Mechanism of superior cardiovascular protection: Clinical perspective on LIFE Tony ABDEL - MASSIH, MD. Cardiologist Hotel-Dieu de France

ESH/ESC Guidelines: Definitions and Classification of BP Levels (mmHg) ESH/ESC Guidelines: Definitions and Classification of BP Levels (mmHg) 6254 M CategoryOptimalNormal High normal Grade 1 hypertension (mild) Grade 2 hypertension (moderate) Grade 3 hypertension (severe) Isolated systolic hypertension Systolic < ≥ 180 ≥ 140 Diastolic < ≥ 110 < 90 < 90 When a patient’s SBP and DBP fall into different categories, the higher category should apply. Isolated systolic hypertension can also be graded (grades 1, 2, 3) according to SBP values in the ranges indicated, provided diastolic values are < 90

ESH/ESC Guidelines: Stratification of Risk to Quantify Prognosis 7772 M Very high added risk Very high added risk Very high added risk High Very high added risk Very high added risk High High Moderate Moderate Moderate Low Blood Pressure (mmHg) Other Risk Factors and Disease History No other risk factors 1-2 risk factors Associated Clinical Conditions Grade 1 SBP or DBP Grade 2 SBP or DBP Grade 3 SBP ≥ 180 or DBP ≥ or more risk factors or TOD or diabetes Very high added risk High High Moderate Averagerisk Low Low Averagerisk Normal SBP or DBP High Normal SBP or DBP Low risk: 30%

Cuspidi et al, J Hypertens 2002 Echocardiography and US TSA in Low Risk Hypertensives APROS STUDY RISK RE-CLASSIFICATION

2313 Association of Hypertension with Other CAD Risk Factors: Framingham Study Kannel, Am J Hypertens 2000; 13: 3S-10S Two25% One26% None19% Four or more 8% Three22% Two24% One27% None17% 12% Three20% MenMenWomenWomen

8175 = 6397 alt. M StrokeMorevs less CHDMorevs less Heart failure Morevs less Major CV events Morevs less CV death Morevs less Total mortality Morevs less Mean BP  (mmHg) -4 / -3 Relative Risk (95% CI) 0.77 ( ) 0.86 ( ) 0.84 ( ) 0.86 ( ) 0.93 ( ) 0.96 ( ) FavoursactiveFavourscontrol Relative risk

ESH/ESC Position statement: Choice of antihypertensive drugs The main benefits of antihypertensive therapy are due to lowering of blood pressure per se. There is also evidence that specific drug classes may differ in some effect, or in special groups of patients. Drugs are not equal in terms of adverse disturbances, particularly in individual patients. The major classes of antihypertensive agents - diuretics, β-blockers, calcium antagonists, ACE inhibitors, angiotensin receptor antagonists - are suitable for the initiation and maintenance of therapy.

Weighted Average Change in DBP at Trough Losartan Valsartan Irbesartan Candesartan N = Los 50 mg Val 80 mg Irb 150 mg Can 8 mg Los mg Val mg Irb mg Can mg Los 50 ± Hctz 12.5 mg Val 80 ± Hctz 12.5 mg Irb 150 ± Hctz 12.5 mg Can 8 ± Hctz 12.5 mg Conlin et al. Am J Hypertens 2000

Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACE I vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ß blockers/Diur Number of Patients 10,98510, Number of Primary Endpoints Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = 0.89 No Hypertension Trial Has Shown Superiority on Combined CV Morbidity and Mortality vs. an Active Comparator Hansson L et al Lancet 1999; Hannson L et al Lancet 2000;356: ; Hannson L et al Lancet 1999;354(9192):

