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Scompenso cardiaco e sindromi correlate: non trascuriamo lo “sleep disorder”. Michele Emdin, Claudio Passino U.O. Medicina Cardiovascolare Fondazione Toscana Gabriele Monasterio Istituto di Fisiologia Clinica CNR, Pisa Scuola Superiore Sant’Anna. Congresso tosco-umbro FIC
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Scompenso cardiaco e sindromi correlate:non trascuriamo lo “sleep disorder” Michele Emdin,Claudio Passino U.O. Medicina Cardiovascolare Fondazione Toscana Gabriele Monasterio Istituto di Fisiologia Clinica CNR, Pisa Scuola Superiore Sant’Anna Congresso tosco-umbro FIC Montecatini Terme, 14 novembre 2007
60 sec. 30 sec. …of a patient with probable cardiac asthma: I have little doubt that this was a case of weakened and probably fatty heart, with disease of the aorta…” 0 1 2 3 4 5 6 7 8 9 1 0 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 .
Chronic heart failure:PREVALENCE of Cheyne-Stokes Respiration and Obstructive Apneas % 20* 75 * 450# 100* 34 * NB OA CSR Creteil 1994 Toronto 1999 Grenoble 1999 Cincinnati 2005 Melbourne 1999 * prospective # retrospective
Chronic heart failure: PREVALENCE of Cheyne-Stokes Respiration and Obstructive Apneas 679 patients 5 studies 44% NB AB OA 56% CSR 16% 40%
Sleep characteristics - 81 HF patients Minutes * * * Javaheri S Ital. Circulation 1998-97: 2154
Sleep characteristics - 81 HF patients Sleep efficiency Arousal/h Javaheri S Ital. Circulation 1998-97: 2154
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
CSR/PB - 85 pts CSR/PB + 65 pts Prevalence of day-time CSR/PB: Pisa 57% 43% Prevalence in previous studies: - Mortara et al, Circulation 1997: CSR/PB - 64% pts - Ponikowski et al, Circulation 1999: CSR/PB - 66% pts
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
baroreflex ergo-chemoreflex BNP - ANP system activation >>> Sympathetic - RAA activation Na - H20 retention – vasoconstriction arrhythmogenesis – tissue ischaemia arrhythmias dyspnoea fatigue sudden death oedema NEURO-HORMONAL IMBALANCE IN HEART FAILURE LV DYSFUNCTION
Cheyne-Stokes e Mortalità nello SCC 16 pazienti con SCC severo in fase di stabilità clinica età media 64 aa, FE < 35% CSR 9/16 (AHI 41± 17 vs 6 ± 5) Hanly PJ, Am J Resp Crit C M 1996;153:272
Valore prognostico del CS notturno nello SCC 62 pz con FE < 35%, NYHA II-III P Lanfranchi et al, Circulation 1999; 99:1435
Valore prognostico RP/CS durante la veglia MT LA Rovere et al., Eur Heart J 2003;
60 sec. 1 AHI < 30 / hour 0.8 EOV 0.6 AHI > 30 / hour 0.4 proportion surviving AHI > 30 / hour + EOV 0.2 p=0.0001 6 7 8 9 1 0 AHI = apnea-hypopnea index 0 0 10 20 30 months Exercise Recovery Corrà, Circulation 2006 Cheyne-Stokes Respiration during exercise in CHF: impact on PROGNOSIS .
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
16 HVR slope 15 14 R= -0.87, p<0.001 Slope = -0.378 13 12 VE/MIN (L/min) 11 10 9 8 7 6 5 SaO2 (%) 80 82 84 86 88 90 92 94 96 98 100 Hypoxic Ventilatory Response 1050 RR interval ms 700 30 Minute Ventilation L/min 0 90 PET CO2 mmHg 0 SaO2 100 % 65 0 6 TIME (min)
20 HCVR slope 18 R = 0.93, p<0.001 Slope = 1.001 16 VE/MIN (L/min) 14 12 10 8 6 36 38 40 42 44 46 48 50 52 Pet CO2 HypercapnicVentilatory Response 1050 RR interval ms 700 Minute Ventilation 30 L/min 0 90 PET CO2 mmHg 0 100 SaO2 % 65 0 6 TIME (min)
* † 20 15 Prevalence of diurnal CSR (%) Nocturnal apnea-hypopnea index 10 5 Normal chemoreflex Increased HVR Increased HCVR Increased HVR+HCVR 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]
VE/VCO2 slope peakVO2 ** 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]
NT-proBNP NorEPI BNP pg/ml ** *** *** NB CS NB CS NB 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)
CO2-sensitivity andBNP aspredictors of CSR HCVR slope Sensitivity AUC 0.93 P<0.001 BNP AUC 0.89 P<0.001 Specificity
chemoceptors Norepi BNP, ANP CSR hypoxia LV dysfunction altered haemodynamics
baroreflex ergo-chemoreflex BNP - ANP system activation >>> Sympathetic - RAA activation Na - H20 retention – vasoconstriction arrhythmogenesis – tissue ischaemia arrhythmias dyspnoea fatigue sudden death oedema NEURO-HORMONAL IMBALANCE IN HEART FAILURE LV DYSFUNCTION
60 sec. CSR in CHF: therapeutical target? • 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?
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 di Cheyne-Stokes Cheyne-Stokes persiste Considerare un trattamento specifico O2 terapia CPAP o altri device (Trapianto Cardiaco) Metilxantine
Grazie per l’attenzione! emdin@ifc.cnr.it passino@ifc.cnr.it
NYHA CLASS 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 breathing pattern of CSR-CSA better than CPAP. Therefore, bi-level PAP improves an abnormal breathing pattern more immediately and effectively than CPAP. In a recent study, it has been reported that 57% of patients showed no response to CPAP
Benefit of Atrial Pacing in Sleep Apnea SyndromeNEJM 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
CHF-N CHF-OSA CHF-CSA 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 pazienti LVEF 19.9 ± 7.2% PCP 16.5 ± 8.3 mmHg
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
Overall CO2 sensitivity vs adrenergic activation and ventilatory efficiency 70 10000 R=0.322 P<0.05 R=0.549 P<0.001 60 1000 50 NEPI (pg/ml) VE-VCO2 SLOPE 40 100 30 20 10 0.5 0.0 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 CO2 SENSITIVITY CO2 SENSITIVITY
Overall CO2 sensitivity vs B-type Natriuretic Peptides 70 10000 R=0.411 P<0.01 R=0.400 P<0.01 R=0.549 P<0.001 R=0.322 P<0.05 60 1000 50 NT-proBNP (pg/ml) BNP (pg/ml) 40 100 30 20 10 0.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 0.5 1.0 1.5 2.0 CO2 SENSITIVITY CO2 SENSITIVITY
CONCLUSIONS CSR is associated with: • Enhanced chemoceptive sensitivity to O2 and CO2 • Symptom severity and systolic dysfunction • Functional capacity and ventilatory efficiency • Adrenergic activation • BNP/NT-proBNP levels CSR is predicted by: • Enhanced chemoceptive sensitivity to CO2 • BNP plasma level