Background The risk of sudden death from cardiac causes in thegeneral population peaks from 6 a.m. to noon and has a nadirfrom midnight to 6 a.m. Obstructive sleep apnea is highly prevalentand associated with neurohormonal and electrophysiological abnormalitiesthat may increase the risk of sudden death from cardiac causes,especially during sleep.
Methods We reviewed polysomnograms and the death certificatesof 112 Minnesota residents who had undergone polysomnographyand had died suddenly from cardiac causes between July 1987and July 2003. For four intervals of the day, we compared therates of sudden death from cardiac causes among people withobstructive sleep apnea and the following: the rates among peoplewithout obstructive sleep apnea, the rates in the general population,and the expectations according to chance. For each interval,we assessed the median apnea–hypopnea index and the relativerisk of sudden death from cardiac causes. We similarly analyzedsudden death from cardiac causes during three time intervalsthat correlate with usual sleep–wake cycles.
Results From midnight to 6 a.m., sudden death from cardiac causesoccurred in 46 percent of people with obstructive sleep apnea,as compared with 21 percent of people without obstructive sleepapnea (P=0.01), 16 percent of the general population (P<0.001),and the 25 percent expected by chance (P<0.001). People withsudden death from cardiac causes from midnight to 6 a.m. hada significantly higher apnea–hypopnea index than thosewith sudden death from cardiac causes during other intervals,and the apnea–hypopnea index correlated directly withthe relative risk of sudden death from cardiac causes from midnightto 6 a.m. For people with obstructive sleep apnea, the relativerisk of sudden death from cardiac causes from midnight to 6a.m. was 2.57 (95 percent confidence interval, 1.87 to 3.52).The analysis of usual sleep–wake cycles showed similarresults.
Conclusions People with obstructive sleep apnea have a peakin sudden death from cardiac causes during the sleeping hours,which contrasts strikingly with the nadir of sudden death fromcardiac causes during this period in people without obstructivesleep apnea and in the general population.
Obstructive sleep apnea affects 17 to 24 percent of North Americanadults.9 In people with obstructive sleep apnea, nocturnal repetitiveepisodes of acute apnea elicit hypoxemia, hypercapnia, increasedsympathetic drive,10 surges in blood pressure,10 increases incardiac-wall stress,11 and cardiac arrhythmias.12,13,14 Obstructivesleep apnea is also associated with hypercoagulability, vascularoxidative stress, systemic inflammation, and endothelial dysfunction.15Thus, people with obstructive sleep apnea have severe perturbationsof autonomic, hemodynamic, humoral, and vascular regulationduring sleep that contrast with the physiology of normal sleep.It is not known whether these nocturnal abnormalities are associatedwith an increased risk of sudden death from cardiac causes duringthe night, a time when the risk of sudden death from cardiaccauses is at its lowest level for the general population.1
We tested the hypothesis that people with obstructive sleepapnea are more likely to have sudden death from cardiac causesfrom midnight to 6 a.m. than during the other six-hour intervalsof the day. We also tested the hypothesis that the frequencyof sudden death from cardiac causes from midnight to 6 a.m.is higher in people with obstructive sleep apnea than in peoplewithout obstructive sleep apnea, the general population, andwhat is expected by chance (i.e., 25 percent per six-hour interval).
Methods
Study Population
We included subjects who authorized their records to be usedfor research, and the institutional review board of the MayoFoundation approved the study. We identified Minnesota residentswho underwent diagnostic polysomnography at the Mayo ClinicSleep Disorders Center from July 1, 1987, to July 31, 2003,and confirmed their vital status (available for 99.6 percent)with the use of records from the Minnesota Department of Healthand the Mayo Clinic. We then manually reviewed the deceasedpersons' death certificates (available for 83.8 percent) andincluded in our study those who died of sudden death from cardiaccauses before July 31, 2003 (112 people).
Classification of Sudden Death from Cardiac Causes
Manual review of death certificates and data from the MinnesotaDepartment of Health provided the immediate and underlying causesof death, time of death, and time interval from onset of symptomsto death. A state nosologist used the methods of the NationalCenter for Health Statistics to assign causes of death. We classifiedthe following causes of death as sudden death from cardiac causes:"sudden cardiac death," "cardiac dysrhythmia," "cardiac arrhythmia,""cardiac arrest," "cardiorespiratory arrest," or "coronary heartdisease" or "myocardial infarction" in which the interval fromsymptoms to death was an hour or less.