5487 M Trials on “New” vs “Old” Treatments Primary Endpoints (RR + 95% CI) Mancia G. et al., 2003 CAPPP*STOP2*ANBP2*ALLHAT°STOP2*NORDIL*INSIGHT*ALLHAT°INVEST*ALLHAT°SCOPE*LIFE*ACE-IACE-IACE-IACE-ICCBCCBCCBCCBCCB  B ARBARB n = n = 4418 n = 6083 n = 9054 n = 4209 n = n = 6321 n = 9048 n = n = n = 4506 n = New better Old better 1.05 ( ) 1.01 ( ) 0.89 ( ) 0.99 ( ) 0.97 ( ) 1.00 ( ) 1.10 ( ) 0.98 ( ) 0.98 ( ) 1.03 ( ) 0.89 ( ) 0.87 ( ) * CVD; ° CHD

ANBP2: Primary End-Points among All, Male, and Female Subjects 5370 M Wing et al., N Engl J Med 2003; 348: All Subjects End Point All CV events or death from any cause First CV event or death from any cause Death from any cause Male Subjects End Point All CV events or death from any cause First CV event or death from any cause Death from any cause Female Subjects End Point All CV events or death from any cause First CV event or death from any cause Death from any cause Hazard Ratio (95% CI) 0.89 ( ) 0.89 ( ) 0.90 ( ) Hazard Ratio (95% CI) 0.83 ( ) 0.83 ( ) Hazard Ratio (95% CI) 1.00 ( ) 1.00 ( ) 1.01 ( ) P Value ACE-I superior Diuretics superior ACE-I superior Diuretics superior ACE-I superior Diuretics superior

LIFE Study: Blood Pressure During Follow-up Study Month Systolic Diastolic Mean Arterial mmHg Atenolol Losartan

LIFE Study Primary Composite Endpoint Losartan (n) Atenolol (n) Study Month Proportion of patients with first event (%) Intention-to-treat Losartan Atenolol Adjusted risk reduction 13·0%, P=0·021 Unadjusted risk reduction 14·6%, P=0·009

LIFE Study Fatal and Non-Fatal Myocardial Infarction Intention-to-treat Proportion of patients with first event (%) Atenolol Losartan Adjusted Risk Reduction -7·3%, P=0·49 Unadjusted Risk Reduction -5·0%, P=0·63 Study Month

LIFE Study Fatal and Non-Fatal Stroke Proportion of patients with first event (%) Intention-to-treat Losartan Atenolol Adjusted risk reduction 24·9%, P=0·001 Unadjusted risk reduction 25·8%, P=0·0006 Study Month

Farsang C et al. J Hpertens 2000, NentelJ M et al. Clin Ther 2000, Manolis AJ et al. (Aramis study), J HYpertens SBPDBPPP mm Hg ANGIOTENSIN II ANTAGONISTS IN ISOLATED SYSTOLIC HYPERTENSION

LIFE Study ISH Subgroup Composite of CV Death, Stroke, and MI Study month Endpoint rate (%) Atenolol Losartan Unadjusted relative risk=29%; P=0.02 Adjusted relative risk reduction=25%; P=0.06 CV=cardiovascular MI=myocardial infarction

LIFE Study Diabetes Subgroup Primary Composite CV Endpoint Adjusted risk reduction 24·5%, P=0·031 Unadjusted risk reduction 26.7%, P=0· Proportion of patients with first event (%) Losartan Atenolol Losartan (n) Atenolol (n) Study Month

Effect of Losartan on Sudden Cardiac Death in People with Diabetes: Data From the LIFE Study CV Death CHD Death Sudden Death Non SD Non Coronary CV Death # p<0.052 Lindholm LH, et al: Lancet 2003 Adjusted HR (95% CI) #: p< 0.03 #

12,1 7, Atenolol n=330 Losartan n=332 % * Cornell Voltage < 2400 and Sokolow-Lyon < 24 RR: 45% p=0.019 LIFE Primary Composite Endpoint in Subgroup: Patients without LVH* (n=662)

Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACEI vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ßbockers/Diur Losartan vs. Atenolol Number of Patients10,98510, Number of Primary Endpoints Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease MI, Stroke, CV Death Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = % RR p = Losartan Is the First Antihypertensive to Provide Superior Benefits on Combined CV Morbidity and Death vs. an Active Comparator LIFE

LIFE: Conclusions Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects * Defined as composite of CV death, MI, and stroke

How Could Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Potential Sites of Action Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Ref 3, p 831, C1, ¶1, L1 Ref 4, p 469, C2, L4 Ref 9, p 493, C1, ¶3, L1; p 496, C1, ¶3, L10 Ref 5, p 1439, Fig 74-1 Ref 27, p 1653, ¶2 Please refer to notes page for reference citations.

