JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 70, NO. 11, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2017.07.740
Prognostic Significance of Central Apneas Throughout a 24-Hour Period in Patients With Heart Failure Michele Emdin, MD, PHD,a,b Gianluca Mirizzi, MD,a,b Alberto Giannoni, MD, PHD,b Roberta Poletti, MD,b Giovanni Iudice, BSC,b Francesca Bramanti, BSC,b Claudio Passino, MDa,b
ABSTRACT BACKGROUND Large trials using noninvasive mechanical ventilation to treat central apnea (CA) occurring at night (“sleep apnea”) in patients with systolic heart failure (HF) have failed to improve prognosis. The prevalence and prognostic value of CA during daytime and over an entire 24-h period are not well described. OBJECTIVES This study evaluated the occurrence and prognostic significance of nighttime, daytime, and 24-h CA episodes in a large cohort of patients with systolic HF. METHODS Consecutive patients receiving guideline-recommended treatment for HF (n ¼ 525; left ventricular ejection fraction [LVEF] of 33 9%; 66 12 years of age; 77% males) underwent prospective evaluation, including 24-h respiratory recording, and were followed-up using cardiac mortality as an endpoint. RESULTS The 24-h prevalence of predominant CAs (apnea/hypopnea index [AHI] $5 events/h, with CA of >50%) was 64.8% (nighttime: 69.1%; daytime: 57.0%), whereas the prevalence of predominant obstructive apneas (OA) was 12.8% (AHI $5 events/h with OAs >50%; nighttime: 14.7%; daytime: 5.9%). Episodes of CA were associated with neurohormonal activation, ventricular arrhythmic burden, and systolic/diastolic dysfunction (all p < 0.05). During a median 34-month follow-up (interquartile range [IQR]: 17 to 36 months), 50 cardiac deaths occurred. Nighttime, daytime, and 24-h moderate-to-severe CAs were associated with increased cardiac mortality (AHI of $15 events/h; log-rank: 6.6, 8.7, and 5.3, respectively; all p < 0.05; central apnea index [CAI] of $10 events/h; log-rank 8.9, 11.2, and 10.9, respectively; all p < 0.001). Age, B-type natriuretic peptide level, renal dysfunction, 24-h AHI, CAI, and time with oxygen saturation of <90% were independent predictors of outcome. CONCLUSIONS In systolic HF patients, CAs occurred throughout a 24-h period and were associated with a neurohormonal activation, ventricular arrhythmic burden, and worse prognosis. (J Am Coll Cardiol 2017;70:1351–64) © 2017 by the American College of Cardiology Foundation.
T Listen to this manuscript’s audio summary by
wo centuries ago, a periodic breathing
who were awake. Episodes of CA were thought to
pattern was described in patients with heart
occur only during sleep at nighttime and were
failure (HF) by the Irish physicians Cheyne
referred to as “central sleep apnea” (CSA) (4), analo-
(1) and Stokes (2). Cheyne-Stokes respiration (CSR)
gous to episodes of obstructive sleep apnea (OSA).
(3) is a rhythmic waxing and waning of respiration,
Polysomnographic studies show that CSA actually
with alternating periods of central apnea (CA)
predominates over OSA during the night in patients
episodes and deep, rapid breathing (3). Increased
with systolic HF (5–7). Central sleep apnea is associ-
central/peripheral chemosensitivity and circulatory
ated with adrenergic activation and life-threatening
time delays are pathophysiological triggers (3).
arrhythmia and has independent prognostic value in
Notably, both Cheyne and Stokes described patients
most studies (5–7).
JACC Editor-in-Chief Dr. Valentin Fuster. From the aInstitute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy; and the bFondazione Toscana Gabriele Monasterio, Pisa, Italy. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Emdin, Mirizzi, and Giannoni contributed equally to this work. Manuscript received April 17, 2017; revised manuscript received July 7, 2017, accepted July 9, 2017.
1352
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
ABBREVIATIONS AND ACRONYMS AHI = apnea/hypopnea index
Treatments for CA in HF have thus been
derivatives, theophylline, oxygen, benzodiazepines,
applied primarily during the night (8–12),
acetazolamide, continuous positive airway pressure,
with
or servoventilation.
disappointing
CANPAP
CA = central apnea CAI = central apnea index CRT = cardiac resynchronization therapy
CSA = central sleep apnea CSR = Cheyne-Stokes respiration
eGFR = estimated glomerular filtration rate
HF = heart failure IQR = Interquartile range LVEF = left ventricular ejection fraction
NB = normal breathing NT-proBNP = N-terminal pro– B-type natriuretic peptide
results.
(Canadian
Indeed,
Continuous
the
Positive
All patients underwent 2-dimensional transthoracic
Airway Pressure [C-PAP] for Patients with
echocardiogram examinations (model IE33 ultrasound
Central Sleep Apnea and Heart Failure) and
machine
SERVE-HF (Treatment of Sleep-Disordered
Systems, Palo Alto, California) (20,21), 24-h electro-
Breathing with Predominant Central Sleep
cardiography Holter recording (Elamedical, Paris,
Apnea by Adaptive Servo Ventilation in
France), symptom-limited cardiopulmonary exercise
Patients with Heart Failure) trials failed to
testing
show survival benefit and showed poor
Pennsylvania), 24-h cardiorespiratory monitoring
compliance (13,14). These negative results
(see
have been interpreted as evidence support-
including plasma catecholamines, aldosterone, renin
ing a compensatory, beneficial role of CSR in
activity, and N-terminal pro–B-type natriuretic pep-
HF (15,16), suggesting that this phenomenon
tide (NT-proBNP) levels (22). All patients also under-
should not be treated (17). Alternatively, the
went 24-h cardiorespiratory polygraphic recording for
failure of noninvasive mechanical ventilation
screening of CA occurrence during daytime, nighttime,
may be because it targets CA only during
and the entire 24-h period. All examinations were
sleep, with no effect on or even a potential
performed within a 3-day period.
rebound in daytime apnea (18).
OA = obstructive apnea
Over
OAI = obstructive apnea index OSA = obstructive sleep apnea T90 = time with oxygen
the
last
2
with
X5-1
(VMAX,
below),
transducer;
Philips
Sensormedics,
and
biohumoral
Medical
Conshohocken, characterization,
All patients gave informed consent for the study,
decades,
short-term
which was approved by the Institutional Ethics
(20-min) polygraphic recordings in up to
Committee and conducted in accordance with Decla-
500 HF patients have demonstrated that CAs
ration of Helsinki of the World Medical Association.
are present even under waking conditions
saturation <90%
(13,19) and are associated with detrimental
24-H CARDIORESPIRATORY POLYGRAPHIC RECORDING.
outcomes in HF (13,19). One study performed with a
All patients underwent 24-h continuous polygraphic
24-h polygraphic recordings (14) in 62 patients
recording, including electrocardiography, respiration
demonstrated that CSR occurred in 62% of patients
by chest and abdominal inductance plethysmography
at night and 16% of patients during the day, using
belts, nasal airflow detection, and oxygen saturation
an
(SaO 2) (Somté model PSG2, Compumedics, Abbots-
apnea/hypopnea
index
(AHI)
cutpoint
of
>15 events/h.
ford, Australia). Cardiorespiratory polygraphy was performed by experienced sleep technicians (G.I. and
SEE PAGE 1365
F.B.), who reviewed the raw data. Each analysis was
We hypothesized that sleep studies alone may not
then checked by a physician with specific relevant
adequately characterize CA, and we prospectively
clinical and research experience (A.G., M.E., or C.P.).
tested the presence, time course, and severity of CAs
According to guidelines on portable respiratory
throughout a 24-h period in a large cohort of consec-
systems (23), 3 signals were used to score respiratory
utive patients with systolic HF to define the clinical
events and to distinguish between central and
relevance and prognostic value of daytime, nighttime,
obstructive apnea episodes: 1) nasal airflow; 2) res-
and 24-h CA burden and compare it to those of OSA.
piratory activity recorded from thoracic/abdominal belts; and 3) oxygen saturation. In case of technical
METHODS
issues that made the recording indecipherable, the cardiorespiratory
PATIENT
December
POPULATION. From
2013,
525
January
consecutive
2006
patients
to
monitoring
was
immediately
repeated.
with
There were only 29 recording failures (5%) that
systolic HF (stage C [American College of Cardiology/
could not be repeated. These failures were due to
American Heart Association criteria]) and echocar-
technical issues such as loss of airflow signal (n ¼ 7),
diographic evidence of impaired left ventricular
loss of both thoracic and abdominal bands (n ¼ 10), or
systolic function (left ventricular ejection fraction
loss of oxygen saturation signal (n ¼ 12).
