Context Exertion has been reported to acutely increase the
risk of sudden coronary death, but the underlying mechanisms are
unclear.
Objective To determine the frequency of plaque rupture in sudden
deaths related to exertion compared with sudden deaths not related to
exertion.
Design Autopsy survey. Coronary arteries were perfusion fixed and
segments with more than 50% luminal narrowing were examined
histologically. Ruptured plaques were defined as intraplaque hemorrhage
with disruption of the fibrous cap and luminal thrombus. Exertion
before death was determined by the investigator of the death.
Setting Medical examiner's office.
Patients A total of 141 men with severe coronary artery disease
who died suddenly, including 116 whose deaths occurred at rest (mean
[SD] age, 51 [11] years) and 25 who died during strenuous activity
or emotional stress (age, 49 [9] years).
Main Outcome Measures The frequency and morphology of plaque
rupture was compared in men dying at rest vs those dying during
exertion. Independent association of risk factors (total cholesterol,
high-density lipoprotein cholesterol, glycosylated hemoglobin,
cigarette smoking) in addition to acute exertion with plaque rupture
were determined.
Results The mean (SD) number of vulnerable plaques in the coronary
arteries of men in the exertional-death group was 1.6 (1.5) and in the
at-rest group was 0.9 (1.2) (P=.03). The
culprit plaque in men dying during exertion was plaque rupture in 17
(68%) of 25 vs 27 (23%) of 116 men dying at rest (P<.001).
Hemorrhage into the plaque occurred in 18 (72%) of 25 men in the
exertional-death group and 47 (41%) of 116 men in the rest group
(P=.007). Histological evidence of acute
myocardial infarction was present in 0 of 25 in the exertion group and
in 15 (13%) of 116 in the rest group. Men dying during exertion had a
significantly higher mean (SD) total cholesterol–high-density
lipoprotein cholesterol ratio (8.2 [3.0]) than those dying at rest
(6.2 [ 2.7]; P=.002), and the majority
(21/25) were not conditioned. In multivariate analysis, both exertion
(P=.002) and total cholesterol–high-density
lipoprotein cholesterol ratio (P=.002) were
associated with acute plaque rupture, independent of age and other
cardiac risk factors.
Conclusion In men with severe coronary artery disease, sudden
death related to exertion was associated with acute plaque
rupture.
The health benefits
of regular exercise are well-known, and an association between exercise
and reduced risk of coronary heart disease has been
demonstrated.1-4 Proposed beneficial effects of physical
activity in reducing cardiac mortality include metabolic influences on
risk factors, hematologic variables, direct effects on the myocardium,
and indirect effects on mortality risk.5,6
Despite the benefits of exercise, acute exertion may trigger acute
cardiac events,7 and emotional and physical stress may
trigger acute myocardial infarction.8 It has been
theorized, but not demonstrated pathologically, that acute exertion may
predispose to sudden coronary events by precipitating rupture of a
vulnerable coronary artery plaque. The purpose of this study was to
examine the association between acute plaque rupture and
exertion-related sudden coronary death in a series of carefully studied
autopsy hearts.
Hearts from men who died of sudden coronary death were studied in a
prospective fashion. These hearts were seen in consultation with the
medical examiner in the state of Maryland between January 1994 and May
1997. Coronary artery fixation, cardiac dissection, and tissue sampling
were performed as previously described.9 Coronary deaths
were defined as natural deaths that occurred without evidence of
extracardiac cause of death and in which at least 1 epicardial coronary
artery had more than 75% cross-sectional lumen narrowing by
atherosclerotic plaque or plaque with superimposed thrombus. Sudden
death was defined as symptoms commencing within 6 hours of death
(witnessed arrest) or death occurring within 24 hours after the victim
was last seen alive in his normal state of health. Coronary deaths with
acute thrombus were further categorized as plaque rupture and plaque
erosion as previously defined.10
Healing plaque ruptures were defined as an interruption of the fibrous
cap with disorganizing thrombus, generally with proteoglycan and smooth
muscle cell–rich intimal proliferation surrounding the area of
interruption.11 Vulnerable plaques were defined as a
fibrous cap thinner than 65 µm that was infiltrated by macrophages
overlying a necrotic core as previously defined.9 The
maximum and minimum thickness of the fibrous cap overlying the necrotic
core at sites of plaque rupture was measured by ocular micrometer to
the nearest micrometer. The number of vasa vasorum was quantitated
manually with the aid of computerized morphometry on sections stained
immunohistochemically for endothelial cells with antibodies against
factor VIII–related antigen.
