Cardiovascular diseases in the United States

Cardiovascular

Diseases

in the United

States*

JEREMIAH STAMLER, M.D. Chicago,

Illinois

T

HE CHIEF GOAL of this presentation is to summarize contemporary knowledge concerning the occurrence of the major cardiovascular diseases in the United States. It attempts to delineate the scope of the problems they present and to highlight recent progress in practical approaches for their control.

to their fifth birthday. The corresponding figure for 1959 was almost 97 per cent. In 1901 a little over 75 per cent of newborn infants could be expected to reach their fifteenth birthday; the figure for 1959 was over 96 per cent. Appreciable decreases in mortality among middle-aged and older people also have occurred during recent decades, largely as a result of advances in the control of infectious diseases, particularly pneumonia and tuberculosis (Fig. 1 and 2, Tables I and IV). A major consequence of these developments has been a marked increase in the number of middle-aged and elderly persons in the United States. By 1960 there were almost 17 million persons aged 65 and over-more than five times as many as in 1900. In the same period the number of middle-aged persons (45-64) increased from 10 million to 36 million. Persons 65 and over and those 45 to 64 constituted 4 per cent and 14 per cent, respectively, of the total population in 1900; by 1960 these percentages had increased to 9 per cent and 20 per cent9 Howeuer, for the incwusing millions of middleaged and elderly persons, the outlook for life rxpctancy today is only moderately better than it was at the turn of the century. The death rates for persons aged 45 to 64 and those 65 and over have declined much less than death rates for children and young adults (Fig. 2). Therefore, for white males and females aged 40, life expectancy has increased only 3.8 and 4.7 years, respectively, since 1900-l 902 ; for nonwhites, the corresponding figures are only 4.7 and 6.9 years (Table I). The situation is similar at age 60. Males have generally done less well than females, white males the least well. The fundamental reason for this is the slow against the cardiovascular diseases progress (Fig. l-3 and Table IV). In fact, for middleparticularly white males, the aged males,

BACKGROUND-THE EVOLVING HEALTH PICTURE IN THE UNITED STATES For an adequate understanding of the problem of cardiovascular diseases in the United States today, it is valuable to review the evolution of the health picture during the last 50 to 100 years. This has been a period of remarkprobably unparalleled in any ahle advance, previous era of human history. Progress has tjeen particularly great in lengthening the expectation of life at birth (Fig. 1 and 2, Tables For all persons, life expectancy at I--IIIt).r-8 birth has increased more than 20 years, from ahout 48 years in 1900 to about 69 years in 1959. For white males the increase has been 19.1 years (39.6 per cent), from 48.2 to 67.3 years, since the turn of the century; for white females it has increased by 22.8 years (44.6 per cent), from 51.1 to 73.9 years. Longevity of the nonwhite (chiefly Negro) population has also improved greatly during the twentieth century; the difference between whites and nonwhites in average length of life has decreased considerably, to 6.4 years for males and 7.7 years for females (Table I). This phenomenal advance in life expectancy is attributable first of all to the conquest of infectious diseases, particularly acute infectious diseases in young children, which previously took a heavy toll (Fig. 1 and 2, Tahle III).~-~ In 1901 less than 80 per cent of newborn infants in the United States could he expected to survive t Tables noted author’s reprints.

throughout

paper

* From the Heart Disease Control partment of Medicine, Northwestern

SEP’rEMBER1962

will

appear

in

Program, Chronic Disease Control Division, Chicago University Medical School, Chicago, Illinois.

319

Board

of Health,

and the De-

320

(1950

‘Trends of death rates from specific causes, 1900 to 1353, U. S. death to 1953 ratrs corrected to level of prior revisions of international list.)

Trends of annual death rates FIG. 2. death registration states, 1900 to 1952.

from

all rauscs

for each

cardiovascular-renal death rates tended to rise until the early 1950’s (Fig. 3).5,‘0-‘” Two disease processes, lryi>erte?zsionand atherosclerosis, are responsible for these phenomena. The

of eight

age groups-total

registration

population

states

of the expanding

continuing high morbidity and mortality rates from these diseases and the huge increases in the numbers of middle-aged and elderly persons are the phenomena decisively responsible for THE

AMERICAN

,JOURNAL

OF

CARDIOLOGY

Cardiovascular

Diseases

in the United

States

55-64

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100 (ID

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FIG. 3. Age-specific cardiovascular-renal 1955, by sex and race.*0

the massive impact United States today.

of these

diseases

in

the

MAJOR SPECIFIC CARDIOVASCULAR DISEASES It has been customary to use the terms “cardiovascular disease” and “heart disease” in discussions of the public health problem in this area. An important advance in this field in recent years has been the detailed study of the major individual entities unsatisfactorily lumped together in the foregoing two terms. It is evident that the specific entities grouped in these arbitrary nosologic combinations differ markedly in etiology, pathogenesis and natural history. Progress in dealing with each of them has, and will, come from specific application of discrete information concerning each disease. To the extent, therefore, that the older terms have any relevancy, they should be used only in the plural, e.g., cardiovascular diseases, heart diseases. The discussion in the previous section dealt with the broad grouping, cardiovascular-renal diseases, only because limitations in the long-term trend data necessitated SEPTEMBER

1962

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this approach. The remainder of this presentation deals with the four specific major entities, treated separately, except insofar as there may be significant interrelationships (e.g., between hypertensive and atherosclerotic diseases). Four spec$c diseases are the major components of the cardiovascular complex today: (1) congenital, (2) rheumatic, (3) hypertensive and (4) atherosclerotic cardiovascular diseases. In contrast to earlier decades, certain other etiologic processes affecting the cardiovascular system, e.g., diphtheritic and syphilitic heart diseases, are no longer large-scale problems. Morbidity and mortality rates for other types of infectious heart disease are also low. Similarily, beriberi and other types of nutritional cardiovascular disease are of little significance in the United States. In terms of over-all morbidity and mortality, both among middle-aged and elderly persons, hypertensive and atherosclerotic cardiovascular diseases are undoubtedly the most important health problems confronting the United States today. A fifth disease process merits attention, i.e., car pulmonale, secondary to chronic bronchopulmonary disease (chronic bronchitis, bronchiectasis, emphysema,

Stamler

322

asthma, etc.). It is possible that this entity, a major health problem in Great Britain today, is I)ecoming increasingly significant in the United States during these decades of the second half of the twentieth century. Several sources of data are a\~ailal)lc concerning the patterns of occurrence of specific cardiovascular diseases in the United States toda!-. ,4s already indicated, nlortalit)- statistics represent a readil?- accessil)le, vast array of information of great \,alue, within the confines of their known and identifialjle limitations. Other sources of data utilized for man\- !.rars include physicians’ experience with patiehts and hospital deaths and records (admissions, discharges. autopsy reports). Studies Ijased on these types of data ha\-e yielded valual)le inferences, within the context of their major limitation. i.r., the fact that they are Ijascd on nonrepresentative patient groups and therefore yield conclusions of questionable validit!. in terms of occurrence rates of disease in the population at lar,qc or its
HEAR?.

DISEASE

Ocrurrmw Rates: .4 recent comprehensive paper presents an excellent review of the available data on the occurrence of congenital almormalities in general, including those involving It notes that two the heart and great vessels.** types of information are generally. available in this area, i.e., Ijirth certificate data from a given geographic area and data on births in hospitals The former yield over a gi\.en period of time. * ‘Thr two rpidcmiologic terms, /I~P~YJ/~WP and inodmcp, have ckarly defined, different mranings. Incidmcr is the ratr of occurrence of nrw disease within a delincd This ratr is frrpopulation over a given prriod of time. quently cxprcssrd as the nwnhrr of case prr thousand population per year. PFPMIYI~CPis the nurnbrr of cases of a disease in a given population at any onr time, without It is frcconsideration of the time of onset of illness. quently expressed as the numbrr of cases per 1,000 population. Incidence data are thy mow dynamic, comprrhcnsive and meaningful statistics; prrvalrncc data arc morr static and limited.

rough approximations, usually underestimating the rate of occurrence of congenital defects. Studies analyzing hospital statistics yield more meaningful data. They indicate that 20 to 30 per 1,000 live-born infants show one or more significant congenital malformations requiring medical attention soon after birth. At the end of one year this figure is douljlcd I)y discover). of malformations not manifest at l)irth. It is further increased I))r the diagnosis of conyrnital malformations, including cases of congenital heart disease (see lIelow), in additional individuals later in life.” ‘I’LVOrecent studies in thr United States present data on the occurrence of congenital heart disease. One of these’” was a one year follow-up of the offspring delivered at the Columbia-Presbyterian Medical Center in New \.ork City during 1946 to 1953. Among 6,053 inrants, 50 were diagnosed as having congenital cardiovascular malformations, a rate oi 8.3 per 1.000. The other study’” was conducted in I ht. summer of 1957 among 1.400 registered nurses in Minnesota. Among 8,546 children. 38 (4.4 per 1.000) were evaluated as being proved and 8 as Ixobablr cases of congenital heart disease, an over-all ratr ol 5.4 per 1.000. Of the 38 children with proved cases. 24 (63.2%,) were dead at the time of the WI-vry, most of the deaths having occurred within weeks alter birth. Interventricular septal defect was the most common malformation. coarctation of the aorta the next most common. In agreement with other investigations, this study noted no significant differences in maternal age or birth rank between children with congenital heart disease and normal

controls drawn from the same base population. C’ongmital Heart Disvasr Mortalit_y Data: From studies of this t);pc it may l)e estimated that more than 20,000 babies with rongmital hart disease This aharp horn annually in the (‘nited States. normality accounted for more than 11,000 deaths in 1959, aljout two thirds of these occurring during the first year of life. The death rate from congenital heart disease in the first year of life may I)e estimated from the Minnesota This ma)- t)e study as 2.8 per 1,000 live births. compared with availaljle vital statistics data from Chicago. the State of Illinois and the Cinited States for a corresponding period The mortality rates for (Taljles v and VI).‘~~‘!’ all congenital malformations are in the order of 2 to 4 deaths during the first year of lift peg 1,000 live Ijirths, with congenital heart disease deaths making up approximately 50 per cent of all congenital malformations. deaths from 0l)viously these different types of data yield similar death rates. 7‘HEAMERICAN Jo”RNA’.