[LVEF] of <50%) receiving stable ($3 months)
An apnea was defined as a cessation of airflow
guideline-recommended treatment were prospec-
lasting at least 10 s. A hypopnea was defined as an
tively
severe
abnormal respiratory event lasting at least 10 s, with
pulmonary or neurological disease; thyroid dysfunc-
enrolled.
Exclusion
criteria
were
at least a 50% reduction in airflow compared to
tion; or concurrent therapy with morphine
baseline, without complete cessation, usually in
or
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
C ENTR AL I LL U STRA T I O N Apnea Spectrum in Systolic Heart Failure Patients
Emdin, M. et al. J Am Coll Cardiol. 2017;70(11):1351–64.
The prevalence of patients with NB (AHI of <5 events/h), OA (AHI of $5 events/h and >50% prevalence of obstructive apnea episodes), and CA (AHI of $5 events/h and >50% prevalence of central apnea episodes) during nighttime, daytime, and the whole 24-h period. The circadian prevalence of CA scored by AHI class of severity (mild: AHI 5 to 14.9 events/h; moderate: AHI 15 to 29.9 events/h; severe: AHI $30 events/h) is also reported. AHI ¼ apnea/hypopnea index; CA ¼ central apnea; NB ¼ normal breathing; OA ¼ obstructive apnea.
association with a reduction in SaO 2. An obstructive
previously reported (26). The average value of AHI
apnea (OA) was defined as a pause in respiration of
during the whole 24-h recording at night (10:00
>10 s associated with ongoing ventilatory effort
6:59
recorded by thoracic and abdominal bands. A central
were computed and graded in apnea severity for both
apnea was defined as a >10-s pause in respiration
OA and CA, according to the following grading
with no associated respiratory effort recorded by
system: negligible (AHI of 0 to 4.9 events/h);
thoracic and abdominal bands. Without the avail-
mild (AHI of 5 to 14.9 events/h); moderate (AHI of 15
ability of an esophageal pressure transducer or dia-
to 29.9 events/h); and severe (AHI of $30 events/h).
phragmatic
electromyogram
to
correctly
AM )
and during the daytime (7:00
AM
PM
to 9:59
to
PM )
score
Considering the potential to misclassify hypopneas
hypopneas as either central or obstructive and, given
(24,27), an analysis was also performed based only on
the poor reliability of indirect algorithms (24), hypo-
apnea episodes by using the central apnea index (CAI)
pneas were considered to follow the distribution of
and OA index (OAI). The burden of desaturation was
most of the apneic events (25). Therefore, the severity
evaluated as the minimum SaO 2 value reached and
of either CA or OA was primarily quantified by the
the time spent with SaO 2 below 90% [T90].
frequency of apnea and hypopnea episodes per hour,
ENDPOINTS. All patients were followed at the hos-
or the AHI (26). Patients were randomized to the CA
pital outpatient clinic until December 31, 2013, and
group if their AHI was $5 events/h, with >50% of
outcome status was determined from the medical
apneic events being central, or to the obstructive
records or telephone interviews with patients, rela-
apnea group if they had an AHI of $5 events/h, with
tives, or general practitioners. No patient was lost at
>50%
follow-up. The endpoint was death attributable to
of
apneic
events
being
obstructive,
as
1353
Emdin et al.
1354
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
F I G U R E 1 24-h Time Course of AHI and Central and Obstructive Apnea Indexes in Patients With Central and Obstructive Apnea
CENTRAL APNEA PATIENTS 25
25
20
20
Th
Abd
CAI, Events/h
AHI, Events/h
NF
15
10
5
SaO2
15
10
5
1 min 0 07.00 AM
11.36 AM
11.00 03.00 07.00 PM AM PM
11.00 03.00 07.00 PM AM AM
0 07.00 AM
11.00 03.00 07.00 AM PM PM
11.00 03.00 07.00 PM AM AM
OBSTRUCTIVE APNEA PATIENTS 25
25
20
20
Th
Abd
SaO2
OAI, Events/h
AHI, Events/h
NF
15
10
15
10
5
5
0 07.00 11.00 03.00 07.00 11.00 03.00 07.00 PM PM AM AM AM AM PM
0 07.00 11.00 03.00 07.00 11.00 03.00 07.00 AM AM PM PM PM AM AM
1 min 01.25 AM
(Left) Two examples of central apnea (top) and obstructive apnea (bottom). (Middle) Hourly distribution of AHI in patients with central apnea episodes (n ¼ 363 [top]) and obstructive apnea episodes (n ¼ 77 [bottom]). (Right) Hourly distribution of CAI in patients with central apnea episodes (top), and OAI in patients with OA episodes (bottom). Abd ¼ abdominal movements; AHI ¼ apnea/hypopnea index; CAI ¼ central apnea index; NF ¼ nasal flow; OA ¼ obstructive apnea; OAI ¼ obstructive apnea index; SaO2 ¼ arterial oxygen saturation; Th ¼ thoracic movements.
cardiac cause (sudden death, progressive HF-related
were stratified according to an AHI of $15 events/h
death, or acute myocardial infarction). Patients
and a CAI of $15 events/h over the 24-h, the night-
who died of noncardiac causes and those who un-
time, or the daytime period.
derwent heart transplantation or left ventricular
For univariate Cox regression analysis, the candi-
assist device implantation were censored at the time
date independent variables were selected on the basis
of the event.
of the strength of association with outcome shown by previous studies in similar populations, that is, age, were reported as
estimated glomerular filtration rate (eGFR), assessed
mean SD for normally distributed variables; other-
using the Modification of Diet in Renal Disease
STATISTICAL
ANALYSIS. Data
wise, they were expressed as median (interquartile
(MDRD) formula; plasma NT-proBNP concentrations;
range [IQR]). Mean differences between groups were
and LVEF. Other assessed variables were AHI and
evaluated using the analysis of variance or Kruskal-
CAI, computed during the night, daytime, and during
Wallis test for variables with skewed distribution,
the whole 24-h period; and OAI and T90 over the
with Bonferroni post hoc analysis. Discrete variables
whole 24-h period, all considered continuous vari-
were compared by using the chi-square test with
ables to reduce the potential loss of power associated
Yates correction or the Fisher exact test when
with dichotomization. All univariate predictors were
appropriate. Survival analysis was estimated by
entered in the backward stepwise multivariate anal-
Kaplan-Meier method and log-rank statistics; patients
ysis where AHI during the night, day, and the whole
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
F I G U R E 2 Relationship Between Nighttime and Daytime Central Apnea
A
Nighttime CAI≥10 (n = 93)
Nighttime AHI≥15 (n = 262)
Daytime CAI≥10 45% (n = 77)
Daytime AHI≥15 53% (n = 138)
Daytime CAI≥20 39% (No. = 36)
Daytime AHI≥30 15% (No. = 39)
B 80
80
R = 0.73 p = 0.001
60 Daytime CAI
Daytime AHI
60
R = 0.82 p = 0.001
40
20
40
20
0
0 0
20
40
60
80
0
20
Nighttime AHI
40
60
80
Nighttime CAI
(A) Central apnea phenomenon continuum: relative prevalence of daytime over nighttime central apnea according to graded severity with AHI and of CAI. (B) Linear correlation of nighttime and daytime AHI and CAI. Abbreviations as in Figure 1.
