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1、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,The Great Wall International Congress of Cardiology 2008,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
2、 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;102:1014-1019,CHF event rate (%),0
3、,5,10,15,20,25,0,3,6,9,12,15,18,21,24,DM+, CVD+,DM-, CVD+,DM+, CVD-,DM-, CVD-,Months,Acute Coronary Syndrome,Diabetes increases the risk of HF by 82% and adversely affects the prognosis,OASIS Registry (n=8013),Predictors of HF at Multivariate Cox Analysis (6 months),Circulation. 2004;110:1974-1979,糖
4、尿病急性心肌梗死后HF,糖尿病患者急性心肌梗死,早期心衰,晚期心衰,糖尿病急性心肌梗死后早期HF的机制,舒张功能障碍,糖尿病心肌病变,心脏收缩协调性下降,糖尿病急性心肌梗死后早期HF的机制,微循环障碍，组织水平灌注不良,心肌抗缺血生存能力降低，自我恢复减低,心肌代谢障碍，胰岛素抵抗更加明显,血糖升高，影响血流动力学,Diabetes and congestive HF independent of CAD,Endocrine Reviews 2004;25:543-567,Diabetes,Small vessel disease,Diabetic cardiomyopathy,Left ve
5、ntricular dysfunction,Symptomatic heart failure,Cardiac autonomic neuropathy,Cardiac insulin resistance,糖尿病急性心肌梗死后晚期HF的机制,梗死区心肌收缩的恢复降低,左室重构更趋明显,Diabetes mellitus can accerate the progression of post-infarction genetic regulatory expression in untreated Streptozotocin-induced Diabetic Rat Model -Gene
6、tic findings in the remote zone of LV free wall post acute myocardial infarction Guang-Yuan Song1, Yong-Jian Wu1*, Yue-Jin Yang1, Jian-Jun Li1, Rui Li2, Ru-Tai Hui3, Han-Jun Pei1, Zhen-Yan Zhao1 From the 1Center of Coronary Heart Disease, 3Center of Hypertension, Cardiovascular Institute Center of C
7、oronary 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: ,Study Design 217 Sprague-Dawley (SD) rats were randomized into one of the four fol
8、lowing 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
9、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,
10、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
11、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
12、 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 g
13、enes 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 b
14、y Real Time-PCR.,GeneChip Microarray Analysis and Real Time-PCR,Hierarchical Clustering Gene 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 displa
15、yed 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
16、 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-
17、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 relat
18、ed 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
19、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
20、-Kakizaki (GK) heart failure groups expressed as a ratio of their respective sham groups. *P 0.05, 8 wk GK vs. 8 wk WKY groups,Changes 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 A
21、NOVA analysis),Circulation. 2004;110:1974-1979,糖尿病和急性心肌梗死早期HF的特点,发病率高,微小的心肌梗死即可诱发HF,持续时间长,治疗反应差,老年患者尤其是女性易发HF,糖尿病和急性心肌梗死相关发现,HF的发生与糖尿病的病程极其伴随的危险因素有关,尿微量白蛋白升高，肾功能恶化是HF发生强有力的预测因子,肥胖是重要的影响因素,早期心衰的治疗策略,常规治疗更要积极，强度加大（利尿剂的使用）,再灌注治疗 早期再灌注能否受益？ b/a受体拮抗剂 中药,针对血糖异常的治疗（Insulin focus or Glucemia focus）,万爽力,b/a受
22、体拮抗剂的应用,EPIC EPILOG EPISTENT 早期应用可以显著减少DM患者1年死亡率 对于胰岛素使用，死亡率减少50%,糖尿病患者AMI再灌注治疗时同时使用 可能改善微循环灌注，从而改善预后,两组室壁运动异常节段评分指数,两组左心室舒张末容积（ml）,The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI-5) Study,Results A total of 240 subjects were recruited. Insulin/dextrose infusion did not reduce mortal
23、ity at the inpatient stage (4.8 vs. conventional 3.5%, P=0.75), 3 months (7.1 vs 4.4%, P =0.42), or 6 months (7.9 vs. 6.1%, P 0.62). There was, however, a lower incidence of cardiac failure (12.7 vs. 22.8%, P =0.04) and reinfarction within 3 months (2.4 vs. 6.1%, P =0.05). When analyzed by mean BGL
24、achieved during the first 24 h, mortality was lower among subjects with a mean BGL 8 mmol/l, compared with subjects with a mean BGL 8 mmol/l (2 vs. 11% at 6 months, P=0.02),Activation of PPAR enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF ra
25、ts,Am J Physiol Endocrinol Metab 289: E328E336, 2005,Cardiac 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 olea
26、te 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 isolated perfused working hearts from fed ZL-V (), ZL-A (OE), ZDF-V (), and ZDF-A () rats (6063 days old
27、) during 40 min of aerobic perfusion. Values are means SE for 1013 independent observations in each treatment group,谢谢！,Induction of DM DM was induced with a single intraperitoneal injection of STZ (65 mg/kg in 0.1mmol/L, pH 4.5 sodium citrate buffer) 18. Age and body weight matched rats that used a
