糖尿病心肌病课件

糖尿病心肌病糖尿病心肌病 Diabetic Diabetic cardiomyopathycardiomyopathy mechanisms, diagnosis and treatmentmechanisms, diagnosis and treatment LiaoLiao Yu Yu Hua Hua Institute of CardiologyInstitute of Cardiology WuhanWuhan Union Hospital Union Hospital HuazhongHuazhong University of Science and University of Science and Technology, Technology, WuhanWuhan China China ClinicoepidemiologicClinicoepidemiologic studies studies Ashok Kumar Das.INT. J. DIAB. DEV. COUNTRIES 1995,15:199-122 Diabetic Diabetic CardiomyopathyCardiomyopathy Autopsy : many diabetics died of CHF Autopsy : many diabetics died of CHF no CAD, HT or VHD no CAD, HT or VHD Rubler Rubler 19721972 22% 11% HambyHamby CMCM no no CMCM DMDM systolic and diastolic dysfunctionsystolic and diastolic dysfunction 59% DM+Renal failure no CAD DDeliaelia Definitions Diabetic cardiomyopathy refers to a disease refers to a disease process which affects the myocardium in diabetic process which affects the myocardium in diabetic patients causing a wide range of structural patients causing a wide range of structural abnormalities eventually leading to LVH and abnormalities eventually leading to LVH and diastolic and systolic dysfunction or a combination diastolic and systolic dysfunction or a combination of theseof these 糖尿病心肌病糖尿病心肌病 是指糖尿病是指糖尿病微血管病变微血管病变所引起所引起 心肌结构异常、心室肥厚和舒张心肌结构异常、心室肥厚和舒张/ /收缩功能不全收缩功能不全 的的心肌病心肌病 Rubler S, et al. Am J Cardiol 1972; 30: 595602 Diabetic Diabetic cardiomyopathycardiomyopathy PathologyPathology PathologyPathology DMDM + CM Liang QR，et al. DIABETES 2002; 51: 174-181. Sylvia A, et al. ILAR Journal 1990; 32: 204-212. D. Hileeto et al. Diabetes Metab Res Rev 2002; 18: 386394. Vascular changes - Arterial wall thickening - Intimal fibroblastic proliferation - Basement membrane thickening - Intimal hyaline deposition Extra-vascular changes - PAS + glycoprotein deposition - Wavy myocardium - Periarteriolar and scattered fibrosis - Fatty degeneration. 400 8500 Structural changes-Structural changes-LVHLVH ParasternalParasternal short- short- axis view in axis view in systole (a) and systole (a) and diastole (b) and diastole (b) and parasternalparasternal long- long- axis view (c) in a axis view (c) in a patient with patient with severe concentric severe concentric LVHLVH Hayat SA,et al.Clinical Science 2004; 107:539557 Salient featuresSalient features PreclinicalPreclinical cardiac dysfunction cardiac dysfunction Prolonged pre-ejection period (PEP) Prolonged pre-ejection period (PEP) Shortened LV ejection time (LVET) Shortened LV ejection time (LVET) Increase in PEP/LVET ratio Increase in PEP/LVET ratio Prolonged Prolonged isovolumicisovolumic relaxation relaxation Prolongation of early diastolic filling Prolongation of early diastolic filling Increased LVEDP and depressed end diastolic Increased LVEDP and depressed end diastolic volumevolume Latent cardiac dysfunction failure of ejection Latent cardiac dysfunction failure of ejection fraction to rise with exercisefraction to rise with exercise Ashok Kumar Das.INT. J. DIAB. DEV. COUNTRIES 1995,15:199-122 Functional changesFunctional changes Diastolic dysfunctionDiastolic dysfunction refers to refers to echocardiographicechocardiographic features of an abnormal LV features of an abnormal LV relaxation pattern without clinical HFrelaxation pattern without clinical HF Diastolic HFDiastolic HF refers to a clinical syndrome of refers to a clinical syndrome of HF with a preserved LV ejection fractionHF with a preserved LV ejection fraction