OF CARDIOI.OCY

Cardiovascular

Diseases

The deaths from congenital heart disease during the first year of life account for 8 to 10 per cent of the total infant mortality in whites, a lower per cent in nonwhites (Table v). This figure probat)ly understates the actual toll, because the reporting of congenital heart disease as a cause of death in early infancy is incomA sex differential is to be noted in these plete. death rates, as well as in those for all congenital malformations, with rates higher for males than The rates for whites are females (Table v). generally slightly- higher than for nonwhites. No differences are apparent between rates for Chicago residents and for Illinois residents exclusive of Chicago. These data suggest that a moderate decrease has occurred

in the death

mations

and .from

rate from

congenital

all heart

congenital disease

malforduring

the

A similar trend has been recorded for the United States as a whole. The decline is particularly apparent since 1950 and may reflect the recent advances in the diagnosis and surgical treatment of congenital heart defects. While the death rate for congenital malformations during the first year of life has decreased in recent vears, the trend has been in the opposite direction for children aged 5 to 9 In these age groups and 10 to 14 (Table VII).~(’ the death rates for all other causes have declined during the last decade. However, those for congenital malformations and malignant neoThese increases may be plasms have increased. attributat)le to more frequent recognition and delayed mortality (i.e., prevention of some congenital heart deaths in infancy and preschool years). However, they may also reflect a true increase. This is almost certainly the case for Particularly in view of leukemia, for example. the radiation problem, continuous close surveillance and careful epidemiologic study are needed concerning the long term incidence trends for congenital malformations. Prevalence of Congenital Heart Disease: A consideratjle body of literature exists concerning the prevalence of congenital heart disease in school children in the United States. A recent mass survey in Chicago, field-testing a newly developed heart sounds tape recording procedure for detecting heart disease in children, yielded data generally in agreement with recent reThe prevalence rate of congenital ports.“‘-28 heart disease in elementary school children was found to be aproximately 2 per 1,000.25 last

two decades

From estimate

(Table

the previously was made that

V).

cited Minnesota study, an 5.4 cases of congenital heart

in the United

States

323

disease occur per 1,000 live births, with 2.6 per 1,000 surviving beyond the first year of life. With an over-all mortality rate of about 0.3 per 1,000 for the nine years from age 1 through 9 (Table VI), it would be anticipated that the prevalence rate of congenital heart disease among elementary school children ‘l‘he recent should be about 2.4 per 1,000 at age 10. prevalence estimates for Chicago and other parts of the United States are generally consistent with this figure. It may be concluded, therefore, that the recent data summarized here are internally consistent and acceptable as fairly reliable estimates of the present-day occurrence and prevalence rates of this disease entity. Early

Detection

and

Secondary

Prevention

of Con-

From the Chicago survey data and the extrapolations based on it, it was estimated that about 35 to 40 per cent of congenital heart disease among Chicago public The elementary school children is undetected. demonstration of a significant percentage of previously undetected congenital heart disease has been the consistent experience of mas‘i surveys Presently, in various parts of the United States. medicine is in an unparalleled position to aid the school-age child with congenital heart disboth surgical treatment and ease, through prophylactic measures to prevent concomitant rheumatic fever and subacute bacterial endoEffective large-scale measures are, carditis. therefore, highly in order to detect this disease in school children. Etiology of Congenital Heart Disease: Little is known concerning the causes of congenital malformations. The factors implicated include genetic and chromosomal, and such environmental influences as infections (rutjella, influenza and other viral diseases, syphilis, tut )erculosis, toxoplasmosis), attempted abortion. drugs (busulfan, to1 tjutamide, cortisone), * anoxia and nutritional deficiency, immunologic mechanisms (including autoimmunization, e.g., thyBased on the elucidaroidal) and irradiation.‘l tion of environmental etiologic factors. particularly rubella, limited means are novv available to approach the primary prevention of some congenital malformations. The demonstration in 1940 that German measles during early pregnancy could deform an eml,ryo was an historic event, primarily be-

genital

Heart

Disease:

* The foregoing was written before information became available on congenital defects produced by the sedative drug thalidomide. (See the paper by Dr. The ScientiJic Amrrican, p. 29, Helen B. Taussig, August 1962.)

Stamler

324

cause it estaljlished without a doubt that congenital malformations can t,c due to environmental factors; thcv arc I,)- no means cxclusively genetic in origln. This concept has t)een reinforced I)!- a wealth of data from experiments with mammals demonstrating that practicall) all human congenital malformations can IX produced at will I,!- a variety of external teratogenic factors.‘& It has also I)cen supported 1)~ recent in\,estigations further implicating such environmental factor.5 as infection and radiation.‘J Both high and low dosage exposures arc apThis conclusion is supparently significant. ported ‘I)y
Il’itlt ruspc‘t to tlir rolr oj genetic jalai.lors, it has recentl!. teen noted that “apparently identical or similar congenital malformations ma) result from qcnetic or environmental circumIn man it is often not possit)lc to stances. determine whether an)- particular congenital malformation is a gencticatty determined and hereditary defect or a phcnocopy due to en\-ironmental agent.“” \Vith respect to congenital cardiovascular lesions, the)- can rareI\- IX accounted for in Ne\,ertheless, e\iclassical Mcndelian terms.” dence may at times indicate that genetic factors relatives of patients are invol\.cd, e.g., when ha1.e a slightl) higher prevalence of a yi\,cn dcfeet than the general population. This ma)reflect the fact that, “such defects are caused t)!; several complementary gcncs or, more prot)al)l\.. colnplex genetic situations in cori,junction \viLti circumstances. environmcntat precipitating The analysis of such a scheme in mm seems at present I)eyond possil)ility. Even wit11 such favorat,le which

nlatcrial all

almost

the

coniptcLclp

and

are

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to

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that

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elucidation

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in

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No credence and simplilnalformations

whether inborn

they

imply

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disease,

of metabolism

RHEUMATIC: FEVER

‘heredity,’

or radiation.” AND

RHEUMATIC

HEART DISEASE Mortality

Data:

tality

rate ,from

disease

among

In

rflrumatic-

cfrildrm

tfrr l:nitrd fear

and

States

tfrr mar--

rheumatic

and .young adults

fleart

flus declined

during tfv twentieth century (Tables VII and vIII).fi.?” ,30~3? This fall began well tIefore the era of sulfa drugs and antibiotics; their introduction served to increase the rate of decline. Durin,g the 1950’s the fall was 73 to 74 per cent in children aged .5 to 14 years (Table VII). Correspondingly, a decreased mortality due to rheumatic heart disease in the middle-aged has also tIeen recorded. During the last decade, this was aljout 26 to 46 per cent for persons a,qcd 45 to 49, and 8 to 38 per cent for persons aqed 50 to S4.F,“3* continuously

.A more detailed examination of’ the rheumatic fever-rheumatic heart disease mortality trend by race reveals that nonwhites (essentially Negroes) have exhibited a pattern different from whites over the recent decades. Thus, mortality due to rheumatic fever and diseases of the heart has declined less significantly for nonwhite than for white children, adolescents and young adults since 1920 (Table \w).“,~~+~~ .4t ages 5 to 14 years the mortality rates for both rheumatic fever and diseases of the heart bvere actually lower in 1920 for nonwhites than whites. Whereas these death rates for whites exhibited a marked drop from 1920 to 1930 and from 1930 to 1940. for nonwhites they remained virtually stationary. By 1940, therefore, the rates for whites were lower than those for nonwhites (Table VIII). All sexcolor groups have exhibited declines since 1940, but the decreases for nonwhites are less than for whites. ‘l‘he trends are similar for the age group 15 to 24, except that mortality rates for nonwhites (especially females) were higher than for whites from 1920 on. ‘l’hr question arises, of course? whether the lower mortality rates for the nonwhite age group 5 to 14 in the rarlier decades might not reflect inadequate rcportingpa problem impossible to resolve definitively. However, additional data suggest that this probably is not the essence of the matter. On the contrary, they suggest that rheumatic fever incidence rates for the entire nation were actually no higher in nonwhite than white children early in this century. ‘l‘hus. in 1950 whites and nonwhites aged 35 to 44 had similar death rates from rheumatic heart disease * It is difficult to assess thv degree to which such changes in mortality reflect altered reporting, brtter therapy or an absolute decrease in the prevalence of this discasc amon,q adults (thr last a consequence of the declining- rheumatic frvcr incidence rates among childrn carlkr in this century). THE AhlERICAN

