Ndei Cardiovascular Disease In Diabetes Pathophysiology

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  • Ndei Cardiovascular Disease In Diabetes Pathophysiology

    1. 1. Pathophysiology of CVD in Type 2 Diabetes
    2. 2. <ul><li>Please visit ndei.org to download these slides. </li></ul><ul><ul><li>Website registration is free and takes just a minute or two. </li></ul></ul><ul><ul><li>All slide downloads are free </li></ul></ul>These slides are available for download from www.ndei.org
    3. 3. Atherosclerosis in Diabetes <ul><li>Accelerated atherosclerosis is multifactorial and begins years/decades prior to diagnosis of type 2 diabetes </li></ul><ul><li>>50% of patients with newly diagnosed type 2 diabetes have CHD </li></ul><ul><li>Risk for atherosclerotic events is 2- to 4-fold greater in people with diabetes than in those without diabetes </li></ul><ul><li>Atherosclerosis accounts for  65% of all diabetic mortality </li></ul><ul><ul><li>40% due to ischemic heart disease </li></ul></ul><ul><ul><li>15% due to other heart disease </li></ul></ul><ul><ul><li>10% due to cerebrovascular disease </li></ul></ul>Garber AJ. Clin Cornerstone . 2003;5:22-37. Garber AJ. Med Clin North Am . 1998;82:931-948. National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
    4. 4. Implicated Determinants of Heart Disease in Diabetes <ul><li>Coronary artery disease and vulnerable plaques </li></ul><ul><li>Small-vessel disease </li></ul><ul><li>Determinants of peripheral vascular disease </li></ul><ul><li>Cardiomyopathy </li></ul>
    5. 5. The Vessel Wall Endothelial cell Internal elastic lamina Intimal smooth muscle cell Resident macrophage Medial smooth muscle cell Vasa vasorum Fibroblast External elastic lamina Intima Media Adventitia Sobel BE. Proc Assoc Am Physicians . 1999;111:313-318.
    6. 6. Atherosclerosis: Lesion Initiation Lusis AJ. Nature . 2000;407:233-241. Fluid shear stress Phospholipid Chol LDL ApoB ApoAII HDL PON1 ApoAI 12-LO ROS (HPETE) Permeability gene expression, EC NOS Matrix Seeding, oxidation Trapping Transport Transport (–) Minimally oxidized LDL Specific ApoB interaction
    7. 7. Human Plaque Progression Davies MJ. Br Heart J . 1993;69(suppl):S3-S11. Fatty streak Complicated plaque with thrombus formation Transitional plaque Advanced fibrolipid plaque Foam cell (Intracellular lipid) Extracellular lipid Smooth muscle cell Thrombus
    8. 8. Glagov’s Coronary Remodeling Concept Glagov S et al. N Engl J Med . 1987;316:1371-1375. Normal vessel Minimal CAD Moderate CAD Severe CAD Compensatory expansion maintains constant lumen Expansion overcome: lumen narrows
    9. 9. Vulnerable and Stable Plaques Libby P. Circulation . 1995;91:2844-2850. “ Stable” plaque Lumen Lumen - T-lymphocyte - Macrophage foam cell (Tissue Factor + ) - “Activated” intimal SMC (HLA-DR + ) - Normal medial SMC Lipid core Lipid core Area of detail “ Vulnerable” plaque Fibrous cap Media
    10. 10. Robust VSM Cell Accumulation Yielding an Obstructive, Stable Plaque Endothelial cell VSM Cell Macrophage T-lymphocyte Sobel BE. Proc Assoc Am Physicians . 1999;111:313-318. VSM=vascular smooth muscle.
    11. 11. Matrix Skeleton of Unstable Coronary Artery Plaque Fissures in the fibrous cap Davies MJ. Circulation . 1996;94:2013-2020.
    12. 12. PAI-1 Activity in Patients With Type 2 Diabetes McGill JB et al. Diabetes. 1994;43:104-109. PAI-1 activity (AU/mL) Lean Obese 0 5 10 15 20 No diabetes Diabetes PAI-1=plasminogen activator inhibitor type 1.