Persons were excluded if the time of sudden death from cardiaccauses was not stated or if the death certificate provided informationthat explicitly contradicted the following definition of suddendeath from cardiac causes: "natural death due to cardiac causes,heralded by abrupt loss of consciousness within one hour ofthe onset of acute symptoms; preexisting heart disease may havebeen known to be present but the time and mode of death areunexpected"16 and nontraumatic.16 The occurrence of sudden deathfrom cardiac causes during sleep was an exception to the criteriafor "loss of consciousness within one hour of the acute onsetof symptoms,"16 since some instances of sudden death from cardiaccauses occurring during sleep may preclude awakening and thedevelopment of symptoms, or the witnessing of these events byothers. The death certificates of six people stated that suddendeath from cardiac causes was unwitnessed or presumed, but theirtime of death was noted, and these people were included in thestudy. The death certificates of all other persons did not statewhether sudden death from cardiac causes was witnessed or unwitnessed.Thirty-six death certificates (32 percent) provided specificinformation about the time interval from symptoms to death.
Classification of Obstructive Sleep Apnea
The sleep evaluations of all 112 persons were conducted by asleep specialist at the Mayo Clinic Sleep Disorder Center. Wereviewed each person's first diagnostic polysomnogram, whichincluded measures of the electroencephalogram, electro-oculogram,electromyogram, electrocardiogram, thoracoabdominal excursions,pulse oximetry, and naso-oral airflow.
We collected data on the demographics, coexisting conditions,height, and weight of each person at the time of polysomnography.We considered that continuous positive airway pressure had beenused if it was prescribed after the sleep study (which was notedby the sleep-medicine physician reviewing the study resultsand plan of care) and if a subsequent note in the medical recordstated that continuous positive airway pressure was being used.The personnel who collected data from polysomnograms and confirmedsleep diagnoses were different from those who collected datafrom death certificates and confirmed death diagnoses, and theprocedures were performed in a masked fashion.
Statistical Analysis
Characteristics of the study population were described as means±SD and counts (with percentages) and were compared accordingto the status of obstructive sleep apnea and the time of suddendeath from cardiac causes with the use of the two-tailed t-test,Fisher's exact test, and analysis of variance. The frequencydistribution of sudden death from cardiac causes for the foursix-hour intervals was compared between persons with and personswithout obstructive sleep apnea with the use of Fisher's exacttest. The proportion of people with obstructive sleep apneawho had sudden death from cardiac causes during each time intervalwas compared, with the use of the binomial distribution, withthe proportion of people who had sudden death from cardiac causesduring the same time interval in a historical control population(from a meta-analysis of 19,390 persons with sudden death fromcardiac causes in the general population)1 and with the proportionthat was expected by chance to have sudden death from cardiaccauses during each quarter of the day (i.e., 25 percent).
The apnea–hypopnea indexes of persons who had sudden deathfrom cardiac causes during each time interval were expressedas medians (with interquartile ranges) and compared with theuse of the Kruskal–Wallis test. For persons with and withoutobstructive sleep apnea, we calculated the relative risk and95 percent confidence interval of sudden death from cardiaccauses during each 6-hour interval as compared with the remaining18 hours of the day.
We also performed similar analyses of sudden death from cardiaccauses in persons with and persons without obstructive sleepapnea for three eight-hour intervals of the day (6 a.m. to 2p.m., 2 p.m. to 10 p.m., and 10 p.m. to 6 a.m.). These intervalsbetter represent usual sleep–wake cycles.
