Sudden unexpected nontraumatic death in 54 young adults: A 30-year population-based study

Sudden Unexpected Nontraumatic Death in 54 Young Adults: A 3OmYear PopulatIonlBased Study Win-Kuana

Shen, MD, William D. Edwards, MD, SteDhen C. Hammill, MD, david J. Ballard, MD, PhD, and Bern&d J. Gersh, MB;ChB,‘DPhil

Kent R. BaileyrPhD,

The objective of this stud was to evaluate the incidence and correlates of sud J en unexpected nontraumatic death among young adults in a well-surveyed population. The incidence and pathogenesis of sudden unexpected nontraumatic death in a young adult population (a ed 20 to 40 years old) have not been well defined. Air residents 20 to 40 years old from Olmsted County, Minnesota, who had nontraumatic sudden death between 1960 and 1989 were included. Histologic and gross cardiac specimens were examined. The incidence of sudden death was estimated based on the ratio of number of observed events to relat’nre census data for the Olmsted County population from the last 3 decades. Statistical corn risons between age decades were obtained with Jr e chi-square test. Incidence trends were tested using Poisson regression. Of the 54 subiects, 19 were women (4.1 /lOs population annually) and 35

were men (8.7/105 po ulation annually). An increase in incidence of sudden s eath was evident in men. Causes of death included coronary artery disease, noncardiovascular disease, suspected primary arrhythmia, vascular disease, myocarditis, hypertro hit cardiomyopathy, and unknown causes. Gross an t! histologic features suggestive of right ventricular dysplasia were found in 9 subjects (17%), but 6 of these 9 had other established causes of death. Of the 27 sudden deaths between 1980 and 1989,9 (33%) had a history of cocaine abuse. A trend in increasing incidence of sudden death in young men is noted. A high prevalence of cocaine abuse was observed in youn adults who died suddenly. Histol ic features of rig F1t ventricular dys7 ent but were not necessarily the priplasia were preva mary cause of death. (Am J Cardiol 1995;76: 148-l 52)

udden cardiac death is uncommon in the pediatric population (aged 520 years),1,2but it is frequently S associatedwith a known cardiac disease,particularly af-

METHODS

From the Division of Cardiovascular Diseases and Internal Medicine, the Division of Anatomic Pathology, and the Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Dr. Ballard was a Visiting Scientist, Section of Epidemiology. Manuscript received lanuarv 16. 1995: revised manuscriDt received and acceatedMay”l1, lb9.5: Address for reprints: Win-Kuang Shen, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Definition: “Sudden death” was defined as witnessed nontraumatic death occurring instantaneously or within 1 hour after the onset of acute symptoms or signs. If the event was not witnessed, sudden death was defined as the interval between the time the subject was last seen and the time the body was found within 6 hours. “Unexpected death” was defined as death that occurred in a subject without previous overt disease. Selection of subiects: All residents 20 to 40 years old from Olmsted County, Minnesota, who died suddenly and unexpectedly during the period from January 1,196O to December 31, 1989 were included in the study. In Olmsted County, autopsy examination is mandatory for every caseof suddenunexpectednontraumatic death.All autopsy examinations were performed in the pathology department at the Mayo Clinic. A complete list (100%) of all residents dying suddenly in Ohnsted County during the study period was obtained for this study. County residents who died elsewherewere not included in the study. Data collection: Death certificates, complete community outpatient and inpatient medical records, coroner’s reports, and autopsy reports were reviewed. Data for each patient were extracted from these medical records. Myocardial structure and coronary artery anatow were examined grossly in each patient, and the examiners were blinded to historical information concerning the cause of death. Evaluations included measurementof heart weight and wall thickness, examination of the valves and the origin, course, and patency of the coronary arteries,and identification of chamberdilatation and myocardial scarsand adiposity, with special attention to

