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(Circulation. 1996;94:26-34.)
© 1996 American Heart Association, Inc.
Articles |
Coronary Heart Disease Risk Factors in Men and Women Aged 60 Years and Older
Findings From the Systolic Hypertension in the Elderly Program
From the Cardiovascular Research Institute, University of California, San Francisco (P.H.F.); University of Texas School of Public Health, Houston (B.R.D.); Kaiser Permanente Medical Center, Sacramento, Calif (A.J.B.); University of Hawaii School of Medicine, Honolulu (J.D.C.); University of Kentucky College of Medicine, Lexington (G.P.G.); Christ Hospital, Cincinnati, Ohio (J.L.I.); Albert Einstein College of Medicine, Bronx, NY (S.W.-S.); Robert Wood Johnson Medical School, New Brunswick, NJ (A.C.W.); and Northwestern University Medical School, Chicago, Ill (J.S.).
Correspondence to Philip H. Frost, MD, University of California, San Francisco, CA 94143-0326. E-mail phf{at}itsa.ucsf.edu
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Abstract |
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Background Coronary heart disease (CHD) is the most common cause of death in men and women aged 60 years and older. Although a number of studies support the concept that CHD risk factors that have been defined in younger adults are significantly associated with CHD events in older adults, others do not support this thesis, and further definition of the risk-factor concept in older adults is required.
Methods and Results The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years); 14% were black, and 43% were men. Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. About 13% of participants were current smokers; 10% had a history of diabetes; 5%, a prior myocardial infarction; 5%, angina pectoris; 2.3%, intermittent claudication; and 7%, a carotid bruit. Mean total cholesterol value was 6.11 mmol/L. Mean follow-up was 4.5 years. In multivariate Cox regression analyses for CHD, variables that were significant were baseline total cholesterol value, smoking, history of diabetes, presence of carotid bruit, and treatment group in the trial. Active treatment yielded a 27% reduction in CHD risk. For each 1.03 mmol/L increase in total cholesterol value, there was an increase in risk of about 20%. Current smokers had a 73% increase, diabetics a 121% increase, and those with carotid bruit a 113% increase in CHD risk.
Conclusions The results of this study support the concept that CHD risk factors are important in older men and women with isolated systolic hypertension.
Key Words: aging • coronary disease • risk factors • hypertension
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Introduction |
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Factors that contribute to the risk of CHD have been investigated in many populations, notably in individuals residing in Framingham, Mass, and middle-aged men studied in the National Cooperative Pooling Project and screened as potential participants in the Multiple Risk Factor Intervention Trial.1 2 3 4 5 6 7 8 9 These studies and others10 11 12 described and confirmed that risk for the development of CHD is related to cigarette smoking, levels of serum cholesterol and blood pressure, and diabetes mellitus. The risk-factor concept and the results of completed clinical trials designed to test the efficacy of intervention to control specified risk factors are the foundation of current recommendations for smoking cessation and the treatment of hypertension, hypercholesterolemia, and diabetes.
CHD, although an important contributor to death and disability among middle-aged adults, is most frequently manifested in older groups and is the most common cause of death in men and women aged 60 years and older. In contrast to the extensive study of CHD risk factors in middle-aged adults, only limited opportunities have been available for such study in older individuals. The general conclusion from these studies is that CHD risk factors as defined in middle-aged adults are significantly associated with CHD events in older adults,13 14 15 16 17 18 19 20 but some reports do not support this thesis,14 17 21 22 23 24 and further definition of the risk associated with classic risk-factor abnormalities in older adults is required. CHD risk-factor associations in older adults, especially when supported with data from intervention trials, have important healthcare consequences both for development of population-wide preventive strategies and for delivery of health care to individuals.
Data are presented here from the 4.5-year follow-up of participants in SHEP, a study designed to test the hypothesis that treatment of isolated systolic hypertension would reduce stroke incidence. SHEP recruited 4736 adults aged 60 years and older with SBP of 160 to 219 mm Hg and DBP <90 mm Hg. Mean age of the subjects was 72 years; 57% were women, and 14% were black. In this large sample of older adults, we examined the association of CHD events with cigarette smoking, hypercholesterolemia, diabetes, and evidence of clinical atherosclerosis.
