Is Italy losing the “Mediterranean advantage?” Report on the Gubbio population study: Cardiovascular risk factors at baseline

PREVENTIVE

MEDICINE

18, 3544 (1989)

Is Italy Losing the “Mediterranean Advantage?” Report on the Gubbio Population Study: Cardiovascular Risk Factors at Baseline’ MARTINO LAURENZI, M.D., M.P.H. ,*,t ROSE STAMLER, M.A.,*12 MAURIZIOTREVISAN, M.D.,$ ALAN DYER, PH.D.,* AND JEREMIAH STAMLER, M.D.*

For the Gubbio Collaborative Study Group *Northwestern University Medical School, Morton Bldg. l-615, 303 East Chicago Avenue, Chicago, Illinois tXW11; Wenter for Epidemiologic Research, Merck Sharp and Dohme (Italy), Rome, Italy, and Center for Preventive Medicine, Gubbio, Italy; Slnstitute of Internal Medicine and Metabolic Diseases, Second Medical School, University of Naples, Naples, Italy, and Department of Social and Preventive Medicine, State University of New York, Buffalo, New York 14214 The coronary heart disease mortality rate in Italy-lower than in many other industrialized countries-has changed little in the last 20 years, whereas in the United States, a major decline in deaths resulting from coronary heart disease has occurred. These differing trends have reduced considerably the gap between the two countries in coronary mortality rates. Several recent population studies in Italy have found a change in the previously more favorable risk factor proflle. In the northern hill town of Gubbio, studied in 1983-1985, median serum cholesterol level of men ages 40-59 was 223 mg/dl, considerably higher than was found in the 1960 Italian population samples of the Seven Countries Study (197-206 m&il). In the earlier study, the cholesterol levels in the Italian men who were still mainly consuming the traditional Mediterranean diet were 30-40 mg&l lower than in the U.S. sample. The 1980 Gubbio levels, however, were at least as high as those of their U.S. contemporaries. Cigarette smoking was much higher among the middle-aged men of Gubbio than among a similar U.S. population sample (56% vs 36%). Hypertension prevalence was high, and several risk factors for hypertension-obesity, high salt intake, and alcohol-were common in the Gubbio as well as in other recent Italian population studies. The changing coronary risk profde in Italy, which now includes higher population levels of serum cholesterol as well as the other major coronary heart disease risk factors of cigarette smoking and hypertension, threatens to reduce markedly the “Mediterranean advantage” enjoyed by Italy in the past. 0 1989 Academic Pmss, Inc.

INTRODUCTION

Until the 196Os,while death from coronary heart disease (CHD) was increasing in Western industrialized countries, European populations in the Mediterranean area, most notably Italy and Greece, had lower CHD mortality rates. When population samples from Italy were studied in the Seven Countries Study beginning in 1960, risk factors for coronary disease were assessed(5). At that time, in the three ’ Supported, planned, and carried out by the Center for Epidemiologic Research, Merck Sharp and Dohme (Italy) in cooperation with the Center for preventive Medicine in Gubbio, Italy. ’ To whom reprint requests should be addressed. 35 0091-7435/89$3.00 Copyright 0 1989 by Academic Press. Inc. All rights of reproduction in any form reserved.

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samples (Crevalcore and Montegiorgio-rural areas in central and north Italyand Rome railroad workers), Italy was found to resemble most other industrialized countries with regard to the proportion of the population with elevated blood pressure (BP) levels and percentage of cigarette smokers. However, with regard to elevated blood cholesterol levels, a critical prerequisite of mass coronary disease,Italian men were in a much more favorable position that their counterparts in most Western industrialized countries (5, 10, 11). What has happened to this favorable aspect of the risk profile for middle-aged Italian men, termed the “Mediterranean advantage?” Does the cholesterol level of these men resemblethat of men in, for example, the United States?If there has been an increase in cholesterol levels in the Italian population, what does this portend for future CHD trends? Have there been changes in other CHD risk factors that could be additive to (or possibly ameliorating) the effect of raised cholesterol? An opportunity to examine this question is provided in the population study whose baseline (prevalence) phase took place in 1983-1985,in the north central Italian town of Gubbio. The major concerns of this study are the epidemiology of BP, and the control and prevention of hypertension, an unsolved mass public health problem in Italy. As part of this investigation, a large body of data was collected on major cardiovascular risk factors, and these data contribute toward answering the question: Are the major CHD risk factors at a favorable or unfavorable level today in Italy? Is Italy losing the “Mediterranean advantage?” This question is relevant particularly as one compares trends in CHD mortality in the major industrialized countries with those observed in Italy. Countries such as Canada, Australia, and the United States have witnessed marked downward trends in coronary mortality since the 1960s.In Italy, on the other hand, while CHD death rates are still below those of the cited countries, coronary mortality rose in Italy from 1960to1975, levelled off over the next 3 years, and had only a slight decline thereafter (13, 14). POPULATION AND METHODS The City of Gubbio and the Study Population

