Mitochondria as a Therapeutic Target to Promote Cardio Vascular Health and Micronutrients

1. Mihai Gheorghiade MD, FACC Professor of Medicine and Surgery Director of Experimental Therapeutics Center for Cardiovascular Innovation Northwestern University Feinberg School of Medicine Mitochondria as a Therapeutic Target to Promote Cardio Vascular Health and Micronutrients

2. Cardiovascular Health • Related to : • Age • Diabetes • Hypertension • Obesity (metabolic syndrome) • Lifestyle • Occult cardiovascular abnormalities not being treated

3. Global Burden of Hypertensive Disease in 2000 and Projections to 2025 Projected global increase = 60% 2000 E. Eur India ME China Other Asia LAC EME Africa 2025 Men: +4.2 +3.8 +2.6 +3.8 +2 +5.1 +1.8 +0.1 Women: +5.3 +6.8 +2.7 +5.4 +3.3 +7.3 +2.6 -0.1 Kearny PM. Lancet 2005; 365: 217

4. Prevalence and Estimates of Diabetes by Region, 2010 and 2030 Increase in the % of adults with diabetes 42% 94% 72% 20% 65% 47% 98% Shaw et al. Diabetes Res and Clin Practice 2010; 87: 4

5. Definition “Heart failure (HF) is a life-threatening condition in which the heart isn't able to pump enough blood to the rest of the body. The failing heart continues to work, but not as efficiently as it should. Many conditions that lead to congestive heart failure can't be reversed, but heart failure can often be treated with medications and lifestyle changes. “

7. Ejection FractionIMPROVE-HF registry American Heart Journal 2012

8. ACC/AHA 2009 Guideline: Classification of “HF” Stage Patient Description High risk for(60mil.) developing HF • HTN • CAD • Diabetes mellitus • Metabolic syndrome A B Asymptomatic HF 10 mil. • Previous MI • LV systolic /diastolic dysfunction • Asymptomatic Valvular disease C Symptomatic HF 5 mil. • Known structural heart disease • Shortness of breath and fatigue • Reduced exercise tolerance D Refractory end-stage HF(200000) • Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions) • Hunt SA et al. J Am CollCardiol. 2009.

9. Therapeutic Recommendations Gheorghiade and Peterson JAMA 2011 Gheorghiade and Braunwald JAMA 2011 Gheorghiade et al, JACC 2013 Gheorghiade et al, JAMA 2013 Treat beyond clinical congestion Evidence based therapy for heart failure Treat cardiac co-morbidities Address the metabolic needs

11. Therapeutic Recommendations Gheorghiade and Peterson JAMA 2011 Gheorghiade and Braunwald JAMA 2011 Gheorghiade et al, JACC 2013 Gheorghiade et al, JAMA 2013 • Treat beyond clinical congestion • Evidence based therapy for heart failure • Treat cardiac co-morbidities • Address the metabolic needs

13. Human Heart • The human heart weighs between 200-425 g • Consumes more energy (adenosine triphosphate - ATP) than any other organ • Pumps 5 liters of blood per minute, 7200 liters per day, and over 2.6 million litersper year • Over 6 kilograms of ATP is hydrolyzed by the heart daily • Every 30 days, an entire heart is reconstructed with brand new protein components Soukoulis et al JACC 2010

14. Neurohormonal stress • Neurohormonal activation is present in all pts with LV dysfunction regardless of symptoms • Excessive and continuous • Results in myocyte damage

15. Viable but Dysfunctional Myocardium:Possibility for Recovery Etiologic Factors Neurohormones (e.g. NE) Ischemia/Hibernation Myocyte Cytokines (e.g. TNF a) Hemodynamics Metabolic Gheorghiade M. JACC 2009

17. Heart Failure Potential for Recovery • The majority of patients with heart failure have a viable but dysfunctional myocardium • Total or partial recovery is possible • For recovery improving mitochondrial function is essential

18. Mitochondria in “Heart Failure” “Mitochondria are taking the center stage in our search for novel cardio vascular protective therapies, as their dysfunction appears early and invariably in the development of LV dysfunction and vascular abnormalities” Gheorghiade et al, JACC 2012

19. Translating the Basic Knowledge of Mitochondrial Functions to Metabolic Therapy Mitochondrial dysfunction is at the basis of a constellation of metabolic abnormalities that significantly contribute to Chronic conditions and diseases.

20. TreatingMitochondrialAbnormalities

21. Micronutrients in Heart Failure “Micronutrient supplementation offers the opportunity to correct deficiencies in critical myocyte pathways, including those associated with the provision of ATP (CoQ10,L-carnitine, thiamine and the B vitamins, amino acids),protein production (amino acids), intracellular calcium balance (taurine), and the reduction of oxidative stress (CoQ10 and taurine).” Gheorghiade et al, JACC 2011

24. Cardiovascular Health Recipe • Exercise • Diet • Lifestyle changes • Aggressive management/prevention • Diabetes • Hypertension • Evidence based therapies • Target mitochondrial abnormalities* *Consider micro/macro nutrients

25. Conclusion Mitochondria dysfunction contributes to the pathophysiology of insulin resistance, obesity, diabetes, vascular disease ad chronic heart failure.