Systolic dysfunctionSystolic dysfunction systolic dysfunction occurs late in diabetic systolic dysfunction occurs late in diabetic cardiomyopathycardiomyopathy, often when patients have , often when patients have already developed significant diastolic already developed significant diastolic dysfunctiondysfunction Vasan, R.,et al. J. Am. Coll. Cardiol.1999,33:19481955 PrognosisPrognosis Annual mortality (%)Annual mortality (%) 1%1% 5% - 8% 15%-20% DM+CM DM+CM diastolic HFdiastolic HF DM+CM DM+CM systolic HFsystolic HF DM DM controlcontrol Vasan, R.,et al. J. Am. Coll. Cardiol.1999,33:19481955 Diabetic Diabetic cardiomyopathycardiomyopathy PathogenesisPathogenesis PathogenesisPathogenesis Factors contributing to diabetic cardiomyopathy Diabetic autonomic neuropathy Microangiopathy leading to tissue anoxia and fibrosis Metabolic derangements Growth hormone Ashok Kumar Das.INT. J. DIAB. DEV. COUNTRIES 1995,15:199-122 Molecular basis (1) CauseCauseMechanismMechanism HyperglycaemiaHyperglycaemia- excess AGE and ROS formation with deactivation of NO - excess AGE and ROS formation with deactivation of NO - myocardial collagen deposition and fibrosis- myocardial collagen deposition and fibrosis Fatty acids Fatty acidsImpaired Impaired glycolysisglycolysis, , pyruvatepyruvate oxidation, lactate uptake : oxidation, lactate uptake : - apoptosis - apoptosis - perturbation of myocardial bioenergetics and - perturbation of myocardial bioenergetics and contraction/relaxation coupling contraction/relaxation coupling PKC PKCActivation of DAG/PKC signal Activation of DAG/PKC signal transductiontransduction pathway : pathway : - reduction in tissue blood flow - reduction in tissue blood flow - increased vascular permeability - increased vascular permeability - alterations in - alterations in neovascularization neovascularization - enhanced - enhanced extracellularextracellular matrix deposition matrix deposition RAS RASCardiomyocyteCardiomyocyte hypertrophy and apoptosis hypertrophy and apoptosis Hayat SA,et al.Clinical Science 2004; 107:539557 CauseMechanism ALD-Induced fibrosis Myofibroblast growth with interstitial and focal perivascular accumulation of collagen. HIF-1 /VEGF HIF-1 activation via hypoxia/free radicals - production of angiopoietin, PGF, PDGF- and VEGF VEGF, VEGF-R1 and VEGF-R2 are decreased significantly - impaired angiogenesis. Endothelial dysfunction Impaired endothelial NO production and increased vasoconstrictor prostaglandins, glycated proteins, endothelium adhesion molecules and platelet and vascular growth factors : - enhance vasomotor tone and vascular permeability and limit growth and remodelling Hayat SA,et al.Clinical Science 2004; 107:539557 Molecular basis (2) CauseMechanism Arterial stiffness Increased central aortic pressure and left ventricular afterload and lowered central diastolic and coronary perfusion pressures - subendocardial ischaemia - interstitial fibrosis Autonomic neuropathy Decreased sympathetic/parasympathetic myocardial innervation with impaired coronary resistance vessel vasodilator response and impaired ventricular diastolic filling Hayat SA,et al.Clinical Science 2004; 107:539557 Molecular basis (3) Cardiac-specific Cardiac-specific overexpressionoverexpression of the of the kdkd-PFK-2 -PFK-2 transgenetransgene Northern blot Western blot Rajakumar V. Donthi,et al. J Bio Chemistry 2004，279:4808548090 kd-PFK-2 = kinase-deficient 6-phosphofructo-2-kinase Mb for the myosin heavy chain promoter and the bisphosphatase