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
P < 0.001
P < 0.001
P < 0.001
P 0.002
Cubbon et al, Diabetes & Vascular Disease Research 2013
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 II
SCD-HeFT
• 20% pts
• MADIT II
SCD-HeFT
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– 46
Kramer 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 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
La sinapsi
noradrenergica
Lo studio in vivo?
Cao et al., Circulation 2000
SNS and
ventricular
myocardium
SNS and HR
Sinus node
function
Easily
interrogated by
ECG and Holter
More complex to
interrogate
Limited
relevance in HF
progression
Possible role in HF
progression
Sympathetic preganglionar
Simpathetic postganglionar presynaptic
Parasympathetic preganglionar
Parasympathetic postganglionar presynaptic
Visceral efferent
Visceral afferent (sensory)
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
Normal
Heart failure subject
Sympathetic nervous
terminal
Sympathetic nervous
terminal
DHPG
DHPG
DHPG
DHPG
Monoamine
oxidase
Noradrenaline
80%
AdreView
Monoamine
oxidase
Noradrenaline
<80%
AdreView
Normal
Noradrenaline
reuptake
AdreView
AdreView
Noradrenaline
Noradrenaline
β1
α1
α1
>20%
Impaired
Noradrenaline
reuptake
20%
β1
β1
α1
α1
Myocite
β1
Myocite
H
H
AdreView: come misura l’innervazione simpatica
• 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
Normal
Diseased
Sympathetic
nervous terminal
Sympathetic
nervous terminal
DHPG
Monoamine
oxidase
Monoamine
oxidase
Noradrenaline
Noradrenaline
80%
AdreView
Normal
Noradrenaline
reuptake
AdreView
AdreView
α1
β1
Mortalità = rapporto tra il numero delle morti
in un popolo, durante un periodo di
tempo, e la quantità della popolazione
media dello stesso periodo.
>20%
Impaired
Noradrenaline
reuptake
20%
Noradrenaline
Noradrenaline
α1
<80%
AdreView
β1
α1
α1
β1
β1
Myocite
Myocite
M
M
• Più basso è il rapporto H/M,
maggiore è il rischio di
morbilità e di mortalità
Morbilità=frequenza di malattia nella
popolazione
DHPG
DHPG
DHPG
H
Healthy subject
Normal EF >60%)
H/M ratio: 2.33
H
Heart failure subject
Class III
EF = 35%
H/M ratio: 1.18
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: new evidence from a Heart Failure patient study
ADreView Myocardial Imaging for
Risk Evaluation in Heart Failure
Study
Jacobson et al., JACC, 2010
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
Patients characteristics
Variable
Data
Range
Mean Age (yr)
62.4
20-90
Gender (M/F) (%)
80/20
-
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
-
12.8
-
Race (White/Black/Other) (%)
2-year mortality rate (%)
*ACE inhibitors: Angiotensin Converting Enzyme Inhibitors
**ARB: Angiotensin Receptor Blockers
***ARA: Aldosterone Receptor Antagonist
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
Kaplan-Meier estimates of ACE free probability
H/M ratio
237 subjects had an adverse cardiac event on primary analysis
ACE free probability (%)
201 subject
25 events
H/M ratio ≥1.60;
ACE free probability = 85%
35%
22 %
760
subjects
212 events
*p=0.0001
vs H/M ratio≥1.60
H/M ratio <1.60;
ACE free probability =
63%
Time (months)
Separation from
groups is evident
within the
first two months
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
18
Estimates of arrhythmia free probability H/M ratio
Negative Predictive
Value of arrhythmia
likelihood is 96%
201 subjects
6 arrhythmias
NPV 96% for
arrhythmias21
Arrhythmia free probability (%)
64 patients had an arrhythmia on secondary analysis
H/M ratio≥1.60: 2-year
event-free survival 96%
Greater arrhythmiafree survival at 2 years
for patients with H/M
ratio ≥1.6 vs. those
with H/M ratio of <1.6
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)
Kaplan-Meier estimates of ACE incidence LVEF
ACE Cumulative incidence (%)
LVEF 30% MADIT II threshold on ACE
50
p<0.0001
490 subjects
154 events
40
30
LVEF<30%
LVEF≥30%
20
471 subjects
83 events
10
0
0
6
12
18
24 Months
ACE incidence H/M ratio vs. LVEF
ACE Cumulative incidence (%)
H/M ratio 1.6 ADMIRE-HF threshold vs. LVEF 30% MADIT II threshold on ACE
50
LVEF<30%, H/M<1.60*
409 subjects
142 events
*p=0.0004
40
†p=0.024
LVEF≥30%, H/M<1.60†
30
81 subjects
12 events
LVEF<30%, H/M≥1.60*
20
351 subjects
70 events
LVEF≥30%, H/M≥1.60†
10
120 subjects
13 events
0
0
6
12
18
24
Months
H/M ratio 1.6 threshold provides additional information over EF 30% threshold
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
Difference in appropriate ICD therapy between patients
with a large or small 123-I MIBG SPECT
Boogers MJ et al, J Am Coll Cardiol 2010
Incidence of Death and Arrhythmic Events according to
LVEF & Heart/Mediastinum Ratio
Shah et al, JACC: Cardiovascular Imaging 2012
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