Postmortem evaluation of levels of total cholesterol (TC),
high-density lipoprotein cholesterol (HDL-C), glycosylated hemoglobin,
and thiocyanate as a marker for cigarette smoking and evaluation for
hypertension was performed as previously described.9 In
every case, available history was used to corroborate autopsy
determination of risk factors. In exertion-related deaths, information
from the scene and next of kin was obtained to estimate if the
individual performed exercise routinely as part of a regimen (several
times per week) or was sedentary. Cases were excluded if there was
gross hemolysis or if evaluation of total protein and serum albumin
levels indicated hemoconcentration or hemodilution. The body mass index
was estimated as weight in kilograms divided by the square of height in
meters.
Investigators at the scene of death recorded the circumstances of
death, including the decedent's activity, in each case. In deaths that
were not witnessed, the location of the body and clothing were
recorded, and an assessment to the probable activity prior to the
terminal event was made in each case. The exertional status was defined
as rest (patient found in bed, in a reclining position, or apparently
ambulating in the performance of day-to-day activities), physical
exertion, or emotional stress. Physical exertion was defined as the
performance of a sport during or within 1 hour of the cardiac arrest,
heavy lifting, strenuous digging or shoveling, or sexual activity.
Emotional stress was defined as a witnessed verbal altercation with
physical involvement (eg, chasing, hitting, or posturing) occurring
within 2 hours of the cardiac event, public speaking, or involvement in
another fear-inducing activity (eg, fire fighting).
For univariate analysis, unpaired t tests were used to
compare continuous variables of risk factors and other parameters in
the exertion group vs the rest group. When these parameters were
analyzed for the different groups of exertion, an analysis of variance
(ANOVA) means table with Fisher ad hoc test was used. For categorical
variables, a 2×2 contingency table (Fisher exact
test) was used. Multiple logistic regression was performed with risk
factors (independent variables, including exertional status) and
presence of plaque rupture (dependent variable) for multivariate
analysis. For multivariate analysis examining the association of risk
factors with numbers of vulnerable plaques, for both exertion and
traditional risk factors, ANOVA was performed.
A total of 141 hearts were studied. One hundred thirteen cases,
comprising the earliest two thirds of the current cases, have been
published previously but without data regarding activity at death or
medication use.9 The mean (SD) age of all men was 51 (11)
years. There were 106 whites, 34 blacks, and 1 Asian. The deaths were
witnessed in 90 cases and not witnessed in 51 cases. The deaths were
categorized into 2 groups: exertion (n=25) and rest
(n=116) (Table 1).
Fourteen of the 25 deaths related to exertion occurred in
previously sedentary men who were engaged in sudden strenuous activity:
carrying heavy objects (unloading a truck [2], moving heavy furniture
[2], pushing a car [1]); lawn mowing (2); having sexual intercourse
(2); ditch digging (1); playing basketball (2); bicycling (1); and
shoveling snow (1). In 4 men, death occurred during
physical activity that had been performed on a regular
basis: swimming (1), exercising on a stationary cross-country ski
machine (1), and running (2). Seven of the 25 exertion deaths occurred
during emotional exertion: verbal presentations before an audience
(2), verbal and physical altercation (3), court appearance (1), and
fire fighting (1).
Of the 116 nonexertional deaths, 62 occurred at home, 13 while
driving, 4 in hotel rooms, 26 at work, and 11 outdoors. Of the 62 men
who died at home, 20 died apparently while sleeping, 5 died while in
the bedroom watching television, 3 died in the kitchen, 26 died in the
living room or family room, and 8 died in a workshop or the basement.