active kd-PFK-2 gene FruFru-2,6-P2 is reduced in transgenic heart-2,6-P2 is reduced in transgenic heart . Asterisk (*) indicates that the values of Mb1 and Mb7 are significantly different from FVB (p 0.001). The number of animals used are: FVB, n=8; Mb1,n=3; and Mb7,n= 4. Rajakumar V. Donthi,et al. J Bio Chemistry 2004，279:4808548090 Insulin-stimulated phosphorylation of Akt in FVB and Mb7 hearts Hearts were Hearts were perfusedperfused without insulin without insulin for 20 min or with 200 for 20 min or with 200 microunitsmicrounits/ml /ml insulin for 50 min, homogenized, and insulin for 50 min, homogenized, and 20 g of protein analyzed by Western 20 g of protein analyzed by Western blotting. blotting. * *p p 0.003 0.003 Rajakumar V. Donthi,et al. J Bio Chemistry 2004，279:4808548090 GlycolysisGlycolysis is important to cardiac is important to cardiac metabolism and reduced metabolism and reduced glycolysisglycolysis may may contribute to diabetic contribute to diabetic cardiomyopathycardiomyopathy. . Potential mechanisms linking diabetes Potential mechanisms linking diabetes mellitus to heart failuremellitus to heart failure Christophe Bauters,et al.Cardiovascular Diabetology 2003, 2:1-16 Diabetic Diabetic cardiomyopathycardiomyopathy DiagnosisDiagnosis DiagnosisDiagnosis Diabetics with LVH and diastolic and systolic LVH and diastolic and systolic dysfunction or a combination of thesedysfunction or a combination of these，but no CAD, HT or VHDCAD, HT or VHD Routine electrocardiographyRoutine electrocardiography Echocardiography remain the gold standard Echocardiography remain the gold standard toolstools EchocardiographyEchocardiography In a normal subject, In a normal subject, E/A E/A wave ratio 1.5 to 1.0wave ratio 1.5 to 1.0 In a patient with mild In a patient with mild diastolic dysfunction, diastolic dysfunction, E/A E/A wave ratio 1.0wave ratio 1.0 In a patient with severe In a patient with severe diastolic dysfunction, diastolic dysfunction, the the E/A wave ratio isE/A wave ratio is abnormally high and A wave abnormally high and A wave velocity is very lowvelocity is very low Trans-mitral valve spectral Doppler flow pattern Hayat SA,et al.Clinical Science 2004; 107:539557 Intravenous contrast echocardiographyIntravenous contrast echocardiography Frame i)Frame i) is immediately is immediately following a high power following a high power ultrasound flash which ultrasound flash which destroys the micro-bubbles destroys the micro-bubbles within the myocardiumwithin the myocardium Frames ii)iv)Frames ii)iv) show show replenishment ofreplenishment of micro-bubbles in the septum micro-bubbles in the septum and lateral walls within 2 and lateral walls within 2 heartbeats. A clear apical heartbeats. A clear apical perfusion defect (A) is perfusion defect (A) is demonstrated which persistsdemonstrated which persists Porter TR，et al. J Am Coll Cardiol. 27, 14971501 Diabetic Diabetic cardiomyopathycardiomyopathy TreatmentTreatment Diabetic TherapyDiabetic Therapy Control HyperglycaemiaHyperglycaemia ACEI Beta-Blockade Aldosterone antagonist StatinsStatins ThiazolidinedionesThiazolidinediones TrimetazidineTrimetazidine Diabetic Therapy for Diabetic Patients Diabetic Therapy for Diabetic Patients With Heart Failure:With Heart Failure: Potential for HarmPotential for Harm Insulin:Insulin: - increased sympathetic nervous system activation - increased sympathetic nervous system activation - increased vascular resistance - increased vascular resistance - increased cardiac and vascular hypertrophy, and - increased cardiac and vascular hypertrophy, and endothelial dysfunction endothelial dysfunction SulfonylureasSulfonylureas: : - abolish - abolish ischemic ischemic preconditioning preconditioning - leave more susceptibility to myocardial injury - leave more susceptibility to myocardial injury - further increasing insulin levels - further increasing insulin levels MetforminMetformin: : Renal dysfunction common in heart failure raises Renal dysfunction common in heart failure raises concerns regarding the risk of lactic acidosis concerns regarding the risk of lactic acidosis ThiazolidinedionesThiazolidinediones: : Potential for weight gain, edema, and Potential for weight gain, edema, and worsened heart failureworsened heart failure ACE-I in Diabetic andACE-I in Diabetic and NondiabeticNondiabetic Patients With HF Patients With HF CONSENSUS= COoperative North Scandinavian Enalapril SUrvival Study. SAVE= Survival And Ventricular Enlargement. SMILE= Survival of Myocardial Infarction Long-term Evaluation. SOLVD= Studies of Left Ventricular Dysfunction. TRACE= Trandolapril Cardiac Evaluation. Shekelle P et al. J Am Coll Cardiol. 2003;41:1529-1538. Relative Risks Analysis StudyNNondiabeticDiabetic Relative Risk, Nondiabetic (95% CI) Relative Risk, diabetic (95% CI) Ratio of Relative Risks (95% CI) CONSENSUS25319756 0.64 (0.46, 0.88) 1.06 (0.65, 1.74) 1.67 (0.93, 3.01) SAVE22311739492 0.82 (0.68, 0.99) 0.89 (0.68, 1.16) 1.09 (0.79, 1.50) SMIL0.79 (0.54, 1.15) 0.44 (0.22, 0.87) 0.56 (0.25, 1.22) SOLVD (Prevention) 42283581647 0.97 (0.83, 1.15) 0.75 (0.55, 1.02) 0.77 (0.54, 1.09) SOLVD (Treatment) 25691906663 0.84 (0.74, 0.95) 1.01 (0.85, 1.21) 1.21 (0.97, 1.50) TRAC0.85 (0.74, 0.97) 0.73 (0.57, 0.94) 0.87 (0.65, 1.15) Random Effects Pooled Estimate 101882398 0.85 (0.78, 0.92) 0.84 (0.70, 1.00) 1.00 (0.80, 1.25) Cardiovascular Benefits of ACE InhibitionCardiovascular Benefits of ACE Inhibition Anti-ischemic - Stimulation of endothelial NO production - Reduced myocardial oxygen consumption Antiatherogenic Lowers systemic vascular resistance and mean blood pressure Reduces cardiac afterload and systolic wall stress Attenuates remodeling in heart failure Pepine CJ. Clin Cardiol.1997;20:II58-II64. Edwin JK et al. Renin and angiotensin. In: Hardman JG et al, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996: chap 31. Beta-Blockers in Diabetic and Nondiabetic Patients With Heart Failure Shekelle P et al. J Am Coll Cardiol. 2003;41:1529-1538. Study Name Total N Non- Diabetic N Diabetic N Relative Risk, Nondiabetic (95% CI) Relative Risk, Diabetic (95% CI) Ratio of Relative Risks (95% CI) CIBIS II26472335312 0.66 (0.54, 0.81) 0.81 (0.52, 1.27) 1.23 (0.75, 2.02) COPERNIC US 22871701586 0.67 (0.52, 0.85) 0.68 (0.47, 1.00) 1.02 (0.65, 1.61) MERIT-HF39913006985 0.62 (0.48, 0.79) 0.81 (0.57, 1.15) 1.32 (0.86, 2.02) Random effects (pooled estimate) 70421883 0.65 (0.57, 0.74) 0.77 (0.61, 0.96) 1.19 (0.91, 1.55) Tse WY, Kendall M. Diabet Med. 1994;11:137-144. Cardiovascular Benefits of Beta-Blockade Reverses cardiac remodelingReverses cardiac remodeling Prevents sudden deathPrevents sudden death Anti-Anti-ischemicischemic - Decreases heart rate and blood pressure - Decreases heart rate and blood pressure - Prolongs diastole (filling coronary arteries) - Prolongs diastole (filling coronary arteries) Decreases myocardial wall stress,which reduces risk of Decreases myocardial wall stress,which reduces risk of cardiac