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Methods |
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As described in detail elsewhere,25 SHEP was a randomized, placebo-controlled, double-blind, multicenter clinical trial designed to determine whether pharmacological treatment of isolated systolic hypertension (SBP
160 mm Hg and DBP <90
mm Hg) among persons aged 60 years and older would reduce the incidence
of fatal and nonfatal strokes. A secondary end point was CHD
events. From among 447 921 adults aged 60 years or older who were screened in 16 clinical centers, there were 4736 men and women eligible who were randomized, in double-blind fashion, to either active therapy or matching placebo. Stratification at randomization was by clinical center and by whether or not the participant was taking antihypertensive medication at initial contact. The study was approved by the review board at each institution, and participants gave informed consent for screening and later study participation.
Detailed criteria for SHEP enrollment were published previously.25 Blood pressure was determined with a Hawksley random zero manometer. Blood pressure eligibility for randomization was determined after four seated blood pressure measurements, two each at two baseline visits. The average had to yield an SBP of 160 to 219 mm Hg and a DBP <90 mm Hg.
Trial exclusion criteria included the presence of major cardiovascular disease or other major disease such as cancer or alcoholic liver disease, renal dysfunction, or presence of medical-management problems. Participants eligible after the second baseline visit were allocated randomly to either active drug or matching placebo in a double-blind fashion.
Each participant had a target blood pressure established as follows:
persons with SBP 180 mm Hg had a goal of reduction to <160 mm Hg,
whereas those whose SBPs were 160 to 179 had a goal of reduction of at
least 20 mm Hg, so that a patient with a baseline SBP of 165 had a goal
of 145 mm Hg. The drug used was chlorthalidone 12.5 mg/d (step 1). If
step 1 medication did not achieve the goal, the active drug (or
matching placebo) dosage was doubled. If the goal was not achieved at
this maximal dose of step 1 medication, then atenolol 25 mg/d or
matching placebo was added as the step 2 drug unless contraindicated,
in which case reserpine 0.05 mg/d could be substituted. If necessary,
the dosage of the step 2 drug could be doubled. Participants with serum
potassium concentration <3.5 mmol/L at two consecutive visits were
given a potassium supplement.
Monthly visits were required until participants reached the target SBP
or until the maximal level of stepped-care treatment was attained.
If blood pressure rose above predefined escape levels despite maximal
stepped-care therapy, then known active-drug therapy could be
prescribed. These escape criteria were SBP 250 mm Hg or DBP 115 mm
Hg at a single visit, sustained SBP 220 mm Hg, or sustained DBP 90
mm Hg.
All participants had quarterly visits with assessment of blood pressure, heart rate, body weight, medical history, and medication use. ECGs were recorded at baseline and at selected follow-up visits; they were read centrally by standard methods.26 27 LVH was defined as the sum of "hard" and "moderate" LVH (Minnesota codes 3.1 plus 4.1 to 4.3 or 5.1 to 5.3 and Minnesota codes 3.3 plus 4.1 to 4.3 or 5.1 to 5.3). In SHEP, 4.9% and 2.5% of the group had hard and moderate LVH, respectively. Baseline ECG abnormalities were defined as the sum of one or more of the following Minnesota codes: 1.1 to 1.3 (Q/QS), 3.1 to 3.4 (high R waves), 4.1 to 4.4 (ST depression), 5.1 to 5.4 (T-wave changes), 6.1 to 6.8 (AV conduction defects), 7.1 to 7.8 (ventricular conduction defects), 8.1 to 8.6 (arrhythmias), and 9.1 to 9.3 and 9.5 (miscellaneous items).
Blood Sampling and Laboratory Methods
Baseline blood samples were procured at the second baseline
visit, immediately before randomization. Participants who were taking
antihypertensive medication previously had not taken these medications
for 2 to 8 weeks before sample collection. A defined protocol for
venipuncture was followed and included having the
participant in the seated position, minimal tourniquet time, and
centrifugation of the sample 30 to 60 minutes after
sample collection to harvest serum.28 Whenever feasible,
the samples were collected in the morning after an overnight fast.
Sixty-four percent of all blood samples were collected after the
subjects had fasted. Serum samples were collected by courier and
transported under refrigeration to the central laboratory (MetPath
Laboratories, Teterboro, NJ), where all measurements were made within 2
days of sample collection. Lipid values determined were total
cholesterol, HDL cholesterol, and
triglycerides. Methods of analysis and external
laboratory surveillance have been described.28 Total
cholesterol values are presented and discussed
here. Results of other baseline lipid measures and subsequent CHD will
be published separately.