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Cardiovascular

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(Table IX)~‘~~~This is the anticipated pattern, if the rheumatic fever incidence rate of nonwhites aged 5 to 14 in 1920 was actually no greater than for whites of the same age. The death rates for rheumatic fever and rheumatic heart disease in persons aged 45 to 54 in 1950 were also consistent with this interpretation. being 24.3 and 24.3 per 100,000 for whites and nonwhites respectively.31~3” Data on mortality from this disease among middle-aged Chicagoans during the years 1950 to 1958 are also consistent with this interpretation, the ratio of nonwhite to white death rates being less than unity at ages 35 to 44, 45 to 54, 55 to 64 and 65 or over. In contrast, this ratio is 3.3 at ages 5 to 14 and 15 to 24 (Table x).~; Prior to the first major wave of migration during and after World War I, the overwhelming majority of the Negro population in the United States was southern and rural in residence. During the last four decades, millions of Negroes have migrated to urban centers, particThe new social ularly to northern centers. surroundings have frequently been slums, with substandard and overcrowded housing, inadequate access to medical care and hospital facilities, and a generally poor microclimate in terms of risk of acute rheumatic fever in childhod, adolescence and young adulthood.34 Against this background, it is not surprising that mortality from acute rheumatic fever actually increased for nonwhite children from the earlier decades of this century through 1950. It is only during the last decade that this trend began to be reversed (Tables VIII and x). As has been noted in a comprehensive monograph3” on the epidemiology of rheumatic fever, “The picture of rheumatic fever and rheumatic heart disease in Negroes in the United States today is This cana more serious one than in whites. not be ascribed to a racial predisposition. Much more to the point seem to be the adverse social conditions in which urban Negroes find A similar point is made with themselves.” respect to the observed phenemenon of severe, ,fulminating, often fatal j-first attacks of rfleumatic fever in young adult :Vegro and Puerto Rican recent migrants to nortfrern CT.S. cities. “This cannot be ascribed to a special racial susceptibility but rather to a sudden change in ways of living.“34 This conclusion is buttressed by a considerable array of evidence from the United States, Great Britain and other countries demonstrating that rheumatic fever-rfleumatic freart disease is a social ailment increased in incidence (irrespective of race) t)y poverty, substandard and overcrowded housing, etc., and decreased in incidence by imSEPTEMBER

1962

in the United

States

325

provement in living standards. It is also supported by data indicating lower death rates from this disease in rural than in urban children, adolescents and young adults (irrespective of race) .34 The U. S. mortality data also indicate that the disease is influenced by climate and altitude, with generally lower death rates in the Pacific and Southern states, and higher rates in the Middle Atlantic, Mountain, East North Central and New England states.3” Prevalence of Rheumatic Heart Disease: Several recent studies are available yielding information on the prevalence rates of rheumatic heart disease among children and adults. Data on school children indicate that the prevalence rates are low at the present time, compared with reports from previous decades, and reflect a true decline in the incidence of the disease, attributable in all likelihood both to improved living standards and antibiotics.3.‘x”6 The recent survey of Chicago elementary public school children yielded a prevalence rate of less than 2 per 1,000. As a consequence of this decline in rheumatic fever, congenital heart disease now predominates as the major form of heart disease among elementary school children.2s Further work is necessary to ascertain whether differences observed in previous decadesbased on race, socioeconomic status, climate, altitude-still are manifest for rheumatic heart disease prevalence rates. It is likely that they persist, but at lower rates for all groups. With respect to young adults, studies in the 1930’s and 1940’s yielded prevalence rates of rheumatic heart disease in the range 1 to 11 per 1,000 among college students.34 Among selective service registrants during World War II the prevalence rates of rheumatic heart disease were 16 to 18 per 1,000. The rates are probFor adults above ably lower at the present time. age 30, reliable current data are apparently not available on prevalence among random samples of the population. It may t)e anticipated that these will be forthcoming from current epidemiologic studies and the National Health Survey.Y7 Etiology, Incidence and Primary Prwmtmn of KheuRheumatic Few-Rheumatic Heart Disease: matic fever is a late nonsuppurative complication of untreated or inadequately treated group Under A fi-hemolytic streptococcal infection. conditions of epidemic streptococcosis, e.g., in new recruits in military installations, up to 30 per 1,000 of infected, untreated individuals may develop acute rheumatic fever.3” A recent

326

Stan&r

C:hicago study indicates a consideral)lllower rheumatic fcvcr attack rate (about 3 per 1,000) in association with endemic group A /ShemuIytic streptocvccal respiratory infection among children.“’ This lower rate of acute rheumatic fever was related to the relative Inildncss of the atreptocuccal disease encountered, compared with its severity in previously studied militar) populations with epidemic streptococcal disease. Thus,

in

this

studp

among

children,

onI>.

14

per cent of the infections were cornparal~lr~~~l~~ clinical, bacteriologic and immunologic criteria --to epidemic infections. The cases of rhcuma tic fever and a case of ~lomerulonephritis occurred among this more \irulcntl\~ infected group, the attack ratr in thctn lacing 24 per 1,000, which approached the level of 30 per 1,000 experienced among militar). recruits with epidemic streptococcosis. Unfortunately, it \vas not possit)lc on the basis of clinical criteria alone to select these “high risk” patients during; the acute stage of infection.“’ In agreement wit11 the experiences in ttiilitar)r recruits, this recent study in children dcmonstrated that rheumatic fever can l)c completely pre\.cntad when group A a-hemolytic strcptococcal infection is treated with udPquntr dosnp qf pmuillrn for an adequate period of time (at least 10 da) s). HOP, orlttr r-hrumatk Jrwr is n /IIPurntahlr

di.rm.cc~, al lm.5t

in ~~~~rsor~.~~ wifI1

~,vm/)tnmatic

provided medical care is \ou+t for thr antcccdcnt clinical illnc55, and Inodern diagnostic and therapeutic approachr\ arc utilized. In a recent stud) of 110 children admitted consecutiveI) to LaRal)ida Sanatariuln in Chicago fur first attacks of acute rheumatic fc\,er, it was dernonstratcd that over 90 per cent had a definite illness (chiefly respirator!- infection) within five weeks prior to onset of acute rheumatic fc\w. A mqjority of thr’w children ~verc taken to physicians. For onl!~ ;I frw were ttlroat cultures taken 1)~ their doctors. Most \vcrc siven an antil)iotic, Ijut the t)pc, dosage, duration of trcatmcnt, or all of these wcrc qenrtrr/hcocuA

wall!-

inadcquatc

eradicate

group

to prevent eluded attacks

~n[uc tton,

acute

from

1)~

accepted

.4 /J-lwmolytic rheumatic

frver.‘“’

this study

of OCII~‘Prhcumtltir

~ranclarclu streptococci

ttlat

fwrr

a

today

to and

It wa.s COIlmcljnrih

01 first

art’ f~uvrntahl~~.

It ha!, been repeatedly demonstrated in recent studies that during the fall, winter and spring months, the months of incidcncc of most acute rheumatic fever, 15 to 45 per cent of respirator) infections in children are due to group -4 @-

hemol~tic streptococci.“” Physical examination technics alone are inadequate to distinguish streptococcal from nonstreptococcal respirator)infection.+‘-” In contrasti a single throat culture is ‘10 per cent effective in making the diagnosis. l” Thus, it is clear that t)otli effecti1.c therapy of streptococcal disease, and avoidanct of unnecessary antibiotic treatment, require extensive use of throat culturing in cases oi respirator) infection in children, particularI\when symptoms and signs involve more than simple coryza, and include sore throat. fever. s\\.ollen glands, otitis, rash and the like. Recently, procedure< have I)cen developed for inexpensive and convenient, mass scale throat culturing for group A &hemolytic streptococci. The!. involve mail-in methods suitable for largeEfforts are scale use in metropolitan areasa” proceeding to disseminate the essential knowled,qe among parents and physicians in order to mount a more effective pre\,entive effort against acute rheumatic fever. Despile the decline over rt’cenl decades, all too man)- cases of this largely preventable disease still occur. Chicago, for example. is reporting over 500 cases of acute rheumatic fever per year, over 300 oi thtw being first attacks. A few simple statistics clearly reveal the basis of this phenomenon. In 1960, Chicago had a population of 584,000 children aged S LO 14. It may he conservatively estimated

thal they experience at lrast one respiratory infection annually during the Fall, win&r and spring months. about 600,000 respiratory infections per year. only 20 prr ct‘nt of these are srreptococcal in origin. If the endemic rate fl tht,\- constitute 120.000 cases. acute rheumatic fever by estimated at 3 cases pcx 1 .OOO untreated or inadequately wcated strcptococcal infections. and if 100.000 of the 120,000 cases be assumed to be in this category. then 300 new first altacks (11‘acute rheumatic fww Inight be anticipated. L.ndoubtedly lhcsc cstimatcs aw crude and could wsily be in error by IWO- or threefold. Nevertheless. rhc!- yield a first attack rate of acute rheumatic f&w in the order of lnagnitudr currently being reporwd Further. the foregoing calcuby (Chicago ph!;sicians. lation would yield an attack rate of acutr rhrumatit fcv~ of about 50 prr 100,000 Chicago children aged ‘l‘his may bc compared with an 5 IO 14 ,“‘r year. cstirnated rate of 100 to 120 per 100.000 children aged 5 10 14 per year rvportcd for 84 cities and towns in 19 states for 1935 to 19?~6.:~” .Igain, these calculations for Chicago are in the nature of “guesstimates”: newrthcless. they arc consistent with the conclusion thar a true decline has occurred in the incidence 01 this diseaw. Despire

the

t)\- no means

decline,

the

insignificant.

