13°International Symposium Heart Failure & Co. “ My sweet Heart ” Napoli, 12-13 Aprile 2013

1. 13°International Symposium HeartFailure & Co. “MysweetHeart” Napoli, 12-13 Aprile 2013 Suscettibilità alla aritmie del miocardio nel diabetico e non: la morte improvvisa Possiblearrhythmicsusceptibilityof the myocardium in diabetes: the issueofsuddendeath. Prof. Luigi Padeletti Università degli Studi di Firenze

2. CardiovascularMortality In DiabetesMellitus Juntilla MJ et al, HeartRhythm 2010

3. CardiovascularMortality In DiabetesMellitus Juntilla MJ et al, HeartRhythm 2010

4. CardiovascularMortality In DiabetesMellitus Juntilla MJ et al, HeartRhythm 2010

5. DiabetesMellitus and Mortality P < 0.001 P < 0.001 P < 0.001 P 0.002 Cubbonet al, Diabetes & VascularDiseaseResearch 2013 P < 0.001

6. DiabetesMellitus & CardiacArrest Jouven X et al, EuropeanHeart Journal 2005

7. CardiacDamage in DiabetesMellitus Adeghate E & Singh J, HeartFailureReviews 2013

8. CardiovascularAutonomicDysfunction Pop-Busui R, J ofCardiovsc Trans Res 2012

9. CardiovascularAutonomicDysfunction Pop-Busui R, J of Cardiovasc Trans Res 2012

12. La Visione Bidimensionale dell’Appropriatezza Il concetto di appropriatezza, anche se affonda salde radici nella performance professionale, rappresenta una delle modalità per fronteggiare la cronica carenza di risorse, attraverso una loro ottimizzazione.

13. 2-years total mortalityrisk • 20-30 % pts • MUSTTMADIT IISCD-HeFT • 20% pts • MADIT IISCD-HeFT 5-8% 30-50%

14. ICD benefit as a functionof cumulative riskfactors Goldenberg I et al, J AmCollCardiol 2008

15. The MADIT-II Long-Term Risk Score Barsheshetet al,J Am CollCardiol 2012

16. Predicting Early Mortality in Recipients of ICDs Kramer D. et al. Heart Rhythm 2012;9:42– 46 Kramer DB et al, HeartRhythm 2012

17. La razionaleapplicazionedelleindicazioni per l’impiantodi ICD e CRT-D evidenzia la necessitàdiintrodurrenellacorrentepraticaclinicanuovemetodichediagnostiche in gradodiidentificareilrealerischioaritmicodeipazienti.

18. What about the neuronal side of the synaptic cleft? • In HF cardiac norepinephrine spillover is increased • In HF pts, cardiac norepinephrine spillover is a powerful prognostic predictor • In HF pts, cardiac content of norepinephrine is reduced Cardiac storage of Norepinephrine is altered in HF

19. La sinapsi noradrenergica Lo studio in vivo? Cao et al., Circulation 2000

20. SNS and ventricular myocardium SNS and HR Sinus node function Easily interrogated by ECG and Holter Limited relevance in HF progression More complex to interrogate Possible role in HF progression Sympathetic preganglionar Simpathetic postganglionar presynaptic Parasympathetic preganglionar Parasympathetic postganglionar presynaptic Visceral efferent Visceral afferent (sensory)

21. AdreView I123-Iobenguano AdreView is an imaging agent indicated for functional studies of the myocardium (sympathetic innervation) • • AdreView is 123Iodine labeled meta-iodobenzylguanidine (mIBG) • AdreView is an inactive analogue of noradrenaline, with similar uptake & storage • • AdreViewscintigraphy helps visualize the noradrenaline uptake & storage, a measure of sympathetic innervation • • AdreView uptake has been shown to be reduced in heart failure • • AdreView is therefore a marker of sympathetic damage, a potential causative factor in lethal arrhythmias AdreView Noradrenaline

22. Cardiac sympathetic innervation Normal Heart failure subject Sympathetic nervous terminal Sympathetic nervous terminal DHPG DHPG DHPG DHPG Monoamine oxidase Monoamine oxidase Noradrenaline Noradrenaline 80% <80% AdreView AdreView >20% Normal Noradrenaline reuptake Impaired Noradrenaline reuptake 20% AdreView AdreView Noradrenaline Noradrenaline β1 β1 β1 β1 α1 α1 α1 α1 Myocite Myocite H H

23. AdreView: come misura l’innervazione simpatica • L'innervazionesimpaticacardiaca è misurata dal RapportoCuore/mediastino (H/ M) =quantifica la captazionecardiaca di AdreView rapportotra uptake radioattivi: tra la ROI del cuore (H) e la ROI del Mediastinosuperiore(M), regionesenzaattivitànoradrenergica • ilrapporto H / M ha dimostrato di avere un elevatovaloreprognosticoneipazienticardiopatici • Più basso è ilrapporto H/M, maggiore è ilrischio di morbilità e di mortalità Morbilità=frequenza di malattianellapopolazione Mortalità = rapportotrailnumerodellemortiin un popolo, durante un periodo di tempo, e la quantitàdellapopolazione media dellostessoperiodo. Normal Diseased Sympathetic nervous terminal Sympathetic nervous terminal DHPG DHPG DHPG DHPG Monoamine oxidase Monoamine oxidase Noradrenaline Noradrenaline <80% 80% AdreView AdreView >20% Impaired Noradrenaline reuptake Normal Noradrenaline reuptake 20% AdreView AdreView Noradrenaline Noradrenaline β1 β1 β1 β1 α1 α1 α1 α1 Myocite Myocite M M H H Healthy subject Normal EF >60%) H/M ratio: 2.33 Heart failure subject Class IIIEF = 35% H/M ratio: 1.18

