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Scompenso cardiaco e sindromi correlate:
non trascuriamo lo “sleep disorder”
Michele Emdin, Claudio PassinoU.O. Medicina Cardiovascolare
Fondazione Toscana Gabriele MonasterioIstituto di Fisiologia Clinica CNR, Pisa
Scuola Superiore Sant’Anna
Congresso tosco-umbro FICMontecatini Terme, 14 novembre 2007
Cheyne, J.
“A case of Apoplexy, in Which the Fleshy Part of the Heart Was Converted into Fat.”Dublin Hospital Reports, 1818, II, 216.
“…For several days his breathing was irregular; it would entirely cease for a quarter of minute, then it would become perceptible, though very low, then by degrees it became heaving and quick, and then it would gradually cease again: this revolution in the state of his breathing occupied about a minute during which there were about thirty acts of
respiration...”
Stokes, W.
“Observations on some Cases of permanently slow Pulse.” Dublin Quart. Jour. Med. Sc.,1846,II,83.
“…Then a very feeble, indeed barely perceptible inspiration would take place, followed by another somewhat stronger, until at length high heaving, and even violent breathing was established, which would then subside till the next period of suspension… This
was frequently a quarter of minute in duration . I have little doubt that this was a case of weakened and probably fatty heart,
with disease of the aorta…”
…of a patient with probable cardiac asthma:60 sec.
0 1 2 3 4 5 6 7 8 9 10
30 sec.
POLYSOMNOGRAPHY
0
10
20
30
40
50
60
70
80
90
100C
inci
nnati
2005
Gre
nob
le 1
999
Cre
teil 1
994
Melb
ourn
e
1999
Toro
nto
1999
* prospective# retrospective
Chronic heart failure: PREVALENCEof Cheyne-Stokes Respiration and Obstructive
Apneas %
100* 34 * 20* 450# 75 *
NBOACSR
679 patients5 studies
NB
OACSR
44%
56%
16%
40%
AB
Chronic heart failure: PREVALENCE of Cheyne-Stokes Respiration and Obstructive
Apneas
-10
10
30
50
70
90
110
130
150
1 2 3 REM
No SASA
* *
Javaheri S Ital. Circulation 1998-97: 2154
Minutes
*
Sleep characteristics - 81 HF patients
0
20
40
60
80
100
0
20
40
60
80
100
No SASA
Javaheri S Ital. Circulation 1998-97: 2154
Sleep characteristics - 81 HF patients
Arousal/hSleep efficiency
Andamento temporale su un’epoca di 12 min della potenza dell’EEG nelle bande caratteristiche in un soggetto con scompenso cardiaco senza respiro di Cheyne-Stokes.
Andamento temporale su un’epoca di 12 min della potenza dell’EEG nelle bande caratteristiche in un soggetto con scompenso cardiaco con respiro di Cheyne-Stokes.
Analisi tramite algoritmo GSTFT
Rappresentazione tempo-frequenza del segnale EEG (C4 –A1) in un soggetto con scompenso cardiaco e respiro di Cheyne-Stokes
METODI
REGISTRAZIONE CARDIORESPIRATORIA
BREVE
CHF
patient
Prevalence in previous studies:- Mortara et al, Circulation 1997: CSR/PB - 64% pts- Ponikowski et al, Circulation 1999: CSR/PB - 66% pts
Prevalence of day-time CSR/PB: Pisa
CSR/PB -
85 pts
CSR/PB +
65 pts
57%43%
REGISTRAZIONE
CARDIORESPIRATORIA AMBULATORIALE
METODI
REGISTRAZIONE CARDIORESPIRATORIA AMBULATORIALE
Effetti clinici del respiro di CS
• Cicli di desaturazione arteriosa» Ipossia disfunzione d’organo/danno endoteliale,
vasocostrizione polmonare
• Iperattivazione simpatica» Diretta» Indiretta in risposta all’ipossia
• Effetti emodinamici (prevalentemente indiretti) FC, vasocostrizione
Aumento del post-carico e del lavoro cardiaco
• Effetti sulla variabilità della FC e PA
Effetti clinici del respiro di CS
0 200 400 600 800 1000 1200 1400 1600 1800 2000400
700
1000R-R intervals
msec
0 200 400 600 800 1000 1200 1400 1600 1800 200010
0
10Respiration
A.U.