Gubbio is a long-established hill town, in north central Italy, at the lower reaches of the Appennine mountain chain (Fig. 1). It is one of the Umbrian towns with a well-preserved wall-enclosed medieval central area. For the purposes of this research, the population was defined as all persons age 5 years and over dwelling within the confines of the original medieval town, i.e., within the city wall (in 1983the town list included 4,150 such persons). All persons who could be located (3,836) were invited to participate, by letter and follow-up visit. While others outside the town wall also took part in the baseline screening (mainly in response to public request), this report is based on findings for the defined population inside the wall. Data are for males and females age 15 and older. The Baseline Examination

A comprehensivebaseline medical examination was performed that included a

CHD RISK FACTORS

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POPULATION

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37

FIGURE 1

battery of standard laboratory tests, and also included measurements of special interest to the Gubbio Study in view of its focus on hypertension (e.g., RBC intracellular Na and K, sodium-lithium countertransport). These latter are reported separately. The main variables of concern in the present report are BP, serum total cholesterol (TC), cigarette smoking, and body massindex (BMI). Data are also presented on self-reported history of diabetes, serum uric acid, and urinary electrolytes. The baseline examination was based on a detailed protocol and standard forms. The examination took place at a clinical facility specially set up on premises made available by the municipality, and was staffed by four physicians well-trained in the protocol. They underwent special training in BP measurement at the Istituto Superiore di Sanita (National Institute of Health) in Rome. Blood pressure measurements were made with mercury manometers and one of five cuffs of varied size. These cuffs were used beginning with the fifth month of the survey; before then, one adult cuff and one pediatric cuff were used. Blood pressure was measured in the right arm at the start of the examination, in a sitting position, three consecutive times, after an initial S-min rest. Blood pressure values reported are the average of these three readings, Kl for systolic and K5 for diastolic. Participants were requested to refrain from eating for at least 2 hr before the visit, and from smoking or strenuous activity for 0.5 hr prior to the visit. They were asked to bring with them a sample of first-voided morning urine. Participants were weighed and measuredwithout shoesand without heavy clothing. A beam balance and stadiometer were used. Body massindex was calculated as weight (kg)/height (m*). Information was collected on smoking, personal medical history, use of medications, and alcohol consumption. Serum TC was determined by the enzymatic method and uric acid by enzymatic calorimetry. Urinary electrolytes were measured by flame photometry. To monitor technical error, more than 30% of laboratory sampleswere split and submitted as blind replicates to the laboratories performing the above analyses.

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Data Handling

All forms were processed locally, using the microcomputer available at the Gubbio facility. Programs provided for data editing, rejection of extreme values, and other ongoing monitoring of quality control. Based on the computerized data tile, appropriate referral was made to family doctors of individuals with abnormal values. All participants were mailed their results and were asked to take the report to their doctors for review and evaluation. Statistical Methods

Descriptive statistics on the baseline risk factor findings of the Gubbio Study include age-sex-specific mean or median values for continuous variables. For BP, medians were calculated with those on antihypertensive medication assigned to the upper half of the distribution. Prevalence rates were computed for hypertension, cigarette smoking, self-reported diabetes, hypercholesterolemia, hyperuricemia, and obesity. In analyzing BP data, analysis was performed both with and without those examined in the earlier period when two (rather than five) cuffs were used. Since findings in the two sets of analyses were similar, this report includes all persons. When making comparisons with findings in other studies, the age used for the Gubbio samplewas either 40-59 or 45-64 years, depending on the age range in the comparison group. Data are also presented for a younger male cohort (2544 years old) and for women ages 45-64 years. RESULTS

Of the 3,836 persons invited to participate in the study, 3,536 (92.2%) took part in the baseline examination. Results on major coronary and other cardiovascular risk factors are presented below. Serum Cholesterol