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ter surgical repair of congenital heart disease.In the older adult population (aged245 years), coronary artery disease is by far the most common condition associated with sudden cardiac death.3 The incidence and pathogenesis of sudden unexpected nontraumatic death in a young adult population (between 20 and 40 years old) have not been well defined. In this age group, the following diseaseentities have been associatedwith sudden cardiac death: subclinical or premature coronary atherosclerosis (or both),4 hypertrophic obstructive cardiomyopatby,5-7acutemyocarditis,Wolff-Parkinson-White syndrome,* long QT syndrome,9 right ventricular dysplasia,l”Tu and acute and chronic cocaine abuse.12-l4With these considerations in mind, the current investigation was undertaken to determine the incidence and correlates of sudden, unexpected, nontraumatic death among young adult residents of Olmsted County, Minnesota. Cardiac tissue (coronary artery,myocardium, conduction system) was carefully examined grossly and rnicroscopically to study the possible mechanisms of sudden cardiac death.

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the right ventricle. Microscopic examination was perTABLE I Causes of Sudden Unexpected Nontraumatic Death formed on the coronary arteries and on transmural secAmong Residents 20 to 40 Years Old of Olmsted County, Minnesoto, 1960 to 1989 tions of myocardium from both ventricular free walls and the ventricular septum. Step sections of the atriovenNumber of Subjects tricular conduction system were obtained when an ar1980rhythmogenic cause of death was suspected. Multiple 196019701989 sections of specimens were obtained from the left and Cause 1969 1979 (cocaine)* Total right ventricular free wall and the interventricular sepCardiac disease tum. The pathologic definition of right ventricular dysCoronary artery disease 3 5 10 (1) 18 plasia variesn,15;in our study, right ventricular dysplaPrimary arrhythmia 0 2 4(11 6 sia was suspected histologically when adipose tissue Drug-induced arrhythmia 1 0 0 PI Myocarditis 1 1 2(l) 1 infiltrated 275% of the free wall thickness. Hypertrophic cardiomyopathy 1 0 2 1 PI Analysis: The incidence of sudden unexpected nonVascular disease traumatic death in persons 20 to 40 years old was estiCerebral hemorrhage 2 0 1 (11 3 matedoverall aswell asby sex andby decade.Age adjustPulmonary embolism 0 0 2 (21 2 ment to the Minnesota population” used 5-year age Splenic artery rupture 0 1 0 (01 1 Aortic dissection 0 1 strata. The Olmsted County population estimates were 0 (01 1 Noncardiovascular disease basedon censusdata for the years 1960,1970,1980, and Seizure 1 2 3 (0) 6 1990 and an interpolation method of Bergstralh et all7 Infection 0 2 2 0 PI Estimates of effects of sex on incidence, as well as Aspiration 0 0 1 (0) 1 Unknown 2 2 time trends, were based on the Poisson regression mod3 (3) Tota I 11 16 27 (9) 5; el, assuming the incidence rate to be related to an exponential function of sex and calendar year. This was *Numbers in parentheses indicate patients who had o history of cocaine abuse between 1980 and 1989 (none were identified between 1960 accomplished through the generalized linear interactive and 1979). modeling (GLIM) program by using a logarithmic link function and Poisson error term. Comparison of the proportion of coronary artery disease-related deaths in the acute plaque rupture, acute thrombotic occlusion, acute 2 age decadeswas done with Pearson’s chi-square test myocardial ischemia, or any combination of these, were for 2-by-2 tables. observed among subjects with coronary artery disease. The frequency distribution of coronary artery diseaseas RESULTS a causeof death was comparedbetween the 2 age groups Incidence: During the period from January 1, 1960, of 20 to 29 and 30 to 40 years (Figure 2). Of the 16 subthrough December 31, 1989, 54 cases of sudden unex- jects 20 to 29 years old, only 2 (13%) died of coronary pected nontraumatic death occurred among the residents artery disease.In contrast, among 38 subjects aged 30 between 20 and 40 years old of Olmsted County, Min- to 40 years old, 16 (42%) had coronary artery disease(p nesota, producing an overall cohort incidence rate of = 0.04). 6.2/100,000 annually. Of the 54 cases, 19 were women Noncoronaty cardiac disease: The diagnosis of pri(4.1/100,000 population annually) and 35 were men mary cardiac arrhythmia as a cause of sudden death is (8.7/100,000 population annually) (p = 0.012). Eleven, difficult and presumptive at best. A clinical history pos16,and 27 suddendeathsoccurred in the decadesof 1960 itive for syncope, aborted sudden death, or documented to 1969, 1970 to 1979, and 1980 to 1989, respectively. arrhythmia suggests significant arrhythmia. Of the 54 For the period 1980to 1989,the overall rate appearedto subjects,only 1 (no. 39) had a history of documentedfrehave increased (Figure 1). The time trend for sudden quent ventricular ectopy and syncope before sudden death occurring in women was relatively flat throughout death. Although a long QT syndrome or Wolff-Parkinthe period of observation, but an increasing trend was clearly evident in men, although it did not reach the level of statistical significance (p = 0.07). No overall time - Male trend was observed (p = 0.57).

