Η ΚΑΡΔΙΑΚΗ ΑΝΑΔΙΑΜΟΡΦΩΣΗΕΝΑ ΠΡΟΒΛΗΜΑ ΣΕ ΑΝΑΖΗΤΗΣΗ ΛΥΣΕΩΝ

CARDIAC REMODELINGA PROBLEM TO BE SOLVED

Η ΚΑΡΔΙΑΚΗ ΑΝΑΔΙΑΜΟΡΦΩΣΗΕΝΑ ΠΡΟΒΛΗΜΑ ΣΕ ΑΝΑΖΗΤΗΣΗ ΛΥΣΕΩΝ

CARDIAC REMODELINGA PROBLEM TO BE SOLVED

36ₒ ΠΑΝΕΛΛΗΝΙΟ ΚΑΡΔΙΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ36ₒ ΠΑΝΕΛΛΗΝΙΟ ΚΑΡΔΙΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ

Dennis V. CokkinosProfessor Emeritus, University of Athens

Director Emeritus, Onassis Cardiac Surgery CenterDirector Heart and Vessel Department

Biomedical Research Foundation Academy of Athens

Dennis V. CokkinosProfessor Emeritus, University of Athens

Director Emeritus, Onassis Cardiac Surgery CenterDirector Heart and Vessel Department

Biomedical Research Foundation Academy of Athens

29-10-201529-10-2015

ΤΙ ΕΙΝΑΙ Η ΚΑΡΔΙΑΚΗ ΑΝΑΔΙΑΜΟΡΦΩΣΗΤΙ ΕΙΝΑΙ Η ΚΑΡΔΙΑΚΗ ΑΝΑΔΙΑΜΟΡΦΩΣΗ

Οι δυσμενείς μεταβολές μυοκαρδίουΜετά κάποια βλαπτική επίδρασηΑρχικά: αντιρροπιστική, φυσιολογική ΥπερτροφίαΤαχέως: δυσμενής, παθολογικήΣτο οξύ έμφραγμα: ώρες, ημέρες

εβδομάδες, μήνες

..

Cleland JGF Vol. 20, No. 2 Dialogues in Cardiovascular Medicine 2015

REMMUST BE VIEWED AS

A UNIVERSAL PHENOMENON

REMMUST BE VIEWED AS

A UNIVERSAL PHENOMENON! Post-MIIDC, HCMValvular HDHypertensionNoxious agentsDiabetesObesityHarmancey, Wilson, Taegtmeyer Hypertension 2008;52:181-7Swynghedaw B Physiol Rev 1999;79:215-62GeneticSeidman Cell 2001;104:557-67TachycardiomyopathyVentricular excitation- sequence changes:

-RV pacing-LBBB-DyscynchronopathyBraunschweig F JACC 2013;61:1096-98

LOOKING FOR A DEFINITION OF REMLOOKING FOR A DEFINITION OF REM

go far back ↑ LVEDVI > 20% (2weeks)but : ↑ LVESVI, ↑ CI, = EF, ↓CW P, ↓LVEDP11/15 ant MI, 6/15 inf MIMc Kay et al Circ 1986;74:693-702also used in AMICI trialGaliuto JACC 2008;51:552-9↑LV ESDTardif Eur Heart J 2041;32:2507-15determines CHF incidence –GUSTO IMann Eur J Heart fail 2010;12:789-96Probably continuous measurements more correctReverse REMReduction > 10% LVESVFunaro S Eur Heart J 2004;30:566-575

With all modern Rx modalities (pPCI big 4)28-31 REM/yr post anterior MI in anterior infarctsSavoye Am J Cardiol 2006;98:1444-49Papadopoulos Am J Cardiol 2007;99:1024-25Galiuto JACC 2008;51:522-9anterior: 30% vs 17% inferiorMasci PG Eur Heart J 2011;32:1640-48By hospital discharge:19% > 20% LVEDVI, ! Anterior (38%)Giannuzzi P Am Heart J 2001;141:131-8We need to reduce LV MI size to < 20%Miura T, Miki T Basic Res Cardiol 2008;103:501-13Post –MIEarly HF onset: r infarct sizeLate >> >> : new infarctLystash JC Am J Cardiol 1995;75:653-58

MOLECULAR CHANGES OF REM!FETAL PROGRAM REEXPRESSION

MOLECULAR CHANGES OF REM!FETAL PROGRAM REEXPRESSION

Genes reexpressedββ-myosin heavy chain

Α3-Subunit of Na+-, K+-ATPaseVentricular expression of ANFGene directing myocyte lengthening (?)