Median serum cholesterol level in Gubbio men ages 4&59 (223.0 mg/dl) was markedly higher in 1983-1985than had been found in several samples of Italian men 20 to 25 years earlier (Table 1). The three Italian population samples examined in the Seven Countries Study in 1960-1962had median serum total cholesterol levels of 197mg/dl in the two rural areas and 206 mg/dl among Rome railroad TABLE 1 SERUMTOTAL CHOLESTEROL(mgkll), MEN AGES40-59 Seven Countries Study 196&1%2 IdY Crevalcore Median 09

197.5

wm

Montegiorgio

Rome railroad

United States railroad

Gubbio Studp 19834985

197.2 (710)

206.5 (764)

237.0 (2076)

223.0b ww

n Measured as plasma total cholesterol; for comparability, converted to serum cholesterol by increasing the plasma cholesterol value by 3%. b 95% confidence interval for Gubbio, median = 217-229 mg/dl.

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STUDY

workers (5). By contrast, the median level in Gubbio in 1983-1985more closely resembled that seenin the U.S. cohort of the Seven Countries Study two decades ago, i.e., when the U.S. coronary death rate was at its highest. A comparison with a more recent U.S. study, the National Health and Nutrition Examination (NHANES II, 19761980), finds again that Gubbio men had median cholesterol level similar to that of their U.S. counterparts ages 45-64 (225 in Gubbio vs 223 mg/dl in the United States) (7). The younger cohort in Gubbio (men ages 254) also already had levels similar to those of their age counterparts in NHANES II (a mean of 210 in Gubbio vs 208 mg/dl in the United States). If serum cholesterol levels of 240 mg/dl or greater are considered marked hypercholesterolemia (1,9), then both the older and younger Gubbio cohorts had rates of this risk factor identical to those found among U.S. men (37% for the older and 22% for younger men) (7). Cigarette Smoking

The percentage of current cigarette smokers among men ages 40-59 in Gubbio was 56%. This was somewhat lower than the proportion reported smoking in the earlier (1960-1962) population samples from the Seven Countries Study, both Italian and US. (Table 2); however, this prevalence rate of smoking in Gubbio (1983-1985)was more than 50% higher than that seen among men in the United States in those later years (36%) (15). The percentage of all middle-aged Gubbio men who were heavysmokers (20+ cigarettes per day) was higher than in the earlier samples(31% vs lO-30%) and is similar to the proportion of heavy smokers among U.S. middle-aged men in the 1980s(15). For the younger men of Gubbio, a comparison can be made for those ages25-44 with a similar age group in the United States in the same time period (1983). In Gubbio, the prevalence of cigarette smoking was 57%; in the United States among men in the age group 25-44, smoking prevalence was 40%. In Gubbio, the proTABLE 2 CIGARETTE SMOKING,

MEN AGES 4CL59

Seven Countries Study 1960-1%2

Crevalcore Never Quit Current Smokers All 20 + /day (N)

Montegiorgio

Rome railroad

United States railroad

Gubbio Study 1983-1985

25% 12%

26% 15%

19% 15%

21% 21%

16% 28%

63% 18%”

59% 10% (714)

66% 30% (765)

58% 24% (2101)

56% 31% ww

(978)

Note. x23, comparing percentage current smokers in Gubbio with the three earlier Italian samples = 14.74, P < 0.01. D Percentage of all men.

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portion of smokers in this age group who had quit smoking was 21%, in the United States it was 37% (15). Blood Pressure

Median BP in Gubbio measuredin men ages40-59 years (13l/8 1) was somewhat lower than that observed in the four 1960-1962Seven Countries Study samples used here for comparison (three Italian, one U.S.) (Table 3). In comparison with U.S. men ages 45-64 in the more recent U.S. NHANES II survey (19761980), however, median systolic pressures in Gubbio were higher than in the United States (138 vs 132 mm Hg); diastolic pressures were essentially the same-83 vs 84 mm Hg (8). For younger men (2544 years), the Gubbio median was somewhat lower than that in the United States-121/75 vs 124/79(8). The proportion of men ages 45-64 in Gubbio with screening values at levels defined as elevated was high, using multiple criteria: those with a BP average of 160/95or on antihypertensive treatment, 31%; a BP average of 140/90or on BP treatment, 51%. Using similar criteria, the comparable percentages among U.S. males ages 45-64 in the years 1976-1980were 29 and 47%, which were also high (10). The younger men in Gubbio also resembled their age counterparts in the U.S. NHANES II study, with approximately 14% having BP level of >140/90 or on BP treatment (8). Overweight

