Cardioprotezione ed invecchiamento

55 Congresso SIGG Invecchiamento e longevità: più geni o più ambiente? Firenze, 30/11/2010-04/12/2010 Palazzo dei Congressi SESSIONE DI BIOGERONTOLOGIA Cardioprotezione ed invecchiamento P. Abete, MD, PhD Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Cattedra di Geriatria, Università di Napoli Federico II

Cardioprotection and aging Cardioprotection: definition Myocardial stunning, hibernation, and ischemic preconditioning Cardioprotection and aging: why? Age-related reduction of cardioprotection Restoration of age-related reduction of cardioprotection Future directions

Cardioprotection: definition Myocardial ischemia is the result of an imbalance between myocardial oxygen supply and demand and it was thought to result in irreversible myocyte damage. anti-ischemic It is now demonstrated that in cardiac tissue, submitted to the vaccination!! stress of oxygen and substrate deprivation, endogenous mechanisms of cell survival may be activated. These molecular mechanisms result in physiological conditions of adaptation to ischemia defining the concept of endogenous cardioprotection. Boengler K et al. Cardiovasc Res 2009

MYOCARDIAL HIBERNATION Rahimtoola SH Circulation 1985 MYOCARDIAL STUNNING Heyndrickx GR et al. J Clin Invest 1975 ISCHEMIC PRECONDITIONING Murry CE et al. Circulation 1986

Myocardial stunning Prolonged and fully reversible dysfunction of the ischemic heart which persists after reperfusion despite the normalization of blood flow. Stunning can occur in a number of conditioning following: exercise in the presence of a flow limiting stenosis myocardial infarction where the subendocardium is infarcted and the subepicardium may be stunned for a prolonged period of time; ischemic bout that is induced by angioplasty; ect. Depre C & Vatner SF, Heart Fail Rev 2007

Myocardial stunning stunning FLOW-FUNCTION MISMATCH Reperfusion CS=Coronary Stenosis CS 100% Depre C & Vatner SF, Heart Fail Rev 2007

Myocardial hibernation Myocardial hibernation represents a condition of chronic ventricular dysfunction in patients with coronary artery disease, which is progressively reversible after revascularization. Myocardial hibernation represent a condition in which: a concomitant reduction in coronary blood flow is present; myocardial necrosis is not present; consequently, myocardial metabolism and function are both reduced. Depre C & Vatner SF, Heart Fail Rev 2007

Myocardial hibernation hibernation SMART HEART HYPOTHESIS Flow reduction to 20% Depre C & Vatner SF, Heart Fail Rev 2007

Ischemic preconditioning Ischemic preconditioning represents a protection against irreversible damage conferred by brief and repetitive episodes of occlusion/reperfusion preceding a longer episode of potentially lethal Ischemia. The phenomenon is independent of increased collateral blood flow. Ischemic preconditioning occurs in the following conditions: Preinfarction angina Warm-up phenomenon Walk through angina Coronary angioplasty Murry CE et al., Circulation 1986

Ischemic preconditioning Infarct size (%) Murry CE et al., Circulation 1986

Linking stunning, hibernation, and ischemic preconditioning There is some evidence that myocardial viability cannot be maintained during sustained moderate ischemia for more than a few hours but that chronic hibernation results from repetitive bouts of ischemia-reperfusion; Accordingly, repetitive episodes of ischemic dysfunction followed by stunning create a sustained depression of contractile function; In this context, ischemic preconditioning seems to play a key role in the cardioprotection.

Metabolic adaptation during a sequence of no-flow and low-flow ischemia Preconditioning triggers for hibernation? low-flow 2.2 ml/min 10 min. 0 - flow, Ischemic preconditioning! low-flow 2.2 ml/min Ferrari R et al., Circulation 1996

SURVIVAL HYPOTHESIS CORONARY STENOSIS Decreased blood flow at rest Decreased metabolism Decreased fuction HIBERNATION Mantained blood flow at rest Repetitive ischemia and reperfusion Chronic STUNNING Chronically depressed Contractile function activation of PRECONDITIONING Depre C & Vatner SF, Heart Fail Rev 2007

Number of patients in the USA with a heart attack according to age and sex Health Statistics, National Heart, Lung, and Blood Institute, Circulation 2007

Age-related increase in mortality among patients with first myocardial infarctions treated with thrombolysis Odds Ratio (OR) 20 15 10 61-65 10.1 5.3 (1.5-18.2) 5 76-80OR 18.9 % 20 66-70 12.214.7 (3.5-42.3) 8.5 (2.4-29.1) 0 Age CK >6 x normal 30 40 50 60 70 80 90 Age (years) Age % Mortality OR (95%CI) 80 <40 1.9 1 Mortality 41-45 OR 2.2 (95%CI) 3.7 (0.9-14.7) 60 46-50 3.1 2.0 (0.5-7.7) 51-55 3.5 % 3.1 (0.8-10.9) > 6 leads 40 (%) 0 51-55 3.5 3.1 (0.8-10.9) 56-60 5.8 3.9 (1.1-13.6) 71-75 18.9 10.1 (2.9-34.8) 76-80 18.9 12.2 (3.5-42.3) >80 31.9 18.8 (5.3-66.8) Maggioni AP et al., N Engl J Med 1993

