Personalized Medicine: An

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1 Comparative Effectiveness and Personalized Medicine: An Essential interface Clinical exemplers of personalized medicine i Clyde Yancy, MD, FACC, FAHA, MACP Medical Director, Baylor Heart and Vascular Institute Chief, Cardiothoracic Transplantation Baylor University Medical Center Dallas, TX

2 DISCLOSURES Consultant/speaker/honoraria: None since 06/30/08 Editorial Boards: American Heart Journal, American Journal of Cardiology; Circulation; Circulation-Heart Failure; Circulation- Quality Outcomes; Congestive Heart Failure Guideline writing committees: ACC/AHA, chronic HF; Guideline Taskforce Federal appointments: FDA: Immediate Past Chair, Cardiovascular Device Panel; member, NIH study sections Volunteer Appointments: American Heart Association; ACC; HFSA

3 The Saga of Heart Failure in African Americans

4 Evolution of Cardiovascular Events HTN MI Metabolic Syndrome (Insulin resistance, diabetes) HF Cardio- myopathy Adapted from Pharmacotherapy. 2000;20:495.

5 Hypertension as a risk factor for HF Bibbins-Domingo et al. New England Journal of Medicine. 360(12):

6 CARDIA: Incident Heart Failure among White and Black Men and Women 6 Bibbins-Domingo K et al., Racial Differences in Incident Heart Failure among Young Adults, NEJM. 2009;360:

7 Evolution of Cardiovascular Events: HTN to Heart Failure HTN MI Metabolic Syndrome (Insulin resistance, diabetes) Cardio- myopathy HF Adapted from Pharmacotherapy. 2000;20:495.

8 Heart Failure In African Americans: Overview Affects 3% of the African American population Atypical Natural History Unique Epidemiology lower incidence id of associated epicardial coronary artery disease more likely to be associated with a history of hypertension Worrisome Prognosis higher rate of hospitalization??increased mortality rate: 1.8 for AA men; 2.4 for AA women Question of Altered Responses to Medical Therapy Yancy CW. J Card Fail. 2000;6:

9 Etiology of Heart Failure in African Americans 80 % of Patients With Coronary Artery Disease-Based HF 60 % V-HeFT I V-HeFT II SOLVD US Carv BEST MERIT-HF 80 % of Patients With Hypertension-Based HF 60 % V-HeFT I V-HeFT II SOLVD US Carv BEST MERIT-HF % AA % non-aa The BEST Investigators. N Engl J Med. 2001;344: ; Packer M et al. N Engl J Med. 1996;334: ; MERIT- HF Study Group. Lancet. 1999;353: ; Cohn JN et al. N Engl J Med. 1986;314: ; Cohn JN et al. N Engl J Med. 1991;325: ; The SOLVD Investigators. N Engl J Med. 1991;325:

10 Hypertension Is Associated With Vascular Damage Along the Entire CV Continuum Atherosclerosis Transmural MI Ventricular Remodeling Ventricular Dilatation Heart Failure (HF) Endothelial Dysfunction Hypertension Oxidative Stress End Stage CVD Angiotensin II Vascular Damage Adapted from Dzau V et al. Am Heart J. 1991;121:

11 Endothelial Function/Dysfunction --Levine et al., NEJM 1995

12 NO Synthesis and Action L-Arginine L-Citrulline cgmp Inhibition NADPH O 2 NO Synthase NO + [Ca ++ i ] + + Platelet Endothelial Cell Thrombin Serotonin Acetylcholine Shear Stress K + Channels Guanylyl Cyclase GTP cgmp Vasodilation Relaxation Smooth Muscle Cell Vasodilation

13 Potential Mechanisms of NO Deficiency Diminished NO release Increased inactivation of NO due to increased oxidant stress (ROS species) Impaired antioxidant defenses

14 Endothelial Dysfunction in AA Plethysmographic Response to Mental Stress Cardillo et al. Hypertens sion 1998; 31: NO-dependent vasodilator response absent in AA

15 100 ml / min) Forear m Blood Flow (ml / Endothelial Dysfunction in AA Vasodilator Reserve in Hypertension White (n=9) Black (n=11) P< Nitroprusside ( g/min) White (n=9) Black (n=11) P= Methacholine ( g/min) Stein CM et al. Clin Pharmacol Ther r. 1997;62:

16 Race-Specific Differences in Endothelial Function: HUVECs Density its) Whites AAs Mean SEM Band (Ar rbitrary Un kda enos HUVEC=human umbilical vein endothelial cell; enos=endothelial nitric oxide synthase. *P<.01. Adapted from Kalinowski L, et al. Circulation. 2004;109:2514.