24-h period, alongside CAI during the night, daytime,
the daytime, the OA prevalence decreased, and the
and 24-h; and T90 values were entered in separate
CA prevalence remained predominant throughout the
models to avoid multicollinearity. The number of
24-h period.
variables included in the multivariate analysis was
Using an AHI cut off of $5 events/h, the prevalence
weighted against the number of cardiac events to
rates of patients with CA at night, during the day, and
minimize the risk of overfitting.
throughout the 24-h period were 69.1%, 57.0%, and
The predictive power of a variable was quantified
64.8%, respectively, whereas the prevalence rates of
as the area under the receiver operating characteristic
patients with OA were 14.7%, 5.9%, and 12.7%,
(ROC) curve. Analyses were performed using R
respectively (Central Illustration). In patients with
version 3.1.1 software (Vienna, Austria). A p value
predominantly CA, 94.5% of apnea episodes were of
of #0.05 was considered statistically significant.
central origin, whereas in patients with predominantly OA, 85.8% of apnea episodes were
of
RESULTS
obstructive origin.
DISTRIBUTION OF APNEA OVER 24-H. Using guide-
identifies patients with moderate-to-severe apnea,
By using a higher AHI cutoff of $15 events/h, which line definitions, prevalence rates of patients with
the prevalence rates of CAs at nighttime, daytime,
normal breathing (NB) (AHI of <5 events/h) and
and throughout the 24-h were 49.9% (24.3% AHI
those with obstructive and central apnea episodes
of $15 but <30 events/h; 25.5% AHI of $30 events/h),
($5 events/h, respectively) at night, during the day,
28.4% (20.7% AHI of $15 but <30 events/h; 7.7% AHI
and over the whole 24-h period are shown in the
of $30 events/h), and 38.2% (26.8% AHI of $15
Central Illustration. The prevalence of NB increased in
but <30 events/h; 11.4% AHI of $30 events/h),
1355
1356
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
T A B L E 1 Population Characteristics According to the Presence of Normal Breathing, Obstructive Apnea Episodes, and Central Apnea
Episodes During Nighttime All Patients
NB
OSA
CSA
Patients
525 (100.0)
85 (16.2)
77 (14.7)
363 (69.1)
Age, yrs
66 12
59 16
66 11*
67 11*
77
53
79*
81*
27.5 1.0
26.1 5.4
29.8 6.1*
27.3 4.7†
Male BMI, kg/m2 Ischemic causes NYHA functional classes I–II/III–IV
44
28
47*
47*
66/34
73/27
62/34
65/35
66 26
71 33
67 24
64 25*
LVEF, %
33 9
35 9
34 8
31 9*†
LVEDD, mm
62 8
59 8
61 8
62 8
LVEF 40%–50%
23
33
31
18*†
Moderate-to-severe mitral regurgitation
51
44
41
55†
Diastole grades II–III
44
28
35
51*†
eGFR, ml/min
18 5
19 4
19 5
17 5†
435 (295–636)
332 (243–472)
427 (321–609)
484 (309–703)*
NT-proBNP, ng/l
1,308 (502–3,333)
791 (284–2,170)
692 (345–2,487)
1,611 (708–3,744)*†
PVO2, ml/kg/min
14.9 5.2
16.8 7.0
14.8 4.3*
14.6 5.0*
33 8
30 9
31 7
34 8
Atrial fibrillation
27
19
25
30*
NSVT
44
27
27
40*†
Beta-blockers
96
94
97
96
ACE-i/ARB
93
92
95
93
MRA
76
79
71
77
CRT
26
23
23
27
TAPSE, mm Norepinephrine, ng/l
VE/VCO2 slope
ICD
28
39
40
54
19 (8.0–32.0)
3.0 (1.0–4.0)
19.0 (12.0–29.0)*
24.0 (14.0–35.0)*†
Daytime AHI, events/h
8 (2.0–16.0)
0.0 (0.0–2.0)
7.0 (4.0–11.0)*
11.0 (4.0–21.0)*†
24-h AHI, events/h
12 (5.0–21.0)
2.0 (1.0–2.5)
12.0 (8.0–18.0)*
16.0 (9.0–25.0)*†
Nighttime OAI, events/h
0.0 (0.0–1.1)
0.0 (0.0–0.0)
5.6 (2.4–13.2)*
0.0 (0.0–0.2)†
Nighttime CAI, events/h
3.0 (0.2–14.2)
0.0 (0.0–0.5)
0.4 (0.0–2.1)*
8.4 (2.0–23.0)*†
Daytime CAI, events/h
0.7 (0.0–5.5)
0.0 (0.0–0.0)
0.0 (0.0–0.7)*
2.7 (0.0–9.1)*†
24-h CAI, events/h
2.0 (0.2–9.8)
2.0 (0.2–9.8)
0.2 (0.0–1.3)*
5.5 (1.3–15.0)*†
Nighttime AHI, events/h
Minimum SaO2, % T90, min
85 (81–89)
89 (84–91)
84 (79–87)*
85 (80–88)*
7.0 (2.0–13.0)
3.0 (1.0–7.0)
9.0 (2.2–17.2)*
7.0 (2.0–14.2)*
Values are n (%), mean SD, %, or median (interquartile range [IQR]). *p < 0.05 versus NB. †p < 0.05 versus OSA. ACEi ¼ angiotensin-converting enzyme inhibitor; AHI ¼ apnea-hypopnea index; ARB ¼ angiotensin receptor blockers; BMI ¼ body mass index; CAI ¼ central apnea index; CRT ¼ cardiac resynchronization therapy; CSA ¼ central sleep apnea episodes; eGFR ¼ estimated glomerular filtration rate from Modification of Diet in Renal Disease formula; ICD ¼ implantable cardioverter-defibrillator; LVEDD ¼ left ventricular end-diastolic diameter; LVEF ¼ left ventricular ejection fraction; MRA ¼ mineralocorticoid receptor antagonists; NB ¼ normal breathers; NSVT ¼ nonsustained ventricular tachycardia; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; NYHA ¼ New York Heart Association; OAI ¼ obstructive apnea index; OSA ¼ obstructive sleep apnea; PVO2 ¼ peak oxygen consumption; SaO2 ¼ oxygen saturation; T90 ¼ time spent under 90% of oxygen saturation; TAPSE ¼ tricuspid annular plane systolic excursion; VE/VCO2 ¼ ventilation carbon dioxide production slope.
respectively, whereas the prevalence rates of OSA
at night, during the day, and over the whole 24-h
were 9.9% (6.7% AHI of $15 but <30 events/h; 3.2%
period, respectively; and for OAI of $10 events/h,
AHI of $30 events/h), 1.5% (1.1% AHI of $15 but
rates were 3.0%, 0.2%, and 0.6% for OAI of $15
<30 events/h; 0.4% AHI of $30 events/h), and 4.5%,
events/h at night, during the day, and over the whole
respectively (3.7% AHI of $15 but <30 events/h; 0.8%
24-h period, respectively.
AHI of $30 events/h) (Central Illustration).
