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13°International Symposium Heart Failure & Co. My sweet Heart Napoli, 12-13 Aprile 2013 Suscettibilità alla aritmie del miocardio nel diabetico e non:

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Presentazione sul tema: "13°International Symposium Heart Failure & Co. My sweet Heart Napoli, 12-13 Aprile 2013 Suscettibilità alla aritmie del miocardio nel diabetico e non:"— Transcript della presentazione:

1 13°International Symposium Heart Failure & Co. My sweet Heart Napoli, Aprile 2013 Suscettibilità alla aritmie del miocardio nel diabetico e non: la morte improvvisa Possible arrhythmic susceptibility of the myocardium in diabetes: the issue of sudden death. Prof. Luigi Padeletti Università degli Studi di Firenze

2 Cardiovascular Mortality In Diabetes Mellitus Juntilla MJ et al, Heart Rhythm 2010

3 Cardiovascular Mortality In Diabetes Mellitus Juntilla MJ et al, Heart Rhythm 2010

4 Cardiovascular Mortality In Diabetes Mellitus Juntilla MJ et al, Heart Rhythm 2010

5 Diabetes Mellitus and Mortality Cubbon et al, Diabetes & Vascular Disease Research 2013 P < P P < 0.001

6 Diabetes Mellitus and Mortality Cubbon et al, Diabetes & Vascular Disease Research 2013 P < 0.001

7 Diabetes Mellitus & Cardiac Arrest Jouven X et al, European Heart Journal 2005

8 Cardiac Damage in Diabetes Mellitus Adeghate E & Singh J, Heart Failure Reviews 2013

9 Cardiovascular Autonomic Dysfunction Pop-Busui R, J of Cardiovsc Trans Res 2012

10 Cardiovascular Autonomic Dysfunction Pop-Busui R, J of Cardiovasc Trans Res 2012

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13 La Visione Bidimensionale dellAppropriatezza 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.

14 2-years total mortality risk % pts MUSTT MADIT II SCD-HeFT 20% pts MADIT II SCD-HeFT 30-50%

15 ICD benefit as a function of cumulative risk factors Goldenberg I et al, J Am Coll Cardiol 2008

16 The MADIT-II Long-Term Risk Score Barsheshet et al, J Am Coll Cardiol 2012

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

18 La razionale applicazione delle indicazioni per limpianto di ICD e CRT-D evidenzia la necessità di introdurre nella corrente pratica clinica nuove metodiche diagnostiche in grado di identificare il reale rischio aritmico dei pazienti.

19 What about the neuronal side of the synaptic cleft? 1.In HF cardiac norepinephrine spillover is increased 2.In HF pts, cardiac norepinephrine spillover is a powerful prognostic predictor 3.In HF pts, cardiac content of norepinephrine is reduced Cardiac storage of Norepinephrine is altered in HF

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

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

22 AdreView I123-Iobenguano AdreView is an imaging agent indicated for functional studies of the myocardium (sympathetic innervation) AdreView is 123 Iodine labeled meta-iodobenzylguanidine (mIBG) AdreView is an inactive analogue of noradrenaline, with similar uptake & storage AdreView scintigraphy 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 Noradrenaline AdreView

23 Cardiac sympathetic innervation H H NormalHeart failure subject DHPG Monoamine oxidase 80% 20% Normal Noradrenaline reuptake Noradrenaline DHPG Monoamine oxidase <80% >20% α1α1α1α1α1α1α1α1 β1β1 β1β1 β1β1 β1β1 Noradrenaline Sympathetic nervous terminal Myocite Sympathetic nervous terminal Myocite Impaired Noradrenaline reuptake Noradrenaline AdreView

24 Healthy subject Normal EF >60%) H/M ratio: 2.33 Heart failure subject Class III EF = 35% H/M ratio: 1.18 L'innervazione simpatica cardiaca è misurata dal Rapporto Cuore/mediastino (H/ M) =quantifica la captazione cardiaca di AdreView rapporto tra uptake radioattivi: tra la ROI del cuore (H) e la ROI del Mediastino superiore(M), regione senza attività noradrenergica il rapporto H / M ha dimostrato di avere un elevato valore prognostico nei pazienti cardiopatici Più basso è il rapporto H/M, maggiore è il rischio di morbilità e di mortalità Morbilità=frequenza di malattia nella popolazione Mortalità = rapporto tra il numero delle morti in un popolo, durante un periodo di tempo, e la quantità della popolazione media dello stesso periodo.morti NormalDiseased DHPG Monoamine oxidase 80% 20% Normal Noradrenaline reuptake Noradrenaline DHPG Monoamine oxidase <80% >20% H H M M α1α1α1α1 α1α1α1α1 β1β1 β1β1 β1β1 β1β1 Noradrenaline Sympathetic nervous terminal Myocite Sympathetic nervous terminal Myocite Impaired Noradrenaline reuptake Noradrenaline AdreView AdreView: come misura linnervazione simpatica

25 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:

26 Jacobson et al, J Am Coll Cardiol 2010 Incidence of Cardiac Death and H/M Ratio

27 Pre-ganglionic fiber Sympatetic nor-adrenergic Ach (nicotinic) Post-ganglionic fiber NA Pre-ganglionic fiber Sympatetic nor-adrenergic Ach (nicotinic) Post-ganglionic fiber NA !