End-Point Ascertainment
End points included in the present report are (1) CHD
(nonfatal MI or CHD death) and (2) all CHD (CHD, CABG, or PTCA). A
nonfatal MI was defined as typical symptoms of acute MI plus either
typical ECG changes or significant enzyme elevations but did not
include silent MI. CHD death was defined as either sudden cardiac death
(death within 1 hour of onset of severe cardiac symptoms) or rapid
cardiac death (death within 1 to 24 hours of severe cardiac symptoms)
or fatal MI (diagnosis at autopsy or on death certificate with
preterminal hospitalization data). Occurrence of nonfatal and fatal
events was confirmed by a panel of three physicians blinded to
randomization status, including one cardiologist for cardiac
events.
Statistical Methods
Descriptive statistics for several baseline characteristics are
presented. Cox regressions and univariate RRs (and
95% CIs) for each of these baseline factors were calculated for the
two CHD outcomes and total mortality.29 RR is defined as
e(coefficientxinterval tested), ie, antilogarithm to e
(base for natural logarithm). For example, if the coefficient for the
relation of total cholesterol value to CHD risk
(multivariate)=0.1678344 and the interval of interest
is 1.03 mmol/L higher, then
RR=e(0.1678344x1.03).
Multivariate Cox regressions were also performed with
the following variables: randomization group, age, race, sex, DBP,
alcohol use, total cholesterol value, smoking, history of
diabetes, history of CHD, angina by Rose questionnaire, presence of
carotid bruit, and serum uric acid level.
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Results |
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SHEP baseline data were presented previously.25 30 Baseline characteristics pertinent to the present report are included in Table 1
. Mean total
cholesterol value was 6.11 mmol/L (236 mg/dL). This value
was not different for the 64% of subjects whose blood was drawn after
they had fasted.
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CHD Events: Univariate Analysis
In the average 4.5 years of follow-up, SHEP participants
experienced 245 definite nonfatal and fatal CHD events and underwent 79
CABG and PTCA procedures.25 Table 2
presents the results of univariate Cox regressions,
with nonfatal MI or CHD death as the outcome, for each baseline
variable listed. The actively treated group had a significant 27%
reduction in CHD events compared with the placebo-treated group
(104 versus 141 events). Other variables with significant
regressions were age, sex, current smoking, history of diabetes,
history of CHD, Rose angina, presence of carotid bruit, serum total
cholesterol value, any ECG abnormality, uric acid, and
fasting glucose level (but fasting glucose level was not significant
for participants with no history of diabetes).
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Estrogen use in women was associated with a decrease in CHD events (RR=0.34, yes versus no; P=.07).
Table 3 presents results for the second CHD end
point, which included nonfatal MI, fatal CHD, CABG, and PTCA. The
findings in Table 3 were unchanged from those described for Table 2
except that there was a significant increase in events associated with
hematocrit.
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In univariate analyses by sex, the findings for both men and women were similar to those described for the group as a whole (data not shown). For the variables of age, smoking status, history of diabetes, and Rose angina, RRs for CHD were greater for women than for men.
CHD Events: Multivariate
Analyses
Results of the multivariate analyses for
the two CHD end points are presented in Tables 4 and 5. With control for other variables listed,
significant variables were randomization group (active-drug
treatment or placebo), age, sex, serum total cholesterol
value, smoking, history of diabetes, and carotid bruit on physical
examination.
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Total Mortality
In the average 4.5 years of follow-up, SHEP participants
experienced 455 deaths (132 CHD deaths, 70 other
cardiovascular deaths, 212
noncardiovascular deaths, and 41 deaths of
indeterminate cause).25 Results of univariate
and multivariate analyses for end-point
total mortality are presented in Tables 6 and 7. Seventeen of the 29 listed variables, including
current smoking, history of diabetes, history of CHD, and presence of
carotid bruit, were univariate predictors of total
mortality. With control for other listed variables, significant
variables in the multivariate analysis were
age, sex, current smoking, and history of diabetes. Serum total
cholesterol value was not a significant predictor in these
analyses.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the SHEP cohort, cigarette smoking, history of diabetes, history of CHD, carotid bruit, ECG abnormalities, and serum total cholesterol value measured at baseline were predictors of CHD events. These observations extend the study of defined CHD risk factors to a mixed-race (predominantly white) cohort of men and women aged 60 years and older recruited to participate in SHEP.