    13. 13. Fibrinolytic System Variables From Young Survivors of MI Hamsten A et al. N Engl J Med . 1985;313:1557-1563. Patients Controls (n=71) (n=50) Patients Controls (n=71) (n=50) t-PA inhibitor (PAI-1) t-PA activity 0.0 1.5 3.0 4.5 6.0 4 3 2 1 0 * * * P <0.001. MI=myocardial infarction. t-PA=tissue plasminogen activator. U/mL U/mL
    14. 14. PAI-1 in Internal Mammary Arteries Pandolfi A et al. Arterioscler Thromb Vasc Biol . 2001;21:1378-1382. No Diabetes Diabetes No Diabetes Diabetes
    15. 15. PAI-1 Is Increased in Atheroma From Patients With Diabetes 0 15 30 45 60 75 0 10 20 30 40 Urokinase PAI-1 Pixel intensity Pixel intensity Sobel BE. Circulation . 1998;97:2213-2221. * * No diabetes Diabetes * P <0.05.
    16. 16. Factors That Affect PAI-1 Concentration and Activity <ul><li>Increased PAI-1 expression </li></ul><ul><ul><li>serotonin (5-HT) </li></ul></ul><ul><ul><li>cyclosporin A </li></ul></ul><ul><ul><li>N-3 fatty acids </li></ul></ul><ul><ul><li>transforming growth factor-beta and thrombin </li></ul></ul><ul><ul><li>angiotensin II </li></ul></ul><ul><ul><li>nicotine </li></ul></ul><ul><ul><li>lipoprotein (a) </li></ul></ul><ul><ul><li>FFA </li></ul></ul><ul><ul><li>VLDL </li></ul></ul><ul><li>Decreased PAI-1 expression </li></ul><ul><ul><li>ethanol </li></ul></ul><ul><ul><li>thiazolidinediones </li></ul></ul><ul><ul><li>metformin </li></ul></ul><ul><ul><li>ACE inhibitors </li></ul></ul><ul><ul><li>ARBs </li></ul></ul><ul><ul><li>gemfibrozil </li></ul></ul>Buechler C et al. Blood . 2001;97:981-986. Kawano H et al. Blood . 2001;97:1697-1702. Lundgren CH et al. Circulation . 1994;90:1927-1934. Ma LJ et al. Kidney Int . 2000;58:2425-2436. Miyamoto A et al. J Biol Chem . 1999;274:12055-12060. Nordt TK et al. Circulation . 1997;95:677-683. van den Dorpel MA et al. Arterioscler Thromb Vasc Biol . 1999;19;1555-1558. Zhang S et al. Atherosclerosis . 2001;154:277-283.
    17. 17. Plaque Vulnerability Plaque Evolution Plaque Rupture Sobel BE. Circulation . 1999;99:2496-2498. Decreased proteolysis secondary to increased PAI-1 Decreased vascular smooth muscle cell migration and matrix metalloproteinase activation Extracellular matrix accumulation Increased lipid:vascular smooth muscle cell ratio Thin fibrous cap Increased proteolysis secondary to cytokines Shoulder macrophage activation, increase in matrix metalloproteinases Extracellular matrix degradation Lipid peroxidation Rupture
    18. 18. Insulin Resistance: Causes and Associated Conditions PCOS=polycystic ovary syndrome. Medications Aging Atherosclerosis Genetics Obesity and inactivity Rare disorders PCOS Dyslipidemia Hypertension Type 2 diabetes INSULIN RESISTANCE
    19. 19. Interrelationship Between Insulin Resistance and Atherosclerosis <ul><li>Insulin Resistance </li></ul>Hypertension Impaired fibrinolysis Hyper- insulinemia Hyper-glycemia Hyper- coagulability Atherosclerosis Endothelial dysfunction Inflammation Dyslipidemia –  TG – low HDL-C –  small, dense LDL particles
    20. 20. Insulin Resistance and Atherosclerosis: Proposed Relationships Accelerated atherosclerosis Clinical diabetes Hyperinsulinemia Impaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Insulin resistance
    21. 21. Association of MI* With the Metabolic Syndrome and Individual Components <ul><li>Odds Ratio 95% CI P Value </li></ul><ul><li>Metabolic syndrome 2.01 1.53-2.64 <0.0001 </li></ul><ul><li>Syndrome components </li></ul><ul><ul><li>Abdominal obesity 1.15 0.86-1.54 0.3475 </li></ul></ul><ul><ul><li>High triglycerides 1.51 1.04-2.20 0.0311 </li></ul></ul><ul><ul><li>Low HDL-C 1.41 1.03-1.95 0.0353 </li></ul></ul><ul><ul><li>Hypertension 1.42 0.94-2.15 0.0947 </li></ul></ul><ul><ul><li>Insulin resistance † 1.25 0.92-1.71 0.1461 </li></ul></ul>Ninomiya JK et al. Circulation . 2004;109:42-46. *Self-reported. † Defined as fasting plasma glucose  110 mg/dL, or self-report of current insulin or oral hypoglycemic use.
