13°International Symposium Heart Failure & Co.

“My sweet Heart”Napoli, 12-13 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

Cardiovascular Mortality In Diabetes Mellitus

Juntilla MJ et al, Heart Rhythm 2010

Cardiovascular Mortality In Diabetes Mellitus

Juntilla MJ et al, Heart Rhythm 2010

Cardiovascular Mortality In Diabetes Mellitus

Juntilla MJ et al, Heart Rhythm 2010

Diabetes Mellitus and Mortality

Cubbon et al, Diabetes & Vascular Disease Research 2013

P < 0.001 P < 0.001

P 0.002

P < 0.001

Diabetes Mellitus & Cardiac Arrest

Jouven X et al, European Heart Journal 2005

Cardiac Damage in Diabetes Mellitus

Adeghate E & Singh J, Heart Failure Reviews 2013

Cardiovascular Autonomic Dysfunction

Pop-Busui R, J of Cardiovsc Trans Res 2012

Cardiovascular Autonomic Dysfunction

Pop-Busui R, J of Cardiovasc Trans Res 2012

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.

2-years total mortality risk

• 20-30 % pts • MUSTT

MADIT IISCD-HeFT

• 20% pts• MADIT II

SCD-HeFT

5-8%

30-50%

ICD benefit as a function of cumulative risk factors

Goldenberg I et al, J Am Coll Cardiol 2008

The MADIT-II Long-Term Risk Score

Barsheshet et al, J Am Coll Cardiol 2012

Predicting Early Mortality in Recipients of ICDs

Kramer D. et al. Heart Rhythm 2012;9:42– 46Kramer DB et al, Heart Rhythm 2012

La razionale applicazione delle indicazioni per l’impianto 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.

What about the neuronal side of the synaptic cleft?

1. In HF cardiac norepinephrine spillover is increased2. In HF pts, cardiac norepinephrine spillover is a powerful

prognostic predictor3. In HF pts, cardiac content of norepinephrine is reduced

Cardiac storage of Norepinephrine is altered in HF

La sinapsi noradrenergica

Lo studio in vivo?

Cao et al., Circulation 2000

Sympathetic preganglionarSimpathetic postganglionar presynapticParasympathetic preganglionar Parasympathetic postganglionar presynaptic Visceral efferentVisceral afferent (sensory)

SNS and HR Sinus nodefunction

Easily interrogated by ECG and HolterLimited relevance in HF progression

SNS and ventricular myocardium

More complex to interrogatePossible role in HF progression

AdreView I123-IobenguanoAdreView 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• 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 arrhythmiasNoradrenaline AdreView

Cardiac sympathetic innervation

H H

Normal Heart failure subject

DHPGDHPG

Monoamine oxidase

80%

20%Normal Noradrenaline

reuptake

Noradrenaline

DHPGDHPG

Monoamine oxidase

<80%

>20%

α1 α1 α1 α1β1β1

β1β1

Noradrenaline

Noradrenaline

Sympathetic nervous terminal

Myocite

Sympathetic nervous terminal

Myocite

Impaired Noradrenaline

reuptake

Noradrenaline

AdreView

AdreView AdreView

AdreView

Healthy subjectNormal EF >60%) H/M ratio: 2.33

Heart failure subjectClass IIIEF = 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.

Normal Diseased

DHPG

DHPG

Monoamine oxidase

80%

20%Normal Noradrenaline

reuptake

Noradrenaline

DHPG

DHPG

Monoamine oxidase

<80%

>20%

H H

MM

α1 α1 α1 α1β1β1 β1

β1

Noradrenaline

Noradrenaline

Sympathetic nervous terminal

Myocite

Sympathetic nervous terminal

Myocite

Impaired Noradrenaline

reuptake

Noradrenaline

AdreView

AdreView AdreView

AdreView

AdreView: come misura l’innervazione simpatica

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

ADreView Myocardial Imaging for Risk Evaluation

in Heart Failure Study

Jacobson et al., JACC, 2010

AdreView: new evidence from a Heart Failure patient study

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

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 IVLife threatening arrhythmia• Sustained ventricular tachyarrhythmia• Appropriate ICD discharge• Aborted cardiac arrestTerminal cardiac death• Sudden Cardiac Death• Progressive heart failure death• Myocardial Infarction• Cardiac surgery complication

Variable Data RangeMean Age (yr) 62.4 20-90Gender (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 (%) 27 5-35Median Follow-up (mo) 17 0.1-27ACE Inhibitor*/ARB** (%) 94Beta Blocker (%) 92ARA*** (%) 35 -2-year mortality rate (%) 12.8 -

Patients characteristics

*ACE inhibitors: Angiotensin Converting Enzyme Inhibitors **ARB: Angiotensin Receptor Blockers ***ARA: Aldosterone Receptor Antagonist

The study supports a cut-off value for stratifying the risk of an adverse cardiac eventH/M ratio ≥1.6 – low riskH/M ratio <1.6 – high risk

Finding

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 probability18

H/M ratioAC

E fr

ee p

roba

bilit

y (%

)

Time (months)

*p=0.0001 vs H/M ratio≥1.60

H/M ratio ≥1.60; ACE free probability = 85%

22 %35%

201 subject 25 events

760 subjects212 events

H/M ratio <1.60; ACE free probability = 63%

Separation from groups is evident within the first two months

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

Arrh

ythm

ia fr

ee

prob

abili

ty (

%)

*p=0.002 vs H/M ratio≥1.60

H/M ratio<1.60: 2-year event-free survival 85%*

H/M ratio≥1.60: 2-year event-free survival 96%

201 subjects6 arrhythmias

760 subjects 58 arrhythmias

Negative Predictive Value of arrhythmia likelihood is 96% NPV 96% for arrhythmias21

Time (months)

Kaplan-Meier estimates of ACE incidence LVEF

LVEF 30% MADIT II threshold on ACEAC

E Cu

mul

ativ

e in

cide

nce

(%)

Months

LVEF<30%

LVEF≥30%

0

10

20

30

40p<0.0001

50

0 6 12 18 24

471 subjects 83 events

490 subjects 154 events

H/M ratio 1.6 ADMIRE-HF threshold vs. LVEF 30% MADIT II threshold on ACE

ACE

Cum

ulat

ive

inci

denc

e (%

)

Months

LVEF<30%, H/M<1.60*

LVEF<30%, H/M≥1.60*

0

10

20

30

40 *p=0.0004†p=0.024

50

LVEF≥30%, H/M≥1.60†

LVEF≥30%, H/M<1.60†

H/M ratio 1.6 threshold provides additional information over EF 30% threshold

ACE incidence H/M ratio vs. LVEF

0 6 12 18 24

120 subjects 13 events

351 subjects 70 events

81 subjects 12 events

409 subjects 142 events

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

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

Shah et al, JACC: Cardiovascular Imaging 2012

Incidence of Death and Arrhythmic Events according to LVEF & Heart/Mediastinum Ratio

DIABETIC PATIENTS: PROGRESSION TO HF

Gerson MC et al, Circ Cardiovasc Imaging 2011

Il Ruolo delle Società Scientifiche

Affidarsi ai principi dell’Appropriatezza, richiede una duplice revisione di posizioni, spesso estreme e conflittuali:

1. i professionisti, non devono inquadrare il principio dell’appropriatezza nella strategia dei tagli incondizionati

2. i decisori, 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.

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.

European Journal of Public Health 2011