17 Concentrations In Caucasian Americans (Single HUVEC) 500 NO 400 ONOO - NO And ONOO - (nm) O 2- (nm x 10 - ) 300 O Calcium ionophore Kalinowski et al. Circulation. 2004;109: Time (min)

18 Concentrations In African Americans (Single HUVEC) 800 ONOO O NO And ONOO - (nm) O 2- (nm x 10 - ) NO Calcium ionophore Kalinowski et al. Circulation. 2004;109: Time (min)

19 What are the consequences of nitric oxide deficiency?

21 Ref. Liu et al. Hypertension 2002;39:

22 The NO Hypothesis in HF A System Out of Balance in AAs? Vasoconstricting and growth promoting Norepinephrine Angiotensin II Endothelins Arginine Worsen vasopressin hemodynamics, progressive Aldosterone remodeling Vasodilating and growth inhibiting Natriuretic peptides Bradykinin NO Improve hemodynamics, prevent remodeling Yancy CW. Heart Failure in African Americans: The State of the Art. Presented at 8th Annual Scientific Meeting of the Heart Failure Society of America. September 12, 2004; Toronto, Canada.

pathway Pathologic pathway Formation of cyclic guanosine monophosphate Peroxynitrite (ONOO ) DNA damage S-nitrosylation:

23 Consequences of Nitric Oxide and Super Oxide Balance Disruption in Heart Failure Patients Isosorbide dinitrate Hydralazine Stimulation Nitric oxide synthase Citrulline Oxidase Inhibition L-Arginine NO O O 2 Physiologi c pathway Pathologic pathway Formation of cyclic guanosine monophosphate Peroxynitrite (ONOO ) DNA damage S-nitrosylation: post-translational modification of effector molecules Hare JM. N Engl J Med. 2004;351: Inhibition Oxidized proteins Cell damage

24 V-HeFT I: Survival Benefit in Subgroups Non-African Americans African Americans 80% 80% Cumu ulative Mortalit ty 70% 60% 50% 40% 30% 20% 10% Cumu ulative Mortalit ty 70% n=324 60% n=128 50% 40% 30% 20% 10% Risk Ratio=0.53 P=.04 Survival by 47% 0% Months I/H 0% Months Placebo Carson P et al. J Card Fail. 1999;5:

25 A-HeFT: Overall Survival % Decrease in Mortality Survival (% %) Fixed-dose ISDN/HYD Placebo Hazard ratio=0.57 P= Days Since Baseline Visit Date HYD/ISDN Placebo Adapted from Taylor AL, Zische S, Yancy C et al. N Engl J Med. 2004;351:

26 Impact of ISDN/HYD in GRAHF Composite Score Primarily in NOS 3' Glu298Glu Subjects Primary end poi int comp posite sc ore P= Placebo (n=189) ISDN/HYD (=169) P= Asp (n=80) Glu-Glu (n=277) McNamara DM, Tam SW, Sabolinski ML, Tobelmann P, Janosko K, Venkitachalam L, Ofili E, Yancy C, Feldman AM, Ghali JK, Taylor AL, Cohn JN, Worcel M. Endothelial nitric oxide synthase (NOS3) polymorphisms in African Americans with heart failure: results from the A-HeFT trial. J Card Fail Apr;15(3):191-8.

27 Impact of therapy with isosorbide dinitrate and hydralazine (I/H) on outcomes in heart failure McNamara, D. M. et al. J Am Coll Cardiol 2006;48: Copyright 2006 American College of Cardiology Foundation. Restrictions may apply.

28 Evolution of HTN to Heart Failure in AAs HTN NO deficiency MI Metabolic Syndrome (Diabetes) OXIDATIVE STRESS HF HTN Heart Disease LV remodeling Fibrosis apoptosis After HFSA. Pharmacotherapy. 2000;20:495.

29 Comparative Effectiveness and Personalized Medicine: An Essential interface It is entirely plausible that what has been previously referred to as heart disease in special populations has been misrepresented and is instead a prime exemplar of the need for personalized medicine according to objective physiological descriptors that t prompt unique evidencebased therapies C. W. Yancy, M.D., 10/20/10

Treating Heart Failure in Biodiverse Patient Populations: Best Practices and Unveiling Disparities in Blacks

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