    22. 22. Association of Stroke* With the Metabolic Syndrome and Individual Components <ul><li>Odds Ratio 95% CI P Value </li></ul><ul><li>Metabolic syndrome 2.16 1.48-3.16 0.0002 </li></ul><ul><li>Syndrome components </li></ul><ul><ul><li>Abdominal obesity 0.97 0.58-1.64 0.9154 </li></ul></ul><ul><ul><li>High triglycerides 1.87 1.22-2.87 0.0052 </li></ul></ul><ul><ul><li>Low HDL-C 1.18 0.73-1.90 0.5012 </li></ul></ul><ul><ul><li>Hypertension 1.56 0.94-2.59 0.0827 </li></ul></ul><ul><ul><li>Insulin resistance † 1.36 0.93-1.98 0.1119 </li></ul></ul>Ninomiya JK et al. Circulation . 2004;109:42-46. *Self-reported. † Defined as fasting plasma glucose  110 mg/dL, or self-report of current insulin or oral hypoglycemic use.
    23. 23. Odds Ratios for IHD According to Plasma Insulin and Lipids Després J-P et al. N Engl J Med . 1996;334:952-957. <12 12-15 >15 Total:HDL-C ratio Insulin (  U/mL) 1.0 3.4 ‡ 4.3 § 7.1 † 10.3 † 9.6 † Low High 0 3 6 9 12 <12 12-15 >15 Apo B Insulin (  U/mL) Odds ratio 1.0 1.8 3.0* 3.2* 9.7 † 11.0 † * P =0.04; † P <0.001; ‡ P =0.05; § P =0.01. IHD=ischemic heart disease. Low High 0 3 6 9 12
    24. 24. IRAS: Negative Association Between Insulin Sensitivity and Atherosclerosis Howard G et al. Circulation . 1996;93:1809-1817. Reduction in mean ICA IMT (  m  per 1-unit increase in S i After adjustment for demographics. IRAS=Insulin Resistance Atherosclerosis Study. 20 10 0 -10 -20 -30 -40 Non-Hispanic White Hispanic African American -30.1 -29.9 6.1
    25. 25. Framingham Offspring Study: Lipid Levels in Men No diabetes Diabetes Siegel RD et al. Metabolism . 1996;45:1267-1272. * P <0.001. 9.3 4.9 22.6* 11.7* 27 22.8 20.3 22.4 18.3 43.9* 0 5 10 15 20 25 30 35 40 45 50 HDL-C <35 TC >240 LDL-C >160 TG >250 HDL-C <35 TG >250 %
    26. 26. Framingham Offspring Study: Lipid Levels in Women Siegel RD et al. Metabolism . 1996;45:1267-1272. No diabetes Diabetes * P <0.001. 3 1 29.3* 23.4* 9.3 22.7 22.2 37.7* 41.1* 35 0 5 10 15 20 25 30 35 40 45 HDL-C <35 TC >240 LDL-C >160 TG >250 HDL-C <35 TG >250 %
    27. 27. Dyslipidemia and Insulin Resistance: Mechanisms (CETP) (lipoprotein or hepatic lipase) Fat cells Insulin IR FFA Liver (CETP) CE TG Apo A-I CE TG LDL TG Apo B VLDL Kidney (hepatic lipase) CE=cholesterol ester; CETP=cholesterol ester transfer protein. VLDL HDL SD LDL
    28. 28. Markers of Inflammation and Coronary Heart Disease <ul><li>Association observed between CHD and </li></ul><ul><ul><li>high-sensitivity C-reactive protein </li></ul></ul><ul><ul><li>serum amyloid A </li></ul></ul><ul><ul><li>PAI-1 activity </li></ul></ul><ul><ul><li>von Willebrand factor </li></ul></ul><ul><ul><li>fibrinogen </li></ul></ul><ul><ul><li>plasma viscosity </li></ul></ul><ul><ul><li>albumin </li></ul></ul><ul><ul><li>neutrophils </li></ul></ul><ul><ul><li>cytokines </li></ul></ul>Hoffmeister A et al. Am J Cardiol . 2001;87:262-266. Saito I et al. Ann Intern Med . 2000;133:81-91. Koukkunen H et al. Ann Med . 2001;33:37-47.