Results
Patient Characteristics
Characteristics of the study population are described in Table 1.The diagnoses for the 34 persons without obstructive sleepapnea were no sleep disorder (53 percent), central sleep apnea(23 percent), periodic leg movement disorder (9 percent), obesity–hypoventilationsyndrome (6 percent), narcolepsy (6 percent), and hypoventilationdue to neuromuscular disease (3 percent). There was a higherproportion of men in the group with obstructive sleep apneathan in the group without obstructive sleep apnea, but the twogroups were similar in terms of age, body-mass index, and coexistingconditions. There were no differences in characteristics, orreported use of continuous positive airway pressure, betweenpersons with sudden death from cardiac causes during the variousintervals of the day. The use of continuous positive airwaypressure was reported in 15 percent of patients with an apnea–hypopneaindex of 5 to 19, 39 percent of patients with an apnea–hypopneaindex of 20 to 39, and 58 percent of patients with an apnea–hypopneaindex of 40 or more (P<0.001).
Table 1. Characteristics of the Study Population at the Time of Polysomnography, According to the Status of Obstructive Sleep Apnea (OSA) and the Time of Sudden Death from Cardiac Causes.
Time Distribution of Sudden Death from Cardiac Causes
Figure 1 shows the primary results. From midnight to 6 a.m.,the frequency of sudden death from cardiac causes was significantlyhigher in persons with obstructive sleep apnea than in personswithout obstructive sleep apnea (46 percent vs. 21 percent,P=0.01), than in the general population (46 percent vs. 16 percent,P<0.001), and than was expected by chance (46 percent vs.25 percent, P<0.001). From 6 a.m. to noon, the frequencyof sudden death from cardiac causes was significantly lowerin persons with obstructive sleep apnea than in persons withoutobstructive sleep apnea (20 percent vs. 41 percent, P=0.04).From noon to 6 p.m., the frequency of sudden death from cardiaccauses was significantly lower in persons with obstructive sleepapnea than in persons without obstructive sleep apnea (9 percentvs. 26 percent, P=0.02), than in the general population (9 percentvs. 29 percent, P<0.001), and than was expected by chance(9 percent vs. 25 percent, P<0.001).
Figure 1. Day–Night Pattern of Sudden Death from Cardiac Causes in 78 Persons with and 34 Persons without Obstructive Sleep Apnea (OSA) and in the General Population.
Data for the general population were derived from Cohen et al.1
Severity of Obstructive Sleep Apnea
Persons with sudden death from cardiac causes from midnightto 6 a.m. had a significantly higher median apnea–hypopneaindex than those with sudden death from cardiac causes from6 a.m. to noon (39 vs. 8, P<0.001) and noon to 6 p.m. (39vs. 11, P<0.001), and a similar median apnea–hypopneaindex to that in persons with sudden death from cardiac causesfrom 6 p.m. to midnight (39 vs. 41) (Figure 2A). As comparedwith persons without obstructive sleep apnea, the relative riskof sudden death from cardiac causes from midnight to 6 a.m.was 1.87 (95 percent confidence interval, 0.86 to 4.04) forpersons with mild-to-moderate obstructive sleep apnea (apnea–hypopneaindex, 5 to 39) and 2.61 (95 percent confidence interval, 1.27to 5.38) for persons with severe obstructive sleep apnea (apnea–hypopneaindex, 40) (Figure 2B).
Figure 2. The Apnea–Hypopnea Index for Persons with Sudden Death from Cardiac Causes during Six-Hour Intervals (Panel A) and the Relative Risk of Sudden Death from Cardiac Causes from Midnight to 6 a.m. for Persons with Mild-to-Moderate Obstructive Sleep Apnea and for Persons with Severe Obstructive Sleep Apnea (Panel B).
In Panel A, the line within each box represents the median apnea–hypopnea index, and the box represents the interquartile range (25th percentile to 75th percentile). Each black square represents one person. The figure includes data from persons with and from persons without obstructive sleep apnea (P<0.001). In Panel B, the reference group consists of 34 persons without obstructive sleep apnea. There are 39 persons in the group with the apnea–hypopnea index of 5 to 39, and 39 persons in the group with the apnea–hypopnea index of 40 or more. The squares represent the relative risk point estimates, and the I bars the 95 percent confidence intervals.