Switch from fatty acid oxidation to glycolysis (not adequate)Swynghedauw B Physiological Reviews 1999;79:215-26Genes whose expression is bluntedCalcium ATPase of SR (SERCA2)β1adrenergic receptorsSwynghedauw B Physiological Reviews 1999;79:215-26tissue hypothyroidism (2-13wks)↑TRα1 (apo), ↓TRβ1Pantos C Eur J Endocrinol 2007;56:1-10↓TRα1 in CHF rats, 34 weeksPantos C…Cokkinos DV Horm Metab Res 2010;42:718-24especially in diabetic ratsCokkinos DV, Pantos C Bull Acad Natl Med 2011;195:151-65

(↑collagen)

..

Mann DL Circ Res. 2011;108:1133-45

↑inflammation, atherosclerosis acceleration↑TLRs, ROS, NF-kB, activities

Peers C…Exp Physiol 2002;87:413-22

The potential ofRanolazine

But can inducelong- termpreconditioning

REALISTIC BIOMARKERSAND CARDIAC REMODELING

REALISTIC BIOMARKERSAND CARDIAC REMODELING

NT-proBNP all around markerST2 MCP-1 galectin, cardiotrophin-1MMP 2, 8, 9Syndecan 1,4GDF 15

Most express an initially compensatory reaction

and many more

Topkara VK, Mann DL Per Med 2010;7:531-548

SYSTEMS-BASED IDENTIFICATION OF CANDIDATEMIRNAS

Devaux Y et al. Circ Cardiovasc Genet 2013;6:290-298Networks: nodes: molecular entitiesLinks: functional interconnectionsChan SY, Loscalzo J Circ Res 2012;111:359-74

Networks:Interaction, combining physicalgraph theory, computationaland statistical analysisMilo R Statistical analysisScience 2002;298:824-7

THE BORDER ZONETHE BORDER ZONE↑inflammation, apoptosis ↓autophagy-determines HFXu w-a Basic Res Cardiol 2011;106:329-42↓SERCA/PLN, contractilityDixon, Spinale J Nucl Med 2010;51:1025-1066↓SERCA/PLN, ↑Bax, caspase3, JNK, p38 MAPK, ↓Akt, Bcl2, HAX1Arvanitis DA….Cokkinos DV European Society of CardiologyCongress 2011, 27-31 August, Paris, FrancepCr/ATP by 50% (energy loss)Hu Am J Physiol 291;H648-52Ttiggers VT Fernandes Radiology 2007;245:712-719↑wall stress contributes to expansionJackson BM Am J Physiol 2003;284:H475-9Moustakidis P Circulation 2002;166:SI168-75But: preferential site of stem cell actionStrauer B-E Steinhoff G JACC 2011;58:1695-704Yap 1 (promotes cardiomyocyte survival)Del Re DP J Biol Chem 2013;288:3977-3988early regenerationMalliaras K, Marban E EMBO Mol Med 2014;6:760-77

A RECENT CONCEPT-CONDITIONING CAN BE LATE AND

CONTINUOUS

A RECENT CONCEPT-CONDITIONING CAN BE LATE AND

CONTINUOUSHypoxia – after 1 week → 1mo post-MI, rat ↓REMXu Basic Res Cardiol 2011;106:329-42remote →1mo, ratWei Circ Res 2011;108:1220-25PharmacologicOpioid δ receptors mimeticWilliams Rrichard Pharmaceuticals 2011;4:470-84Dickson Am J Physiol 2007HSP 90Kaucsár T. PLOs One 2014;9:92004Also: “Hyperconditioning”Whittaker P, Przyklenk K Dose Response 2014;12:650-663

Reduction of infarct size (→20%)Miura T, Miki T Basic Res Cardiol 2008;103:501-13But reperfusion, a mixed blessingresponsible for 40% of the size of infarctionYellon DM, Ηausenloy DJ N Engl J Med 2007;357:101-35Zhao ZQ Am J Physiol 2003;285:H57α-88

