Cardiac Protection across the cardiac continuum Dong-Ju Choi, MD, PhD College of Medicine Seoul National University Renin Angiotensin Cascade ↑ Nitric oxide (NO) Angiotensinogen •t-PA Renin •Cathepsin G A I ↑ Bradykinin CAGE •Tonin ACE Cathepsin G Chymase Degradation A II products ACEI site of action AT1 receptor AT2 receptor • Hypertrophy/proliferation • Antiproliferation • Vasoconstriction • NO Release • Aldosterone release • Differentiation • Antidiuretic hormone release • Vasodilation de Gasparo M, et al. Hypertension. Pathophysiology, Diagnosis, and Management. 2nd ed. New York, NY: Raven Press; 1995:1695–1720. Dzau VJ. J Hypertens. 1989;7:933-936. Pathophysiologic Effects of Angiotensin II Abnormal ↑PAI-1/ vasoconstriction thrombosis ↑Contractility Platelet aggregation Activate SNS Superoxide AngiotensinAngiotensin IIII production ↑Aldosterone Vascular smooth ↑Vasopressin muscle growth ↑Endothelin Myocyte growth ↑Collagen Burnier M, Brunner HR. Lancet. 2000;355:637–645. Adverse Effects of RAS on CV System Vascular change 1. Vascular remodeling 2. Endothelial dysfunction 3. Inflammation Myocardial damage 1. Myocyte sequestration 2. Myocyte isolation Increase BP Ang II Vascular Remodeling AngII-induced Inflammation The inflammatory response by AngII: 1) Increase in vascular permeability, 2) Infiltration of leukocytes, and 3) Tissue remodeling. Myocardial Damage by RAS 1. Myocyte sequestration • Hypertrophy • Apoptosis • Necrosis 2. Myocyte isolation • Interstitial fibrosis • Conduction disturbance Blocking RAS is critical to prevent 1. Vascular change (Vascular remodeling, endothelial dysfunction and inflammation) and 2. Myocardial damage (Myocyte sequestration and myocyte isolation) The Cardiovascular Continuum: Mechanisms and Mediators Oxidative Target Organ Stress/Endothelial Myocardial Pathological Tissue Injury Tissue Loss Damage Dysfunction Infarction Remodeling VascularCAD Disease TargetVentricular Organ DysfunctionEnlargement AtherosclerosisVascular DysfunctionHypertrophy HeartEnd-stage Failure Organ Failure Risk Factors: ANGIOTENSIN II Death Clinical Trials with ACE inhibitors MI CONSENSUS, Vascular and CAD ISIS-4, GISSI-3 HOPE, QUIET, SMILE, SAVE EUROPA, PEACE AIRE, TRACE Myocardial Pathological Infarction Remodeling CAD Ventricular Enlargement Atherosclerosis Hypertrophy Heart Failure Hypertension HF SOLVD Risk Factors: CAPPP, ALLHAT Diabetes DM V-HeFT II Hypertension Hyperlipdemia ABCD, REIN, AASK SAVE, Death ATLAS Clinical Trials with ARB DM/Renal Post-MI RENAAL, IDNT VALIANT, IRMAII, ARVAL OPTIMAL ABCD-2V, VAL-PREST NAVIGATOR Myocardial Pathological Infarction Remodeling Ventricular CAD, Nephropathy Enlargement Atherosclerosis Hypertrophy Heart Failure Hypertension HF Risk Factors: SCOPE, Diabetes ELITE I&II Hypertension VALUE, Hyperlipdemia Val-HeFT Death TROPHY, LIFE CHARM Val-Syst Trial: Powerful Double-digit BP Reductions with Valsartan-based Therapy in Patients with ISH Aged 60–80 Randomised, double-blind, titration to effect study of patients (aged 60–80 years) with ISH: 24 weeks’ treatment SBP DBP DIOVAN- Amlodipine- DIOVAN- Amlodipine- based based based based (n=166) (n=163) (n=166) (n=163) 0 –5 –6.0 –6.5 –10 NS –15 