Olivier CAZORLA. Effet délétère de l exercice sur la fonction cardiaque: modèles animaux

Transcription

1 Olivier CAZORLA Physiologie et Médecine Expérimentale du cœur et des muscles PHYMEDEXP INSERM U1046, CNRS UMR9214, Université de Montpellier CHU Arnaud de Villeneuve Stress physiologique et physiopathologique: le stress dans tous ces états Effet délétère de l exercice sur la fonction cardiaque: modèles animaux Montpellier, 21 septembre 2018 TC4-Physiopathologie Intégrée 2018 olivier.cazorla@inserm.fr

2 Plan du cours 1. Extreme sport and Heart: the facts in Humans 2. Hypothesis 3. Experimental datas (published, unpublished)

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4 Circulation. 2014;129:

5 Lancet, 2016;63

6 Current Physical Activity Guidelines Adults: 30 mins of moderate intensity physical activity at least 5 days per week or 25 min vigorous activity 3 days per week Children: at least 60 minutes per day of moderate intensity physical activity. (Chief Medical Officers Report 2004)

7 The U-shaped relationship between exercise and cardiac morbidity Merghani et al, 2015 Trends in cardiovascular medicine Energy expenditure or metabolic equivalents (METs) while sitting quietly for 1 min

8 No study showed that intense exercise is dangerous for health 60-90% of runners are hurt every year Sport, Good for the health??? Too Much, Too Soon, Too Hard, Too Fast.

9 Philippides Laurent Vidal Battle of Marathon (490 BC) 31 years, 10 November 2015, SCD at home

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11 Better characterize the cardiovascular effects of intense prolonged exercise Exercise Related Sudden Cardiac Death rare event 1/ 50,000 French database estimating 800 sudden deaths of athletes in Hospital cardiology unit of Montpellier, 4 cases of sudden cardiac death were declared in 2015 in highly trained triathletes under 35 years old. Interestingly most of the deaths concern men (90%).

12 Exercice intense? Marathon 42,195 km 2 million marathon participants each year in Europe. High Intensity Moderate Duration 2to 4h of effort Triathlon longue distance (Ironman) 3,8 km 180 km 42,195 km 10to 15h of effort High Intensity High Duration Ultra-trails 80 more 300 km Moderate Intensity VERY High Duration 10to 150h of effort

13 Extreme sport and Heart Introduction Prolonged Exhaustive Exercise Marathon, Triathlon Ironman PEE Transient cardiac dysfunction Cardiac fatigue Neilan et al George et al Shave et al. 2010

14 EXERCISE INDUCED CARDIAC DAMAGE Raised cardiac troponin levels post race Myocardial fibrosis EXERCISE INDUCED CARDIAC FATIGUE Impaired left ventricular function Mostly diastolic function and then systolic

15 Eur Heart J Apr;33(8):

16 Impact à cours terme : la "fatigue cardiaque" Utilisation du Doppler tissulaire Marathon de Londres Diminution de la relaxation intrinsèque

17 Extreme sport and Heart Intrinsic dysfunction Cir Cardiovasc Imaging 2009;2: Before & After 2007 Embrun triathlon in the french Alps (4.000 m height difference) 3.8km swimming, 186 km cycling and 42 km running heures

18 Extreme sport and Heart Intrinsic dysfunction Alteration in untwisting of the heart during relaxation phase reducing LV diastolic suction and early filling

19 Relationship duration- intensity Triathlon Ironman High Intensity High Duration Function RV Function diastolique LV Function systolique LV ctni Marathon High Intensity Moderate Duration FunctionRV Function diastolique LV? Function systolique LV? ctni Nottin et al., Circ Cardiovasc Im, 2009 Oxborough et al., Echocardiography, 2010 Vitielloet al, Int J Cardiol, 2016 Ultra-trails Moderate Intensity VERY High Duration Function RV Function diastolique LV Function systolique LV ctni Maufraiset al, Am J PhysiolHeartCircPhysiol, 2016 George et al., Clin Physiol Funct Imaging, 2016

20 Extreme sport and Cardiac dysfunction Why cardiac dysfunction after each exhausting exercise session???? Dehydratation and reduction of blood volume??? Desensitization of the beta-adrenergic receptors??? Intrinsic alterations??? Oxidative Stress

21 4hours 65% MAV

22 Catecholamines and troponin release

23 In vivo cardiac dysfunction Causes????

24 Causes: Loading conditions? Heart rate? Circulating factor? Intrinsic? Ex-vivo Isolated heart Ex vivo Isolated heart = intrinsic dysfunction

25 ??? Desensitization of the beta-adrenergic receptors Stimulation with isoprenaline Same beta-adrenergic response beta-ar desentization