The circadian distribution of apnea episodes is
For patients with CAI of $5 events/h, the preva-
shown in Figure 1. In patients with predominantly CA
lence rates of CA were 44.0%, 26.5%, and 36.2%,
(n ¼ 363 patients), the mean AHI decreased from 20 at
respectively, at night, during the day, and during the
night to 10 events/h during the day. Central apnea
whole 24-h period; for CAI $10 events/h, rates were
was the main contributor to the AHI in this subset
46.3%, 27.4%, and 37.9%, respectively, at night,
(highest nocturnal CAI was 15 events/h; highest day-
during the day, and during the whole 24-h period,
time CAI was 7 events/h).
respectively. The prevalence rates of OA in patients
Notably, 3% of patients experienced CA during the
with OAI of $5 events/h were 10.5%, 1.7%, and 5.5%
whole 24-h period, whereas 10% of patients showed
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
T A B L E 2 Characteristics of the Population With Predominant Obstructive Apnea According to Grading of Apnea Severity at Night
Patients (% of whole population, N ¼ 525) Age, yrs Male
AHI $30 Events/h
AHI 5–14.9 Events/h
AHI 15–29.9 Events/h
25 (5)
35 (7)
17 (3)
66 10
65 12*
69 12
80
80
76
29.3 5.7
29.1 6.3
31.9 6.2
73 15
70 25
53 24*†
44
37
29
LVEF, %
36 9
32 9
34 9
LVEDD, mm
BMI, kg/m2 eGFR, ml/min NYHA functional classes III–IV
59 7
63 8*
61 7
Moderate-to-severe mitral regurgitation
24
46
35
Diastole, grades II–III
16
43
11
19 4
19 5
19 4
TAPSE, mm Norepinephrine, ng/l
445 (260–656)
420 (308–540)
427 (344–588)
NT-proBNP, ng/l
497 (218–1,151)
818 (460–2,357)
1,614 (484–4,219)*
pVO2, ml/min/kg
14.3 4.5
16.1 4.4
12.7 3.3
31 5
32 7
32 10
Atrial fibrillation
24
29
18
NSVT
24
29
29
VE/VCO2 slope
Apnea indexes Daytime AHI, events/h
4.0 (2.0–7.0)
7.0 (4.0–11.0)*
10.0 (5.0–17.0)*†
10.0 (7.0–12.0)
20.0 (18.0–26.0)*
40.0 (33.0–46.0)*†
6.0 (4.0–8.0)
13.0 (10.0–16.0)*
23.0 (18.0–29.0)*†
2.1 (1.2–4.8)
5.6 (3.2–10.1)*
17.6 (10.7–26.9)*†
Daytime CAI, events/h
0.0 (0.0–0.4)
0.0 (0.0–0.8)
0.0 (0.0–1.6)
Nighttime CAI, events/h
0.0 (0.0–0.9)
0.6 (0.0–1.9)*
1.4 (0.0–5.1)*†
24-h CAI, events/h
0.0 (0.0–0.5)
0.3 (0.0–1.4)*
0.6 (0.0–4.5)*†
85 (81–88)
84 (77–86)
82 (73–87)*
8.0 (1.0–20)
9.5 (2.2–13.5)
9.0 (7.0–24.0)*†
Nighttime AHI, events/h 24-h AHI, events/h OAI, events/h
Minimum SaO2,% T90, min
Values are n (%), mean SD, %, or median (IQR). Data show characteristics of the population with predominant obstructive apnea (AHI $5 events/h, with >50% of obstructive apneas; n ¼ 77 patients [15%]), according to grading of apnea episode severity at night (10 PM to 6 AM). *p < 0.01 versus AHI 5 to 14.9 events/h. †p < 0.01 versus AHI 15 to 29.9 events/h. Abbreviations as in Table 1.
CA for $16 h/day, respectively, well beyond the
CLINICAL CHARACTERISTICS AND APNEA BURDEN.
physiological length of sleep time.
The clinical characteristics of the whole population
In patients with predominantly OA (n ¼ 77), the
and of the subsets with NB, OSA, and CSA are shown in
AHI decreased from 23 at night to 5 events/h during
Table 1. Patients with either CSA or OSA at night were
the daytime, and hypopneas were the main contrib-
older,
utors to the AHI values during the daytime with
frequently with ischemic causes, and had lower func-
respect to OA.
tional capacity (peak maximum rate of oxygen con-
One-half of the patients presented with moderate-
more
frequently
males,
presented
more
sumption [V O2/kg]), compared with patients with NB.
to-severe CA both at night and during the daytime
Patients with OSA had the highest body mass
(AHI of $15 events/h; n ¼ 138 out of 262 [53%])
index, whereas patients with CSA showed the worst
(Figure 2A), whereas only a few patients presented
left ventricular systolic and diastolic function and
with isolated moderate-to-severe daytime apnea
the highest severity of mitral regurgitation, neuro-
(daytime AHI of $15 events/h; nighttime AHI of
hormonal activation, and history of atrial fibrillation.
<15 events/h; n ¼ 11 out of 101 [11%]). Patients with
Nonsustained ventricular tachyarrhythmia episodes
moderate-to-severe apnea during both the day and
were more frequent in CSA patients than in patients
the night also experienced a higher night AHI than
with NB and OSA. No differences in the desaturation
patients with moderate-to-severe CA events only at
burden were found between patients with CSA and
night (39 13 events/h vs. 26 9 events/h; p < 0.001).
those with OSA.
Daytime and nighttime AHI and CAI showed a sig-
Clinical, humoral, functional, and echocardio-
nificant correlation (R ¼ 0.73 and 0.82, respectively;
graphic parameters according to severity of the
both, p < 0.01) (Figure 2B).
OSA and CA (or CSA) occurrence at night (mild vs.
1357
1358
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
T A B L E 3 Characteristics of the Population With Predominant Central Apnea According to Grading of Apnea Severity at Night
AHI 5–14.9 Events/h
AHI 15–29.9 Events/h
AHI $30 Events/h
Patients (% of whole population, N ¼ 525)
101 (19)
128 (24)
134 (26)
Age, yrs
66 12
67 11
68 11
74
81
87*
26.3 4.9
27.4 4.3
27.9 4.8*
68 31
64 21
61 22
31
30
44*
LVEF, %
31 9
31 9
30 9
LVEDD, mm
63 8
Male BMI, kg/m2 eGFR, ml/min NYHA functional classes III–IV
61 8
62 8
Moderate-to-severe mitral regurgitation
43
44
49
Diastole, grade II–III
28
32
47*
17 5
18 5
17 4
419 (275–590)
478 (299–713)
546 (357–759)*
NT-proBNP, ng/l
1,314 (598–2,819)
1,305 (655–3,614)
2,142 (933–4,510)*
pVO2, ml/min/kg
14.5 5.4
14.8 5.4
14.4 4.2
32 9
34 7
35 8
Atrial fibrillation
25
32
31
NSVT
31
39
49*
TAPSE, mm Norepinephrine, ng/l
VE/VCO2 slope
Apnea indexes Daytime AHI, events/h Nighttime AHI, events/h
3.0 (1.0–7.0)
9.5 (5.0–16.0)*
22.0 (15.0–31.0)*†
9.0 (7.0–12.0)
22.0 (18.0–25.0)*
39.0 (34.0–49.0)*† 29.0 (23.0–37.0)*†
24-h AHI, events/h
5.0 (4.0–8.0)
14.0 (11.0–18.0)*
OAI, events/h
0.0 (0.0–0.0)
0.0 (0.0–0.6)
0.0 (0.0–0.7)
Daytime CAI, events/h
0.0 (0.0–0.6)
2.4 (0.3–5.5)*
10.0 (4.1–18.0)*†
Nighttime CAI, events/h
1.2 (0.0–3.9)
7.5 (2.7–12.2)*
27.6 (17.3–37)*†
24-h CAI, events/h
0.5 (0.0–2.2)
4.8 (1.7–8.4)*
17.8 (10.8–26.0)*†
Minimum SaO2, % T90, min
87 (84–89)
86 (82–89)
82 (78–86)*
4.5 (1.2–11.7)
3.0 (1.0–9.0)
11.5 (7.0–22.5)*
Values are n (%), mean SD, %, or median (IQR). Data show characteristics of the population with predominant central apnea (AHI $5 events/h, with >50% of central apneas; n ¼ 363 patients [69%]), according to grading of apnea severity at night (10 PM to 6 AM). *p < 0.01 versus AHI 5 to 14.9 events/h. †p < 0.01 versus AHI 15 to 29.9 events/h. Abbreviations as in Table 1.
moderate vs. severe) are summarized in Tables 2 and 3,
4 to fatal myocardial infarctions). Nonsurvivors were
respectively. Conversely, Tables 4 and 5 show the
older (73 9 years of age vs. 65 12 years of age,
impact of graded severity of CAs during the daytime
respectively; p ¼ 0.001), more symptomatic (NYHA
and throughout the 24-h period, respectively.
functional class III to IV: 56.0% vs. 32.2%, respec-
Patients with severe OSA (i.e., AHI of $30 events/h)
tively; p ¼ 0.001), and showed lower LVEF (29 9%
at night showed lower eGFR and higher plasma
vs. 32 9%, respectively; p ¼ 0.01), reduced eGFR
NT-proBNP levels than patients with mild OSA. They
(44 15 ml/min vs. 68 26 ml/min, respectively;
also showed higher nighttime AHI and OAI and higher
p ¼ 0.001), and higher plasma NT-proBNP levels
daytime and 24-h AHI and OAI episodes. They also
(5475 ng/l [IQR: 2747 to 9596 ng/l] vs. 1197 ng/l
experienced a worse burden of desaturation but not
[IQR: 461 to 2719 ng/l], respectively; p ¼ 0.001).
increased plasma norepinephrine levels or worsened arrhythmic profiles.