LIFE Study Diabetes Subgroup Primary Composite CV Endpoint Adjusted risk reduction 24·5%, P=0·031 Unadjusted risk reduction 26.7%, P=0· Proportion of patients with first event (%) Losartan Atenolol Losartan (n) Atenolol (n) Study Month

Effect of Losartan on Sudden Cardiac Death in People with Diabetes: Data From the LIFE Study CV Death CHD Death Sudden Death Non SD Non Coronary CV Death # p<0.052 Lindholm LH, et al: Lancet 2003 Adjusted HR (95% CI) #: p< 0.03 #

12,1 7, Atenolol n=330 Losartan n=332 % * Cornell Voltage < 2400 and Sokolow-Lyon < 24 RR: 45% p=0.019 LIFE Primary Composite Endpoint in Subgroup: Patients without LVH* (n=662)

Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACEI vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ßbockers/Diur Losartan vs. Atenolol Number of Patients10,98510, Number of Primary Endpoints Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease MI, Stroke, CV Death Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = % RR p = Losartan Is the First Antihypertensive to Provide Superior Benefits on Combined CV Morbidity and Death vs. an Active Comparator LIFE

LIFE: Conclusions Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects * Defined as composite of CV death, MI, and stroke

How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

Hemodynamic factors (central and peripheral blood pressure) Circulating factors (glucose, insulin, RBCs, PAI, TXA 2, uric acid) Cardiac remodeling/ enlargement Vascular remodeling Endothelial dysfunction Prothrombotic state Atherosclerotic plaque formation Emboli formation Thrombus/ platelet aggregation Embolic occlusion Thrombotic occlusion Ischemic stroke Hemorrhagic stroke Vascular hemorrhage Hypothesis: Losartan May Reduce the Risk of Ischemic Strokes by an Effect on Cardiac Remodeling Please refer to notes page for reference citations. Plaque fragments Plaque rupture

LIFE: Losartan vs. Atenolol Reduced ECG–LVH –18 –16 –14 –12 –10 –8 –6 –4 –2 0 Cornell productSokolow-Lyon Change from baseline (%) p< Losartan Atenolol Adapted from Dalhöf B et al Lancet 2002;359:995–1003. Ref 25, p 1001, Fig 7

How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

Hemodynamic factors (central and peripheral blood pressure) Circulating factors (glucose, insulin, RBCs, PAI, TXA 2, uric acid) Cardiac remodeling/ enlargement Vascular remodeling Endothelial dysfunction Prothrombotic state Atherosclerotic plaque formation Emboli formation Thrombus/ platelet aggregation Embolic occlusion Thrombotic occlusion Ischemic stroke Hemorrhagic stroke Vascular hemorrhage Hypothesis: Losartan May Reduce the Risk of Stroke by Altering Vascular Remodeling and Atherosclerosis Please refer to notes page for reference citations. Plaque fragments Plaque rupture

Losartan Reduced Atherosclerosis (Fatty Streaks) in Nonhuman Primates Control Losartan Simian thoracic aorta dissected after 6-month exposure to a high-cholesterol diet (n=4) Adapted from Strawn WB et al Circulation 2000;101:1586–1593. Ref 28, p 1586, C2, ¶1, L1, ¶2, L1,7; p 1590, Fig 4

LIFE: Losartan vs. Atenolol Reduced Carotid Artery Hypertrophy % Change in intima-medial cross-sectional area Intima-medial thickness—change from baseline at year 3 –7.9 % –1.7 % p<0.05 –9 –8 –7 –6 –5 –4 –3 –2 –1 0 Atenolol (n=22) Losartan (n=23) Ref 26, Source C, p 34, Table 5