In addition to data on the three major establishedcoronary risk factors (above), information was also obtained on weight. While the independent relationship of weight to CHD has not been fully clarified, being overweight is associated with such other risk factors as elevated cholesterol levels, hypertension, and diabetes, themselves CHD risk factors. The Gubbio men in 1983-1985had higher median BMI than three of the four cohorts examined two decadesearlier (Table 4). More than half of the Gubbio men ages 4CL-59had a BMI equal to or greater than 26.0, and one in six men had marked obesity (BMI 230.0). Other Variables Related to Cardiovascular

Risk

Salt consumption, as assessedby urinary sodium excretion, was high in this

MEDIAN

TABLE 3 BLOOD PRESSURE (BP), MEN AGES40-59 Seven Countries Study 1960-1962 Italy

Crevalcore Systolic BP Diastolic BP WI

145.5 87.2 (982)

Montegiorgio 135.2 80.5 (718)

Rome railroad 138.2 88.5

6’68)

United States railroad

Gubbio Study 1983-1985

135.2 84.2 (2101)

130.7” 81.3 (405)

a 95% confidence interval for Gubbio medians are systolic BP, 127.3-134.0; diastolic BP, 80.0-82.7.

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STUDY

TABLE 4 BODY MASS INDEX (BMI),” MEN AGES 40-59

Seven Countries Study 1960-1962 IdY

Median %BMI 226.0 230.0 09

Crevalcore

Montegiorgio

Rome railroad

United States railroad

Gubbio Study 1983-1985

25.3

23.9

26.5

25.5

26.5’

43.6% 14.0% (979)

29.6% 7.6% (716)

43.4% 8.3% (2094)

57.3% 16.8% (404)

56.6% 17.7%

(767)

(1BMI, weight (kg)/height (m*). b 95% confidence interval for Gubbio median = 26.1-27.0.

sample of northern Italian men. The mean concentration of sodium in the morning first-void urine in the Gubbio men ages 45-64 was 160 mmovliter. Since average daily excretion is at least 1 liter, this means daily consumption of salt in these men was at least 9 g. The mean NaK ratio was also high--4:2. Self reported diabetes was 9.4% in these men, and prevalence of elevated uric acid (37.0 mg/dl) was 17%. Women in the Gubbio Sample, Ages 4564 Although this report concentrates on factors related to CHD rates, which are several times higher among men than women, findings on the prevalence of cardiovascular risk factors in the Gubbio women are also relevant for defining the public health challenge created by changes in Italian life. Serum cholesterol level among women in this age group was higher than among men (median of 233 vs 225). Median systolic blood pressure was also slightly higher in women (140 vs 138mm Hg). Diastolic pressure was the same among men as among women (83 mm Hg). Prevalence of elevated pressure, using either systolic or diastolic criteria, was slightly higher in women than men. With the World Health Organization criterion of 2160/95 or on antihypertensive drugs, 34% of women had high BP; this proportion was 54% if the criterion was z 140&O (or drugs). Thus, more than half the women in this age group were at increased cardiovascular risk, based on this factor alone. Almost one-third of the women (31.0%) were current cigarette smokers. This is lower than the rate reported by the men, but the age-pattern in cigarette smoking among women indicated increased long-term risk, in that 51% of the Gubbio women ages 25-34 and 39% of women 15-24 years were smoking cigarettes in 1983-1985, rates higher than for the older women. Marked overweight was more common among the women than the men. While a BMI ~26.0 was found in 57% of women (the same proportion as in men), marked obesity (330.0) was present among 24% of the women compared with 18% of men. Diabetes was reported by 7.0%; hyperuricemia (27.0 mg/dl) was present in 2.9%. Mean urinary sodium concentration was 139 mmovliter, i.e., lower than among the men, but NaIK levels were similar, 4.1, reflecting lower potassium excretion in women (41 mmol/liter in women vs 46 in men).

