Prognostic Significance of Central Apneas Throughout a 24-Hour Period in Patients With Heart Failure

Prognostic Significance of Central Apneas Throughout a 24-Hour Period in Patients With Heart Failure

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 ...

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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
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.

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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

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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),

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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.

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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).

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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

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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.

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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,

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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.