C”

Causes of sudden

unexpected

nontraumatic

dearth:

Causes of death were categorized as cardiac, vascular, noncardiovascular, and unknown disease (Table I). Underlying cardiac diseasesaccounted for 31 of the 54 deaths (57%), vascular causes for 7 deaths (13%), and noncardiovascular diseasesfor 9 deaths (17%). In the 7 other subjects (13%), the cause was unknown. Rates of death due to cardiac, vascular, noncardiovascular, and unknown causes did not change significantly when the study period was divided by decades. The clinical characteristics of the 54 subjects are summarized in chronologic order in Table II. Coronary artery disease: Gross and histologic evidence of severe chronic obstructive atherosclerosis, ARRHYTHMIAS

AND

CONDUCTION

FIGURE 1. Trend analysis of sudden unexpected nontraumatic death in residents 20 to 40 years old of Olmsted County, Minnesota, 1960 to 1989.

DISTURBANCES/UNEXPECTED

NONTRAUMATIC

DEATH

149

son-White syndrome was not diagnosedbefore death in any subject,electrocardiogramswere recordedfrom only 5 of the 54 subjects (9%). Among the 6 subjects with presumedprimary arrhythmia, 2 (nos. 22 and 51) had significant conduction system abnormalities. Of the entire study group 4 had myocarditis (nos. 4, 19,40, and 44). Right ventricular dysplasia: Histologic features consistent with right ventricular dysplasia were observed in 9 subjects (17%). Diffuse and segmental interstitial fatty infiltration extended through 275% of the transmural thickness of the right ventricular free wall. The interstitial fatty infiltration was not observed in the left ventricle. Among the 9 subjects, causes of death other than TABLE II

Clinical

Nontraumatic

Characteristics Death,

Ase

(~4 & Sex

Subject

:

i 5 ; t 1’: ;: ;4 16 ;i :z z 23 24 ;z 27 zi i’: iz 34 2 37 E %‘: 42 43 4454 :; it 50 51 2: 54

1960

of Residents to

20

to 40

Years

Old

right ventricular dysplasia were established in 6 (mean age 36 f 2 years; all women); 1 (no. 15) also had acute aortic dissection due to cystic medial necrosis, 2 (nos. 20 and 35) had acute coronary syndromes, and 3 (nos. 23,32, and 36) had seizures.All 3 subjectswith seizures had a long history of recurrent seizures and clinically conlirmed diagnosesof epilepsy before death. Although it is possible that intermittent bradycardia or ventricular tachycardiacould have beenthe underlying causeof their seizures and sudden death, these rhythm disturbances were not observed. Of the remaining 3 subjects (mean age 27 f 6 years, 1 woman and 2 men), death may have been due to right ventricular dysplasia: 1 (no. 22) also

of Olmsted

County,

Minnesota,

Experiencing

Sudden

Unexpected

1989

Year of Death

Presumed Cause of Death

31 29

F F

‘61 ‘62

Seizure Drug-induced

28 36 35 37

F F M M

36 40 39 31 33 38 20 32 32 34 20 26 37 35 40 20 40 32 32 36 36 37 37 31 28 38 38 35 38 35 20 31 29 37 26 36 28 25 26 29 31 38 27 30 22 40 36 39