beats
0 0.03 0.06 0.09 0.12 0.150
2 105
4 105
R-R interval PSD
0.15 0.26 0.37 0.48 0.59 0.70
200
400
R-R interval PSDmsec2/Hz
0 0.03 0.06 0.09 0.12 0.150
200
Respiration PSD
0.15 0.26 0.37 0.48 0.59 0.70
50
100Respiration PSD
A.U.2/Hz
Hz
LV
DYSFUNCTION
-NaH20 retention –vasoconstriction
arrhythmogenesis –tissue ischaemia
dyspnoea
oedema
arrhythmias sudden death
fatigue
NEURO-HORMONAL IMBALANCE IN HEART FAILURE
BNP ANPsystem activation
>>>-
baroreflex ergo-
chemoreflex
-Sympathetic RAA activation
Hanly PJ, Am J Resp Crit C M 1996;153:272
Cheyne-Stokes e Mortalità nello SCCCheyne-Stokes e Mortalità nello SCC
16 pazienti con SCC severo in fase di stabilità clinicaetà media 64 aa, FE < 35%CSR 9/16 (AHI 41± 17 vs 6 ± 5)
P Lanfranchi et al, Circulation 1999; 99:1435
Valore prognostico del CS notturno nello SCCValore prognostico del CS notturno nello SCC
62 pz con FE < 35%, NYHA II-III
.
0
1
10 20 300
0.8
0.6
0.4
0.2
p=0.03
AHI > 30 / hour
AHI < 30 / hour
months
prop
ortio
n su
rviv
ing
AHI = apnea-hypopnea index
MT LA Rovere et al., Eur Heart J 2003;
Time (months)
Pro
port
ion
Sur
vivi
ng
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 10 20 30 40 50 60
Normal Breathing (n=235)Normal Breathing (n=235)
Periodic Breathing (n=145)Periodic Breathing (n=145)
Log Rank 9.25
P = 0.0023
Log Rank 9.25
P = 0.0023
Time (months)
Pro
port
ion
Sur
vivi
ng
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 10 20 30 40 50 60
Normal Breathing (n=235)Normal Breathing (n=235)
Periodic Breathing (n=145)Periodic Breathing (n=145)
Log Rank 9.25
P = 0.0023
Log Rank 9.25
P = 0.0023
Valore prognostico RP/CS durante la vegliaValore prognostico RP/CS durante la veglia
60 sec.
.
6 7 8 9 1 0
0
1
10 20 300
0.8
0.6
0.4
0.2 p=0.0001
AHI > 30 / hour
AHI < 30 / hour
months
pro
port
ion s
urv
ivin
g
AHI = apnea-hypopnea index
EOV
AHI > 30 / hour + EOV
Corrà, Circulation 2006
Cheyne-Stokes Respiration during exercise in CHF:
impact on PROGNOSIS
Exercise Recovery
Pathogenesis of CSR in CHF: hypotheses
Central (?)
Hypocapnic (?!)
“Instability loop” (!)