CHD risk factors have been studied extensively in middle-aged white men,1 2 4 5 8 9 resulting in the identification of hypertension, hypercholesterolemia, cigarette smoking, and diabetes mellitus as CHD risk factors. Fewer observations have been recorded in women and in older populations. Our results support extension of the tenets of the risk-factor concept to older men and women and indicate that individuals at the highest risk for CHD can be identified by use of the CHD risk factors previously described in younger populations. Comparison of these results with other observations is described below.
Cigarette Smoking
Cigarette smoking is an established CHD risk factor in
middle-aged and older adults. This is strongly supported by our
current results. In SHEP, there was a strong and consistent
relation between current cigarette smoking compared with nonsmoking for
all major end points. The RR for nonfatal MI or CHD death in
multivariate analysis is 1.73. Current
cigarette smoking, as opposed to not currently smoking, thus imparts a
73% increased risk of a major CHD event both in older men and in older
women. For end-point total mortality, current cigarette smoking
imparts a 128% increased risk in multivariate
analysis. These findings are strikingly similar to those in
younger populations6 31 32 as well as in other reported
studies conducted in older populations.19 33
In 7178 persons 65 years of age and older without a history of MI, stroke, or cancer at baseline who lived in three communities33 and were followed up for 5 years, rates of total mortality among current smokers were twice those among participants who had never smoked (RR of 2.1 and 1.7 among men and women, respectively). Current smokers had significantly higher rates of cardiovascular mortality than those who had never smoked (RR of 2.0 and 1.6 among men and women, respectively). In both sexes, former smokers had rates of cardiovascular mortality similar to those of participants who had never smoked, regardless of age at cessation.
In an evaluation of smoking cessation in 1893 men and women 55 years of
age and older with angiographically documented coronary artery
disease from the CASS registry,19 the 6-year mortality
rate for the 1086 persons who continued to smoke compared with the 807
individuals who quit during the year before study enrollment and who
abstained throughout the study was significantly higher (RR of 1.7,
95% CI of 1.4 to 2.0). There was no diminution of the apparent
beneficial effect of smoking cessation with increasing age (subjects
aged 55 to 64 and 65 compared with the subgroup aged 35 to 54
years).
Diabetes Mellitus
Diabetes mellitus is established as a CHD risk
factor,34 a result primarily based on population studies
in middle-aged white men and supported by observations in smaller
groups of white women. Our results provide additional support for the
inclusion of diabetes mellitus as an independent CHD risk factor in the
elderly. The SHEP study group included eligible participants with
non–insulin-dependent diabetes controlled by diet or oral
hypoglycemic agents. We found that a history of diabetes at baseline
was significantly associated with an approximate twofold increase in
CHD (RR for nonfatal MI or CHD death of 2.1, univariate and
multivariate analyses) and total mortality
(RR=1.8). Our results in SHEP are similar to those observed in
middle-aged men and women. The 12-year follow-up of MRFIT
screenees for cardiovascular disease death in a cohort
of 5163 men who reported taking medication for diabetes at baseline
screening compared with 342 815 men not taking medication for diabetes
has been reported.7 Overall cardiovascular
disease death (78% of which were CHD deaths) was threefold higher
among diabetics after adjustment for age, race, income, serum
cholesterol level, SBP, and reported number of cigarettes
smoked per day. In the First National Health and Nutrition Examination
Survey,16 4041 female and 3340 male respondents (218 women
and 189 men with self-reported diabetes) aged 40 to 77 years were
traced after an average of 9 years. After adjustment for age, SBP,
serum cholesterol value, body mass index, and smoking, the
RR for death was 2.0 for diabetic women and 2.3 for diabetic men. The
RR for ischemic heart disease mortality was 2.5 for women and
2.8 for men. In the 9-year follow-up data from the Chicago Heart
Association Detection Project in Industry,35 8030
white women and 11 220 white men (170 women and 377 men with a history
of diabetes) aged 35 to 64 years were studied. The RR for CHD mortality
was 4.72 for diabetic women and 3.79 for diabetic men after adjustment
for multiple other risk factors.