F M M M M M M M F M F M F F F F F M F M M M M M M F F M F F F M M M M M M M M M M M F M M M M M

‘63 ‘63 ‘65 ‘65 ‘65 ‘67 ‘67 ‘68 ‘69 ‘71 ‘71 ‘72 ‘72 ‘72 ‘72 ‘73 ‘75 ‘75 ‘75 ‘76 ‘77 ‘78 ‘78 ‘78 ‘79 ‘80 ‘80 ‘80 ‘80 ‘81 ‘83 ‘83 ‘83 ‘84 ‘84 ‘86 ‘87 ‘87 ‘87 ‘87 ‘87 ‘88 ‘88 ‘88 ‘88 ‘89 ‘89 ‘89 ‘89 ‘89 ‘89 ‘89

CNS hemorrhage Myocarditis CAD Unknown CAD

Comments Signs of suffocation Sudden death witnessed, just began chlorpromazine and trifluoperazine treatment Ruptured berry aneurysm Died watching TV Died in bed, severe CAD Autopsy findings negative Died in bed, severe CAD, old AMI Nonobstructive HC Died having chest pain, severe CAD Autopsy findings negative Ruptured left MCA Signs of suffocation Died in sleep Severe CAD Marfan syndrome, RVD Died exercising Possible suicide, no drugs found History of recurrent syncope, documented VF at death Viral pneumonia Severe CAD, high-grade l-vessel disease, RVD Severe CAD, died in bed Stenosis of AVN artery, RVD History of seizures, RVD Acute laryngeal edema 37 weeks’ gestation Pneumonia Severe CAD, history of alcohol abuse Acute AMI, contraction bands Acute AMI, plaque rupture Acute occlusion/thrombosis of LAD Concentric hypertrophy History of seizures, RVD Acute plaque rupture History of cocaine obuse, autopsy findings negative Critical left main coronary artery stenosis, RVD Phenytoin not detected in serum, RVD History of bulemia, cocaine abuse, possible hypokalemio Severe CAD, acute platelet thrombosis History of frequent ventricular ectopy Lymphocytic infiltrate History of cocaine abuse and seizures, RVD History of cocaine abuse and diabetes, RVD Idiopathic fibrosis of SN, AVN, and HP, died during sleep Acute viral illness, history of cocaine abuse, hyperlipidemia Severe CAD, died eating Acute occlusion LAD Acute alcohol intoxication Chest pain before sudden death 36 weeks’ gestation, cocaine abuse History of seizures Hypoplosio of proximal left bundle Cocaine abuse, history of AMI Cocaine abuse, history of AMI Cocaine abuse, history of CVAs and AMI

arrhythmia

Z:D unknown CNS hemorrhage Seizure Unknown CAD Ascending aortic CAD Unknown Arrhythmia FrDcarditis CAD Arrhythmia Seizure Acute pharyngitis Ruptured splenic Sepsis CAD CAD CAD CAD HC Seizure CAD Unknown CAD Seizure Arrhythmia CAD Arrhythmia

dissection

artery

fA;;+C.;;tk

Unknown Arrhythmia Myocarditis CAD CAD Aspiration CAD CNS hemorrhage Seizure Arrhythmia CAD FF

node; CAD = coronary artery disease; CNS = central nervous system; CVA = cerebrovasculor AMI = acute myocordiol infarction; AVN = otrioventricular accident; HC = hypertrophic cardiomyopathy; HP = His-Purkinje system; LAD = left anterior descending artery; MCA = middle cerebral artery; PE = pdmonary embolism; RVD = histologic diagnosis of right ventricular dysplasia; SN = sinus node; VF = ventricular fibrillation.