Very early therapy post pCIpost conditioning can be beneficial but mostly in ↓TnIRentoukas I JACC Intervent 2010;3:49-55pre Bøtker HE Lancet 2010;375:727-34

early reperfusion thrombolysisPrimary Percutaneous Intervention (pPCI)

Cardiov Res 2013;98:7-27

17 Studies negative in STEMI- at reperfusion14 Positive IPSC cyclosporin A*, carperitide,Hypothermia, ↑O2, exenatide, GIK15 “promising”Adenosine, bendavia (MTP)+, Impella, IGF-1Mangafodipir, melatonin, NO, nitrite,Sevoflurane, Thymosine B4, TRO40303#,metoprolol

* failed Kung TT, ESC 2015,NEJM 8/2015 > 933pts

+ failed Gibson M, ACC 2015118pts

# failed Bøtker HE, ESC 201483pts

Ruvinov et al J Cardiovasc Trans Res 2011

Previously healthy, usually one drug testedNo polymorphisms (> 50 in humans)Miura T, Miki T Basic Res Cardiol 2008; 102:59-13

ANIMALS vs HUMANSANIMALS vs HUMANS

Chronic therapyβ-blockers, ACEIs, ARBsStatins, anti-aldosterones+Myocardial Metabolism ModulatorsEtomoxir, trimetazidine. ranolazineExenatideMetformin!, glucagon-like-peptide-1Activators PPARyClenbuterolTétracyclines (doxycycline), peptides Szeto-schiller (bendavia)Anti-oxidants: quercetine. resveratrol. curcumine (alimentaire)+ failed ALBATROSS

1622 PTS, 6mo post-MIno ↓ in HFMontalescot G, ESC 2015

ΦΑΡΜΑΚΑ - ΥΠΟΣΧΕΣΕΙΣDRUG THERAPY

ΦΑΡΜΑΚΑ - ΥΠΟΣΧΕΣΕΙΣDRUG THERAPY

0 days

14 days

28 days

MI+NS 0.9%IP

MI+Rasagiline2mg/kg I

from neuroprotection to cardioprotectionErythropoietin - originally used as a neuroprotective

failed in 4 human studiesValproic acid - cardioprotective anti-REMLee TM Am J Physiol 2007;293:H968-77

Rasagiline anti-Parkinson, anti AlzheimerVarela A Journées Européennes SFC, 14-17 janvier, 2015

↓apoptosisoxidosis

EXERCISEEXERCISEHumans: ELVD-CHF trial: 6mo: ↑EF, ↓EDV, ESV, hospitalizationGiannuzzi P Circulation 2003;108:554-9anti inflammatoryNunes RB Clinics/Sao Paulo 2013;68:876-82Xu X, J Mol Cell Cardiol 2008;44:144-22Complements carvedilol and losartanVanzelli As PloS One 2013;8:e62452combined not superior to aerobic, 812 ptsHaykowsky MJ JACC 2007;49:2329-36Prior training also beneficialFreimann S JACC 2005;45:931-8improves post-LVAD exercise capacity (12-14m)↑tissue T3, TRα1, pAkt, ↓p54 JNK,LVEF: 29.5(1.5) vs 22.6(0.7), p<0.05Adamopoulos S Interactive CV Ther Surg 2013;17:664-68

AN OLD LOVE STORYHOW DOES T3 EXERT ITS ACTION?

AN OLD LOVE STORYHOW DOES T3 EXERT ITS ACTION?

A major deteminant of a -MHC – SERCA 2Van Tuyl Dev Biol 2004;272:104-17antagonizes TNF, reduces apoptosisPantos, Cokkinos Horm Metab Res 2008; 40: 1-4↓TRα1 in failing rat hearts at 34 wks. border zonePantos C…Cokkinos DV Eur J Endocrinol2007;156:415-24Eutropic, + inotropicWe must find waysto ↓ oxygen wasting effectswith β-blockers, ivabradin ?