The 13 automobile drivers who died suddenly were involved in automobile
crashes. However, there were no cases of significant trauma at the time
of the cardiac arrest, and all but 1 police report excluded any
possibility of near collision with another automobile or possible
"road rage" or other inciting event. In most of these cases,
witnesses or passengers indicated that the driver had an apparent
"heart attack." In 1 driving case, the driver lost control of the
vehicle after slumping at the wheel and sideswiped another car before
landing in a ditch. The 4 men who died in hotel rooms were found alone
and apparently had been involved in sedentary activities. The 26 men
who died while at work were involved in nonstrenuous activities or
activities that were repetitive in nature and did not involve lifting
heavy objects. The 11 men who died while outdoors were performing
various activities not related to exercise, heavy labor, or lifting but
were walking in the yard or toward a car or a bus, eating, leaving a
meeting place or entertainment area, or walking by the roadside.
The characteristics of the study subjects are shown in Table 1.
There were no significant differences between men whose deaths occurred
during exertion vs those at rest in age, body mass index, or levels of
TC or HDL-C. The mean (SD) TC/HDL-S ratio was 8.2 (3.0) in the exertion
group vs 6.2 (2.7) in the rest group (P=.002).
There were no significant differences in other risk factors between men
with sudden death occurring during exertion vs rest. The number of
presumed cigarette smokers was 69 (59%) of 116 men in the rest group
and 13 (52%) of 25 men in the exertion group
(P=.50). There were 31 men with hypertension
in the rest group and 7 with hypertension in the exertion group
(P>.99). The mean (SD) glycosylated hemoglobin reading was
7.5% (2.6%) in the rest group and 7.1% (1.5%) in the exertion group
(P=.43).
Five (20%) of 25 men who died during exertion and 40 (34%) of 116 men
who died at rest were taking 1 or more prescription medications. These
included antibiotics (6 at rest, 2 exertion), allopurinol (2 at rest),
angiotensin-converting enzyme inhibitors (11 at rest, 2 exertion),
benzodiazepines (5 at rest), β-blockers (9 at rest), calcium channel
blockers (6 at rest, 1 exertion), psychotropic drugs (10 at rest, 1
exertion), digitalis (2 at rest), diuretics (11 at rest, 2 exertion),
oral hypoglycemics (10 at rest, 3 exertion), nitroglycerin (2 at rest),
and simvastatin (3 at rest). Three (12%) of 25 men who died during
exertion and 22 (19%) of 116 men who died at rest were taking
over-the-counter medications, including aspirin (6 at rest, 2
exertion), bronchodilating inhalants (3 at rest), nonsteroidal
anti-inflammatory (9 at rest, 3 exertion), acetaminophen (9 at rest, 2
exertion), and antihistamines (9 at rest).
The mean (SD) heart weight in the exertion group was 518 (122) g
and 496 (114) g in the rest group (P=.42).
Histologically manifest acute infarcts were present in 15 (13%) of 116
hearts in the rest group and 0 of 25 hearts in the exertion group
(P=.07). The culprit plaque in the 25 hearts
in the exertion group was acute plaque rupture in 17, healing plaque
rupture in 0, stable plaque in 6, and plaque erosion in 2. In the 116
hearts in the rest group, the culprit plaque was acute plaque rupture
in 27, healing plaque rupture in 5, stable plaque in 60, and plaque
erosion in 24. The proportion of acute plaque ruptures in the rest
group (23%) compared with the exertion group (68%) was significantly
different (P<.001, Fisher exact test). The proportion of
abnormal cholesterol values was highest in the plaque rupture exertion
group, followed by men dying at rest with plaque rupture, at exertion
with stable plaque or healing plaque ruptures, and at rest with stable
plaque (Table 2).