Patients were randomised to DIOVAN –20 80 mg or amlodipine 5 mg –25 After 8 weeks, patients with SBP ≥140 mmHg were titrated to DIOVAN –30 160 mg/d or amlodipine 10 mg After an additional 8 weeks, HCTZ 12.5 mg Mean change in BP (mmHg) –35 –33.4 –33.5 NS was added to treatment in patients with SBP ≥140 mmHg Val-Syst: Valsartan in Isolated Systolic Hypertension (ISH); Per protocol population data shown; NS = not significant Clin Ther 2003;25:2765–80 Time Course of Morning BP Changes Mediated by ARBs Morning home BP 165 Patients with essential hypertension: 4 weeks’ treatment 155 145 SBP (mmHg) 135 –7 0 7 14 21 28 Day Start of treatment Valsartan 40–80 mg (n=18) Losartan 25–100 mg (n=18) Telmisartan 10–40 mg (n=18) Candesartan 2–12 mg (n=18) Clin Exp Hypertens 2005;27:477–89 TheThe rolerole ofof arterialarterial stiffnessstiffness The role of arterial stiffness as the major cause of cardio- vascular risk can be seen in recent outcome data. Pulse Wave Velocity aortic pulse wave velocity on entry was used to stratify arterial stiffness in a cohort of ESRD patients into tertiles 1st tertile has almost normal results; 3rd tertile has 6x risk of “all cause’ mortality Clin Exp Hypertens. 2004 Oct-Nov;26(7-8):689-99 Reduces Arterial Stiffness Randomised study of patients with hypertension: 3 months’ treatment Nifedipine 20 mg (n=20) Diovan 80 mg (n=21) 0 –50 –100 –69 –150 –200 p=0.02 Brachial–ankle PWV* (cm/sec) –250 –195 *Brachial-ankle pulse wave velocity (PWV), a measure for systemic arterial stiffness Am J Hypertens 2004;17:1050–5 Reduces Arterial Stiffness Randomised, double-blind, parallel-group design study of patients with essential hypertension: 6 weeks’ treatment Diovan 80 mg HCTZ 25 mg Placebo 0 –0.3 –3.2 (n=20) –10 (n=20) from baseline † –20 • Diovan improves arterial compliance in AIx –21.7* patients with hypertension –30 (n=20) • Effects are independent of BP reduction (BP reductions similar for Diovan and HCTZ) Change in –40 †Augmentation index (AIx), a measure of arterial function *p<0.01 vs HCTZ and vs placebo J Hypertens 2002;20:2423–8 DETECTIV : Valsartan Increases Small Artery Elasticity in Asymptomatic Risk Patients with High CV Risk Results from a 12-month study in 76 asymptomatic patients# with RDS ≥6 and controlled BP and cholesterol levels (DETECTIV study) 6 months 12 months 0 77% 3.5 increase* 3.24 -0.5 3 -1 -1.5 2.5 1.51 -2 2 2.39 -2.5 -2.2 1.5 -3 -3.1 1 -3.5 0.55 -3.6 0.5 Change in RDS from baseline -4 44% -3.9 0 reduction* Change in small artery elasticity from baseline (mL/mmHg x100) 6 months 12 months Placebo DIOVAN 160 mg od for 6 months DIOVAN 160 mg od for 12 months #Individuals completing the study with or without antihypertensive or lipid lowering medications, BP <140/90 mmHg; *p<0.000; RDS=Rasmussen Disease Score Duprez et al. JACC 2007;50:published online Val-MARC: Managing BP Aggressively and Evaluating Reductions in hsCRP Multicentre, open-label, randomised, parallel-group study of patients with Stage II hypertension Objectives, to determine: • If BP reduction with DIOVAN/Co-DIOVAN is effective at reducing hsCRP levels • If there is a difference between moderate and aggressive BP reduction in terms of hsCRP