Relative Risk of Sudden Death from Cardiac Causes
For persons with obstructive sleep apnea, the relative riskof sudden death from cardiac causes from midnight to 6 a.m.(as compared with the remaining 18 hours of the day) was 2.57(95 percent confidence interval, 1.87 to 3.52), from 6 a.m.to noon was 0.77 (95 percent confidence interval, 0.49 to 1.21),from noon to 6 p.m. was 0.30 (95 percent confidence interval,0.15 to 0.61), and from 6 p.m. to midnight was 0.97 (95 percentconfidence interval, 0.64 to 1.46). For persons without obstructivesleep apnea, the relative risk of sudden death from cardiaccauses from midnight to 6 a.m. (as compared with the remaining18 hours of the day) was 0.77 (95 percent confidence interval,0.36 to 1.66), from 6 a.m. to noon was 2.10 (95 percent confidenceinterval, 1.14 to 3.85), from noon to 6 p.m. was 1.08 (95 percentconfidence interval, 0.54 to 2.16), and from 6 p.m. to midnightwas 0.40 (95 percent confidence interval, 0.15 to 1.08) (Figure 3).
Figure 3. Relative Risk of Sudden Death from Cardiac Causes during Six-Hour Intervals as Compared with the Remaining 18 Hours of the Day, for 78 Persons with and 34 Persons without Obstructive Sleep Apnea (OSA).
The squares represent the point estimates of relative risk, and the I bars the 95 percent confidence intervals.
Sleep–Wake Cycles
The sleep–wake cycles are described in Figure 4. Includedare the day–night pattern of sudden death from cardiaccauses (Figure 4A), the severity of obstructive sleep apnea(Figure 4B), and the relative risk of sudden death from cardiaccauses during the three time intervals that represent usualsleep–wake cycles (Figure 4C).
Figure 4. Sudden Death from Cardiac Causes According to Usual Sleep–Wake Cycles.
Panel A shows day–night patterns of sudden death from cardiac causes on the basis of eight-hour time intervals for 78 persons with and 34 persons without obstructive sleep apnea. Panel B shows the apnea–hypopnea index for persons with sudden death from cardiac causes during eight-hour intervals. The line within each box represents the median apnea–hypopnea index, and the box represents the interquartile range (25th percentile to 75th percentile). The figure includes data from persons with and from persons without obstructive sleep apnea (P=0.001) for the comparison of the apnea–hypopnea index according to the time of sudden death. Panel C shows the relative risk of sudden death from cardiac causes during 8-hour intervals, as compared with the remaining 16 hours of the day, for 78 persons with and 34 persons without obstructive sleep apnea. The squares represent the relative risk point estimates, and the I bars the 95 percent confidence intervals.
The mean age at which sudden death from cardiac causes occurredin persons with obstructive sleep apnea was similar to the meanage of sudden death from cardiac causes in persons without obstructivesleep apnea and in the general population.18 Our findings shouldnot be generalized to younger persons with obstructive sleepapnea. Also, this finding suggests that obstructive sleep apneadoes not hasten sudden death from cardiac causes; however, ourstudy cannot address whether obstructive sleep apnea increasesthe overall risk of sudden death from cardiac causes.
Our data may also provide insights into the conventional understandingof the day–night pattern of sudden death from cardiaccauses in the general population. First, obstructive sleep apneamay be implicated in some of the 16 percent of cases of suddendeath from cardiac causes that occur between midnight and 6a.m. in the general population,1 since obstructive sleep apneaaffects at least 25 million adult Americans9 and remains undiagnosedin the vast majority of these people.19 Second, the risk ofsudden death from cardiac causes from 6 a.m. to noon in personswithout obstructive sleep apnea may be even greater than therisk that is currently supported by data from the general population,since those data include people with and people without obstructivesleep apnea, and we showed that the presence of obstructivesleep apnea is associated with a lower risk during this period.
Obstructive sleep apnea is characterized by repetitive collapseof the pharyngeal airway during sleep, resulting in completeor partial cessation of airflow, sometimes hundreds of timesnightly. The resultant hypoxemia can lead to nocturnal cardiacischemia21 and ventricular arrhythmias.22 Apneic episodes elicitincreased sympathetic activity,10 blood-pressure elevations,10and platelet aggregation.23 Obstructive sleep apnea is associatedwith abnormalities in cardiac autonomic and electrophysiologicalfactors, including heart rate variability,24 the duration ofthe QT interval,25 baroreflex function, and chemoreceptor sensitivity.26Serious and potentially fatal arrhythmias occur during sleepin patients with obstructive sleep apnea12,13,14,22,27,28,29,30,31and are attenuated by effective treatment.14,29,30,31,32 Thus,multiple pathophysiological mechanisms occur during sleep inpersons with obstructive sleep apnea and may explain an increasedrisk of nocturnal sudden death from cardiac causes.