In multivariate analysis, using plaque rupture as a dependent variable
and including all men who died suddenly, plaque rupture was associated
with exertion (z=3.1,
P=.002) and the TC/HDL-C ratio
(z=3.1, P=.002).
Other risk factors, including smoking, glycosylated hemoglobin level,
and hypertension, were not associated with plaque rupture in this
multivariate analysis (P>.10).
The mean (SD) number of vulnerable plaques in the coronary arteries of
each heart in the exertion group was 1.6 (1.5) and in the rest group
was 0.9 (1.2) (P=.03). By ANOVA, the mean
number of vulnerable plaques in each heart was associated with the
TC/HDL-C ratio (P=.006), independent of age,
body mass index, smoking, glycosylated hemoglobin level, and
hypertension (P>.10). When exertion was included in the
analysis, both exertion (P=.02) and the
TC/HDL-C ratio (P =.04) were associated with
vulnerable plaques.
In the 44 hearts with acute plaque rupture, the site of rupture
(shoulder region, mid cap, circumferential) could be determined in 36
cases, and in 8 cases the destruction was too great to determine the
exact site of plaque rupture. The 36 cases included 20 men who died
while at rest and 16 men who died during exertion. Of these 20 rest
cases, the site of plaque rupture was the shoulder region in 13
(Figure 1), mid cap in 6, and
circumferential in 1. Of these 16 exertion cases, the site of plaque
rupture was the shoulder region in 4 and mid cap in 12 (Figure
2). Excluding the plaque ruptures with
circumferential or destroyed rupture sites, the proportion of shoulder
ruptures was greater in rest cases
(13/20 [65%]) vs exertion cases (4/16
[25%]) (P=.02). The mean (SD) percentage of
luminal narrowing at the site of plaque rupture was 69% (11%) in the
rest group and 70% (13%) in the exertion group (P = .75)
(Figure 3). The mean (SD) minimum
thickness of the fibrous cap in plaque ruptures associated with
exertion was 5.6 (3.8) µm, vs 9.9 (6.7) µm in cases of plaque
ruptures associated with deaths not related to exertion
(P=.05). There was no difference in the
maximal thickness of the fibrous cap (mean [SD], 27.9 [21.7] µm,
exertion, vs 30.8 [11.2] µm, rest; P=.65).
The mean (SD) number of intraplaque vasa vasorum at the site of
plaque rupture was 40 (20) in the exertion group and 25 (17) in the
rest group (P=.03). Hemorrhages into plaque
(including those at a rupture site) occurred in 18 (72%) of 25 hearts
from men who died during exertion and 47 (41%) of 116 hearts from men
who died while at rest (P=.007).
Circadian variation in sympathetic activity, vascular reactivity,
and platelet aggregability, as well as physical and emotional stress,
may precipitate acute coronary events.12,13 The
vulnerability of the underlying plaque probably affects the likelihood
of such triggers to cause acute coronary events.14 The
current study demonstrates that the mechanism of sudden death in the
majority of men who experienced sudden death during physical or
emotional exertion is plaque rupture, compared with a minority of
sudden deaths in resting men. The number of vulnerable plaques in the
men whose deaths were associated with physical or emotional stress is
greater than in men dying at rest from coronary disease, corroborating
the view that plaque vulnerability is important in exertion-related
sudden death.
The mechanism of plaque disruption likely involves both apoptotic and
necrotic mechanisms of cell death.15-17 Biomechanical
factors affecting plaque rupture include circumferential
stress,18 which has been calculated to be greatest at the
junction of the cap with the normal wall (shoulder
region).19 The thinness of the fibrous cap is the physical
measurement that appears to promote the greatest vulnerability to
rupture.20,21 At the cellular level, the amount of free
cholesterol and the degree of macrophage infiltration are associated
with cap weakness and rupture,22 which may be related
to elaboration of matrix metalloproteases
degrading collagen.23-25
We have previously demonstrated that the numbers of vulnerable plaques
in men dying suddenly with severe coronary disease are increased in men
who are hypercholesterolemic and that plaque rupture occurs more
frequently in men who are dyslipidemic.9 The current study
indicates that acute exertion is an additional independent risk factor
for plaque rupture in men, presumably by disruption of a vulnerable
plaque. Therefore, we suggest that acute exertion should be added as a
potential risk factor for plaque rupture, along with elevated serum
cholesterol level. The mechanism of plaque rupture, as triggered by
exertion, was not investigated fully in the current study. However, the
finding that the fibrous cap is thinner at sites of rupture in
exertion-related deaths suggests that biomechanical forces play a role.
