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 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
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
• 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
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
AdreViewAdreView
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
β1β1
Noradrenaline
Noradrenaline
Sympathetic nervous terminal
Myocite
Sympathetic nervous terminal
Myocite
Impaired Noradrenaline
reuptake
Noradrenaline
AdreView
AdreViewAdreView
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 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
Variable Data Range
Mean Age (yr) 62.4 20-90
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 (%) 27 5-35
Median Follow-up (mo) 17 0.1-27
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
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
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 ratio
AC
E f
ree p
rob
ab
ilit
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
Arr
hyth
mia
fre
e
pro
bab
ilit
y (
%)
*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 ACEA
CE
Cu
mu
lati
ve in
cid
en
ce (
%)
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
AC
E C
um
ula
tive in
cid
en
ce (
%)
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
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