change Primary endpoints: • Change in SBP from baseline to Week 6 with DIOVAN vs Co-DIOVAN • Change in hsCRP from baseline to Week 6 with DIOVAN vs Co-DIOVAN • Change in hsCRP from baseline to Week 12 in the overall group DIOVAN 320 mg DIOVAN 320 mg (n=807) (plus optional HCTZ 12.5 mg) DIOVAN 160 mg (n=836) Screening 0–7 days Co-DIOVAN 160/12.5 mg (n=832) Co-DIOVAN 320/12.5 mg Co-DIOVAN 320/12.5mg (n=808) (or optional Co-DIOVAN 320/25mg) Week 0 Week 2 Week 6 Week 12 Visit 1 Visit 2 Visit 3 Visit 4 (randomisation) (End of study) Hypertension 2006;48:73-79 Val-MARC : DIOVAN Reduces hsCRP Levels Independent of Blood Pressure Reduction Results from a 6-week study* in 1,615 patients with stage II HTN# (Val-MARC study) 6 4.4% 4 2 0 -2 -4 -6 from baseline to 6 weeks* -8 -10 Change in hsCRP plasma level (%) -8.9% DIOVAN Co-DIOVAN 160 - 320 mg od 160/12.5 - 320/12.5 mg od (n=807, median change -0.12) (n=808, median change +0.05) #SBP ≥160 mmHg or DBP ≥100 mmHg, patients completing the study; *Study duration 12 weeks, after 6 weeks of treatment, HCTZ 12.5 mg/day allowed at discretion in both groups to reach BP <140/90 mmHg); p<0.001 for DIOVAN vs. Co-DIOVAN Ridker et al. Hypertension 2006;48:73-79 VALUE: Elective Titration to Target BP(<140/90 mmHg) Patients aged ≥50 years, with treated or untreated hypertension DIOVAN 160 mg + and at high risk of CV events HCTZ 25 mg + ‘Free’ add-on Co-DIOVAN DIOVAN-based Co-DIOVAN 160/25 mg regimen 160/12.5 mg DIOVAN 160 mg DIOVAN 80 mg Rollover from previous therapy Amlo 5 mg (92%) Amlo 10 mg Amlodipine- Amlo 10 mg + based regimen HCTZ 12.5 mg Amlo 10 mg + HCTZ 25 mg Amlo 10 mg + HCTZ 25 mg + ‘Free’ add-on Month –0.5 0 1 2 3 4 6 * 72 Screening Randomisation End of treatment adjustment period *Patient visits every 6 months for Months 6–72; Amlo = amlodipine Lancet 2004;363:2022–31 VALUE: Rate of Cardiac Events Did not Differ Between the Vasarta and Amlodipine Groups 14 DIOVAN-based regimen 12 Amlodipine-based regimen 10 8 6 first event (%) event first 4 Proportion of patients with 2 HR=1.03; 95% CI=0.94–1.14; p=0.49 0 0 6 12 18 24 30 36 42 48 54 60 66 Number at risk Time (months) DIOVAN 7,649 7,459 7,407 7,250 7,0856,906 6,732 6,5366,349 5,911 3,765 1,474 Amlodipine 7,596 7,469 7,424 7,267 7,1176,955 6,772 6,5766,391 5,959 3,725 1,474 Lancet 2004;363:2022–31 LIFE : The Losartan Intervention For Endpoint Reduction in Hypertension Study Patients aged ≥55 years, with treated or untreated hypertensionand at high risk of CV events * Titration to target blood pressure: <140 / 90 mmHg Losartan 100 mg + HCTZ 12.5- 25 mg + others** Losartan 100 mg + HCTZ 12.5 mg* Losartan 50 mg + HCTZ 12.5 mg* Placebo Losartan 50 mg Atenolol 50 mg Atenolol 50 mg + HCTZ 12.5 mg* Atenolol 100 mg + HCTZ 12.5 mg* Atenolol 100 mg + HCTZ 12.5- 25mg + others** Day Day Day Mth Mth Mth Mth Yr Yr Yr Yr Yr Yr Yr Yr −14 −7 1 1 2 4 6 1 1.5 2 2.5 3 3.5 4 5 * Titration encouraged if SiDBP >90 mmHg or SiSBP >140 mmHg but was mandatory if SiBP >160 / 95 mmHg **Other antihypertensives excluding ACEIs, A II antagonists, beta blockers Lancet 2002;359;995-1003-1010 LIFE : BP reductions 180 Atenolol Losartan 160 Systolic 140 120 100 Mean arterial mmHg 80 Diastolic