Contrary to what may be expected given mechanical calculations showing
that plaque weakness is greatest at the shoulder region because it is
the point of greatest stress,18,19,26 our data indicate
that exertion-related plaque rupture is more frequent in the center of
the plaque. This finding agrees with data showing that thinness is a
more important determinant of plaque instability than the
circumferential site along the plaque's cap,20 suggesting
that circulating catecholamines and vasomotor fluctuates may trigger
some cases of plaque rupture.
Microfill injections of coronary arteries demonstrate a positive
correlation between plaque size and neocapillaries in and around the
plaque.27,28 The presence of increased numbers of vasa
vasorum in plaques that rupture during exertion also points to a
possible pathway of plaque rupture. Rupture of vasa vasorum may
increase intraplaque mass and pressure, weakening the fibrous cap and
leading to rupture and luminal thrombus.28 Alternatively,
increased vascularity within the plaque may reflect elaboration of
growth factors or angiogenetic factors that may be expressed in
parallel with metalloproteases. Data on increased plaque hemorrhages in
the exertion-related deaths in this study support a direct role of vasa
vasorum rupture in the pathogenesis of plaque rupture.
The current study has several limitations. The study population was
limited to autopsy cases of sudden coronary death, and the precise
state of physical conditioning was not known in all cases. However, the
association between acute exertion and plaque rupture suggests that a
proportion of sudden deaths in middle-aged men may be decreased if the
potential danger of acute exertion in hypercholesterolemic men is
avoided. To this end, it would seem prudent to incorporate serum
cholesterol reduction as an integral component of an exercise program
in those men with elevated serum cholesterol.
In conclusion, in men with severe coronary artery disease who die
suddenly, acute exertion appears to be an independent risk factor for
plaque rupture, presumably by disruption of a vulnerable plaque.
1.Kannel WB, Wilson P, Blair SN. Epidemiological
assessment of the role of physical activity and fitness in development
of cardiovascular disease.
Am Heart J.1985;109:876-885.Google Scholar 2.Siscovick DS, Weiss NS, Hallstrom AP, Inui TS, Peterson DR. Physical activity and primary cardiac arrest.
JAMA.1982;248:3113-3117.Google Scholar 3.Leon AS, Connett J, Jacobs Jr DR, Rauramaa R. Leisure-time physical activity levels and risk of coronary heart
disease and death: the Multiple Risk Factor Intervention Trial.
JAMA.1987;258:2388-2395.Google Scholar 4.Blair SN, Kohl III HW, Paffenbarger Jr RS, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality.
JAMA.1989;262:2395-2401.Google Scholar 5.Ekelund LG, Haskell WL, Johnson JL, Whaley FS, Criqui MH, Sheps DS. Physical fitness as a predictor of cardiovascular
mortality in asymptomatic North American men: the Lipid Research
Clinics Mortality Follow-up Study.
N Engl J Med.1988;319:1379-1384.Google Scholar 6.Oberman A. Exercise and the primary prevention of
cardiovascular disease.
Am J Cardiol.1985;55:10D-20D.Google Scholar 7.Siscovick DS, Weiss NS, Fletcher RH, Lasky T. The
incidence of primary cardiac arrest during vigorous exercise.
N
Engl J Med.1984;311:874-877.Google Scholar 8.Tofler GH, Stone PH, Maclure M.
et al. Analysis of
possible triggers of acute myocardial infarction (the MILIS Study).