    29. 29. Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Diabetes <ul><li>Predisposition to thrombosis </li></ul><ul><ul><li>platelet hyperaggregability </li></ul></ul><ul><ul><li>elevated concentrations of procoagulants </li></ul></ul><ul><ul><li>decreased concentration and activity of antithrombotic factors </li></ul></ul><ul><li>Predisposition to attenuation of fibrinolysis </li></ul><ul><ul><li>decreased t-PA activity </li></ul></ul><ul><ul><li>increased PAI-1 </li></ul></ul><ul><ul><li>decreased concentrations of  2 -antiplasmin </li></ul></ul>Sobel BE. Circulation . 1996;93:1613-1615. Editorial.
    30. 30. Plasma Homocysteine <ul><li>Linked to pathophysiology of atherosclerosis </li></ul><ul><li>Elevated in CVD patients </li></ul><ul><li>May cause vascular damage to endothelial cells </li></ul><ul><li>Elevated levels linked to </li></ul><ul><ul><li>diet low in folate </li></ul></ul><ul><ul><li>genetic defects (rare) </li></ul></ul><ul><li>Increased dietary intake of folate and vitamin B 6 may reduce homocysteine levels </li></ul><ul><li>Predictor of CVD mortality in general population and in people with diabetes </li></ul>Hoogeveen EK et al. Arterioscler Thromb Vasc Biol . 1998;18:133-138. Kark JD et al. Lancet . 1999;353:1936-1937. McCully KS. JAMA . 1998;279:392-393. Rimm EB et al. JAMA. 1998;279:359-364.
    31. 31. Plasma Homocysteine Is Associated With Albuminuria <ul><li>Lanfredini </li></ul><ul><li>Significant correlation between albumin excretion ratio (AER) and fasting homocysteine </li></ul><ul><li>Elevated homocysteine levels may worsen prognosis of patients with type 2 diabetes </li></ul><ul><li>Chico </li></ul><ul><li>AER showed strongest independent association with homocysteine </li></ul><ul><li>80% of patients with diabetes and hyperhomocysteinemia had nephropathy </li></ul><ul><li>Hoorn study </li></ul><ul><li>Development of microalbuminuria significantly associated with baseline homocysteine, independent of insulin resistance, BP, BMI, CVD, retinopathy, smoking, or glomerular filtration rate </li></ul>Lanfredini M et al. Metabolism . 1998;47:915-921. Chico A et al. Diabetologia . 1998;41:684-693. Jager A et al. Arterioscler Thromb Vasc Biol . 2001;21:74-81.
    32. 32. Effects of Oxidative Stress on Endothelial Dysfunction in Pathophysiologic Conditions Cai H, Harrison DG. Circ Res. 2000;87:840-844. Increased oxidative stress Reduced bioavailable nitric oxide Endothelial dysfunction <ul><li>Loss of vasodilation </li></ul><ul><li>Platelet aggregation </li></ul><ul><li>Vascular remodeling </li></ul><ul><li>Inflammation </li></ul><ul><li>Smooth muscle cell growth </li></ul>Pathophysiologic conditions/states Reactive oxygen species-producing enzymes Xanthine oxidase NADH/NADPH oxidase Endothelial cell nitric oxide synthase Other sources? Hyperlipidemia Diabetes Hypertension Heart failure Smoking Nitrate tolerance
    33. 33. Nitric Oxide–Mediated Vasodilation Is Impaired in Type 2 Diabetes 0 2 4 6 8 10 12 Baseline 0.3 1 3 10 Methacholine chloride (  g/min) No diabetes (23) Diabetes (21) Difference in forearm blood flow (mL/min/100 mL) Modified from Williams SB et al. J Am Coll Cardiol . 1996;27:567-574. * P <0.005. *
    34. 34. Impaired Macrovascular Reactivity in People at Risk for Type 2 Diabetes Caballero AE et al. Diabetes. 1999;48:1856-1862. *C vs R, IGT, and D, P <0.01. 13.7* 10.5 9.8 8.4 Increase over baseline after cuff occlusion (%) Controls (C) Relatives (R) IGT Diabetes (D)
    35. 35. Impaired Microvascular Reactivity in People at Risk for Type 2 Diabetes Caballero AE et al. Diabetes. 1999;48:1856-1862. *C vs R, IGT, and D, and R vs D, P <0.001. Increase over baseline after cuff occlusion (%) 0 100 200 Acetylcholine Sodium nitroprusside 126* 98* 94 74 123* 85* 83 65 Controls (C) Relatives (R) IGT Diabetes (D)
    36. 36. Oxidative Stress in the Development of CVD in Diabetes Rösen P et al. Diabetes Metab Res Rev . 2001;17:189-212. LDL Oxidized LDL Macrophages overloaded with oxidized LDL Increased MI rate Decreased plaque stability Atherogenic plaques Foam cells in arterial walls Modulation of transcription factors Hyperglycemia Free radicals
    37. 37. IRAS: Relation of C-Reactive Protein to Insulin Sensitivity Festa A et al. Circulation . 2000;102:42-47. Low Middle High Insulin sensitivity tertile 0.05 0.25 1.22 6.05 30.0 Log CRP (mean values) IRAS = Insulin Resistance Atherosclerosis Study.