Nonsurvivors had higher T90 levels (18.0 min [IQR: 7.5 to 27.5 min] vs. 6.5 min [IQR: 2.0 to 12.0 min],
Patients with severe CA (i.e., AHI of $30 events/h)
respectively; p ¼ 0.001), higher incidence of apnea
during nighttime, daytime, and throughout the 24 h
episodes during the daytime (AHI of 12 events/h
were more frequently males, more symptomatic, had a
[IQR: 5 to 22 events/h] vs. 8 events/h [IQR: 2 to 16
more severe diastolic dysfunction, and showed higher
events/h], respectively; p ¼ 0.021) and the whole 24-h
neurohormonal activation and ventricular arrhythmic
period (AHI of 15 events/h [IQR: 9 to 26 events/h] vs.
burden. Finally, patients with severe CA also experi-
12 events/h [IQR: 5 to 21 events/h], respectively;
enced a higher burden of desaturation.
p ¼ 0.042) but no significant differences in nighttime
SURVIVAL ANALYSIS. During a median 34-month
CAs (AHI of 24 events/h [IQR: 11 to 36 events/h] vs.
follow-up (IQR: 17 to 36 months), 50 deaths occurred
18 events/h [IQR: 8 to 32 events/h], respectively;
(41 due to HF progression, 5 to sudden cardiac deaths,
p ¼ 0.056).
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
T A B L E 4 Characteristics of the Population With Predominant Central Apnea According to Grading of Apnea Severity in the Daytime
AHI $30 Events/h
AHI 5–14.9 Events/h
AHI 15–29.9 Events/h
Patients (% of whole population, N ¼ 525)
150 (28)
109 (21)
40 (8)
Age, yrs
67 10
69 11
69 10
Males
77
90*
90*
27.4 4.4
27.6 4.5
27.8 4.4
64 23
57 22*
66 21
33
47*
42
LVEF, %
32 9
29 9
31 8
LVEDD, mm
64 8
BMI, kg/m2 eGFR, ml/min NYHA functional classes III–IV
62 9
63 8
Moderate-to-severe mitral regurgitation
47
47
50
Diastole grades II–III
35
46
52*
17 5
17 5
17 5
422 (304–626)
529 (366–797)*
549 (397–833)*
NT-proBNP, ng/l
1,381 (653–3,657)
2,203 (968–5,052)
1,792 (900–5,208)
pVO2, ml/min/kg
14.4 5.1
14.0 4.3
14.1 4.1
33 8
34 7
35 11
Atrial fibrillation
30
32
35
NSVT
45
47
50* 36.0 (32.0–44.0)*†
TAPSE, mm Norepinephrine, ng/l
VE/VCO2 slope
Apnea indexes 9.0 (7.0–11.0)
20.0 (17.0–24.0)*
Nighttime AHI, events/h
Daytime AHI, events/h
20.0 (14.0–28.0)
33.0 (24.0–40.0)*
49.0 (41.0–54.0)*†
24-h AHI, events/h
13.0 (10.0–18.0)
24.0 (20.0–30.0)*
40.0 (35.0–44.0)*†
0.0 (0.0–0.0)
0.0 (0.0–0.0)
0.0 (0.0–0.0)
Daytime CAI, events/h
OAI, events/h
2.1 (0.3–4.5)
7.2 (3.3–13.7)*
22.6 (16.1–29.9)*†
Nighttime CAI, events/h
4.5 (1.2–11.7)
17.0 (7.0–28.1)*
36.2 (26.0–44.9)*†
24–h CAI, events/h
3.4 (1.1–8.1)
12.6 (5.6–19.7)*
26.4 (21.7–33.0)*†
Minimum SaO2,%
85 (81–88)
84 (79–87)
81 (75–85)*
5.0 (1.0–12.0)
10.0 (2.7–20.2)*
16.5 (7.0–25.5)*†
T90, min
Values are n (%), mean SD, %, or median (IQR). Data show characteristics of the population with predominant central apnea (AHI $5 events/h, with >50% of central apneas; n ¼ 299 patients [57%]), according to grading of apnea severity in the daytime (7 AM to 9 AM). *p < 0.01 versus AHI 5 to 14.9 events/h. †p < 0.01 versus AHI 15 to 29.9 events/h. Abbreviations as in Table 1.
The Kaplan-Meier survival analysis comparing NB, OSA, and CSA patients is shown in Figure 3.
0.64, 0.64, and 0.7, respectively; ROC curves for 24-h AHI, CAI, and T90 are shown in Online Figure 1.
Central apnea patients demonstrated the worst prognostic profile (log-rank: 7.2; p ¼ 0.028). Either
DISCUSSION
an AHI of $15 events/h or a CAI of $10 events/h in patients with CAs was able to stratify mortality
This prospective study is the largest performed so far
(Figure 4) during nighttime, daytime, and for the
that includes the 24-h period in systolic HF patients
whole 24-h period. Patients with CAs during both
receiving guideline-recommended treatment (96%
the day and the night showed a worse prognostic
on beta-blockers, 93% on angiotensin-converting
profile than patients with CAs occurring during
enzyme inhibitors/angiotensin II receptor blockers,
nighttime only (Figure 5).
76% on mineralocorticoid antagonists, 26% with car-
Univariate analysis was performed to assess the
diac resynchronization therapy [CRT]).
relative contributions of candidate variables to
Our prospective study confirms a significant prev-
occurrence of major cardiac events. Univariate pre-
alence of CA during the night (69% AHI of $5 events/h;
dictors of increased risk of events were age, LVEF,
50% AHI of $15 events/h; 24% CAI $5 events/h). A
NT-proBNP, eGFR; night, day, and 24-h AHI; night,
significant portion of patients with significant night
day, and 24-h CAI; and T90 (Online Table 1).