Two previous studies evaluated the day–night pattern ofsudden death from cardiac causes in persons with sleep disorders.33,34Neither study specifically examined obstructive sleep apnea.The first study obtained histories of snoring from the cohabitantsof 321 men who had sudden death from cardiac causes. It foundthat habitual snorers were more likely than occasional snorersor nonsnorers to have sudden death from cardiac causes duringsleep and between 4 a.m. and 8 a.m.33 The second study reportedthat among 13 persons with sleep-disordered breathing (not justobstructive sleep apnea) and sudden death from cardiac causes,none died during sleep.34 In contrast, our study assessed theday–night pattern of sudden death from cardiac causesin a large group of nonselected persons with or without confirmedobstructive sleep apnea as determined by the gold standard ofdiagnostic tests.
One limitation of the present study relates to the recognizeddifficulty of establishing the diagnosis and timing of suddendeath from cardiac causes. Our use of data from death certificatesto identify sudden death from cardiac causes has precedent inprevious epidemiologic studies35,36 and has been validated inlarge populations,37,38,39,40 including our regional population.39,40Furthermore, we used information from the death certificatesabout the time interval from the onset of symptoms to deathin order to corroborate the diagnosis of sudden death from cardiaccauses on the basis of current definitions.16 For example, wewere able to exclude persons who were diagnosed with suddendeath from cardiac causes on the basis of old criteria thatallowed a 24-hour interval between symptoms and death.
Our methods also improve on past studies that searched databasesof diagnostic codes to identify potential cases, since we identifiedpersons with sudden death from cardiac causes by our directreview of every available death record from the larger population.Qualifiers such as "witnessed," "unwitnessed," and "presumed"were infrequently noted on the death certificates. Therefore,we included all cases of sudden death from cardiac causes regardlessof these statements. Thus, persons with sudden death from cardiaccauses during sleep, which may preclude the development of symptomsor the witnessing of the event by others, were exceptions tothe criteria that required timing of symptoms and a change inconsciousness, and they were included in the study when a timeof death was noted. It is important to note that we collectedsleep data and death data independently of one another, andin a masked fashion, in order to avoid diagnostic suspicionbias.
Another limitation of the study relates to the ascertainmentand interpretation of treatment with continuous positive airwaypressure. During the years of this study, continuous-positive-airway-pressuredevices that stored the time of use were rarely used. The medicalrecords lacked objective data regarding frequency, duration,or effectiveness of continuous positive airway pressure. Therefore,we could not verify whether continuous positive airway pressurewas used in the days before sudden death from cardiac causesor during the event.
That continuous positive airway pressure may have been generallyineffective is suggested by the finding that the risk of nocturnalsudden death from cardiac causes increased with increasing severityof obstructive sleep apnea despite more reported use of continuouspositive airway pressure with increasing severity of obstructivesleep apnea. Because of the lack of objective data from continuous-positive-airway-pressuredevices, subjective data regarding their use were necessary.This is an important limitation of retrospective assessmentsof treatment of obstructive sleep apnea.
Supported by grants (HL61560, HL65176, HL73211, and M01 R-00585)from the National Institutes of Health, by the Dana Foundation,and by the Mayo Clinic College of Medicine. Dr. Gami is alsosupported by the Dr. Ralph and Marian C. Falk Medical ResearchTrust Fellowship for Clinical Research.
Source Information
From the Divisions of Cardiovascular Diseases (A.S.G., V.K.S.), Pulmonary and Critical Care Medicine (E.J.O.), and Hypertension (V.K.S.), Department of Internal Medicine (A.S.G., D.E.H., E.J.O., V.K.S.), Mayo Clinic College of Medicine, Rochester, Minn.
Address reprint requests to Dr. Somers at the Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, or at somers.virend{at}mayo.edu.
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40) (Figure 2B). 
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