remaining is Consider, for ex-

probiem

‘r1Ib;AMF,‘.RICAN ,JOl:KNAIOF CARDIOLOG1

Cardiovascular

Diseases in the United

ample, the outcry that would be raised by public and profession if over 300 attacks of paralytic poliomyelitis were reported for 1960 or 1961 in Chicago. Yet rheumatic fever-rheumatic heart disease is at least as serious a diseasethough the withered heart valve is not outwardly visible as is the withered limb. As long as streptococcal respiratory infection remains a common phenomenon-and the cited statistics indicate that this is likely until an effective antistreptococcus vaccine is developed-large-scale throat-culturing with appropriate antibiotic therapy for diagnosed cases is a must, if the disease problem is to be reduced to its bedrock present-day minimum. Secondary Prevention of Rheumatic Fever-Rheumatic Heart Disease: In previous decades a major problem with rheumatic fever patients was the tendency for the disease to recur at rates of about 200 per 1,000 or greater per year. For reasons as yet unclear, patients with rheumatic fever are particularly susceptible to recurrences of the acute disease when infected with group A /3-hemolytic streptococci. Correspondingly, when these persons are kept free of streptococci, or when timely diagnosis and effective therapy of streptococcal infections are accomplished, recurrences of acute rheumatic fever can be prevented. Thus, it has been shown that antibiotic therapy for group A P-hemolytic streptococcal infections is effective in preventing rheumatic fever when begun as late as nine days after onset of respiratory symptoms.45 Based on university research studies, largescale public health programs have recently in close cooperation with been developed, practicing physicians, for the secondary prevention of rheumatic fever-rheumatic heart disease. These involve continuous administration of low dosage sulfadiazine or penicillin to prevent streptococcal infection in known cases. The drugs chiefly employed are oral sulfadiazine (0.5 gm. tablet twice daily), oral penicillin (250,000 unit tablet twice daily), or injectable benzathine penicillin (1,200,OOO units, single injection syringes, administered in monthly) .46 Based on present evidence, prophylactic medication must be continued for at least five years after the last acute attack of rheumatic fever, and at least through the teen years of age. The Heart Disease Control Program of the Chicago Board of Health, in cooperation with the Chicago Heart Association, maintains a Rheumatic Fever Registry involving over 6,000 SEPTEMBER

1962

States

327

children, adolescents and young adults; over 3,500 of them receive free prophylactic medication from the Board of Health on prescription from their physicians (clinic or private) .J7+9 In addition to furnishing drugs and maintaining a statistical registry, the program cooperates with the physicians to follow up patients failing to keep regular appointments. In this manner, sustained breaks in prophylaxis have been minimized. This effort has reduced the reported recurrence rate of acute rheumatic fever in registered cases in Chicago to as low as 10 per 1,000 per year, a reduction of more than 90 per cent, compared with experiences in the pre-antibiotic era. HYPERTENSIVE

AND

CARDIOVASCULAR

ATHEROSCLEROTIC DISEASES

At the present time in the Cnited States hypertension and atherosclerosis, our two major contemporary disease problems, are frequently encountered concurrently in individuals. It is, therefore, convenient to discuss them under a joint heading, while recognizing that they are two distinct entities with different pathogenetic and etiologic mechanisms.j” These diseases, singly or in combination, produce clinical morbidity and mortality principally lIecause of pathologic involvement of the arterial circulation of the heart, brain, kidneys, abdomen and lower extremities. E&ertt&on is defined as the disease process characterized by sustained blood pressure elevation, involving diastolic and (in most cases) systolic pressures, cause known (secondary hypertension) or unknown (primary or essential hypertension), with or without clinically demonstrable involvement of blood vessels and their organs. At least under conditions in the United States today, clinical illness in the hypcrtensive individual is usually a manifestation of the hypertensive and atherosclerotic processes occurring concurrently and acting synergistically. Athwxclerosis, the major specific entity in the generic grouping of the arterioscleroses, is a disease process (not a manifestation of physiologic aging), having as its pathologic hallmark the lipid- and cholesterol-containing focal intimal plaque, with or without such complications as ulceration, intimal hemorrhage, thrombosis (usually occurring with severe lesions), expressing itself clinically (if at all) as disease of the heart. brain, kidneys, lower extremities and other organs.“’ HYPERTENSIVEDISEASES

Prevalence and Incidence: Hypertensive disease prevalence and incidence rates are apparently high among all strata of the population of the

Stamler

338 CVhite M

\Vhitr F

Negro M

Negro F

8-14

1 15-24

25-24

35-44 45-54 55-64 65 65

125

FIG. 4. Frequency distribution and race. Columbus, Georgia,

65 125 65 125 Diastolic Pressure in mm. Hg

curves, 1354

United States today (Table XI, Fig. 4 and i).5”~“E~ From the limited data available, the majority of individuals with this disease have primary rather than secondary hypertension. However, further research is needed on this matter, particularly in relation to the prevalences of such entities as pyelonephritic, renovascular. adrenal medullary, and adrenal cortical hypertensions, as compared with essential hypertension. Negroes llave consistently demonstrated significantly higher mean blood pressures and prevalence rates for hypertensive disease than whites throughout the United States (Table ZI, Fig, 4 and j).52,5a,Bfi,5P,T,‘J This racial difference prevails for both sexes; it is generally It is genergreater for females than for males. ally attributed chiefly to higher rates of essential hypertension in Negroes than Lvhites. Other than this racial difference. only limited data are available on differential prevalence and incidence rates for hypertensive disease among various socioeconomic-geographic-ethnic strata of the U. S. population (Taljle XI). Trend oj Blood Pressure with Age: It has I)een repeatedly observed that mean blood pressure levels and prevalence rates for elevated hiood pressure (no matter how defined) tend to increase with age, at lcast over the decades from young adulthood through middle age (i.e., Reages 25-64) (Table XI and Fig. 4 and 5).

diastolic

blood pressure,

65

125

by age, sex

fore a,ge 45, these values are generally lower in women, particularly white women, than men; the reverse phenomenon is generally recorded after age 45 (Fig. 4 and 5).57758 Most of these data on the trend of blood pressure with age are cross-sectional in nature, i.e., they are blood pressure data collected at a fixed point in time on persons of different ages. Therefore, they are of only limited value in relation to the important problem of blood pressure trends in the same persons over the Long term data on the changes decades of life. in blood pressure of individuals over decades ha\,e recently Ijecome available to us in connection with our studies on the epidemiology of and atherosclerotic diseases in hypertensive middle-aged male employees of a Chicago utility company.“?-“” One of these investigations” deals with 1,594 men aged 40 to 59 on Jan. 1, 1958, the total male labor The maforce of this company in this age range. jority of these men have been employed by this company for 20 years or more, about 30 per cent of them for- 30 years or more. Most of them had medical examinations at the time of hiring and at intervals throughout employment. They also had regular periodic examinations during the last several years, electrocardiograms, chest x-ray films, including medical histories and physical examinations and There is, then, an extensive accumulation urinalyses. Of the men unof data over two or three decades. ‘1‘11,’AMERICAN

j”“R”“L

OF

CARDIOI.OGY

Cardiovascular

Diseases

Blood Pressure mm. Hg.

P 5

8

IS

25

35

45

55

65

c-1

Age in Years

FIG. 5.

