急性心肌梗死后心力衰竭 The prevalence of heart failure is about 12% in people with Type 2 diabetes as compared to only 3.2% in non-diabetic subjects At 6 months, the incidence of HF was 24% (n=10) in the diabetics and 11% (n=30) in the non-diabetics (P=0.015) At 5 years, the rate of HF increased to 43% (n=18) in the diabetics and to 20% (n=57) in the non-diabetics (P=0.001). Heart failure in Type 2 diabetic patients following ACS Circulation 2000;102:1014-1019CHF event rate (%)051015202503691215182124DM+, CVD+DM-, CVD+DM+, CVD-DM-, CVD-MonthsAcute Coronary SyndromeOR (95% CI)PAge, y1.0513 (1.02841.0746)0.0001Peak CK, U/L1.0002 (1.00011.0002)0.0004Six-month LV dilation, mL1.0104 (1.00381.0170)0.0021Diabetes1.8026 (1.03743.1321)0.0366Predictors of HF at Multivariate Cox Analysis (6 months)Circulation. 2004;110:1974-1979糖尿病急性心肌梗死后糖尿病急性心肌梗死后HF糖尿病急性心肌梗死后早期糖尿病急性心肌梗死后早期HF的机制的机制糖尿病急性心肌梗死后早期糖尿病急性心肌梗死后早期HF的机制的机制Diabetes and congestive HF independent of CADEndocrine Reviews 2004;25:543-567Small vesselSmall vesseldiseasediseaseDiabeticDiabeticcardiomyopathycardiomyopathyLeft ventricular dysfunctionCardiac autonomicCardiac autonomicneuropathyneuropathyCardiacCardiacinsulininsulinresistanceresistance糖尿病急性心肌梗死后晚期糖尿病急性心肌梗死后晚期HF的机制的机制Diabetes mellitus can accerate the progression of post-infarction genetic regulatory expression in untreated Streptozotocin-induced Diabetic Rat Model-Genetic findings in the remote zone of LV free wall post acute myocardial infarctionGuang-Yuan Song1, Yong-Jian Wu1*, Yue-Jin Yang1, Jian-Jun Li1, Rui Li2, Ru-Tai Hui3, Han-Jun Pei1, Zhen-Yan Zhao1From the 1Center of Coronary Heart Disease, 3Center of Hypertension, Cardiovascular Institute & Fu-Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100037 , China.From the 2Genminix Informatics Ltd.Co*The corresponding author: Yong-Jian Wu, MD, PhD; Center of Coronary Heart Disease, Department of Cardiology, Cardiovascular Institute & Fu-Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 167 BeiLiShi Rd, Beijing, 100037, P.R. China.E-mail: fuwaihospitalgmail.comStudy Design 217 Sprague-Dawley (SD) rats were randomized into one of the four following groups: (1) AMI in diabetic rats (DM + AMI); (2) AMI in non-diabetic rats (N-DM + AMI); (3) Sham in diabetic rats (DM + Sham);(4) Sham in non-diabetic rats (N-DM + Sham). Experimental protocol is shown in Figure 1 Both diabetic and non-diabetic rats were subjected to left anterior descending coronary artery (LADCA) ischemia for 1-56 days without reperfusion. Transmission electron microscopy (TEM) was utilized 10weeks after DM induction. Two-dimensional echocardiography was utilized to obtain LV dimensions and LV percent fractional shortening at baseline, DM 10weeks, and at 1d, 7d, 14d, 28d, 56d after AMI; hemodynamic studies was performed at baseline, DM 10weeks, and at 1d, 28d after AMI; and then the remote zone tissues of LV free wall were taken as samples at day 1, 7, 14, 28, and 56 post AMI for gene chip microarray analysis; in addition, heart-to-body weight ratio and massons trichrome staining was measured as an index of cardiac hypertrophy and fibrosis at baseline, DM 10weeks, and at 1d, 7d, 14d, 28d, 56d after AMI.Aminals were sacrificed just after echocardiographic assessment, and the remote zone tissues of LV free wall were taken as samples at day 1, 7, 14, 28, and 56 post AMI. According to previous studies , we used the sample pooling strategies for microarray analysis in order to reduce the whole cost of the study. RNA fractions from the three rats in each group at the time point were balanced pooled for GeneChip analysis. Significant different expression genes were filtered from Affymetrix Genechip U230 2.0 array by GCOS software (P0.01). Genetic changes post myocardial infarction were classified by hierarchical clustering. And then, the differential expressions of 10 selected transcripts identified by the microarray were examined in greater detail by Real Time-PCR.GeneChip Microarray Analysis and Real Time-PCRHierarchical ClusteringGene clustering was analyzed