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Thus, in regard to important cardiovascular risk factors, the women of Gubbio did not differ significantly from the men, with exception of the lower cigarette smoking rate among older women. DISCUSSION

Middle- and older age men in prior Italian population sampleshave been high in at least two important cardiovascular risk factors: cigarette smoking and high BP. But until recent years, a prevalence of a critical risk factor for widespread coronary heart disease-elevated serum TC-has been low in most of the Italian populations studied. This pattern of risk factors may be one factor accounting for the pattern of mortality observed in Italy. Age-adjusted rates for ischemic heart diseasedeath in Italian men ages40-69 were 216 per 100,000deaths in 1968,rose to 235per 100,000in 1978,and then fell to 212per 100,008in 1980(14). These rates were very much lower than those, for example, in the same age group in the United States-655,474, and 398 per 100,008for the same 3 years. But while the U.S. CHD death rate was three times that in Italy in 1968,by 1980the U.S. rate was less than twice that recorded in Italy (14). At the same time, stroke death rates have been higher in Italy than in the United States. For the same 3 years, deaths per 100,008for cerebrovascular disease were 134 in Italy vs 107 in the United States in 1968, 110 vs 63 in 1978, and 99 vs 56 in 1980(14). Thus, while rates in both countries are declining-most likely attributable to increased antihypertensive treatment-the decline is steeper in the United States and the gap between the Italian rate and that in the United States is widening. These mortality patterns are consistent with the risk factor patterns described for the Gubbio sample. In the past, the lower population serum TC level in Italy was likely to have been an important factor in the lower CHD mortality level. The dietary pattern associatedwith this lower serum cholesterol level-a considerably lower consumption than, for example, in the United States, of saturated fats and dietary cholesterol-may also have made an independent contribution to the lower CHD mortality (12). On the other hand, the levels of severalrisk factors contributing to hypertension have been and remain high in Italy: high consumption of salt and high average alcohol consumption (4). In addition, prevalence of overweight-another contributor to hypertension incidence-has also increased. The resultant high prevalence of high BP is in keeping with the high stroke mortality rate. The decline in the stroke death rate in recent years is modest, and Italy remains among the countries with high cerebrovascular mortality (14). The Gubbio data on current cardiovascular risk factor status are generally similar to those recorded a few years earlier by the Italian National Research Council (CNR) in nine other Italian communities (3). All these populations-in northern and southern Italy-tended to have high prevalence rates of elevated BP, cigarette use, and overweight; with the exception of the southern and island samples,they all had high rates of hypercholesterolemia as well. A similar pattern emerged in the study of the three Italian samples in the WHO-sponsored MONICA project assessingchanging CHD risk factor status worldwide (2). In these respects, then, the present-day Italian samples,including Gubbio, resemble

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European and U.S. populations at high risk for CHD, and not the traditional Mediterranean populations previously at low CHD risk. Parallel with these changes, particularly in population serum TC levels, are the findings from dietary assessment5 and 10 years after the original baseline examinations in the two rural Italian samplesof the Seven Countries Study (6). Animal fat intake had increased almost 50%, and saturated fat intake by 18% in just 10 years. This trend has increased throughout Italy since then. The challenge represented by these unfavorable changes away from the traditional Mediterranean diet has been highlighted in the recent policy. statement and recommendations of the 1986 Italian Consensus Conference (1). There, public health, professional, research, and various community and social agencies urged a national effort to lower serum TC levels through a return to the more traditional dietary pattern of Italy. The aim was, together with efforts to control the other major risk factors present in Italy, cigarette smoking and high BP, to reduce coronary disease markedly, to prevent Italy from following the path of other Western industrialized countries, and to preserve “the Mediterranean advantage.” ACKNOWLEDGMENTS This study was supported, planned, and carried out by the Center for Epidemiologic Research, Merck Sharp and Dohme (Italy), in cooperation with the Center for Preventive Medicine in Gubbio. Study activities have been supervised and guided by a Scientific Policy Board whose members are Professors P. Angeletti (Chairman), M. Mancini, A. Menotti, J. Stamler, R. Stamler, and A. Zanchetti. The valuable assistance of Dr. E. Roccella is also gratefully acknowledged. An important role in planning and initiating the study was played by Dr. P. Pasquini and Prof. H. Kahn. The Study was made possible thanks to the fine cooperation of the people of Gubbio, its community leaders, and its physicians, particularly Dr. S. Panfili and Mr. 0. Faramelli. It is also a pleasure to express appreciation to the Ospedale Civile Gubbio, particularly Dr. W. Panarelli, Dr. M. Angeletti, Dr. G. Montana& Dr. A. Trenti, and the technical staff of the laboratory there. We are also indebted to the other two laboratories of the Seconda Clinica Medica, Second0 Policlinico, University of Naples and of the Chimica Clinica, Istituto Superiore di Sanita in Rome, respectively, their leadership staffs, including Dr. M. Cirillo of the former laboratory and Prof. G. Morisi and Dr. A. Buongiomo in Rome. It is also a pleasure to acknowledge the tine work of the field survey team: Ms. K. Bartoletti, Dr. F. Biancarelli, Dr. C. Cancellotti, Ms. L. Mastrogiuseppe, Dr. L. Matarazzi, Dr. M. Panfii, Ms. A. Scavizzi, and Dr. 0. Terradura. Thanks are also gratefully extended to Dr. L. Carratelli for his support, to Dr. B. Castagna for his assistance in developing the information systems to process and analyze the data, and to Mr. Dan Garside, Northwestern University Medical School for his aid in transferring data to permit joint analysis in Rome and Chicago.