Mean systolic and diastolic blood pressure, by Columbus, Georgia, 1954-55.68 age, sex and race.

der study, 764 had multiple blood pressure determinations for at least 20 years; for 261 men data extended The slope of blood pressure was calover 30 years. culated for all of them. In approximately 30 per cent with normal blood pressures as young adults, the blood pressure slope over the next 20 or 30 years

was zero or negative, so that the calculated diastolic blood pressure at age 50 was less than 80 mm. Hg.55

Under the conditions of life in the United States, therefore, blood pressure does not invariably rise with 4n essential corollary of this finding is age. that the cross-sectional survey approach, yielding mean over-all data suggesting a rise in blood pressure with age for the entire population, can be misleading. Longitudinal data demonstrate that this is not the invariable “normal” phenomenon; a significant percentMoreover, age of persons do not manifest it. not unexpectedly, men with low normal pressures as young adults and with little or no blood pressure rise over the decades exhibit the lowest rates of heart and vascular disease at middle age.55 *63 Risk- Factors: The risk of developing hypertensive disease is sign$cantly related to body weight and the pattern of weight change from young SEPTEMBER

1962

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States

329

adulthood through middle age. In y-oung adults, there is a correlation between overweight (slight, moderate and marked) and prevalence of hypertension ; marked overweight is associated with a several-fold increase in the risk of hypertension.55 Moreover, men at or near desirable weigh1 as young adults who exhibit little or no gain in weight over the ensuing twenty years have the lowest risk of developing hypertension in middle age.5s Marked gain in weight (irrespective of young adult weight) and obesity in middle age significantly increase the risk of developing hypertension (Table xr1).53*5~ This relationship between body weight and hypertensive disease holds for Negroes (both men and women) as well as whites.“” Finally, obesity is associated with an increa:ed incidence (as well as prevalence) of both hypertension and hypertensive heart disease.“” Incidentally, these last data demonstrate that there is a significant incidence of hypertensive disease in middle age; the onset of this disease is not confined to young adulthood. As has been repeatedly demonstrated, family histoq~ is also related to risk of developing hyWith only one pertensive disease (Table XIII). sibling known to be hypertensive, the incrcasc in risk is of low order; it is greater when one parent is hypertensive> and considerably greater when both are.64 Mortality: Hypertensive disease is a serious problem because of its so-called complications, principally coronary heart disease, congestive heart failure, cerebral hemorrhage and thrombosis, and renal failure. Mortalit)data on hypertensive disease tend to underestimate its significance because of rules for coding deaths to single causes, according to the International Statistical Classification of Diseases and Causes of Death; deaths of hypertensive patients are frequently attributed to arteriosclerotic heart disease or cerebrovascular disease. Despite this significant limitation, data on mortality from hypertensive disease give a pa.rtial measure of the scope of the problem, and indicate the They major age-sex-race patterns (Table XIV).~ demonstrate the marked racial diffencr between Negroes and whites in susceptibility to hypertensive disease. Little or no sex differential is recorded in mortality rates. For whites the mortality rate is slightly lower for women at ages 45 to 54 and 55 to 64 than for men, despite the fact that hypertensive disease is undoubtedly more frequent among women than men from age 45 on. This seeming paradox is in all

330

Starnle~

likelihood the result of a lower rate of occurrence of atherosclerotic disease in women than men during; middle age. It reflects the well-known fact that middle-aged women are more resistant than men to atherosclerosis and the atherosclerotic complications of hypertensive disease that frequently lead to lnorl)idit) and mortality in hypertensi\.c patients under American conditions. From the limited availatjle e\-idencc, the major socioeconomic groups of the L. S. northern urljan population do not exhibit any marked differences in mortality rates in middle age from hypertensive disease (provided the data are simultaneously stratified I)y race as well).““-67 Whites living in nonrnctropolitan cities and towns and in rural areas seeln to have moderately louver rates than tllosc livinq in I)ig cities. The large racial differences persist irrespective of socioeconomic and geographic stratification. Etiology and Patfqenesis: In recent years, considerable progress has txen made in delineating types of secondary hypertension in secondary- to primar). man, e.g., hypertension aldosteronism, pyelonephritis, pheochromocyWith toma and renal artery atherosclerosis. respect to essential h)-pertension, pro,qrcss has apparently been slower. Three different concepts of etlolog), and pathogenesis are current at present. Kecently, considerable attention has heen ,given to the l!vpothrsis tfrat f~v/wtension i.7 fundamentally hereditary. Based on statistical analysis of I)lood pressure clata, proponents of differing hypotheses have vigorously debated the nature of the presumed atxxxmality and have advanced concepts concerning single y‘ene versus multiple gene defects.“” -i’+ The fact that hypertension tends to have a Beyond familial association is well estal)lished. that, all views in this area appear to this writer to I,e at present szrb&dice. The cautions cited in the discussion on the difficulties earlier, inherent in analyzing genetic-environmental interrelationships in the etiology- of congenital heart disease, seem to be fully applicallle to the Extensive research problem of hypertension.‘” is needed to test these hypotheses, to elucidate the causes and mechanisms (genetic and environmental) of the familial tendency to h)-pertension, and to clarify its significance in the etioiog) and pathogenesis of the disease. zj second major f!vpothesis concerning essential hypertension, having wide currency since the 1930’s, relates primarily to pathogenesis (rather

than etiology), and holds that tfre disease id fundamentally humoroflormonai in origin. Recently considerable research related to this hypothe& has lIeen done, particularly with rrspect to possible dietary electrolyte. adrenal mcdullar)-, adrenal cortical, and renal mechan~sms, and their interrelationships.““*‘+7S ,4 bolution has not yet lIeen achieved. Moreover? little is known concerning causatil-e factors possittly responsit)le for initiating the presumed pathog-enetic trend of events. Thusto consider Ixiefly one classical humoral hypothesis, namely that renal arteriolar nephrosclerosis antedates essential hypertension and is responsible for it due to resultant renal &hernia +xactically nothing is known to this da) conccrninS. causes of renal artrriolar nephrosclcrusis in man (if it Ix assumed that this lesion is not xcondary to hypertension itself). .1 tfkf f!v/Jotf/rsr’,r holds that essential hypertension is fundamentally a disease originating in the central nervous systeml primarily at the cortical and sulxortical Icvel.“” Basically this hypothesis llolds tfrat nqatiw life r.~prricnces in suscrjAihle individuals grnrrate psyrhormotional disturbances leading to hypertension. This view -that essential hypertension is basically a type of “neurosis”--does not den\- the rote of humorohormonal factors; rather ‘ir holds that alxiormalities of this type arise secondarily and result in a vicious cycle, with reinforcement of hypertension, primarily neurogenic in origin. Based on the present state of knobvledge concerninx the physiology of I)lood pressure regulation. of the nervous svstem in general and of the higher neural activity in particular, it is evident that formidal)le problems also confront investigators attempting to test this hypothesis. A’I’Hi
COROliARY

HEART

DISEASE

.2lortalitv Data: As already noted, atherosclerotic disease produces morbidity and mortality consequent upon its occurrence in advanced form in multiple arterial beds, e.g., coronary, carotid, basilar, cerebral, renal, peripheral. The principal form of atherosclerotic disease. particularly premature atherosclerotic disease of middle a,qe, is roronary fwwt disease. During the last 10 to 15 years knowledge of of atherosclerotic the occurrence coronary heart disease in the United States has increased greatlv. Analyses of accumulated mortality data have highlighted its importance as the single key entity among the cardiovascular-

Cardiovascular

Diseases

renal diseases, and have delineated the agesex-race patterns of its occurrence-patterns noticeably different from those for hypertensive disease (Table XIV).~~+~ It is evident that this disease is a major problem among middleaged individuals both white and nonwhite, particularly men. Analysis of long-term trend data indicates that, for the middle-aged, mortality ,from t!tis disease has increased since the early decades of this ctxtury, particularly for white males.‘0 A marked sex differential in mortality exists, more so for whites than nonwhites; middlewomen (particularly white women) aged demonstrate a remarkable resistance.05 Considerable evidence has acctimulated indicating that a major factor in this differential is the partial protection against atherosclerosis afforded to premenopausal women by ovarian estrogen secretion.7g,x0 Data on mortality from atherosclerotic coronary heart disease uniformly demonstrate high rates among virtuall)- all socioeconomic-ethnicgeographic strata of the U. S. middle-aged male population. 11,12,65--R7,81-83 Rates for rural resi_ dents are, however, moderately lower than for urban. Prevalence and Incidence Data: Major prospective epideiniologic studies in sizable population groups in the United States have greatly expanded knowledge concerning the prevalence and incidence of this disease. Mortality data on its prevalence and incidence in different socioeconomic strata of the middle-aged populauniformly yield high rates (Table tion Moderate differences have been XI). ‘I .1v~52-54 es1 recorded in some studies, e.g., between toplevel executives and other white-collar workers;X4ax5 between farmers and nonfarmers;8” between semiskilled- and unskilled-service workers and other strata of the labor force;52-54 between the foreign-born and the nativeborn.“’ Such differences remain to be validated. In any case, they are not marked in degree. With the possible exception of atypical or isolated groups (e.g., Seventh Da)- Adventists, American Indians),81~87~8Y Trappist monks, virtually all strata of the U. S. middle-aged male population have high prevalence and incidence rates of this disease. Risk Factors: A major achievement of the recent prospective epidemiologic studies on coronary heart disease has been the quantitative delineation of the association between several abnormalities and risk of middle age coronary It has been unequivocally demondisease. SEPTEMBER