by using Cluster 3.0 and Eisensoftware-Treeview. In this study, hierarchical cluster analyses were done using the Cluster program (complete linkage clustering) and results were displayed using TreeView. The criterion for filtering out a gene is based upon the percentage of expression values for that gene which have at least a minimum fold-change from the median expression value for that gene. (If the dataset contains 250 or more experiments, then the mean will be used instead of the median for computational efficiency.) If less than 50 percentage of expression values meet the minimum fold-change requirement, then the gene is filtered out. Then 164 genes expression were chosen for the clustering, in which we found 118 genes in the foregone genetic database, such as leucine-rich PPR-motif containing (IL-6 signaling pathway), procollagen type I, VI, VIII, and XV, fibronectin 1, RT1, and TIMP-1, that associated with post-infarction cardiac remodeling, etc. Hierarchical Clustering According to hierarchical clustering, we find that the molecular regulatory expression related to cardiac remodeling in the remote zone to myocardial infarction is quite different as time elapses in both diabetic and non-diabetic rats. The gene expression at day 1 and 7 post AMI in both groups is similar, while the genetic changes at day 14 post AMI in diabetic rats and the ones at day 14 and 28 in non-diabetic rats are classified into the same cluster. And then the genetic changes at day 28 and 56 post AMI in diabetic rats and the ones at day 56 in non-diabetic rats are classified into the same cluster. Eight- and 20-wk echocardiography data for the 20-wk Wistar-Kyoto (WKY) and Goto-Kakizaki (GK) heart failure groups expressed as a ratio of their respective sham groups. *P 0.05, 8 wk GK vs. 8 wk WKY groupsChanges in EF (A), IZ WMSI (B), and LV volumes (C and D) during 6 months after AMI in patients with (solid line) and without (dashed line) diabetes (*P0.01 vs baseline, by ANOVA analysis)Circulation. 2004;110:1974-1979糖尿病和急性心肌梗死早期糖尿病和急性心肌梗死早期HF的特点的特点糖尿病和急性心肌梗死相关发现糖尿病和急性心肌梗死相关发现早期心衰的治疗策略b /a受体拮抗剂的应用oEPIC EPILOG EPISTENT 早期应用可以显著减少DM患者1年死亡率 o对于胰岛素使用，死亡率减少50%两组室壁运动异常节段评分指数梗塞梗塞梗塞梗塞24242424小时内小时内小时内小时内一周一周一周一周二周二周二周二周一月一月一月一月三月三月三月三月六月六月六月六月一年一年一年一年通心络组通心络组通心络组通心络组1.75521.75521.69691.69691.61251.61251.50851.50851.40521.40521.37671.37671.32541.3254对照组对照组对照组对照组1.73901.73901.75741.75741.74631.74631.70831.70831.64751.64751.53801.53801.48901.4890P P P P值值值值0.69450.69450.15240.15240.00430.00430.00010.00010.00010.00010.00240.00240.03780.0378两组左心室舒张末容积（ml）梗塞梗塞梗塞梗塞24242424小小小小时内时内时内时内一周一周一周一周二周二周二周二周一月一月一月一月三月三月三月三月六月六月六月六月一年一年一年一年通心络组通心络组通心络组通心络组n=60n=60n=60n=60138.17138.1723.7723.77150.86150.8621.9121.91150.36150.3626.2426.24150.71150.7127.5727.57143.12143.1229.9529.95145.27145.2727.9327.93148.91148.9130.6730.67对照组对照组对照组对照组n=52n=52n=52n=52146.43146.4333.1333.13160.48160.4824.5424.54163.39163.3924.6824.68164.10164.1027.1127.11165.6165.630.9230.92162.38162.3832.6532.65166.79166.7933.58 33.58 P P P P 值值值值0.210.210.210.210.090.090.090.090.040.040.040.040.040.040.040.040.0020.0020.0020.0020.0090.0090.0090.0090.0460.0460.0460.046The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI-5) StudyActivation of PPAR enhances myocardial glucose oxidation and improvescontractile function in isolated working hearts of ZDF ratsAm J Physiol Endocrinol Metab 289: E328E336, 2005Cardiac function and rates of substrate oxidation. A: cardiac power in the presence of 5 mM glucose and 5 mM glucose 0.4 mM oleate (shaded area)as substrates. B: myocardial oxygen consumption (MV O2) with 5 mM glucose and 5 mM glucose 0.4 mM oleate present as substrates. C: glucose oxidation(Ox) rates in the in the presence of 5 mM glucose and 5 mM glucose 0.4 mM oleate as substrates. D: oleate oxidation rate. Functions were assessed in isolatedperfused working hearts from fed ZL-V (), ZL-A (OE), ZDF-V (), and ZDF-A () rats (6063 days old) during 40 min of aerobic perfusion. Values are means SE for 1013 independent observations in each treatment group