- increased chemosensitivity
- prolonged circulation time
Ipotesi periferica- ipersensibilità chemocettoriale
Variazioni di PaCO2
Risposta ventilatoria eccessiva
PaCO2 sotto la soglia apneica
Apnea
PaCO2
Ripresa ventilazione
700
1050
0
30
L/min
%
0
90
65
100
mmHg
0 6TIME (min)
ms
Sa O2
PET CO2
Minute Ventilation
RR interval
Hypoxic Ventilatory Response
SaO2 (%)V
E/M
IN (
L/m
in)
R= -0.87, p<0.001Slope = -0.378
5
6
7
8
9
10
11
12
13
14
15
16
80 82 84 86 88 90 92 94 96 98 100
HVR slope
RR interval
Minute Ventilation
PET CO2
Sa O2
700
1050
0
30
L/min
%
0
90
65
100
mmHg
ms
0 6TIME (min)
HypercapnicVentilatory Response
R = 0.93, p<0.001Slope = 1.001
6
8
10
12
14
16
18
20
36 38 40 42 44 46 48 50 52V
E/M
IN (
L/m
in) HCVR slope
Pet CO2
0
20
40
60
80
Normal chemoreflex
IncreasedHVR
Pre
vale
nce
of
diur
nal C
SR (
%)
IncreasedHCVR
IncreasedHVR+HCVR
5
10
15
20
Noc
turn
al a
pnea
-hyp
opne
a in
dex* †
Giannoni A, Emdin M, Poletti R, Bramanti F, Prontera C, Piepoli M, Passino C.
Clinical significance of chemosensitivity in chronic heart failure: influence on neurohormonal derangement, Cheyne-Stokes respiration and arrhythmias. Clin Sci (Lond). 2007 Oct 26; [Epub ahead of print]
0
2
4
6
8
10
12
14
16
peakVO2
20
25
30
35
40
45
VE/VCO2 slope**
*ml/min/kg
NB CS NB CS* p<0.05, ** p<0.01
Giannoni A, Emdin M, et al.. Clin Sci (Lond). 2007 Oct 26; [Epub ahead of print]
300
350
400
450
500
550
600
650
700
NorEPI
0
100
200
300
400
500
600
700
500
1000
1500
2000
2500
3000
3500
4000
BNP NT-proBNP
pg/ml ** *** ***
NB CS NB CSNB CS
** p<0.01, *** p<0.001
Giannoni A, Emdin M, et al.. Clin Sci (Lond). 2007 Oct 26; [Epub ahead of print]
Multivariate Analysis
• CO2-sensitivity and BNP level are independent predictors of CSR
(also considering O2-sensitivity, peak VO2, VE-VCO2 slope, norepinephrine, NT-proBNP from univariate
analysis)
Specificity
Sen
sit
ivit
y
AUC 0.89P<0.001
AUC 0.93P<0.001
CO2-sensitivity and BNP as predictors of CSR
HCVR slope
BNP
chemoceptors
CSR Norepi
BNP, ANP
LV dysfunctionaltered
haemodynamics
hypoxia
LV
DYSFUNCTION
-NaH20 retention –vasoconstriction
arrhythmogenesis –tissue ischaemia
dyspnoea
oedema
arrhythmias sudden death
fatigue
NEURO-HORMONAL IMBALANCE IN HEART FAILURE
BNP ANPsystem activation
>>>-
baroreflex ergo-
chemoreflex
-Sympathetic RAA activation
60 sec.
Why?
• To improve respiratory pattern • To improve sleep quality/QOL• To improve cardiac performance• To improve prognosis (?)
When?
• Which patient?• Which marker (daytime abnormalities, PSG-AHI,
BNP, …)?How?
CSR in CHF: therapeutical target?
60 sec.Diagramma del trattamento del respiro di Cheyne Stokes nello
scompenso cardiaco Scompenso cardiaco con respiro di Cheyne-Stokes
Ottimizzare la terapia per CHF.(farmaci, CRT)
Assenza diCheyne-Stokes
Cheyne-Stokes persiste
Considerare un
trattamento specifico
(Trapianto Cardiaco)
MetilxantineO2 terapia CPAP o altri device
N Engl J Med 2005;353:2025-33.
0
0,5
1
1,5
2
2,5
3
NYHA CLASS
25
26
27
28
29
30
31
32
33
LVEF
* *%
NB CS NB CS
* p<0.05
Giannoni A, Emdin M, et al.. Clin Sci (Lond). 2007 Oct 26; [Epub ahead of print]
Effect of Theophylline on Sleep-Disordered Breathing in Heart Failure
S. Javaheri et al. NEJM August 22,1996 n8 335:562-567
Protocollo dello studio: 15 pz con scompenso cardiaco e disturbi della respirazione notturni (AHI > 10/ora). Somministrazione orale di Teofillina o placebo 2 volte die per 5 gg con una settimana di washout fra i due periodi.