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had a stenotic atrioventricular nodal artery and 2 (nos. 41 and 42) had a history of cocaine abuse. Of the 6 women with an established cause of death, 1 (no. 20) was taking birth control pills, 1 (no. 35) was receiving estrogen replacement therapy, and 3 (nos. 23, 32, and 36) were taking anticonvulsive medication. History of cocaine use: During the first 2 decadesof the study period, the use of cocaine was not documented in any of the subjects. However, from 1980 through 1989, a history positive for cocaine abuse was documented in the community medical records for 9 subjects. Of these, 1 had coronary artery disease, 1 rnyocarditis, 1 arrhythmia, and 3 died of vascular causes, including cerebral hemorrhage in 1 and pulmonary embolus in another subject. The cause of death was not determined in the 3 others (Tables I and II). Cocaine or cocaine metabolites were not detected postmortem in any of the 9 subjects (at our institution, assays for cocaine and cocaine metabolites have beenperformed routinely since 1984). The finding of an increased incidence of cocaine use among sudden death victims in this ‘age group appearsto be consistent with the increasing illicit use of this drug in the UnitedStates during the period studied.18 Noncardiac causes: Among the subjects,who died of noncardiac causes,the causewas vascular in 7 and noncardiovascular in 9. Of the 7 who died of vascular causes, 3 had cerebral hemorrhage, 1 had acute aortid dissection, 1 had a ruptured splenic artery, and 2 had acute pulmonary emboli. Among the 9 who died of noncardiovascular diseases,6 had seizures, 1 had acute pharyngitis, 1 had aspiration, and 1 had sepsis.

DISCUSSION In this population-based study, the incidence of sudden unexpected nontraumatic death was documented among residents 20 to 40 years old of Olmsted County, Minnesota, from 1960 through 1989. The overall incidence was 4.1/100,000 population annually for women and 8.7/100,000population annually for men. A trend in increasing incidence of sudden death in the last decade was seenin men only. The most frequent causeof death was coronary artery disease (33%) followed by noncoronary cardiac diseases(24%). Of the 18patients with coronary artery disease,only 2 deaths (11%) occurred in the 20- to 29-year-old group, and 16 (89%) occurred in the 30- to 40-year-oid group. Myocarditis, hypertrophic cardiomyopathy,and suspectedprimary arrhythmia were the major causesof noncoronary cardiac disease. A surprisingly high incidence of a history of cocaine abusewas detected among the patients who died during the last decade(33%); however, acute cocaine ingestion was not identified on the basis of blood chemistry in any of thesepatients. Interestingly, 9 patients died with gross and microscopic evidence of arrhythmogenic right ventricuiar dysplasia; it appeared to be the cause of death in 3, and may have contributed to death in another 3 with seizure disorders. Incidence: Sudden death is uncommon in children and adolescents.Approximately 600 such deathsoccur annually in the United States.2In Olmsted County, Minnesota, from January 1950 to October 1982, there were 1.3 sudden unexpected deaths/lOO,OOO population annually in ARRHYTHMIAS AND CONDUCTION