CAs presented with the same phenomenon during the
With multivariate analysis, independent predictors
daytime (with a daytime AHI of $5 events/h: daytime
of events were age, NT-proBNP, eGFR, 24-h AHI;
AHI of $15 events/h was 58%: daytime CAI $5 events/h
night, day, and 24-h CAI; and T90 (Table 6). ROC
was 11%).
analyses performed for 24-h AHI, nighttime CAI,
Use of a portable monitor gave a reliable and
daytime CAI, 24-h CAI, and T90 AUC were 0.59, 0.63,
clinically informative picture of the 24-h apnea
1359
1360
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
T A B L E 5 Characteristics of the Population With Predominant Central Apnea According to Grading of Apnea Severity During the Entire 24-h
Period AHI $30 Events/h
AHI 5–14.9 Events/h
AHI 15–29.9 Events/h
Patients (% of whole population, N ¼ 525)
139 (26)
141 (27)
60 (11)
Age, yrs
65 13
69 10*
67 11
Male
78
84
92*
26.9 4.6
27.6 4.8
27.8 4.0
68 29
61 20*
64 24
29
43*
43*
LVEF, %
32 9
30 9
30 9
LVEDD, mm
64 9
BMI, kg/m2 eGFR, ml/min NYHA functional classes III–IV
62 8
62 9
Moderate-to-severe mitral regurgitation
44
43
57
Diastole grades II–III
29
42
52*
17 5
17 5
17 5
382 (248–572)
525 (317–713)*
587 (441–833)*
NT-proBNP, ng/l
1,338 (536–3,175)
2,024 (944–4,510)*
2,213 (873–4,955)*
pVO2, ml/min/kg
15.6 6.1
14.0 4.3
14.7 4.2
32 8
34 7
35 10
Atrial fibrillation
28
33
28
NSVT
45
43
60*
TAPSE, mm Norepinephrine, ng/l
VE/VCO2 slope
Apnea indexes Daytime AHI, events/h Nighttime AHI, events/h
6.0 (3.0–9.0)
16.0 (12.0–20.0)*
32.0 (26.0–38.0)*†
14.0 (10.0–18.0)
31.0 (24.0–35.0)*
48.0 (42.0–55.0)*† 38.0 (34.0–42.0)*†
24-h AHI, events/h
9.0 (6.0–12.0)
21.0 (18.0–25.0)*
OAI, events/h
0.0 (0.0–0.0)
0.0 (0.0–0.5)
0.0 (0.0–0.3)
Daytime CAI, events/h
0.5 (0.0–2.5)
5.1 (2.4–9.3)*
18.2 (12.0–26.8)*†
Nighttime CAI, events/h
2.7 (1.0–7.4)
13.9 (6.7–24.0)*
37.0 (27.6–45.3)*†
24-h CAI, events/h
1.9 (0.4–4.2)
9.8 (4.8–15.4)*
28.5 (18.8–33.0)*†
Minimum SaO2,% T90, min
86 (82–89)
85 (80–87)
81 (77–85)*
5.0 (1.0–12.0)
8.0 (2.0–13.7)
11.0 (7.0–23.0)*
Values are n (%), mean SD, %, or median (IQR). Data show characteristics of the population with predominant central apnea (AHI $5 events/h, with >50% of central apneas; n ¼ 299 patients [57%]), according to grading of apnea severity during the entire 24-h period. *p < 0.01 versus AHI 5 to 14.9 events/h. †p < 0.01 versus AHI 15 to 29.9 events/h. Abbreviations as in Table 1.
F I G U R E 3 Kaplan-Meier Survival Analysis of Normal Breathing and Obstructive and
phenomenon, with greater patient compliance and
Central Apnea Episodes at Nighttime and Cardiac Events
wider applicability to outpatient clinics than standard polysomnography. The only study using a similar 24-h analytical approach (14) recruited only 60 HF
100
Event-Free Survival (%)
patients (85% on beta-blockers, no CRT, mean LVEF of 26%) and found a similar nocturnal incidence (62%) 90
but a lower diurnal incidence (16%) of CA (using an AHI of $15 events/h). Studies by Poletti et al. (13) and La Rovere et al. (19)
80
found a prevalence of diurnal CAs of 59% and 38%, respectively, by attended 20-min short-term poly-
log-rank = 7.2 p = 0.028
graphic recordings with no grading of CA severity.
70
The higher prevalence of CAs during the night may 0
12
24
36
64 45 237
15 33 171
Months No. at risk NB OA CA
85 77 363
79 62 301
be partially explained by the removal of cortical influences on respiratory centers during sleep and by the rostral fluid shift due to supine position (28). The persistence of CA in patients who are awake in the upright position may be related to a baseline worse
Survival in patients with NB, OA, and CA during nighttime, showing an increased
hemodynamic profile, with increased pulmonary
prevalence of cardiac events in the group of CA. CA ¼ central apnea; NB ¼ normal
venous pressure and activated chemoreflex sensi-
breathing; OA ¼ obstructive apnea.
tivity overcoming the diurnal cortical outflow to respiratory centers. A similar pattern of periodic
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
F I G U R E 4 Kaplan-Meier Survival Analysis of AHI and CAI at Nighttime, Daytime, and Over the 24-h Period and Survival Free From Cardiac Death
Event-Free Survival (%)
Nighttime
24-Hour Period
100
100
90
90
90
80
log-rank = 6.6 p = 0.02 0
No. at risk AHI <15 AHI ≥15
80
80 AHI <15 AHI ≥15
70 60
Event-Free Survival (%)
Daytime
100
12
70 60
24
AHI <15 AHI ≥15 log-rank = 8.7 p = 0.003 0
36
186 262
173 207
24
36
0
147 154
107 109
301 147
268 112
216 85
250 198
160 56 100
90
90
90
80
80
80
70
No. at risk CAI <10 CAI ≥10
CAI <10 CAI ≥10
log-rank = 8.9 p = 0.003 12
70 60
24
36
249 131
24
229 151
145 71
366 82
319 61
190 111
141 75
0
36
CAI <10 CAI ≥10
log-rank = 10.9 p = 0.001 12
24
36
228 73
167 49
Months
Months 202 99
36
70 60
12
Months 280 168
CAI <10 CAI ≥10
log-rank = 11.2 p = 0.001 0
24 Months
100
0
12
Months
100
60
log-rank = 5.3 p = 0.02
60
12
Months
AHI <15 AHI ≥15
70
255 46
319 129
185 31
281 99
Survival according to AHI $15 events/h (orange) and <15 events/h (blue) (upper panels) and CAI $10 events/h (orange) and <10 events/h (blue) (lower panel) during nighttime (left), daytime (middle), and 24-h (right), showing increased cardiac mortality in subgroups with greater central apnea burden. Abbreviations as in Figure 1.
F I G U R E 5 Kaplan-Meier Survival Analysis of Increasing Circadian Apnea
breathing is sometimes observed during exercise and
Burden and Survival Free From Cardiac Death
is named exercise-induced ventilatory oscillations (29,30), although the pathophysiology of this condi-
100
The prevalence of OSA was similar to that reported by Grimm et al. (31) and lower than that reported by disparate studies (32–34). Significant variability in definition criteria, prevalence, and population characteristics may explain these controversial findings.
Event-Free Survival (%)
tion is unknown. 90
80
70
Most studies realized after the release of guidelines for home monitors (23) performed in the HF setting have used portable systems (approximately 60% after 2007) for apnea screening (31–35). Variations in prevalence are related to the apnea definition used, the specific morphometric/demographic characteristics of the
log-rank = 10.7 p = 0.005
60 0
12
24
36
147 77 76
107 58 50
Months No. at risk n-AHI<15, d-AHI <15 185 n-AHI ≥15, d-AHI <15 124 n-AHI ≥15, d-AHI ≥15 136
173 104 102
population, and the severity of HF. Compared to previous studies, no significant differences were found in our cohort in terms of age and body mass index and LVEF. However, the high prevalence of diastolic dysfunction and mitral regurgitation may have increased the rate of CAs over that of OSAs (36–38).
Survival according to combined elevated nighttime apnea/hypopnea index (n-AHI) and daytime apnea/hypopnea index (d-AHI) of $15 events/h versus isolated elevated n-AHI of $15 events/h and d-AHI of <15 events/h versus combined low n-AHI of <15 events/h and d-AHI of <15 events/h. Increasing circadian apnea burden was associated with increased cardiac mortality.