Factors leading to shorter survival after acute myocardial infarction in patients aged 65 to 75 years compared with younger patients Mortality (%) 60 50 40 30 20 65-75 years Not adjusted p < 0.001 Mortality (%) 60 50 40 30 20 Adjusted for COMORBIDITY p < 0.02 65-75 years 10 0 < 64 years 0 12 24 36 48 10 0 < 64 years 0 12 24 36 48 Months Months Tofler GH et al, Am J Cardiol 1988

MYOCARDIAL STUNNING is more evident in senescent than in adult heart Stunning *p<0.01 vs senescent Abete P et al., Exp Gerontol 1999

MYOCARDIAL HIBERNATION reduces contractile function more in senescent than in adult heart 100 Hibernation Developed pressure (% of baseline) 80 60 40 20 * * * * 0 66 59 51 44 37 37 37 37 Coronary perfusion pressure, mmhg Abete P et al., Exp Gerontol 1999

PRECONDITIONING does not prevent postischemic dysfunction in aging heart Ischemic preconditioning B Ischemia Reperfusion B IP Ischemia Reperfusion 100 80 100 80 * * * Adult DP (%) 60 40 Adult Senescent DP (%) 60 40 Senescent 20 20 0-10 0 10 20 30 40 50 60 70 80 90 Time (min) 0-10 0 10 20 30 40 50 60 70 80 90 Time (min) P<0.001 vs senescent P. Abete et al., JACC 1996

Effect of one 5-min preconditioning cycle (1PC) and three 5-min preconditioning cycles (3PC) on infarct size in young-adult, middle-aged, and aged rat hearts Schulman D et al., J Am Physiol 2001

Angina-induced protection against myocardial infarction in adult and elderly patients: a loss of preconditioning mechanism in the aging heart? 16 14 p < 0.01 p = 0.27 (NS) Angina No Angina 12 Mortality (%) 10 8 6 4 2 0 Adults Elderly P. Abete et al., JACC 1997

5-years survival curves in adult and elderly patients with and without preinfarction angina 100 Adults 100 Elderly 80 80 Survival (%) 60 40 20 p=0.007 Preinfarction angina (+) Preinfarction angina (-) Survival (%) 60 40 20 p=0.47 (NS) Preinfarction angina (+) Preinfarction angina (-) 0 0 1 2 3 4 5 Years 0 0 1 2 3 4 5 Years Ishihara M et al., Am Heart J 2000

Myocardial ischemia evaluated by myocardial lactate extraction ratio (MLR) in adult and elderly patients during PTCA MLR (%) 60 p < 0.05 Baseline p < 0.05 Inflation 1 30 Inflation 2 0-30 -60-90 -120 p < 0.01 ADULT ELDERLY Lee T-M et al., Circulation 2002

(A) ISCHEMIC PRECONDITIONING PHASE (B) REPERFUSION INJURY SALVAGE KINASE adenosine opioids NE UCN bradykinin ANP-BNP 1 A δ α 1 UR NP A δ α 1 UR GR B 2 adenosine opioids NE UCN bradykinin IGF1-FGF-2 Reduction of NE release in response to preconditioning stimulus (Abete et al., 1996) B 2 GPCR RISK GPCR MPTP PI13K/Akt Reperfusion Injury PI13K enos NO Akt Salvage Kinase sgp GMP pgp GMP P70S6K PKG enos NO ROS p38 ERK 1/2 GSK3β (Mitochondrial Cx43 Permeability Failure of Transition translocation of Pore) PKC isoforms k ATP 4 Key role of MPTP Reduction of phosphorylating mitochondria connexin-43 (Boengler et al. 2007) 2 (Tani et al. 2001) PKC-ε PKC MPTP Enhanced dephosphorylation by protein phosphatases 3 (Fenton et al. 2005) MYOCARDIAL SURVIVAL

Drugs mimic ischemic preconditioning in different aging experimental model Nicorandil, mithocondrial ATP-K channel opener? Abete P et al., Ageing Res Rev 2009

Physical activity and mortality in older men with coronary heart disease Age-adjusted mortality (rate /1000 person years) 30 25 20 15 10 5 All cause Non-cardiovascular Cardiovascular 0 I nactive Occasional Light Moderate Moderately vigorous Vigorous Wannamethee SG et al., Lancet 1998