1962

in the United

States

331

strated that such abnormalities as hyperrholesterolemia and hypertension, diabetes and heaq cigarette smoking are associated with several-fold increases in risk of occurrence of coronary disease in age (Table XV)~ll,12,3:I.S4.X4,Xh.X9~103 middle Obesity has been similarly implicated, also positive family history of premature (before age 60) vascular disease, hypothyroidism, renal damage, sedentary living and certain personality-beDatahave havior patterns. 11,1?.5~.54,64,84,X5,89--1Ua been obtained indicating that overweight is not only associated with an increased risk of coronary disease, but also is significantly related (both in whites and Negroes) to occurrence of hypercholesterolemia, hypertension, the combination of these two abnormalities, and nonspecific electrocardiographic abnormalities (Table XII).~:~ Data have also been accumulated on the relationship between certain electrocardiographic patterns and risk of coronary disease, e.g., left ventricular hypertrophy-left heart strain patterns and bundle branch block patterns (both associated with several-fold increases in risk), and fixed nonspecific ST-T patterns (associated with an approximately twofold increase in risk). In addition, extensive data have been amassed on the contribution of multiple abnormalities to risk. Middle-aged men free of clinical evidence of coronary disease have markedly different risks, depending upon their status with respect to these several abnormalities combined. Men with certain combinations (e.g., hypercholesterolemia, hypertension, obesityany two or all three; hypertension, hypercholesterolemia, left ventricular hypertrophy-any two or all three) have ten- to thirtyfold greater increases in risk, compared with those having normal electrocardiograms, serum cholesterol, blood pressure and weight levels (Table xv).X9~102,108 Men free of all the foregoing defects, the lowest risk men. have only about one chance in 30 or 40 of developing clinical coronary heart disease before age 65. In marked contrast, men with two or three of the foregoing abnormalities have about one chance in two, two chances in three, or three chances in four. Not unexpectedly, low risk men are relatively rare In our study in our middle-aged male population. among middle-aged male employees of a Chicago utility company, only 136 of 1,466 men (93 per 1,000) were normal with respect to weight, serum cholesterol and blood pressure; further exclusion of diabetics, heavy cigarette smokers and men with a positive family history left only 48 men (33 per 1,000) normal with In contrast, of these respect to all six risk factors. 1,466 men, 334 (225 per 1,000) exhibited the combination-hypercholesterolemia, hypertension, obesity (any two or all three)-associated with a more than tenfold increase in risk of coronary disease, or at least

Stamler one chance in two of developing the disease betore age 65. Virtually all strata of the U. S. middle-aged male population studied to date show high prevalence rates for the foregoing abnormalities, singly and in combination (Table XVI).~~ These observations arr entirely consistent with the available data indicating that prevalence and Incidence rates of coronar)heart disease are high among virtually all thrse strata (cf. Tablr x~).:‘?-jl The elucidation and quantitation of these associations between certain ahnormalities and risk of coronar)’ disease have served to clarif? certain hitherto unexplained parodoxes. FOI example, Negroes-with significant higher pre\.alence rates for hypertension than whites might l)e expected to have higher occurrence rates of coronary heart disease than whites, since hypertensive disease markedly increases risk of coronary disease under American conditions. Yet the availahle facts indicate tllat, at least for Negro Inen, the rates of coronary disease in middle age are no higher than for white Inen (Tal,le x1 and x~v),ll ,1?.51~53.67-iii (Negro women do in fact have hi,ghcr rates than w:hite women.) Recent studies indicate, however, that significant strata of the L!. S. middlcaged Negro male population have lower prcvalence rates of hypercholestcrolemia, ol)esit!. and with cigarette smoking, compared heav) \,hites.““,‘““,‘“” It seems reasonal)le to hypothesize that their more fa\.oral)le situation \vith respect to these other risk factors ma). stAr\‘e to counterbalance. their unfavoral)lr risk status stemming from the hypertensi\rF factor. In women have middle-a,ced Negro contrast, significantI>- higher prevalence rates than white women, not only for hy-pcrtension f)ut also for oljesity and dialjetes, and their patterns of hypercholesterolemia are similar to those of middle-aged white women. Ir WIUM tllrn~fw P

be nntic$~ated that .lyegrci ~~wnen rewild rx/erirnce more roronary Iwart disease in middle-age

than 7cthite

uJo?ncrl. Risk

of

Premature

und

Sudden

Dec7th:

‘IIlC

prospective epidemiologic studies have also added greatI)- to knowledge concernin,? the risks of dying prematurely of coronary disease. Thus, they show that the average middle-aged male, free of this disease on examination, has about one chance in 15 of dying from it hcfore age 65--and the odds are much worse for coronary-prone men. Put differently, 30 to 40 per cent of first attacks of myocardial infarction (the major form of coronar)- disease in middleaged men) are fatal during the initial six weeks

after onset; ahout one-half these deaths are sudden deaths. Of men surviving an acute myocardial infarction or another type of coronary disease in middle age, 20 to 40 per cent die during the ensuing five years.“A.X’j.l”” These statistics emphasize the importance of developing approaches for effective primary prevention. .Cilpnt Mycicardial Infarction: Prospective epidemiolo,gic studies have also shown that silent m),ocardial infarction, totally asymptomatic and dctectahle only t,y periodic electrocardiography. occurs with significant frequency and represents ahout 15 per cent of all myocardial infarction.“‘“~‘“” This observation and tile data on the role o/ electrocardiographic abnormalities as risk factors, emphasize the need for routine periodic electrocardiography on a mass scale as a standard medical procedure for middle-ayed and older persons in the United States. Ci~rehroaascular Diseases.. Cerebrovascular discasps, major causes of morbidity and mortalit), among middle-aged and especially elderl) Americans, arc due chiefly to hypertensive or atherosclerotic diseases, or both. Therefore the term, cerebrovascular diseases, emljraces several distinct disease processes-atherosclerosis of carotid, basilar, cerebral, or other arteries nourishing the ljrain (frequently complicated In. thrombosis and cerebral infarction when clinical disease is present) ; cerebral hemorrha,q=e, Ii)-pertensivc (not atherosclerotic) in origin : cerel)ral emholism (less common than the preccdin,q two entities), secondary to such procczsses as rheumatic or atherosclerotic heart disease.“” An understanding of this heterogeneity of the ccrcl)rovascular diseases is a prerequisite for comprehending the sex-race mortality patterns, c.g., the .several-fold fugher rates in .lPgroes rom/)urcd 7e~Lh whites (attril)utahle to the contrilnltion of h)-pertensive disease), and the low order of the sex differential in middle-aged whites (attril)utal)le to admixture of the hypertensive wit11 the atherosclerotic component Tal)lc XIV). Thus, cerel)ro\,ascular disease occurrence rates cannot be uncritically interpreted ZlS accurate reflections of virtually “pure” atherosclerotic disease, as can be done with coronar). disease rates.“*‘? Today this is not merely a matter of concern for epidemiologists sincr clinicians are being confronted with decisions in relation to therapy (e.g., anticoag-ulants), based on differential diagnosis, ‘THE

AMERICAN

JOURNAL

OF

CARDIOLOGY

Cardiovascular

Diseases

in the United

States

333

abroad to such countries as Guaternala, Italy and Japan. Given large-scale exposure to this dietary factor, the outcome with respect to premature disease among strata of the (i.e., middle-age) population is undoubtedly influenced by an interplay between diet and a host of other factors. These include status with respect to other diseases (diabetes, hypertension, etc.), smoking, physical activity, heredity, endocrine function. In the language of epidemiology, therefore, diet may be viewed as an essential or necessary cause of atherosclerotic disease in this sense (slightly modified from classical concepts): A certain dietary pattern is essential for the large-scale occurrence of this disease in middle-age. However, diet by itself is not a suj’icient cause, since premature disease does not develop in all persons habitually ingesting the implicated diet. Put another way, phenomena of biologic variability and complex interplay among multiple causative factors are manifest as much in the etiology and pathogenesis of atherosclerosis as of tuberculosis. Invariably, in dealing with the role of external causative factors such ATHEROSCLEROTIC DISEASE as diet, the nature of the host (the specific organism in all of its complexities) must be Etiology and Pathogenesis: Extensive research, epidemiologic, clinicopathologic and experimentaken into consideration. This fundamental characteristic of higher living organisms comtal, has been done in recent years on the etiology plicates the task of investigators addressing and pathogenesis of atherosclerotic disease. A comprehensive survey of this area is beyond themselves to problems of etiology. Despite these difficulties, however, great progress has the scope of this presentation, and the reader is reviews 11~12~51~81~109been made in delineating the basic phenomena referred to appropriate operating in the etiology and pathogenesis of Suffice it to note that the accumulated evidence atherosclerotic disease. has made it possible to formulate an integrated general theory, essentially nutritional-metabolic Advances in Preventive Therapy of ,4thtrosclerotic and Hypertensive Diseases: in nature, concerning the etiology and pathoBased on research achievements during the last score of years, genesis of this disease. The overwhelming evidence indicates that the disease is multifaca cautious, restrained optimism has arisen torial in causation, with diet as a key essential among many responsible investi,gators concerning the possibilities of a significant breaketiologic factor in accounting for the occurrence of coronary disease in the middle-aged in through against atherosclerotic and hypertensive diseases in the present decade.“O With respect populations of the economically more developed countries, particularly the United States. to the atherosclerosis problem, this is based first of With respect to this dietary factor, many studies all on the signal advances made on key questions have made it abundantly clear that virtually of etiology and pathogenesis. In addition, it is our entire population is at risk, in that it habitubased on the demonstration that timelv identification of high-risk, coronary-prone individuals ally consumes a diet high in calories, total fats, is now possible before the onset of clinical saturated fats, cholesterol and refined carbohydrates. In fact, to study populations of disease, and on the awareness that identification lower risk with respect to this dietary factor, it of susceptible persons has always been a key to has been essential for American investigators prevention-provided something can be done either to seek out very special groups within the to alter susceptibility. In this last area also, significant advances United States (e.g., Trappist monks, Seventh Day Adventists and true vegetarians) or to go have been recorded. Recent investigations