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

29 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

30 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

31 VariableDataRange Mean Age (yr) Gender (M/F) (%)80/20- Race (White/Black/Other) (%)75/14/11- NYHA II/III (%)83/17- HF Etiology (I/NI) (%) I=Ischemic; NI=Non-ischemic 66/34- Mean LVEF (%) Median Follow-up (mo) ACE Inhibitor*/ARB** (%)94 Beta Blocker (%)92 ARA*** (%)35- 2-year mortality rate (%)12.8- Patients characteristics *ACE inhibitors: Angiotensin Converting Enzyme Inhibitors **ARB: Angiotensin Receptor Blockers ***ARA: Aldosterone Receptor Antagonist

32 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 Finding

33 237 subjects had an adverse cardiac event on primary analysis 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 Kaplan-Meier estimates of ACE free probability 18 H/M ratio ACE free probability (%) Time (months) *p= vs H/M ratio1.60 H/M ratio 1.60; ACE free probability = 85% 22 % 35% 201 subject 25 events 760 subjects 212 events H/M ratio <1.60; ACE free probability = 63% Separation from groups is evident within the first two months

34 Greater arrhythmia- free survival at 2 years for patients with H/M ratio 1.6 vs. those with H/M ratio of <1.6 Estimates of arrhythmia free probability H/M ratio 64 patients had an arrhythmia on secondary analysis Arrhythmia free probability (%) *p=0.002 vs H/M ratio1.60 H/M ratio<1.60: 2-year event-free survival 85%* H/M ratio1.60: 2-year event-free survival 96% 201 subjects 6 arrhythmias 760 subjects 58 arrhythmias Negative Predictive Value of arrhythmia likelihood is 96% NPV 96% for arrhythmias 21 Time (months)

35 Kaplan-Meier estimates of ACE incidence LVEF LVEF 30% MADIT II threshold on ACE ACE Cumulative incidence (%) Months LVEF<30% LVEF30% p< subjects 83 events 490 subjects 154 events

36 H/M ratio 1.6 ADMIRE-HF threshold vs. LVEF 30% MADIT II threshold on ACE ACE Cumulative incidence (%) Months LVEF<30%, H/M<1.60* LVEF<30%, H/M1.60* *p= p= LVEF30%, H/M1.60 LVEF30%, H/M<1.60 H/M ratio 1.6 threshold provides additional information over EF 30% threshold ACE incidence H/M ratio vs. LVEF subjects 13 events 351 subjects 70 events 81 subjects 12 events 409 subjects 142 events

37 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

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

39 Shah et al, JACC: Cardiovascular Imaging 2012 Incidence of Death and Arrhythmic Events according to LVEF & Heart/Mediastinum Ratio

40 293 patients had an adverse cardiac event in total 176 patients had heart failure progression 64 patients had an arrhythmic event 53 patients died of cardiac death Cardiac death split with 23 Sudden Cardiac Death, 24 progressive end stage heart failure, 5 Myocardial Infarction and 1 cardiac surgery complication Endpoints 21 endpointsHF Progression Arrhythmic Event Cardiac Death Total Patients # having events of the 3 types 176 subjects (60%) 64 subjects (22%- 7% of 961) 53 subjects (18%) 293

41 DIABETIC PATIENTS: PROGRESSION TO HF Gerson MC et al, Circ Cardiovasc Imaging 2011

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43 Il Ruolo delle Società Scientifiche Affidarsi ai principi dellAppropriatezza, richiede una duplice revisione di posizioni, spesso estreme e conflittuali: 1.i professionisti, non devono inquadrare il principio dellappropriatezza nella strategia dei tagli incondizionati 2.i decisori, accettando che perseguire lappropriatezza non serve a ridurre i costi, ma solo ad ottimizzare limpiego delle risorse, devono mettere a fuoco la dimensione dellinappropriatezza in difetto, per non rischiare di rallentare la diffusione delle innovazioni di provata efficacia.

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

45 European Journal of Public Health 2011


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