Body-mass index (BMI) and rate of death from cardiovascular disease Age-standardized rate (100.000 person/year) 8000 7000 6000 5000 4000 3000 2000 1000 0 23.5-24.9 28.0-29.9 >35 30-64 yr 65-74 yr 75 yr BMI Calle EE et al., N Engl J Med 1999

Lifestyle interventions in the elderly Usual aging Successful aging

Age-related reduction of ischemic preconditioning by exercise or food-restriction LVDP (% of baseline) 100 80 60 40 Exercised: 30 minutes swimming 5/days/week for 1months. Food-restriction: 60% of ad libitum fed from 12 to 24 months of age * * Ischemia - no IP Ischemia - IP 20 0 *p<0.05 vs no IP Controls Exercised Food-restricted Abete P et al., Ageing Res Rev 2009

Age-related reduction of ischemic preconditioning by exercise or food-restriction 30 Physical activity: PASE (Physical Activity Scale for the Eldelry) BMI: Body-mass index no ANGINA ANGINA In-hospital mortality (%) 20 10 0 *p<0.05 vs no ANGINA All patients * PASE >90 * BMI 19-24 Abete P et al., Ageing Res Rev 2009

Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart B IP Ischemia Riperfusion DP (%) 100 80 60 40 ADULTs SENESCENTs sedentary food-restricted trained trained and food-restricted 20 * * * 0-10 0 10 20 30 40 50 60 70 80 90 Time (mins) *p<0.05 vs SENESCENTs food-restricted and trained <0.01 vs ADULTs and SENESCENTs trained and food-restricted Abete P et al, Exp Gerontol, 2005

Mortality in elderly patient with AMI stratified for physical activity (PASE) and BMI 80 70 Mortality (%) 60 50 40 30 20 p < 0.002 p < 0.025 >27.0 p < 0.027 25.0-26.9 10 0 0-40 41-56 57-90 >90 p < 0.017 22.0-24.9 19.9-21.9 BMI PASE P. Abete et al., Eur J Card Rehab Prev 2009

Mortality in elderly patient with acute myocardial infarction stratified for physical activity (PASE) and BMI No Angina 80? 70 Mortality (%) 60 50 40 30 20 10 0 0-40 41-56 57-90 >90 p < 0.820 (NS) p < 0.452 (NS) >27.0 p < 0.3710 25.0-26.9 p < 0.392 (NS) 22.0-24.9 19.9-21.9 BMI PASE P. Abete et al., Eur J Card Rehab Prev 2009

Mortality in elderly patient with acute myocardial infarction stratified for physical activity (PASE) and BMI Angina 50% 80 70 Mortality (%) 60 50 40 30 3% p < 0.008 p < 0.028 >27.0 20 10 0 0-40 41-56 57-90 >90 25.0-26.9 p < 0.042 22.0-24.9 p < 0.023 19.9-21.9 BMI PASE P. Abete et al., Eur J Card Rehab Prev 2009

Role of preinfarction angina on mortality in elderly patient with acute myocardial infarction stratified for physical activity (PASE) and BMI Odds ratio % 7,0 3,0 2,5 2,0 1,5 1,0 0,5 0,0-0,5 sedentary overweight trained normal weight >27 26.9-25.0 24.9-22.0 21.9-19.0 PASE 0-40 41-56 57-90 > 90 BMI P. Abete et al., Eur J Card Rehab Prev 2009

Ischemic PRE-conditioning I R I R ISCHEMIA REPERFUSION PRE Ischemic POST-conditioning ISCHEMIA R I R I REPERFUSION POST

Aging mouse hearts are refractory to infarct size reduction with POST-CONDITIONING (post-pc) 100 Control Infarct size (% of LV) 80 60 40 20 * * Post-PC 0 Adult Senescent *p<0.05 vs control Przyklenk K et al., JACC 2008

AUTOPHAGY Induced by ischemic preconditioning (IPC) is essential for cardioprotection SHAM Non-IPC Transgenic mice expressing fluorescent fusion of protein mcherry-lc3 allow visualization of autophagosomes IPC Huang C et al., J Cardiovasc Trans Res, 2010

Inhibition of AUTOPHAGY reduces cardioprotection autophagy inhibitor=atg5 K130R Huang C et al., J Cardiovasc Trans Res, 2010

TAKE HOME MESSAGES Molecular mechanisms of adaptation to ischemia represent the endogenous cardioprotection. Myocardial sunning, hibernation and ischemic preconditioning represent the mechanism against myocardial ischemia in both animal and human studies. Experimental and clinical studies have demonstrated an age-related reduction of cardioprotection mechanisms. Exercise and caloric restriction are able to restore cardioprotection in the aging heart. Post-conditioning and autophagy should be taken into account in the next future.