Farsang C et al. J Hpertens 2000, NentelJ M et al. Clin Ther 2000, Manolis AJ et al. (Aramis study), J HYpertens SBPDBPPP mm Hg ANGIOTENSIN II ANTAGONISTS IN ISOLATED SYSTOLIC HYPERTENSION

LIFE Study ISH Subgroup Composite of CV Death, Stroke, and MI Study month Endpoint rate (%) Atenolol Losartan Unadjusted relative risk=29%; P=0.02 Adjusted relative risk reduction=25%; P=0.06 CV=cardiovascular MI=myocardial infarction

LIFE Study Diabetes Subgroup Primary Composite CV Endpoint Adjusted risk reduction 24·5%, P=0·031 Unadjusted risk reduction 26.7%, P=0· Proportion of patients with first event (%) Losartan Atenolol Losartan (n) Atenolol (n) Study Month

Effect of Losartan on Sudden Cardiac Death in People with Diabetes: Data From the LIFE Study CV Death CHD Death Sudden Death Non SD Non Coronary CV Death # p<0.052 Lindholm LH, et al: Lancet 2003 Adjusted HR (95% CI) #: p< 0.03 #

12,1 7, Atenolol n=330 Losartan n=332 % * Cornell Voltage < 2400 and Sokolow-Lyon < 24 RR: 45% p=0.019 LIFE Primary Composite Endpoint in Subgroup: Patients without LVH* (n=662)

Mega-trialsCAPPPNORDILSTOP-2 Comparator Treatments ACEI vs. ß blockers/Diur CCB vs. ß blockers/Diur ACEIs/CCBs vs. ßbockers/Diur Losartan vs. Atenolol Number of Patients10,98510, Number of Primary Endpoints Composite Primary Endpoint MI, Stroke, CV Death MI, Stroke, CV Death Fatal MI, Fatal Stroke, Fatal CV Disease MI, Stroke, CV Death Differences on Primary Endpoint NS p = 0.52 NS p = 0.97 NS p = % RR p = Losartan Is the First Antihypertensive to Provide Superior Benefits on Combined CV Morbidity and Death vs. an Active Comparator LIFE

LIFE: Conclusions Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects Losartan with LIFE is the only antihypertensive that has demonstrated a superior benefit over another active treatment, atenolol, in reducing the risk of combined CV morbidity and death in patients with hypertension and LVH* The superior benefit of losartan therapy on combined CV morbidity and death* compared to atenolol was: – beyond blood-pressure control – only partially explained by superior LVH regression – potentially linked to molecule-specific effects * Defined as composite of CV death, MI, and stroke

How Could Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Potential Sites of Action Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Ref 3, p 831, C1, ¶1, L1 Ref 4, p 469, C2, L4 Ref 9, p 493, C1, ¶3, L1; p 496, C1, ¶3, L10 Ref 5, p 1439, Fig 74-1 Ref 27, p 1653, ¶2 Please refer to notes page for reference citations.

How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

Hemodynamic factors (central and peripheral blood pressure) Circulating factors (glucose, insulin, RBCs, PAI, TXA 2, uric acid) Cardiac remodeling/ enlargement Vascular remodeling Endothelial dysfunction Prothrombotic state Atherosclerotic plaque formation Emboli formation Thrombus/ platelet aggregation Embolic occlusion Thrombotic occlusion Ischemic stroke Hemorrhagic stroke Vascular hemorrhage Hypothesis: Losartan May Reduce the Risk of Ischemic Strokes by an Effect on Cardiac Remodeling Please refer to notes page for reference citations. Plaque fragments Plaque rupture

LIFE: Losartan vs. Atenolol Reduced ECG–LVH –18 –16 –14 –12 –10 –8 –6 –4 –2 0 Cornell productSokolow-Lyon Change from baseline (%) p< Losartan Atenolol Adapted from Dalhöf B et al Lancet 2002;359:995–1003. Ref 25, p 1001, Fig 7