28、s non-diabetic controls were injected with the same dose of sodium citrate buffer (0.1mmol/L, pH 4.5). All animals in groups DM with serum glucose levels 300 mg/dl (16.8mmol/L), polyuria and weight loss were included in the study. The rats with the serum glucose level 300mg/dl once were eliminated f
29、rom the study.,Weight Body (A) and Serum Glucose Levels (B) in STZ-induced diabetic rats. *P 0.001 compared with nondiabetic rats. DM 3d = 3 days after DM induction, DM 7d = 7 days after DM induction, etc.,Picture A-D show the myocardium of STZ-induced diabetic hearts for 10 weeks (the arrows show t
30、he histopathological changes); Picture E and F show the myocardium of non-diabetic hearts. mitochondrial damage (swelling and disrupted cristae), cardiac muscle fibers, the basal lamina of regional small vessels, glycogen particles, lipid droplets.,TEM These results indicate that there already were
31、histopathological and ultrastructural changes related to DM in the heart 10 weeks after STZ injection.,Experimental AMI 10 weeks after DM induction, AMI models were made as previously described. Sham-operated rats in group (3) and group (4) were treated similarly except that the suture around the co
32、ronary artery was not tied.,Fifty six-day Kaplan-Meier survival curves representing percentage of surviving rats in 4 groups. Survival in diabetic rats after AMI was significantly (P 0.01) less than that observed in sham group, and similarly, the 28-day survival was significantly attenuated in diabe
33、tic rats subjected to AMI compared with non-diabetic ones with AMI (P 0.05).,Early and Prolonged Survival,Cardiac hypertrophy,The data about heart to body weight ratios and the heart weight to tibial length ratios are presented.,HW, heart weight; BW, body weight; TL, tibial length. HW/BW = heart to
34、body weight ratio; HW/TL= heart weight to tibial length. The data in bracket means the increased proportion of HW/BW and HW/TL changes compared with DM 70d.*P 0.05 vs. DM 70d in the same group; * P 0.001 vs. DM 70d in the same group. P 0.01 vs. N-DM + AMI at the same time point; P 0.001 vs. N-DM + A
35、MI at the same time point.,CONCLUSION The different patterns of the genetic changes in this untreated STZ-induced diabetic non-perfusion myocardial infarction rat model might suggest that DM could accerate the progression of post-infarction cardiac remodeling in STZ-induced untreated diabetic rat mo
36、del.,糖尿病患者急性心肌梗死后死亡,Survival improvements. KaplanMeier survival curves from 1995 and 2003 are displayed for cohorts with and without DM. The highlighted area refers to survival improvement within each group between 1995 and 2003,糖尿病患者PCI术后,Measurements of epicardial coronary flow, myocardial reperfu
37、sion, and final infarct size for diabetic patients (white bars) and nondiabetic patients (black bars),Am J Cardiol 2007;100:206 210,Adjusted myocardial blood flow (MBF) reserve measured by PET,Circulation 2005;111:2291-2298,IS,IR,IGT,T2DM,T2DM+HT,0.0,1.0,2.0,3.0,*,*,* p0.001,p=0.002,MBF, mL min-1 g-
38、1,Coronary circulatory dysfunction worsens with increasing severity of insulin resistance,Endothelial dysfunction in Type 2 diabetes is characterized by unbalanced activity of vascoactive factors,Circulation 2002;106:1783 Circulation 1999;100:820 Diabetes 2002;51:3517,Endothelium,Vascular tone,Vasod
39、ilators,Vasoconstrictors,NO (eNOS) Prostacyclin (COX),Endothelin-1,Insulin mediated myocardium glucose uptake measured by PET,Diabetes 2002;51:3020-30,Control,CAD,T2DM,CAD+T2DM,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,Myocardial glucose uptake (mmolmin-1 g-1),*,*,*,*p0.001,Independent association of Type
40、 2 diabetes and CAD with myocardial insulin resistance,Insulin resistance as a predictor of the severity and extend of CAD,Graner M et al. Unpublished,1.8, 1.8,Type 2DM,20,40,1.8, 1.8,Type 2 DM,10,20,Global PDS index,Global extend index,Insulin resistance is associated with increased severity and extent of CAD,HOMA-IR,HOMA-IR,Finnish cohort (n=108),The risk of CHF in patients with diabetes,Circulation 2001;103;2668-2673,7,7 to8,8 to9,9 to 10,10,0,2,4,6,8,10,Hemoglobin A1c (%),CHF Rate/Year per 1000,Each 1% increase in HbA1c is associated with 8% increased risk of HF,n=48858 p0.0001,