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.

Grazie per l’attenzione!

emdin@ifc.cnr.it passino@ifc.cnr.it

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