Risultati: Significativa riduzione degli episodi di apnea/ipopnea rispetto al placebo:
Placebo 47 37
Teofillina 47 18
Possibili meccanismi della Teofillina:
Competizione a livello centrale con il sito recettoriale dell’Adenosina (depressore respiratorio)
Incremento del deficit ventilatorio polmonare restrittivo associato allo scompenso cardiaco
Effetto inotropo
Analisi tramite algoritmo GSTFT
Rappresentazione tempo-frequenza del segnale EEG (C4 –A1) in un soggetto con scompenso cardiaco senza respiro di Cheyne-Stokes
Bi-level PAP may fit the abnormal breathingpattern of CSR-CSA better than CPAP. Therefore,
bi-level PAP improves an abnormal breathing patternmore immediately and effectively than CPAP. In a recentstudy, it has been reported that 57% of patients showed no
response to CPAP
Benefit of Atrial Pacing in Sleep Apnea Syndrome
NEJM February 7, 2002 n 6, 346: 404-412
Stephane Garrigue, M.D., Philippe Bordier, M.D., Pierre Jaïs, M.D., Dipen C. Shah, M.D., Meleze Hocini, M.D.,
Chantal Raherison, M.D., Manuel Tunon De Lara, M.D., Michel Haïssaguerre, M.D., and Jacques Clementy, M.D.
15 pz con OSA e PM bicamerale
AHI in ritmo spontaneo: 28
AHI in ritmo elettroindotto 11 (P<0.001)
PRO CONTRO
Increased long-term mortality in heart failure due to sleep apnoea is not yet proven
T. Roebuck1, P. Solin1, D.M. Kaye2,4, P. Bergin2, M. Bailey3 and M.T. Naughton1
Eur Respir J. 2004 May; 23: 735-40
78 pazientiLVEF 19.9 ± 7.2%PCP 16.5 ± 8.3 mmHg
CHF-NCHF-N
CHF-OSACHF-OSA
CHF-CSACHF-CSA
Effetti clinici del respiro di CS
• Cicli di desaturazione arteriosa» Ipossia disfunzione d’organo/danno endoteliale,
vasocostrizione polmonare
• Iperattivazione simpatica» Diretta
» Indiretta in risposta all’ipossia
• Effetti emodinamici (prevalentemente indiretti)
FC, vasocostrizione
CO2 SENSITIVITY0.0 0.5 1.0 1.5 2.0 2.5
NEP
I (p
g/m
l)
10
100
1000
10000 R=0.322P<0.05
Overall CO2 sensitivity vs
adrenergic activation and ventilatory efficiency
CO2 SENSITIVITY
VE-V
CO
2 S
LO
PE R=0.549
P<0.001
20
30
40
50
60
70
0.0 0.5 1.0 1.5 2.0 2.5
CO2 SENSITIVITY
BN
P (
pg
/ml)
R=0.549P<0.001
20
30
40
50
60
70
0.0 0.5 1.0 1.5 2.0 2.5
CO2 SENSITIVITY0.0 0.5 1.0 1.5 2.0 2.5
NT-p
roB
NP
(p
g/m
l)
10
100
1000
10000R=0.322P<0.05
R=0.411P<0.01
R=0.400P<0.01
Overall CO2 sensitivity vs
B-type Natriuretic Peptides
CSR is associated with:
Enhanced chemoceptive sensitivity to O2 and CO2
Symptom severity and systolic dysfunctionFunctional capacity and ventilatory efficiencyAdrenergic activation BNP/NT-proBNP levels
CSR is predicted by: Enhanced chemoceptive sensitivity to CO2BNP plasma level
CONCLUSIONS