How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

Losartan vs. Atenolol Improved Structure of Small Gluteal Arteries Adapted from Schiffrin EL et al Circulation 2000;101(14):1653–1659. Structure Media/lumen ratio (%) Before 1 year Before 1 year LosartanAtenolol Ref 27, p 1654, C2, ¶4, L1; p 1656, Table 2, Row 4

How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

Losartan vs. Atenolol Improved Endothelial Function of Small Gluteal Arteries Adapted from Schiffrin EL et al Circulation 2000;101(14):1653–1659. Endothelium-dependent relaxation * Maximal acetylcholine response (%) Before 1 year Before 1 year LosartanAtenolol Ref 27, p 1654, C2, ¶4, L1; p 1656, Table 2, Row 4; p 1657, Fig 3

How Did Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Losartan Data Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

Losartan Had Effects on Platelet Aggregation and Thrombus Formation Losartan –Reduced TXA 2 –dependent platelet activation (platelets from 15 healthy men) –Reduced plasma levels of PAI-1 antigen, PAI-1 activity, and sTM level in 12 hypertensive patients –Increased the concentration of thrombin receptor- activating peptide (SRLRRN-NH2) required to induce platelet aggregation in 10 hypertensive patients –Reduced plasma PAI-1 levels in hypertensive postmenopausal women –Reduced the aggregatory response to thromboxane but not thrombin in hypertensive patients Please refer to notes page for reference citations.

Losartan Inhibited Platelet Aggregation in Man (via EXP3179) Adapted from Krämer C et al Circ Res 2002;90:770–776. Ref 36, p 774, Fig 4A Platelet aggregation (%) Time (months) * * *p< vs. placebo Placebo Losartan

Hemodynamic factors (central and peripheral, blood pressure) Circulating factors (Glucose, Insulin, RBCs, PAI, TXA 2, uric acid) Cardiac remodeling/ enlargement Vascular remodeling Endothelial dysfunction Prothrombotic state Atherosclerotic plaque Emboli formation Thrombus formation Embolic occlusion Thrombotic occlusion Ischemic stroke Plaque fragments Plaque rupture Hemorrhagic stroke Vascular hemorrhage Losartan May Reduce the Risk of CV events by Molecular-Specific Effects Please refer to notes page for reference citations. Losartan reduces uric acid

LIFE: Losartan vs. Atenolol Reduced the Rise in Serum Uric Acid without Affecting Renal Function Adapted from Høieggen A et al Kidney Int 2004;65:1–9. NS µmol/L Atenolol Losartan p< Ref 40, p 4, C2, ¶2, L1,3; p 5, C1, ¶1, L1, ¶2, L1 + calc Calc: 96.9–87.4= –86.5=9.6

CRP -at Concentrations Known to Predict CV Events- Upregulates AT-1 Receptors in Vascular Smooth Muscle Wang CH et al, Circulation. 2003;107:1783

CRP stimulates VSM cell migration. This effect was inhibited by losartan. Losartan per se did not affect VSM migration in the basal state. Ang II increased VSM migration; this effect was potentiated in the presence of CRP and attenuated by N-acetylcysteine (an anti- oxidant) Wang CH et al, Circulation. 2003;107:1783

Conclusions Cardiac remodeling/ enlargement Endothelial dysfunction Prothrombotic state Vascular remodeling Reduced ECG–LVH Improved endothelial function Inhibition of platelet aggregation Reduced proaggregatory factors Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Please refer to notes page for reference citations.

Atherogenesis Atherogenesis Inflammation Insulin Resistance Thrombogenesis Conditions Associated with CV Disease Obesity/MS/Diabetes, PCOS, HTN, Dyslipidemias, COPD, Systemic Inflammatory Disorders, CRF, Chronic Infections, Homocystenemia, Pschyosocial Stress CV DISEASES CHD, PVD, CVD, Cardiomyopathy, Arrhythmias, Restenosis, Valvular HD, Vein Graft failure, Cardiac Allograft Vasculopathy, Pulmonary Arterial Hypertension