26 conclusion Animal model with transient in vivo dysfunction Intrinsic cardiac dysfunction No beta-adrenergic desentization Molecular mechanisms During intense exercise????? Oxidative Stress

27 Involvement of Oxidative Stress in Myocardial Dysfunction APO = apocynin = NADPH oxidase inhibitor Oxidative Stress = Yes it is

28 ROS and contractile -métabolisme- function Oxidative stress = overproduction of ROS and/or decrease of antoxidant defenses ROS:reactive oxygen species contraction Myeloperoxydase

29 Cardiac factories -métabolisme- of oxidants contraction 0 2 NADPH oxidase

30 Cardiac oxidants -métabolisme- & targets ROS:reactive oxygen species RNS:reactive nitrogen species contraction 0 2 NADPH oxidase superoxide R0 R00 0H ROS RNS peroxide H hydroxyl ONOO - N0 N0 2 Peroxynitrite Ca 2+ release Basal level Normal function High level (heart failure) Cell dysfunction Cell death

31 Excitation-contraction -métabolisme- coupling: antioxidants contraction gluthatione peroxidase (GPX) Allen, Lamb & Westerblad, Physio Rev 2008 (hydroxyl radical) gluthatione (GSH)

32 Excitation-contraction -métabolisme- coupling: antioxidants contraction gluthatione peroxidase (GPX) gluthatione (GSH) Allen, Lamb & Westerblad, Physio Rev 2008 (hydroxyl radical) Moderate exercise training is well recognized today as one of the most efficient cardioprotective strategies, notably through the enhancement of myocardial antioxidant status ( for review Radak et al, Systemic adaptation to oxidative challenge induced by regular exercise. Free Radic Biol Med Jan 15;44(2): )

33 Excitation-contraction -métabolisme- coupling: antioxidants contraction Allen, Lamb & Westerblad, Physio Rev 2008

34 Post-translationnal modifications of proteins: example the contractile machinery oxydation phosphorylation

35 Post-translationnal modifications of proteins: example the contractile machinery oxydation phosphorylation

36 Objective : Explore the molecular mechanisms underlying the transient cardiac dysfunction induced by acute prolonged intense exercise. Cardiac function in vivo? GS-MyBP-C Chakouri et al, Int J Cardiol 2018

37 Acute moderate and Prolonged Exhaustive Exercise Exercise protocol Isolated Langendorff perfused heart (ex vivo) Skinned myocyte (in vitro) Biochemical analysis

38 Ex vivo cardiac alterations Langendorff isolated heart LV Developped Pressure (mmhg) Ctrl PEE PEE+ NAC dp/dt max (mmhg.s -1 ) Ctrl PEE PEE+ NAC dp/dt min (mmhg.s -1 ) * Ctrl PEE PEE+ NAC Diastolic dysfunction

39 Ex vivo cardiac alterations Langendorff isolated heart NAC= N-acetyl cysteine (ROS scavenger and GSH precursor) LV Developped Pressure (mmhg) Ctrl PEE PEE+ NAC dp/dt max (mmhg.s -1 ) Ctrl PEE PEE+ NAC dp/dt min (mmhg.s -1 ) * Ctrl PEE PEE+ NAC Diastolic dysfunction Oxidative stress dependent

40 Myofilament contractility Unpublished data Permeabilized myocyte Ctrl PEE CTRL PEE Decreased maximal tension Increased calcium sensitivity and passive tension

41 Take home message Prolonged Exhaustive Exercise

42 Take home message Prolonged Exhaustive Exercise

43 Répétition de l exercise intense

44 Arrhythmia/Electrophysiology Cardiac Arrhythmogenic Remodeling in a Rat Model of Long-Term Intensive Exercise Training Begon a Benito, MD*; Gemma Gay-Jordi, PhD*; Anna Serrano-Mollar, PhD; Eduard Guasch, MD; Yanfen Shi, MD; Jean-Claude Tardif, MD; Josep Brugada, MD, PhD; Stanley Nattel, MD ; Lluis Mont, MD, PhD Circulation. 2011;123: m/min

45 CONCLUSIONS: cardiac fibrosis after long-term intensive exercise training, together with changes in ventricular function and increased arrhythmia inducibility. If our findings are confirmed in humans, the results would support the notion that long-term vigorous endurance exercise training may in some cases promote adverse remodeling and produce a substrate for cardiac arrhythmias.

46 Repeated EEE may be associated with cardiac fibrosis and dysrhythmias, particularly AF exercise-induced cardiomyopathy

47 Take home message Although the risks of long distance, intense exercise, such as marathons is low, this is not necessary from a health stand-point! For health, More is Not Better and may be Worse!