Ndei Cardiovascular Disease In Diabetes Pathophysiology

Pathophysiology of CVD in Type 2 Diabetes

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Atherosclerosis in Diabetes

Accelerated atherosclerosis is multifactorial and begins years/decades prior to diagnosis of type 2 diabetes

>50% of patients with newly diagnosed type 2 diabetes have CHD

Risk for atherosclerotic events is 2- to 4-fold greater in people with diabetes than in those without diabetes

Atherosclerosis accounts for  65% of all diabetic mortality

40% due to ischemic heart disease

15% due to other heart disease

10% due to cerebrovascular disease

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.

Implicated Determinants of Heart Disease in Diabetes

Coronary artery disease and vulnerable plaques

Small-vessel disease

Determinants of peripheral vascular disease

Cardiomyopathy

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.

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

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

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

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

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.

Matrix Skeleton of Unstable Coronary Artery Plaque Fissures in the fibrous cap Davies MJ. Circulation . 1996;94:2013-2020.

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.

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

PAI-1 in Internal Mammary Arteries Pandolfi A et al. Arterioscler Thromb Vasc Biol . 2001;21:1378-1382. No Diabetes Diabetes No Diabetes Diabetes

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.

Factors That Affect PAI-1 Concentration and Activity

Increased PAI-1 expression

serotonin (5-HT)

cyclosporin A

N-3 fatty acids

transforming growth factor-beta and thrombin

angiotensin II

nicotine

lipoprotein (a)

FFA

VLDL

Decreased PAI-1 expression

ethanol

thiazolidinediones

metformin

ACE inhibitors

ARBs

gemfibrozil

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.

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

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

Interrelationship Between Insulin Resistance and Atherosclerosis

Insulin Resistance

Hypertension Impaired fibrinolysis Hyper- insulinemia Hyper-glycemia Hyper- coagulability Atherosclerosis Endothelial dysfunction Inflammation Dyslipidemia –  TG – low HDL-C –  small, dense LDL particles

Insulin Resistance and Atherosclerosis: Proposed Relationships Accelerated atherosclerosis Clinical diabetes Hyperinsulinemia Impaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Insulin resistance

Association of MI* With the Metabolic Syndrome and Individual Components

Odds Ratio 95% CI P Value

Metabolic syndrome 2.01 1.53-2.64 <0.0001

Syndrome components

Abdominal obesity 1.15 0.86-1.54 0.3475

High triglycerides 1.51 1.04-2.20 0.0311

Low HDL-C 1.41 1.03-1.95 0.0353

Hypertension 1.42 0.94-2.15 0.0947

Insulin resistance † 1.25 0.92-1.71 0.1461

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.

Association of Stroke* With the Metabolic Syndrome and Individual Components

Odds Ratio 95% CI P Value

Metabolic syndrome 2.16 1.48-3.16 0.0002

Syndrome components

Abdominal obesity 0.97 0.58-1.64 0.9154

High triglycerides 1.87 1.22-2.87 0.0052

Low HDL-C 1.18 0.73-1.90 0.5012

Hypertension 1.56 0.94-2.59 0.0827

Insulin resistance † 1.36 0.93-1.98 0.1119

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.

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

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

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 %

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 %

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

Markers of Inflammation and Coronary Heart Disease

Association observed between CHD and

high-sensitivity C-reactive protein

serum amyloid A

PAI-1 activity

von Willebrand factor

fibrinogen

plasma viscosity

albumin

neutrophils

cytokines

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.

Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Diabetes

Predisposition to thrombosis

platelet hyperaggregability

elevated concentrations of procoagulants

decreased concentration and activity of antithrombotic factors

Predisposition to attenuation of fibrinolysis

decreased t-PA activity

increased PAI-1

decreased concentrations of  2 -antiplasmin

Sobel BE. Circulation . 1996;93:1613-1615. Editorial.

Plasma Homocysteine

Linked to pathophysiology of atherosclerosis

Elevated in CVD patients

May cause vascular damage to endothelial cells

Elevated levels linked to

diet low in folate

genetic defects (rare)

Increased dietary intake of folate and vitamin B 6 may reduce homocysteine levels

Predictor of CVD mortality in general population and in people with diabetes

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.

Plasma Homocysteine Is Associated With Albuminuria

Lanfredini

Significant correlation between albumin excretion ratio (AER) and fasting homocysteine

Elevated homocysteine levels may worsen prognosis of patients with type 2 diabetes

Chico

AER showed strongest independent association with homocysteine

80% of patients with diabetes and hyperhomocysteinemia had nephropathy

Hoorn study

Development of microalbuminuria significantly associated with baseline homocysteine, independent of insulin resistance, BP, BMI, CVD, retinopathy, smoking, or glomerular filtration rate

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.

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

Loss of vasodilation

Platelet aggregation

Vascular remodeling

Inflammation

Smooth muscle cell growth

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

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. *

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)

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)

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

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.

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

C-Reactive Protein and the Risk of Cardiovascular Disease

Elevated C-reactive protein is

a good predictor of major coronary events

a strong predictor of future coronary events in apparently healthy subjects

of prognostic value in patients with acute coronary syndromes

a marker of carotid atherosclerotic activity

possibly an independent risk factor for the development of hypertension

Bautista LE et al. J Hypertens . 2001;19:857-861. Hashimoto H et al. Circulation . 2001;104:63-67.

Advanced Glycation End-Products (AGEs)

AGEs result from initial nonenzymatic reactions of glucose with proteins and nucleic acids, followed by irreversible cross-linking of these macromolecules

Levels of AGEs correlate directly with chronic levels of glycemia, reflected by A1C

AGEs may affect molecules that are short-lived (eg, plasma albumin) or long-lived (eg, collagen)

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.

Advanced Glycation End-Products (AGEs) (cont.)

AGEs may play a role in initiation and progression of diabetic macrovascular and microvascular complications and tissue changes associated with aging

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

AGE-modified apolipoprotein B can lead to hyperlipoproteinemia, reduce LDL clearance, facilitate LDL deposition in vessel walls, and promote atherosclerosis

Vlassara H, Bucala R. Diabetes . 1996;45(suppl 3):S65-S66. Vlassara H. In: Diabetes and Cardiovascular Disease . 2001:81-102.

AGEs in Diabetes, Atherosclerosis, Plaque Vulnerability, LV Remodeling AGEs

Chemotactic monocytes (PDGF)

Increased mast cell activity

Induce production of cytokines (eg, TNF, IL-1)

Increase levels of matrix-degrading proteinases

Induce production of Mac-1, ICAMs

Oxidative stress

Inactivation of NO

Increased endothelin

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

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.