THYROID HORMONESTHYROID HORMONES

Can prevent REM at 2wksPantos C…Cokkinos DVEur J Cardiothorac Surg 2007;32:333-913wksPantos C …Cokkinos DV Basic Res Cardiol 2008;103;308-18Also – in diabetic rats 2wksKalofoutis C Mol Cell Biochem 2000;345:161-9The post infarct diabetic 1 rat heart :tissue hypothyroidismFavorable effect of T3Cokkinos DV…Pantos C Bull Acad 2011;195:151-165Can reverse REM 13wks after MI-ratsPantos C…Cokkinos DV J Physiol Pharmacol 2009;60:49-56THiRST Preliminary results encouragingA. Pingitore ESC 2015

WHAT DRUGS DO NOT CURE IRON / FIREDOES (HIPPOCRATES )

WHAT DRUGS DO NOT CURE IRON / FIREDOES (HIPPOCRATES )

Surgery- but STICH disappointing as regards volume reductionJones N Engl J Med 2009;360:1705-17But value of surgery with viabilityHills Circulation 2006;114:I 414-19CABG probably better than PCIGimelli Inter CV Thor Surg 2003;2:301-6Slaughter N Engl J Med 2009;361:2241-51CRT- reverses REM if earlySt John Sutton Circ 2009;120:1858-65Daubert JACC 2009;54:1837-46Valve replacementLVADsIngenious interventions (parachute)

TIME and Swiss-AMI disappointingLATE TIME (2-3wks)Wollert KC Heart 2005;101:337-38Peripheral cells no EF benefit, increased 5 year mortalityDelewi R Heart 2015;101:363-368Probably: in EF < 35%, 5U gainbig studies ongoingBAMI Trial 3000ptsEF ≤ 45%, 7 daysmortality, EF: 3yrs

Progenitor cells –many seriesProgenitor cells –many series

9.2%±3.6%

6.8%±2.4%

Goussetis E, Manginas A et al, Stem Cells,2006;24:2279-83

MYOCARDIAL RETENTIONMYOCARDIAL RETENTION24ώρες επιβίωση

GENE THERAPY- real lifeGENE THERAPY- real life

SERCA-2: transport – activation-good results 3years35ptsZsebo K…Circ Res. 2014 Jan 3;114:101-8But failed : CUPID 2 234pts, EF < 35%Greenberg B ESC 2015Protein –phosphatase1 targeting smaller molecular-easierRats 3months: ↓REMMiyazaki Y…PLoS One. 2012;7:e35875del Monte F. WO 20060 29319 A2none can be effective if great myocardial loss/ fibrosisAngiogenesis: still clinically inconclusiveCochain C Antioxid redox Signal 2013;18:1100-13REGENERATION STILL A DREAM

WHERE ARE WE TODAYWHERE ARE WE TODAY

really-effective only early reperfusion

Big 2

still- always in quest for answers

β-blockersACEIs, ARBs

Άγγελος Σικελιανός

+D.D. VARONOS,CHRISTINA SPYRAKI

Prof. Zetta DaifotiC. Pantos

S. Tzeis, I. Mourouzis,P. Moraitis, I. Paizis,

D.D. Cokkinos,Ch. Xynaris,

A.D. Kokkinos,Α. Charlabas,Ε. Karamanoli,

Elissavet Kardami,Β. Swynghedauw

C. Limas,V. Voudris, A. Manginas,

G. Kolovou, S. Mavrogeni,G. Hatzigeorgiou, A. Dritsas,

E. Leontiadis, A. Demopoulos,E. Demerouti,A. Karydas

E. KraniasD. Sanoudou

K. KaraliD. Beis

Th. Tzanavari

S. ChrisanthopoulosN. Athanassiadis

C. KarpouziA.Varela

Alessandro Pingitore, MD,PhDClinical Physiology Institute, CNR, Pisa, Italy

ESC Congress, London 2015

A modest CMR improvement)

REM is becoming a major long-term problem: ↓hospital mortalitybut ↑long-term HF (71% in pts > 65 yrs)Offset by: revascularization, ACE-ARB,b-blockers, statins, nitrates, diuretics,anticoagulantsEzekowitz JACC 2009;53:13-20

..

Cleland JGF Vol. 20, No. 2 Dialogues in Cardiovascular Medicine 2015

Nicolini G et al Journal of Thyroid Research 2013

Alessandro Pingitore, MD,PhDClinical Physiology Institute, CNR, Pisa, Italy

ESC Congress, London 2015