as between cerebral hemorrhage (hypertensive and not atherosclerotic) and cerebral thrombosis (atherosclerotic, with or without hypertension). Cerebrovascular diseases account for about one fifth qf the total mortality from the cardiouascularrenal diseases and for one in every nine deaths from The death rate all causes in the United States. rises steeply with age (Table XIV). Practically all cerebrovascular deaths occur at ages 45 and over? and no less than half occur in persons aged Both overweight and hyper75 and over. tension, singly or in combination, are associated with sizable increases in risk of cerebrovascular n70rtality1”8 as is a positive family history of premature cardiovascular-renal disease. Aside from the foregoing facts, few additional data are as yet available on the epidemiology of cerebrovascular diseases in the United States. This is undoubtedly an area meriting intensive research efforts. It may be anticipated that the prospective epidemiologic studies will contribute significant new findings on cerebrovascular diseases in the next few years.

SEPTE’MBER

1962

Stamler

334 DEATH RATES PER 100.000 POPULATlON 30s

250

IO0

50

0

WHITE MALE FEMALE

45 -49 FIG. 6.

IJnited

States

NON - WHITE MALE FEMALE 45 -49

MALE

FEMALE 50 -54

MALi

FEMALE 50 -54

tq

Irave unequivocally shown that hypercholesterolemia can he reduced in most cases either In diets low in total fats and cholesterol or In diets low in saturated fats and cholesterol and containing vegetable and fish oils.““~“‘“,“’ ---I’~ Other risk factors too can tre influenced I)>-nutritional-hygienic-medical means, for example, obesity, hypertension, heave, cigarette smoking and physical inactivity. ‘The possil)ilitv of prevention and therefore of correction of the almormalities making for coronarv proneness thus arises. Both primary- and’ secondary. prevention of atherosclerotic diseases, especially coronary heart disease, might l)t’ achieved in this way. With rrs$ect to rrsfntinl hy,bf7tmsion tlic situation Progress in appears to be somewhat different. sol\Gug tjasic prol)lems of etiology and pathogencsis has apparently l)een less rapid and profound. Nevertheless, in the totality- of the hypertensive disease problenr, significant advances have hern registered. Consideralrle progress Itas been made in identifying specific types 01 hypertension Ijascd on demonstration of specific causative factors --for example. renal, adrenal medullar)-, adrenal cortical and renovascular factory-and these are often amenalrle to correction A I,eginning has lIeen made in delineating specific factors contrilnrting to increased risk of hypertensive disease, for example. po4tiv.e family history, blood pressure lability, obesity and ,genitourinar)- tract disease. Therefore, it is now possible, within limits. to idmtifysusceptible persons.

The clarification of the role of hypertension as a risk factor in atherosclerotic disease has >erved to deepen understanding of the hypertensiv-e process itself, the interplay between these two diseases, and the factors contrihutingtn the clev:elopment of such complications as my-ocardial infarction and cerebral thrombosisimportant causes of morbidity and mortalityMost dramatic of all in. hy,pertensive patients. to date, perhaps, is the development of a series of new pharmacologic agents for the effective control of hypertension. With the development of rauwolfia preparations, chlorothiazides, Ii\-dralazine, ganglionic blocking agents, guanethidine, etc.. the ability to control mild and severe hypertension has I,ecorne outstanding--and the effect on long-term morbidity and mortalit!appears to IX highly- si,gnificant.“” In fact, this achievement is almost certainly one of the key contributors to an important, if neglected. phcnomenonPmthe decline in cardiovascularrenal mortality rates for middle-aged American men in recent years, after many years of steady*.ise (Fig, i. 6!,1--“.“7,IIR--I?:! Data are availahle to document the possitrilitv of at least a limited carlv I)reakthrou~gh against hypertensive disease, despite the failure thus far to solve the frasic prol~lem of the etiopathogenesis of essential hppei-tension.“C’ Such a development is I+ no means without precedent in the history of medicine. .Jenner first vaccinated successfullya,gainst smallpox in 1776, decades before there was any science of medical microbiology and virology : and Lind successfully treated scurvy‘rHE .ALIERICAN

[OURhAl.

OF CARDIOt.OT.\

Cardiovascular

l&eases

with oranges, lemons and cider in 1747, a centur?- and a half before the new science of nutrition began clearly to delineate the avitaminoses. ?‘he mere possibility of a breakthrough against hypertensive and atherosclerotic diseases is a tremendous achievement. For the first time in medical history, insofar as the major problems of chronic, noninfectious disease are concerned, research has advanced far enough to pose the possibility This of large-scale prevention and control. accomplishment-skeptically denied by some, matter-of-factly accepted by others, acclaimed by but a few-deserves to be heralded, first of all, because it is a unique and exciting leap forward for Medicine. Whatever the outcome, the fact that the problem of preventing and controlling these diseases can be put on the agenda for possible practical solution indicates that a great barrier has been breached. This is a far cry from the intellectual atmosphere of only a few years ago, when these diseases were regarded by many as inevitable consequences of aging.51 The achievement needs to be heralded, in the second place, because of its practical implications .for both medical practitioners and investigators. For the former, it implies a marked change in approach to the practice of general and internal medicine. The concept that prevention of disease and maintenance of health is a key task for the practicing physician is by now well established in obstetrics and pediatrics. To a large degree, obstetricians today are preoccupied with the management of normal pregnancy and the maintenance of optimal health pre- and postpartum. Correspondingly, pediatricians are extensively engaged in the supervision of healthy infants and children. Thus, preventive medicine is a conspicuous feature of their daily practice. Prartiral Clinical Implications and Interim Appoach IO Preventive Therapy: This phenomenon does not as yet have its counterpart in the work of general practitioners and internists among adults. By and large, these key members of the medical profession are still overwhelmingly concerned with the care of the sick. But the possil,ility of a breakthrough against hypertensive and atherosclerotic diseases has a critically- important implication, for any effort to take advantage on a large scale of the possibility of preventing these diseases requires the periodic examination and long-term supervision of healthy adults. This is a sine qua non for the SEPTEMBER

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timely detection of signs of increased susceptibility and early occult disease. Only in this way does timely preventive intervention become possible- -that is, the utilization of the multiple weapons of the present-nutritional, hygienic and pharmacologic-which may help to check the development of gross illness and frank disability. In emphasizing these implications for clinical practice of the possibility of a breakthrough against hypertensive and atherosclerotic diseases, the writer is fully aware of the over-all remaining uncertainties. Thus, it is not yet certain whether the available preventive measures can in fact significantly retard the development of overt clincal vascular disease. Although the accumulated research evidence points overwhelmingly in this direction, the definitive answer is yet to come. Five or ten years of hard work in mass field trials still lie aheacl. Until such definitive data are collected, disagreements among scientists are bound to persist concerning the theoretic and practical significance of the research to date. This situation is virtually unavoidable. Such a phase has occurred with almost every significant new advance in medicine. The important problem is to avoid disorientation amid the continuing discussion and developing research. On the one hand, the disagreements are a product of indubitably important advances concerning hypertensive and atherosclerotic diseases-advances significant enough to indicate the possible value of new approaches to practical prophylaxis and therapy. On the other hand, the work is as yet unfinished. Definitive evidence from experimental-applied epidemiology and clinical investigation is not yet available. Incidence and mortality rates from hypertensive and atherosclerotic diseases have not yet been dramatically reduced by controlled scientific intervention. Decisive efforts along these lines are being made, but their results are several years in the offing. From the aspect of clinical practice, therefore, the problem is one of a sound interim approach. For this interim period, there is widespread agreement that it is advisable to take advantage This is particuof the possibility of prevention. larly applicable in dealing with susceptible individuals, for example, those with positive family histories, hypercholesterolemia, elevated blood pressure, obesity, positive genitourinary tract findings, diabetes, hypothyroidism and early signs of vascular involvement such as nonspecific electrocardiographic findings. It is

336

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obvious that, particularly during this transitional phase of our knowledge, recomrrendations for prophylaxis should IW virtualI\, without danger of an)’ type-m biologic, sociologic 01 psychologic. For this reason and I~~ausc the‘ accumulated evidence strong-ly suggest< thal the Lest results are likely to ))c achieved through regimens placing a high priority on alterations in the mode of life, particularly in nutritional, smoking and physical activit) hal)its, general recoinliirnclations focus on this apOf course, \zJlertx spccifiproach. *1,“1’I”‘!’ I” tally indicated. for example, in thr correction of hypertension, judicious use of well-tested, safe drugs is in order, along- with nutri(ionalhygienic measures. The wisdom of this interim approacll is confirmed I)! the grim facts on morl)idit)- and mortality rates from hypertensive and atherosclerotic diseases. There is no reason to I )clievc that a polic), of watchful Lvaiting or judicious neglect, pending the completion of rcscarch studies on prevention during tile next decade, will decisi\.elb, alter this picture. on the other hand, the measures proposed for long: term prevention, control and treatment, including the nutritional, hy+enic, and pharmacologic ~nc’asurcx, are safe, moderate, sound and fire from danger; and a wealth of e\.idencr points to thr widespread likelihood of their \,aluc. Their prophylactic use would therefor? scc~n to I)( the order of the da)-.