rupture due to decrease in heart rate and cardiac rupture due to decrease in heart rate and b bl lo oo od d p pr re es ss su ur re e AntiatherogenicAntiatherogenic reduces sheer stress and endothelial reduces sheer stress and endothelial dysfunction dysfunction Standard post-AMI careStandard post-AMI care ASA, BB, ACEI, ASA, BB, ACEI, statinstatin, revascularization , revascularization Post-AMI, LVEF 40, Post-AMI, LVEF 40, ralesrales or S3 or S3 RandomizationRandomization (n=6644)(n=6644) EplerenoneEplerenone initiation initiation 25 QD, 50 mg at 4 wk25 QD, 50 mg at 4 wk Matching Matching placeboplacebo Follow-upFollow-up Pitt B. N Engl J Med. 2003;348:1309-1321 . All-cause mortality reduced: HR 0.85 (95% CI 0.75-0.96) EPHESUS (EPHESUS (EplerenoneEplerenone Post-AMI Heart Post-AMI Heart Failure Efficacy and Survival Study)Failure Efficacy and Survival Study) Effect of Eplerenone on Mortality Post-MI in Diabetics and Nondiabetics 0.511.5 No DM Heterogeneity P=0.59 CV Mortality orCV Mortality or CV HospitalizationCV Hospitalization N=6632, 32% diabetic. Pitt B. N Engl J Med. 2003;348:1309-1321. Diabetes Eplerenone betterPlacebo better StatinsStatins The HPS among the 5963 diabetic patients there was a 22% reduction in the vascular event rate. Alarmingly, it was 27% among the 2426 diabetic patients who had pretreatment LDL-c concentrations below 3.0 mmol/l This therefore argues for treating all Type II diabetic patients with a statin independent of their LDL levels. 4S. Lancet 1994,344:13831389 Collins R, et al. Lancet 2003,361:20052016 StatinsStatins CORONA TrialsCORONA Trials (Controlled (Controlled RosuvastatinRosuvastatin Multinational Study in Heart Failure) are currently Multinational Study in Heart Failure) are currently underway to assess the efficacy of underway to assess the efficacy of statinsstatins in HF in HF The recent analysis of the The recent analysis of the PRAISEPRAISE data has data has demonstrated the safety and efficacy of demonstrated the safety and efficacy of statinstatin therapy in therapy in patients with moderate to severe HF patients with moderate to severe HF There is a significant reduction in mortality in patients There is a significant reduction in mortality in patients with a non-with a non-ischaemicischaemic HF, adding further support to the HF, adding further support to the additional effects of additional effects of statinsstatins beyond their reduction in beyond their reduction in cholesterol and prevention of progression of CADcholesterol and prevention of progression of CAD Horwich TB, et al. J Am Coll Cardiol 2004, 43: 642648 ThiazolidinedionesThiazolidinediones ( (TZDsTZDs) ) TZDsTZDs act by increasing insulin sensitivity in skeletal act by increasing insulin sensitivity in skeletal muscle and adipose tissue through binding and muscle and adipose tissue through binding and activation of PPAR- and also act on PPAR- and activation of PPAR- and also act on PPAR- and increase serum HDL-c, decrease TG and increase LDL c increase serum HDL-c, decrease TG and increase LDL c levelslevels The The TZDsTZDs, apart from insulin-sensitizing fat and , apart from insulin-sensitizing fat and skeletal muscle, increase the expression and function of skeletal muscle, increase the expression and function of glucose transporters in the heart, leading to improved glucose transporters in the heart, leading to improved glucose metabolism, and reduce NEFA utilization by the glucose metabolism, and reduce NEFA utilization by the my