    38. 38. Relation of C-Reactive Protein to Insulin Sensitivity Festa A et al. Circulation . 2003;108:1822-1830. CRP (mg/L) High resistance Low secretion Non-converters High resistance vs low secretion, P =0.005 High resistance vs nonconverters, P <0.0001 Low secretion vs nonconverters, P =NS
    39. 39. C-Reactive Protein and the Risk of Cardiovascular Disease <ul><li>Elevated C-reactive protein is </li></ul><ul><ul><li>a good predictor of major coronary events </li></ul></ul><ul><ul><li>a strong predictor of future coronary events in apparently healthy subjects </li></ul></ul><ul><ul><li>of prognostic value in patients with acute coronary syndromes </li></ul></ul><ul><ul><li>a marker of carotid atherosclerotic activity </li></ul></ul><ul><ul><li>possibly an independent risk factor for the development of hypertension </li></ul></ul>Bautista LE et al. J Hypertens . 2001;19:857-861. Hashimoto H et al. Circulation . 2001;104:63-67.
    40. 40. Advanced Glycation End-Products (AGEs) <ul><li>AGEs result from initial nonenzymatic reactions of glucose with proteins and nucleic acids, followed by irreversible cross-linking of these macromolecules </li></ul><ul><li>Levels of AGEs correlate directly with chronic levels of glycemia, reflected by A1C </li></ul><ul><li>AGEs may affect molecules that are short-lived (eg, plasma albumin) or long-lived (eg, collagen) </li></ul>Aso Y et al. Acta Diabetol . 2000;37:87-92. Vlassara H, Bucala R. Diabetes . 1996;45(suppl 3):S65-S66. Vlassara H. In: Diabetes and Cardiovascular Disease . 2001:81-102.
    41. 41. Advanced Glycation End-Products (AGEs) (cont.) <ul><li>AGEs may play a role in initiation and progression of diabetic macrovascular and microvascular complications and tissue changes associated with aging </li></ul><ul><li>AGEs involving plasma proteins and lipoproteins, extracellular proteins, cytoplasmic proteins, and nucleic acids may disrupt molecular structures, alter enzyme action, affect degradation and removal of age-related molecules, and reduce receptor recognition of ligands </li></ul><ul><li>AGE-modified apolipoprotein B can lead to hyperlipoproteinemia, reduce LDL clearance, facilitate LDL deposition in vessel walls, and promote atherosclerosis </li></ul>Vlassara H, Bucala R. Diabetes . 1996;45(suppl 3):S65-S66. Vlassara H. In: Diabetes and Cardiovascular Disease . 2001:81-102.
    42. 42. AGEs in Diabetes, Atherosclerosis, Plaque Vulnerability, LV Remodeling AGEs <ul><li>Chemotactic monocytes (PDGF) </li></ul><ul><li>Increased mast cell activity </li></ul><ul><li>Induce production of cytokines (eg, TNF, IL-1) </li></ul><ul><li>Increase levels of matrix-degrading proteinases </li></ul><ul><li>Induce production of Mac-1, ICAMs </li></ul><ul><li>Oxidative stress </li></ul><ul><li>Inactivation of NO </li></ul><ul><li>Increased endothelin </li></ul>Leads to increased leukocyte adherence, B- and T-cell activation, matrix metalloproteinase production, and decreased interstitial collagen Ligands bind RECEPTOR (RAGE) Glycemic Control Nonreceptor Actions Alter vessel structure and function Alter lipid clearance and oxidation state Adapted from Basta G et al. Cardiovasc Res. 2004;63:582-592. Inflammation and atherogenesis
    43. 43. AGEs and the Severity of Coronary Arteriosclerosis in Diabetes 0 4 8 12 Single vessel Two vessel Three vessel AGE (mU/mL) P <0.017 P <0.017 Kiuchi K et al. Heart . 2001;85:87-91. AGE=advanced glycation end-products.
    44. 44. <ul><li>Please visit ndei.org to download these slides. </li></ul><ul><ul><li>Website registration is free and takes just a minute or two. </li></ul></ul><ul><ul><li>All slide downloads are free </li></ul></ul>These slides are available for download from www.ndei.org

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