Established Atherosclerotic Vascular Disease
Patients with established atherosclerotic vascular disease are at
increased risk for CHD (first or recurrent event), a finding confirmed
for the SHEP cohort. In SHEP, the presence of atherosclerotic disease
at baseline was assessed clinically by history of MI, coronary
angioplasty, or CABG surgery, and a standard questionnaire for angina
pectoris (Rose angina) and on physical examination by the presence of
carotid bruit. In the present study group of older men and women,
each of the clinical measures of atherosclerotic vascular disease was
significantly associated with the two CHD end points in
univariate analyses (RR range, 1.62 to 2.41), and
history of CHD and presence of carotid bruit were significant for total
mortality (RR of 1.52 and 1.73, respectively). In
multivariate analyses, carotid bruit was
significant for the two CHD end points.
Again, our results are similar to results observed in younger populations. In the 10-year mortality follow-up of 2541 white men aged 40 to 69 years who participated in the Lipid Research Clinics Prevalence Study,36 17% had some evidence of cardiovascular disease at baseline. Included in the cardiovascular disease group were 83 men with definite MI, 253 with abnormal results on a graded exercise tolerance test but with no definite MI, 31 with specific abnormalities on resting ECG, 64 with angina pectoris (Rose questionnaire or atypical angina), and 40 with other signs or symptoms of cardiovascular disease. Men who had cardiovascular disease at baseline had considerably higher rates of CHD death than those without manifest cardiovascular disease.
The risk associated with asymptomatic carotid bruit was examined in Framingham, Mass,37 and Evans County, Georgia.38 Carotid bruit was routinely sought in the Framingham cohort (1590 men and 2119 women aged 44 to 79 years) and during an 8-year period appeared in 66 men and 105 women, all of whom were asymptomatic. Subsequent to this finding, those individuals with an asymptomatic carotid bruit experienced a stroke rate that was more than twice that expected for their age and sex, and the incidence of MI was also increased twofold. All-cause mortality was also significantly increased in this group (1.7-fold in men and 1.9-fold in women), with 79% of the deaths due to cardiovascular disease. In Evans County, the study group included 1620 persons (919 women, 701 men; 604 black, 1016 white), 72 with carotid bruit (18 men, 54 women). During the 6-year period of follow-up observation, the odds ratios for CHD death were 3.4 for men and 1.9 for women, with 90% CIs of 1.1 to 10.9 and 0.7 to 5.0, respectively. After considering the data for stroke, stroke location, and the increase in CHD mortality, both study groups concluded that the finding of an asymptomatic carotid bruit should be viewed chiefly as a general and nonfocal sign of advanced atherosclerotic disease and not necessarily as an indicator of local arterial stenosis, a conclusion supported by our data.
Total Cholesterol Value
Our results confirm the observation that elevated total blood
cholesterol value is an independent CHD risk factor for
older men and women. A high total cholesterol value is well
established as a CHD risk factor in middle-aged men, but early
reports from the Framingham study1 2 3 4 and
others17 did not support this conclusion in subjects aged
65 years and older. Our results and results from other
studies,13 14 15 18 39 including more recent Framingham
results,9 20 now confirm the significant association
between serum total cholesterol value and CHD in the
elderly.
In SHEP, we found that the total cholesterol value was a
significant predictor of total CHD events both as a
univariate measure and in multivariate
analysis after controlling for other CHD risk factors. Our
analysis is based on a single measurement of venous blood
obtained at conclusion of the final eligibility (baseline) visit. In
the multivariate analysis, a 1.03 mmol/L (40
mg/dL) increase in total cholesterol value (about 1 SD) was
associated with an 
20% increase in CHD events. A 10% higher total
cholesterol value (0.61 mmol/L; 23.6 mg/dL) was associated
with about an 11% to 12% higher event rate. Our results are in accord
with findings from population studies in older men13 15 18
and women.14
In the Honolulu Heart Study,13 1480 men aged 65 to 74 years and free of CHD were followed up for an average of 12 years. The upper-lower quartile RR for serum cholesterol for the end point of nonfatal or fatal CHD was 1.64 (95% CI, 1.14 to 2.36). In that same study, the RR for CHD incidence in middle-aged men was also 1.64. In the 18-year follow-up of 18 296 male civil servants who participated in the Whitehall study,18 56% who died of CHD died after the age of 65. The outcome measures included age at death, cholesterol concentration at baseline (1967 to 1969), and number of years elapsed between testing and death. Although the RR of CHD decreased with age at screening, absolute excess risk attributable to elevated cholesterol concentration increased with age because mortality from CHD increased considerably with age. For every age group at every follow-up interval, there was a positive association between plasma cholesterol concentration and death from CHD. In the Whitehall study, the investigators concluded that plasma cholesterol concentration continued to predict CHD in elderly people, at least up to the age of 80 years.