REFERENCES 1. Consensus Conference Italiana. Abbassare La Colesterolemia per Ridurre la Cardiopatia Coronarica. Edito a cura della Direzione de1 Progetto Finalizatto “Medicina Preventiva e Riabilitiva.” CNR. Universita di Roma, 1986. 2. Feruglio, G. A., and Vanuzzo, D. La Cardiopatia Ischemica in Italia, Le Dimensioni de1 Problema. Proceedings of a National Conference: Prevenzione della Cardiopatia Ischemica. Rome, 1987. 3. Gruppo di Ricerca CNR-ATS-RF2. I fattori di rischio dell’ arteriosclerosi in Italia: La fase A de1 Progetto GNR-RF2. G. Ital. Curdiol. (Suppl3) 10, 1980. 4. INTERSALT Research Group. INTERSALT: An international study of electrolyte excretion and blood pressure. Results for 24-hour urinary sodium and potassium. grit. Med. J. 297, 319-328 (1988).

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5. Keys, A., Aravanis, C., Blackbum, H. W., van Buchem, F. S. P., Buzina, R., Djordjevic, B. S., Dontas, A. S., Fidanza, F., Karvonen, M. J., Kimura, N., Lekos, D., Monci, M., Puddu, V., and Taylor, H. L. Epidemiological studies related to coronary heart disease: Characteristics of men aged 40-59 in seven countries Acta Med. Stand. (Suppl.) 460, l-392 (1966). 6. Keys, A. (Ed.) Seven Countries-A Multivariate Analysis of Death and Coronary Heart Disease, Harvard Univ. Press, Cambridge, MA, 1980. 7. National Center for Health Statistics, “Total Serum Cholesterol Levels of Adults 2&74 Years of Age. United States, 1976-80.” U.S. Department of Health and Human Services, National Health Survey, Series II, No 236, Public Health Service, Govt. Printing Office, Hyattsville, MD, May 1986. 8. National Center for Health Statistics, “Blood Pressure Levels in Persons 18-74 Years of Age in 1976-80, and Trends in Blood Pressure from 1960to 1980in the United States.” U.S. Department of Health and Human Services, National Health Survey, Series II, No 234, Public Health Service, Govt. Printing Gftice, Hyattsville, MD, July 1986. 9. Offtce of Medical Application of Research, National Institutes of Health. Consensus Conference-Lowering blood cholesterol to prevent heart disease. JAMA 253, 2080-2086 (1985). 10. Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight, and ECG abnormalities to incidence of major coronary events: Final report of the Pooling Project. J. Chronic Dis. 31, 201-306 (1978). 11. Rose, G., Reid, D. D., Hamilton, P. J. S., McCartney, P., Keen, H., and Jarrett, R. J. Myocardial ischaemia, risk factors and death from coronary heart disease. Lancer 1, 105-109 (1977). 12. Shekelle, R. B., Shryock, A. M., Paul O., Lepper, M., Stamler, J., Liu, S., and Raynor, W. J., Jr. Diet, serum cholesterol, and death from coronary heart disease-The Western Electric Study. New Engl. J. Med., 304, 65-70 (1981). 13. Thorn, T. J., Epstein, F. H., Feldman, J., and Leaverton, P. E. Trends in total mortality and mortality from heart disease in 26 countries from 1950 to 1978. Znt. J. Epidemiol. 14, 510-520 (1985). 14. Uemura, K., and Pisa, Z. Recent trends in cardiovascular disease mortality in 27 industrialized countries. World Health Stat. Quart. 38, 142-162 (1985). 15. U.S. Department of Commerce, “Statistical Abstract of the United States,” 106th ed, p. 119. Bureau of the Census, Washington, DC, 1986.