1361
1362
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
T A B L E 6 Univariate and Multivariate Cox Regression Analysis of Outcome Predictors
Multivariate Analysis Model 1
Model 2
Model 3
HR (5th–95th CI)
p Value
HR (5th–95th CI)
p Value
HR (5th–95th CI)
Age
1.05 (1.02–1.09)
0.003
1.05 (1.02–1.09)
0.003
1.05 (1.02–1.09)
p Value
0.004
NT-proBNP
1.01 (1.01–1.02)
0.001
1.01 (1.00–1.01)
0.001
1.01 (1.00–1.01)
0.001
eGFR
0.97 (0.95–0.99)
0.001
0.97 (0.95–0.99)
0.001
0.97 (0.95–0.99)
0.001
LVEF
0.98 (0.95–1.02)
0.074
0.98 (0.95–1.02)
0.074
0.99 (0.95–1.02)
0.457
Nighttime AHI
–
1.02 (0.99–1.03)
0.074
–
–
–
Daytime AHI
–
–
1.01 (0.99–1.04)
0.181
–
–
24-h AHI
–
–
–
–
1.02 (1.01–1.04)
0.049
Nighttime CAI
–
–
–
–
–
–
Daytime CAI
–
–
–
–
–
–
24-h CAI
–
–
–
–
–
–
T90
–
–
–
–
–
–
T A B L E 6 Continued Multivariate Analysis Model 4
Model 5
Model 6
Model 7
HR (5th–95th CI)
p Value
HR (5th–95th CI)
p Value
HR (5th–95th CI)
p Value
HR (5th–95th CI)
Age
1.05 (1.02–1.09)
0.004
1.05 (1.02–1.09)
0.004
1.05 (1.02–1.09)
0.004
1.02 (0.95–1.09)
p Value
0.004
NT-proBNP
1.01 (1.00–1.01)
0.001
1.01 (1.00–1.01)
0.001
1.01 (1.00–1.01)
0.001
1.01 (1.00–1.01)
0.001
eGFR
0.97 (0.95–0.99)
0.001
0.97 (0.95–0.99)
0.001
0.97 (0.95–0.99)
0.001
0.97 (0.95–0.99)
0.001
LVEF
0.99 (0.95–1.02)
0.548
0.99 (0.95–1.02)
0.548
0.99 (0.95–1.02)
0.548
0.99 (0.95–1.02)
0.548
Nighttime AHI
–
–
–
–
–
–
–
–
Daytime AHI
–
–
–
–
–
–
–
–
24-h AHI
–
–
–
–
–
–
–
–
1.02 (1.01–1.04)
0.008
–
–
–
–
–
–
Nighttime CAI Daytime CAI
–
–
1.03 (1.01–1.06)
0.010
–
–
–
–
24-h CAI
–
–
–
–
1.03 (1.01–1.05)
0.008
–
–
T90
–
–
–
–
–
–
1.03 (1.01–1.07)
0.016
CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Table 1.
Indeed, patients with CA showed worse hemodynamic
AHI of $15 events/h was accompanied by a negative
and neurohormonal profile than patients with OSA.
prognostic value either at night or daytime, only the
Severe CA phenomena during the night, daytime,
AHI computed throughout the 24-h period was inde-
or the whole circadian period were associated with
pendently associated with detrimental outcomes. The
older age and male sex, more severe symptoms,
Kaplan-Meier, Cox, and the ROC analyses showed
greater LV systolic dysfunction and dilation, and
that CAI measurements are likely more informative
worse renal function. Central apnea patients pre-
than AHI for survival prediction.
sented with neurohormonal activation (increased
In our study, T90 had an independent prognostic
plasma B-type natriuretic peptide level, a higher
value, confirming recent findings by Oldenburg et al.
adrenergic activation), and higher incidence of non-
(34). Origin of T90 is likely determined by prolonged
sustained ventricular tachyarrhythmias at 24-h elec-
circulatory time/apnea and/or increased plant gain,
trocardiography recording than patients with OSA.
due to reduced lung volume or lung diffusivity, and
Our patients with CA had worse outcomes than
may mirror hypoxia-mediated organ damage.
patients with OSA, in line with previous findings in
Conversely, the 24-h AHI and CAI are likely an
patients with HF and reduced ejection fraction
expression of the chemoreflex gain (40,41) and may
(34,39). Patients with CA are exposed to a higher
mirror
number of apnea episodes, as CAs are present
damage. Hypercapnia exerts negative effects on he-
throughout the 24-h period and not at night only as in
modynamics and arrhythmogenesis too, through
the
adrenergic
system-mediated
overactivation,
through
organ
patients with OSA (Figure 2). Patients with CA during
adrenergic
both the day and night showed worse outcomes than
stimulation. Either 24-h AHI or T90 is likely to
chemoreflex
patients with CAs present at night only. Although an
provide different and additive information.
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
STUDY
Daytime and Nighttime Central Apneas in Heart Failure
LIMITATIONS. Hypopnea
were
and worse prognosis; these are best predicted by 24-h
considered to follow the main trend of apnea epi-
episodes
AHI, CAI, and T90 as measurements of the global
sodes in our recordings, as previously suggested (25),
apnea burden. This novel observation may at least
because, first, the use of either an esophageal pres-
partially explain why previous therapeutic attempts,
sure transducer or diaphragmatic electromyography
such as continuous positive airway pressure (11) or
is impractical in a population as large as ours; and,
adaptive servoventilation (12), both targeting “sleep”
second, previous studies showed a low reliability and
apnea episodes, have failed: targeting only “sleep”
feasibility of indirect scoring algorithms for attribu-
apnea may be insufficient in patients who manifest
tion of hypopnea episodes (24). Our approach could
CAs all day. On the other hand, this could explain why
have led to underestimation of obstructive events
only adjustment or upgrade of HF therapy treatment
and imprecision of the AHI due to misclassification of
(by guideline-recommended drug therapy and cardiac
hypopneas. However, when assigning a patient to the
resynchronization) (42,43) have been associated with
CA or OSA subgroup, the percentage of prevailing
a prognostic benefit and with decreasing CA inci-
apnea episodes approached 95% of events, suggesting
dence. These treatments likely act on the patho-
that hypopneas follow the general apnea trend.
physiological triggers of CA (in this case, reduced
Respiratory recordings did not include electroen-
LVEF and hence increased circulatory time) and over
cephalographic tracings, and the sleep/awake state
the whole circadian period, thus including the subset
cannot be clearly identified. However, CA occurs
at major risk.
during the entire 24-h period, and it is unlikely that
Comprehensive evaluation of the apnea burden,
patients slept the entire time. A potential contribu-
addressing the presence of CA throughout the 24-h
tion to phases of sleep (naps) is likely and may
period, could represent a meaningful measure for
explain the peak of AHI in both patients with OSA and
assessing specific therapies for CA in the future.
patients
with
CAs
after
lunch
time.
However,
although this peak occurs on the background of a
ADDRESS
daytime AHI of <5 events/h in OSA patients, AHI is
Emdin, Cardiology and Cardiovascular Medicine Division,
FOR
CORRESPONDENCE:
Dr. Michele
constantly $5 events/h in CA patients. Furthermore,
Fondazione G. Monasterio CNR, Regione Toscana, Via
3% and 10% of patients experienced CAs during the
Giuseppe Moruzzi 1, 56124 Pisa, Italy. E-mail: emdin@
whole 24-h period or at least for $16 h/day, respec-
ftgm.it OR
[email protected].
tively, indicating a respiratory phenomenon that extended well over the physiological sleep time. The presence of CAs during wakefulness is confirmed by
PERSPECTIVES
previously attended short-time recordings (13,19). We also report prevalence rates using OAI and CAI;
COMPETENCY IN MEDICAL KNOWLEDGE: Patients with
the prognostic discriminative power of CAI in our
systolic HF often experience moderate-to-severe CA (AHI of >15
population strengthens the validity of the present
events/h) not only while asleep (60%) but also while awake
analysis and suggests a potential novel prognostic in-
(30%). An AHI of >15 events/h over 24 h (43% of patients) is
dex based on apnea episodes only for future studies.
associated with increased mortality.