Am J Cardiol.1990;66:22-27.Google Scholar 9.Burke AP, Farb A, Malcom GT, Liang Y-H, Smialek J, Virmani R. Coronary risk factors and plaque morphology in patients with
coronary disease dying suddenly.
N Engl J Med.1997;336:1276-1282.Google Scholar 10.Farb A, Burke AP, Kolodgie FK.
et al. Determinants of
coronary thrombosis in sudden cardiac death [abstract].
Mod
Pathol.1997;9:29(A).Google Scholar 11.Mann JM, Davies MJ. Vulnerable plaque: relation of
characteristics to degree of stenosis in human coronary arteries.
Circulation.1996;94:928-931.Google Scholar 12.Johnstone MT, Mittleman M, Tofler G, Muller JE. The
pathophysiology of the onset of morning cardiovascular events.
Am J Hypertens.1996;9:22S-28S.Google Scholar 13.Muller JE, Tofler GH, Stone PH. Circadian variation and
triggers of onset of acute cardiovascular disease.
Circulation.1989;79:733-743.Google Scholar 15.Bjorkerud S, Bjorkerud B. Apoptosis is abundant in
human atherosclerotic lesions, especially in inflammatory cells
(macrophages and T cells), and may contribute to the accumulation of
gruel and plaque instability.
Am J Pathol.1996;149:367-380.Google Scholar 16.Haft JI, Mariano DL, Goldstein J. Comparison of the
histopathology of culprit lesions in chronic stable angina, unstable
angina, and myocardial infarction.
Clin Cardiol.1997;20:651-655.Google Scholar 17.Crisby M, Kallin B, Thyberg J.
et al. Cell death in
human atherosclerotic plaques involves both oncosis and apoptosis.
Atherosclerosis.1997;130:17-27.Google Scholar 18.Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured and stable
atherosclerotic lesions: a structural analysis with histopathological
correlation.
Circulation.1993;87:1179-1187.Google Scholar 19.Hayashi K, Imai Y. Tensile property of atheromatous
plaque and an analysis of stress in atherosclerotic wall.
J
Biomech.1997;30:573-579.Google Scholar 20.Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of
fibrous cap thickness on peak circumferential stress in model
atherosclerotic vessels.
Circ Res.1992;71:850-858.Google Scholar 21.Loree HM, Tobias BJ, Gibson LJ, Kamm RD, Small DM, Lee RT. Mechanical properties of model atherosclerotic lesion lipid pools.
Arterioscler Thromb.1994;14:230-234.Google Scholar 22.Felton CV, Crook D, Davies MJ, Oliver MF. Relation of
plaque lipid composition and morphology to the stability of human
aortic plaques.
Arterioscler Thromb Vasc Biol.1997;17:1337-1345.Google Scholar 23.Lee RT, Schoen FJ, Loree HM, Lark MW, Libby P. Circumferential stress and matrix metalloproteinase 1 in human coronary
atherosclerosis: implications for plaque rupture.
Arterioscler
Thromb Vasc Biol.1996;16:1070-1073.Google Scholar 24.Brown DL, Hibbs MS, Kearney M, Loushin C, Isner JM. Identification of 92-kD gelatinase in human coronary atherosclerotic
lesions: association of active enzyme synthesis with unstable angina.
Circulation.1995;91:2125-2131.Google Scholar 25.Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes:
implications for plaque rupture.
Circulation.1994;90:775-778.Google Scholar 26.Richardson PD, Davies MJ, Born GV. Influence of plaque
configuration and stress distribution on fissuring of coronary
atherosclerotic plaques.
Lancet.1989;2:941-944.Google Scholar 27.Barger AC, Beeuwkes R, Lainey LL, Silverman KJ. Hypothesis: vasa vasorum and neovascularization of human coronary
arteries.
N Engl J Med.1984;310:175-177.Google Scholar 28.Barger AC, Beeuwkes R. Rupture of coronary vasa vasorum
as a trigger of acute myocardial infarction.
Am J Cardiol.1990;66:41G-43G.Google Scholar