persons between 1 and 22 years old.2 Among the older adult population (245 years), approximately 400,000 sudden cardiac deaths occurred each year in the United States.3,19The incidence of sudden death in the adult general U.S. population has ranged from 84 to ZOO/ 100,000 population annually.2@22Our study revealed that the overall incidence of suddendeathin young adults (20 to 40 years old) has been 5.1, 5.5, and 7.5/100,000 population annually in the last 3 decades,respectively, in Olmsted County. Thus, it increasedappreciably in the last decade, and this primarily affected men. Although the underlying reason for this is not clear, it is germane to note the increased prevalence of a history of cocaine abuse among subjects during the sameperiod. This observation does not establish a cause-and-effectrelation, but it is of interest. Cause of sudden death: In the United States, most sudden deaths in children and adolescentsare associated with congenital heart disease, anomalous coronary artery origin, hypertrophic cardiomyopathy,myocarditis, and primary pulmonary hypertension.1,2,23,24 In contra& among older adults (aged 245 years), >90% of sudden deathsare associatedwith coronary artery disease.3,19 For young athletes,much attention has been concentratedon the significance of subclinical coronary artery disease and hypertrophic cardiomyopathy as important mechanisms of sudden death, especially when it occurs during exercise.7 Earlier autopsy studies showed that cardiac disease accounted for approximately 40% of sudden deaths in young adults, of which 60% to 70% resulted from coronary artery disease.25,26 In our study, cardiac disease was the cause of sudden death in 57% of the patients, among which 58% were caused by coronary artery disease. The frequency of heart diseaseas a cause of sudden cardiac death in Olmsted County was somewhathigher than that reported in previous studies. This probably ca.n be attributed to the much lower incidence of acute overdose of toxic substancessuch as alcohol and cocaine in our study. The difference may reflect a selection bias in previous referral center caseseries or an intrinsic differ-

Age_

(w-1 ._.

-.

FIGURE 2. Distribution of sudden unexpected nontraumatic death among residents of Olmsted County, Minnesota, 1960 to 1989. Those with (CAD) are compared to those without (nonCAD) coronary artery disease in the 2 different age groups.

DISTURBANCES/UNEXPECTED

NONTRAUMATIC

DEATH

151

ence in the distribution of causesof sudden unexpected nontraumatic death in Olmsted County in contrast with other regions in the United States. Right ventricular dysplasia hasreceived considerable attention as a possible cause of sudden death.lO In 1 study,” autopsy findings consistent with right ventricular dysplasia were reported in 12 of 60 patients (20%) aged ~35 years who died suddenly between 1979 and 1986 in Northern Italy. In another autopsy study, however, only 3 cases of right ventricular dysplasia were identified among 547 victims of sudden cardiac death (0.55%) in the state of Maryland.27 Our findings that 6 of 9 subjects with histologic features of right ventricular dysplasia also had other established causesof death suggestthat the role of right ventricular dysplasia in cases of sudden death may be complex and variable. Dysplasia may be a cause of death, a contributor to a fatal event, or unrelated to the cause of death. The possibility that acquired changesinduced by drugs, ischemia, or inllammation may mimic right ventricular dysplasia must also be considered.28However, leukocytic and eosinophilic infiltrates were not found in our subjects. In a recent study by Burke et a1F9thickening of the atrioventricular nodal artery was frequently observed in young adults with unexplained sudden cardiac death. They suggestedthat dysplasia of this artery may be an important and a presumably underdiagnosed cause of sudden cardiac death. In our study, we observed 1 subject (no. 22) with narrowing of the atrioventricular nodal artery without atherosclerotic diseasein the presenceof histologic features of right ventricular dysplasia. The interplay of these 2 abnormal findings is uncertain and requires further investigation. Pathgenesis: The most frequent mechanism of sudden death is believed to be ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation), which occurs when the substratefor the rhythm disturbance is present. Static factors, such as myocardial scars or the presenceof accessorypathways,and dynamic factors,such as fluctuation of autonomic tone, transient vasospasm, and electrolyte abnormalities, contribute to the formation of malignant arrhythmia. Sudden death is the result of complex interactions between these potentially lethal mechanisms. Similar interactions have been postulated to occur among cocaine abusers.Furthermore, silent myocardial ischemia may occur in cocaine abusers within the lirst few weeks after withdrawaLis Vasospasm caused by increased sensitivity to o-adrenergic receptor stimulation has also been proposed as a potential mechanism for episodes of ischemia.3oIn this regard, the 9 Olmsted County residents with a history of cocaine abuse are of interest. Six died of cardiovascular disease but the cause of sudden death in the 3 others remains unclear. If transient spasmresulted in cardiac arrhythmia and sudden death, the findings on cardiac examination at autopsy could be normal.

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