CONCLUSIONS
TRANSLATIONAL OUTLOOK: Clinical trials of interventions
In patients with systolic HF, CA occurs throughout the 24-h period and is associated with neurohormonal
targeting pathophysiological triggers of CA over 24 h are needed to assess the impact of treatment on clinical outcomes.
activation, increased ventricular arrhythmic burden,
REFERENCES 1. Cheyne J. A case of apoplexy in which the fleshy part of the heart was converted into fat. Dublin
4. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of
Hospital Reports 1818;2:216–23.
acute and chronic heart failure. Eur J Heart Fail 2016;18:891–975.
2. Stokes W. The Diseases of the Heart and the Aorta. Dublin, Ireland: Hodges and Smith, 1854. 3. Emdin MG, Giannoni A, Passino C. The Breathless Heart: Apneas in Heart Failure. Basel: Springer, 2017.
5. Yumino D, Wang H, Floras JS, et al. Relationship between sleep apnoea and mortality in patients with ischaemic heart failure. Heart 2009;95:819–24. 6. Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes
respiration in chronic heart failure. Circulation 1999;99:1435–40. 7. Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med 1996;153:272–6. 8. Kasai T, Kasagi S, Maeno K, et al. Adaptive servo-ventilation in cardiac function and neurohormonal status in patients with heart failure and
1363
1364
Emdin et al.
JACC VOL. 70, NO. 11, 2017 SEPTEMBER 12, 2017:1351–64
Daytime and Nighttime Central Apneas in Heart Failure
central sleep apnea nonresponsive to continuous positive airway pressure. J Am Coll Cardiol HF 2013;1:58–63. 9. Abraham WT, Jagielski D, Oldenburg O, et al. Phrenic nerve stimulation for the treatment of central sleep apnea. J Am Coll Cardiol HF 2015;3:360–9. 10. Costanzo MR, Khayat R, Ponikowski P, et al. Mechanisms and clinical consequences of untreated central sleep apnea in heart failure. J Am Coll Cardiol 2015;65:72–84. 11. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005; 353:2025–33. 12. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med 2015;373: 1095–105. 13. Poletti R, Passino C, Giannoni A, et al. Risk factors and prognostic value of daytime CheyneStokes respiration in chronic heart failure patients. Int J Cardiol 2009;137:47–53. 14. Brack T, Thuer I, Clarenbach CF, et al. Daytime Cheyne-Stokes respiration in ambulatory patients with severe congestive heart failure is associated with increased mortality. Chest 2007; 132:1463–71. 15. Naughton
MT.
Cheyne-Stokes
respiration:
friend or foe? Thorax 2012;67:357–60. 16. Linz D, Fox H, Bitter T, et al. Impact of SERVEHF on management of sleep disordered breathing in heart failure: a call for further studies. Clin Res Cardiol 2016;105:563–70. 17. Emdin M, Passino C, Giannoni A. After the SERVE-HF Trial, is there still a need for treatment of central apnea? J Card Fail 2015;21:903–5. 18. Oldenburg O, Horstkotte D. Heart failure: central sleep apnoea in HF—what can we learn from SERVE-HF? Nat Rev Cardiol 2015;12:686–7. 19. La Rovere MT, Pinna GD, Maestri R, et al. Clinical relevance of short-term day-time breathing disorders in chronic heart failure patients. Eur J Heart Fail 2007;9:949–54. 20. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18: 1440–63. 21. Chapman CB, Ewer SM, Kelly AF, Jacobson KM, Leal MA, Rahko PS. Classification of left ventricular diastolic function using American Society of Echocardiography Guidelines: agreement among echocardiographers. Echocardiography 2013;30: 1022–31.
22. Emdin M, Passino C, Prontera C, et al. Cardiac natriuretic hormones, neuro-hormones, thyroid hormones and cytokines in normal subjects and patients with heart failure. Clin Chem Lab Med 2004;42:627–36. 23. Collop NA, Anderson WM, Boehlecke B, et al. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable Monitoring Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2007;3:737–47. 24. Randerath WJ, Treml M, Priegnitz C, Stieglitz S, Hagmeyer L, Morgenstern C. Evaluation of a noninvasive algorithm for differentiation of obstructive and central hypopneas. Sleep 2013; 36:363–8. 25. Ryan CM, Floras JS, Logan AG, et al. Shift in sleep apnoea type in heart failure patients in the CANPAP trial. Eur Respir J 2010;35:592–7. 26. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 2008;52:686–717. 27. Luo YM, Tang J, Jolley C, et al. Distinguishing obstructive from central sleep apnea events: diaphragm electromyogram and esophageal pressure compared. Chest 2009;135:1133–41. 28. Yumino D, Redolfi S, Ruttanaumpawan P, et al. Nocturnal rostral fluid shift: a unifying concept for the pathogenesis of obstructive and central sleep apnea in men with heart failure. Circulation 2010; 121:1598–605.
chronic heart failure. Eur Respir J 2007;30:1023. author reply 1023–4. 34. Oldenburg O, Wellmann B, Buchholz A, et al. Nocturnal hypoxaemia is associated with increased mortality in stable heart failure patients. Eur Heart J 2016;37:1695–703. 35. Grimm W, Sosnovskaya A, Timmesfeld N, Hildebrandt O, Koehler U. Prognostic impact of central sleep apnea in patients with heart failure. J Card Fail 2015;21:126–33. 36. Chenuel BJ, Smith CA, Skatrud JB, Henderson KS, Dempsey JA. Increased propensity for apnea in response to acute elevations in left atrial pressure during sleep in the dog. J Appl Physiol (1985) 2006;101:76–83. 37. Solin P, Bergin P, Richardson M, Kaye DM, Walters EH, Naughton MT. Influence of pulmonary capillary wedge pressure on central apnea in heart failure. Circulation 1999;99:1574–9. 38. Bitter T, Faber L, Hering D, Langer C, Horstkotte D, Oldenburg O. Sleep-disordered breathing in heart failure with normal left ventricular ejection fraction. Eur J Heart Fail 2009;11: 602–8. 39. Bitter T, Westerheide N, Prinz C, et al. CheyneStokes respiration and obstructive sleep apnoea are independent risk factors for malignant ventricular arrhythmias requiring appropriate cardioverter-defibrillator therapies in patients with congestive heart failure. Eur Heart J 2011;32: 61–74. 40. Giannoni A, Emdin M, Bramanti F, et al. Combined increased chemosensitivity to hypoxia and hypercapnia as a prognosticator in heart failure. J Am Coll Cardiol 2009;53: 1975–80.
29. Corra U, Giordano A, Bosimini E, et al. Oscillatory ventilation during exercise in patients with chronic heart failure: clinical correlates and prognostic implications. Chest 2002;121:1572–80.
41. Giannoni A, Emdin M, Poletti R, et al. Clinical significance of chemosensitivity in chronic heart failure: influence on neurohormonal derangement, Cheyne-Stokes respiration and arrhythmias. Clin Sci 2008;114:489–97.
30. Leite JJ, Mansur AJ, de Freitas HF, et al. Periodic breathing during incremental exercise predicts mortality in patients with chronic heart
42. Kohnlein T, Welte T. Does beta-blocker treatment influence central sleep apnoea? Respir Med 2007;101:850–3.
failure evaluated for cardiac transplantation. J Am Coll Cardiol 2003;41:2175–81.
43. Sinha AM, Skobel EC, Breithardt OA, et al. Cardiac resynchronization therapy improves cen-
31. Grimm W, Apelt S, Timmesfeld N, Koehler U. Sleep-disordered breathing in patients with implantable cardioverter-defibrillator. Europace 2013;15:515–22.
tral sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure. J Am Coll Cardiol 2004;44:68–71.
32. MacDonald M, Fang J, Pittman SD, White DP, Malhotra A. The current prevalence of sleep disordered breathing in congestive heart failure patients treated with beta-blockers. J Clin Sleep Med 2008;4:38–42. 33. Oldenburg O, Lamp B, Freudenberg G, Horstkotte D. Screening for sleep-disordered breathing is recommended in patients with
KEY WORDS central apnea, heart failure, obstructive sleep apnea, prognosis
A PPE NDI X For a supplemental figure and table, please see the online version of this article.