In the Kaiser Permanente Coronary Heart Disease in the Elderly Study,15 2746 white men aged 60 to 79 years who had no self-reported history of CHD were followed up for 10 years. In this period, the RR for CHD mortality in the highest serum cholesterol quartile was 1.5 (95% CI, 1.2 to 2.0) and did not change greatly with age. In a population study that included women,14 1407 white men and 1780 white women aged 50 to 79 years with no personal history of heart disease were followed up for 10 years. In a separate analysis for age groups 50 to 64 years and 65 to 79 years, total cholesterol value was a significant predictor of fatal ischemic heart disease in younger and older men and in older women.
Baseline ECG Abnormalities
ECG measures of LVH and the grouped major and minor ECG
abnormalities are significant predictors of CHD. This finding is
supported by observations in multiple prospective
studies.8 36 40
Hypertension
SHEP selection criteria yielded a sample with a highly truncated
distribution of both SBP and DBP. In the present study, SBP and DBP
at baseline were not significant independent predictors of CHD, but the
marked, significant, independent relation of active-drug treatment
to CHD outcome confirms that isolated systolic hypertension is
an important risk factor in older men and women. Other studies that
demonstrated a relation between blood pressure and CHD were population
studies that included individuals with a wide range of blood
pressures.41
We have taken the opportunity afforded by SHEP to test the elements of the risk-factor concept in a large population of men and women aged 60 years and older. SHEP was advantageous for study in that a large group of age-eligible individuals was followed up under a standard protocol with baseline measures and systematic recording of cardiovascular and noncardiovascular events. Although the large sample and its heterogeneity in both site of study and racial composition are advantageous for study, the present study is not a population study in that volunteers were recruited on the basis of clinical criteria for isolated systolic hypertension.
The results of the present study support the conclusion that major CHD risk factors influence the probability of developing CHD for older men and women with isolated systolic hypertension. These results may be applicable to the more broad-based older population without hypertension. This statement is based on comparison of the SHEP data presented here not only with data collected in younger adults but also with population-based reports on older adults. Of practical importance is the unanswered question of whether risk-factor reduction in the elderly will be followed by clinical benefit. In support of a positive response are the primary SHEP results. SHEP examined whether treatment of isolated systolic hypertension would reduce incidence of stroke. The result was a definite yes25 ; an additional finding was the significant (27%) reduction in CHD events experienced by the active-treatment group. Other supporting evidence for the clinical benefit of risk-factor reduction in this age group comes from the CASS registry,19 which demonstrated a definite reduction in CHD mortality with smoking cessation. Individual data within trials of intensive lipid lowering42 and lifestyle modification43 and results of the Scandinavian Simvastatin Survival Study44 45 in CHD patients suggest that lipid modification may reduce CHD risk in older persons. However, definitive identification of benefits of lipid modification for primary prevention must await the results of carefully conducted clinical trials.
We have used the SHEP database to assess the strength of association of CHD risk factors in men and women aged 60 years and older. We have found that cigarette smoking, history of diabetes mellitus, clinical evidence of preexisting atherosclerotic disease, and serum cholesterol levels were all independently and significantly predictive of CHD events in both men and women. It is a reasonable inference that older individuals at high risk (identified by the traditional CHD risk factors) can benefit from smoking cessation, control of hypertension, and cholesterol reduction.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by contracts with the National Heart, Lung, and Blood Institute and the National Institute on Aging. A complete listing of the SHEP research group has been published previously.25
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Footnotes |
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The guest editor for this article was Robert A. O'Rourke, MD, University of Texas Health Science Center, San Antonio.
Received September 7, 1995; revision received December 27, 1995; accepted January 2, 1996.
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References |
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