24. Danno postischemico Extent of the MIBG defect correlates with area at risk during acute coronary occlusion. These polar tomograms were obtained from a patient with an acute anterior myocardial infarction. The risk area was quantified with 99mTc-sestamibi prior to reperfusion with percutaneous coronary intervention, and infarct size was documented from repeat imaging 1 week later.31 The defect in sympathetic nerve function assessed with MIBG was significantly larger than the area of infarction and was almost identical to the original extent of myocardial ischemia. Figure source: Dr. Markus Schwaiger. Ant, anterior; Lat, lateral; Inf, inferior; Sep, septum. Fallavolita J et al, J Nucl Cardiol 2010; 17:1107-15

25. AdreView: new evidence from a Heart Failure patient study ADreView Myocardial Imaging for Risk Evaluation in Heart Failure Study Jacobson et al., JACC, 2010

26. Objective • Primary objective • To demonstrate the prognostic value of the H/M ratio of AdreView for identifying subjects at higher risk of an adverse cardiac event • Secondary objectives • To quantify the risks for adverse cardiac events due to heart failure and arrhythmias • To assess myocardial sympathetic innervation H/M ratio as a continuous variable

27. Adverse cardiac events • Heart failure progression • Progression of heart failure stage from one NYHA class to the other • NYHA II to III or IV – NYHA III to IV • Life threatening arrhythmia • Sustained ventricular tachyarrhythmia • Appropriate ICD discharge • Aborted cardiac arrest • Terminal cardiac death • Sudden Cardiac Death • Progressive heart failure death • Myocardial Infarction • Cardiac surgery complication

28. Patients characteristics *ACE inhibitors: Angiotensin Converting Enzyme Inhibitors **ARB: Angiotensin Receptor Blockers ***ARA: Aldosterone Receptor Antagonist

29. Finding The study supports a cut-off value for stratifying the risk of an adverse cardiac event H/M ratio ≥1.6 – low risk H/M ratio <1.6 – high risk

30. Kaplan-Meier estimates of ACE free probability18H/M ratio 237 subjects had an adverse cardiac event on primary analysis Separation from groups is evident within the first two months 201 subject 25 events H/M ratio ≥1.60; ACE free probability = 85% 35% greater probability of not experiencing an adverse cardiac event for patients with an H/M ratio ≥1.6 vs. those with H/M ratio <1.6 35% ACE free probability (%) 760 subjects 212 events 22 % *p=0.0001 vs H/M ratio≥1.60 H/M ratio <1.60; ACE free probability = 63% Time (months)

31. Estimates of arrhythmia free probability H/M ratio 64 patients had an arrhythmia on secondary analysis Negative Predictive Value of arrhythmia likelihood is 96% NPV 96% for arrhythmias21 201 subjects 6 arrhythmias H/M ratio≥1.60: 2-year event-free survival 96% Greater arrhythmia-free survival at 2 years for patients with H/M ratio ≥1.6 vs. those with H/M ratio of <1.6 Arrhythmia free probability (%) 760 subjects 58 arrhythmias *p=0.002 vs H/M ratio≥1.60 H/M ratio<1.60: 2-year event-free survival 85%* Time (months)

32. 50 p<0.0001 LVEF<30% 40 30 LVEF≥30% ACECumulative incidence (%) 20 10 0 0 6 12 18 24 Months Kaplan-Meier estimates of ACE incidence LVEF LVEF 30% MADIT II threshold on ACE 490 subjects 154 events 471 subjects 83 events

33. ACE incidence H/M ratio vs. LVEF H/M ratio 1.6 ADMIRE-HF threshold vs. LVEF 30% MADIT II threshold on ACE 50 LVEF<30%, H/M<1.60* *p=0.0004 †p=0.024 409 subjects 142 events 40 LVEF≥30%, H/M<1.60† 30 ACECumulative incidence (%) 81 subjects 12 events LVEF<30%, H/M≥1.60* 20 351 subjects 70 events 10 LVEF≥30%, H/M≥1.60† 120 subjects 13 events 0 0 6 12 18 24 Months H/M ratio 1.6 threshold provides additional information over EF 30% threshold

34. Correlazione tra morte cardiaca e il rapporto cuore/mediastino (H/M) alla scintigrafia con MIBG con acquisizione tardiva in pazienti con insufficienza cardiaca. Jacobson AF et al, J Am Coll Cardiol 2010

35. Difference in appropriate ICD therapy between patients with a large or small 123-I MIBG SPECT Boogers MJ et al, J Am CollCardiol 2010

36. Incidenceof Death and ArrhythmicEventsaccordingto LVEF & Heart/MediastinumRatio Shahet al, JACC: CardiovascularImaging 2012

37. DIABETIC PATIENTS: progression to HF Gerson MC et al, CircCardiovascImaging 2011

39. Il Ruolo delle Società Scientifiche Affidarsi ai principi dell’Appropriatezza, richiede una duplice revisione di posizioni, spesso estreme e conflittuali: • iprofessionisti, non devono inquadrare il principio dell’appropriatezza nella strategia dei tagli incondizionati • idecisori,accettando che perseguire l’appropriatezza non serve a ridurre i costi, ma solo ad ottimizzare l’impiego delle risorse, devono “mettere a fuoco” la dimensione dell’inappropriatezza in difetto, per non rischiare di rallentare la diffusione delle innovazioni di provata efficacia.

40. Il Ruolo delle Società Scientifiche Per attuare tale meccanismo virtuoso di valutazione occorre che le società scientifiche siano attori proattivi nell’iter di valutazione delle innovazioni tecnologiche e dei percorsi. Valutazioni “ad hoc” condivise con tutti i diversi portatori di interesse.

41. European Journal of Public Health 2011