This review oT cardiovascular disrases in the Cinited States today has focused on four ke) specific diseascs~ ~-congenital, rheumatic, hypertensive and atherosclerotic cardiovascular diseases. It has emphasized that they, particularl! hypertensive and atherosclerotic clisrascs. constitute the ma,jor health and medical prolAms confronting the nation at the present limr. it has noted the significant Concomitantly, progress made in the understanding and control of these diqeascs and the statistical record of this progress in declining mortalit)- rates. Soundirlg a note of cautious restrained optimism, it has t)een estimated that a real possiljility exists for a major breakthrough against tllr.sr diseases in the years immediately ahead.

It is a pleasuw to acknowledsc thr mcouragcment and support of Samuel 1,. Andrlman, M.D., M.P.H.. Commissioner of Hralth, and the Board of Hralth, City of Chicago. Thr rcscarch work of the Hrart Discasc

<&trot Program prrsented in this report has bc-en the joint undertaking of a tars-e group of people, and the contribution of several of these is to be noted in thr coauthorship of our paprrs listed in the bibliography. I am also indrbtcd to the following mrmbers of the Board of HAth staff, who aided significantly in the accomplishmt’nt of these stud&: Eloise Johnson, M.D., Judy Bearii&i, R.N., Faith Bissell, Roberta Crawford, Nancy l)alton, Sandra Ficldc, Efir Gardner, Nancy Gundlach, R.N., Mary Hoskins, Dana King, M.7’.. Arthur McCoo, 111, Florrncc Modlinsky, M.S., Adclr Stamlrr and .Jack Stcinbqg, of the Heart Discas<> Control Program; to Vinc‘cant Saunders , Jack Skillman and Sidnry Stern of the Division of Hralth Education and Information; Frank Banrr, Stanley Klis, Carl Kolometz, Marvin Templcton. and Mrs. .Juanita Ryan and tha staff of thr Vital Statistics aud Information Services; and to Robert P. McFatc, Ph.D., and thr staff of thr I,aboratory Testing and .\nalysis Scrvicc. \Yr arc also qratcful to Harry Kyrn(~. l~onisv C:owan and l’ctvr Pakcltis. of the Computvr (:t.ntrr. Northwcstcrn Lrnivcrsity. It is also a plcasurc to acknowlrdgr the cooprration of Howard A. 1 .indbvrg, hf.D., Xfcdical Director, the Medical Departmvnt and thv Exrcutivc. Ixadrrship of the People’s Gas, I,iqht, and Cokr CZompany. WY arr also grateful to lsabcllc
National Statistics of the United Statvs. Colonial ‘Times to 1957. IJ. S. Department of Commcrcr, Bureau of thv Census, Washington, D. C., p. 24, 1360. 2. l.ongevity at all-time high. .S/a/i..cl. Hull. .\1drop. Lzfe Inrur. Co., 42 : 6, 1961. 3. K(duction in prcmaturc drath. .)‘tn/1.r/. Rull. .Vlt~r@. L~fi IKW. CCL, 41 : 7, 1960. 4. T)rath ratrs by aqr, raw, and sex, United States, 1900~~1953, all causes. Vital Statistics-Spwial Reports, 43: no. 1, 1956. LJ. S. Public Suvicr. -5. I)cath rates by age, race and sex. United States, 1 OOO- 1353, ma.jor cardiovascular-renal diseases. Vital Statistics-Special Rrports, 43: no. 13, 1956. 1.T. S. Public Srrvice. 6. Vital Statistics of the LJnitcd States, 1959, Srction 6. Mortality Statistics. U. S. Department of Health, Education and Wrlfarr, Public Health I.

‘THE AMHRICAN

~OURNAI.

OF CARDIOLOGY

Cardiovascular

7.

8.

9.

10.

11.

12.

13. 14.

15.

16.

17.

18. 19. 20. 21.

22.

23.

24. 25.

Diseases

Service, National Center for Health Statistics, National Vital Statistics Division. Health and Demography. U. S. Department of Health, Education and Welfare, Public Health Service, National Office of Vital Statistics, Washington, D. C., 1956. COLLINS, S. D., LEHMANN. J. L. and TRANT~IAM, K. S. Major Causes of Illness of Various Severities and Major Causes of Death in Six Age Prriods of Life. Public Health Monograph 30, Public Health Reports, U. S. Department of Health, Education and Welfare, Public Health Service, 1955. 1961 White House Conference on Aging-Chart Book, Federal Council on Aging, U. S. Department of Health, Education and Welfare. ~$ORIYAMA, I. M., WOOLSEY, T. D. and STAMLER, J. Observations on possible factors responsible for the sex and race trends in cardiovascularJ. Chron. renal mortality in the United States. I)rs., 7: 401,1958. STAMLER, J. Epidemiology as an investigative method for the study of human atherosclerosis. .J. nht. M. A., 50: 161, 1958. STAAILER, J. The epidemiology of atherosclerotic coronary heart disease. P&pad. Med., 25: 610, 1959. Causes of death in later life. Statist.Bull. M&of. Lq? Imur. Co., 41 : 6, 1960. WARKANY, J. and KALTER, H. Congenital malformations. A:e~e, England J. Med., 265: 993, 1961. RICHARDS, M. R., MERRITT, K. K., SAMUELS, M. H. and LANGMANN,A. G. Congenital malformations of cardiovascular system in series of 6,053 infants. Pediatrics, 15: 12, 1955. KIEI:FER, S. A., ADAMS, P., .JR., ANDERSON, R. C. and BEARMAN, J. E. Incidence of congenital heart disease among the offspring of registered nurses in Minnesota. Minnesota MPd., 42: 222, 1959. Health, Education and Welfare Indicators, U. S. Dept. of Health, Education and Welfare, Washington, D. C., p. G,1961. Improved outlook in congenital heart disease. Statist. Bull., Metrop. Li$c Insur. Co., 38: 8, 1957. Personal Communication, Illinois Department of Public Health, Springfield, Ill., 1960. Health of the school child population. Statist. Bull. .2,lrtrofi. Life Insur. Co., 42 : 1, 1961. SMITH, J. M., MILLER, R. A., MARIENFELD, C., HARNEMANN,B. and WILLARD, J. Use of taperecorded heart sounds in screening of children for heart disease. Circulation, 20: 887, 1959. WEISS, M. M. Incidence of heart disease in school children of Louisville. Am. Heart J.; 22: 112, 1941. WEDUM,E.G.,WEDTJM,A.B.~~~BEAGHLER, A.I.. Prevalence of rheumatic heart disease in Denver schoolchildren. Am. Heart J., 22: 112,194l. .JACKSON, R. Heart disease in a rural Iowa county. J. Pediat., 29: 647, 1946. ROBINSON, S. J., AGGELER, D. M. and DANDLOFF, G. T. Heart disease in San Francisco school children, 1947; registry showing incidence, problems, and supervision techniques. J. Pediat., 33: 49,1948.

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26. DODGE, H. J., MORRIS, N. M. and MARF.L.SH, G. .J. Characteristics of heart disease seen in a casefinding program. Am. .J. Dis. Child., 95: 164, 1958. 27. MORTON, W., BEAVER, M. E. N. and ARNOLD, R. C. Heart disease screening in elementary school children. J.A.M.A., 169: 1163, 1959. 28. MILLER, R. A., SMITH, J., STAMLER, J., HAH~EMANN,B., PAUL, M. H., ARRAMS, I., HAIT, G., EDELMAN, J., WILLARD, J. and STEVENS, W. The detection of heart disease in children. Results of a mass field trial with use of tape-recorded heart sounds. Circulation, 25 : 85, 1962. 29. GENTRY, J. T., PARKHURST, E. and BULIN, G. V. ‘An epidemiological study of congenital malformations in New York State. .4rn. .f. Pub. HeaW, 49: 497,1959. 30. Cardiovascular Diseases in the U. S.-Facts and Figures. New York, 1958. American Heart Association. 31. Death Rates by Age, Race, and Sex, United States, 1900-l 953, Rheumatic Fever. Vital StatisticsSpecial Reports, 43, no. 16, 1956. U. S. Public Health Service. 32. Death Rates by Age, Race, and Sex, United States, 1900-1953, Diseases of Heart. Vital StatisticsSpecial Reports, 43, no. 17, 1956. U. S. Public Health Service. 33. Death Rates for Selected Causes by Age, Color, and Sex: United States and Each State, 1949-51, Chronic Rheumatic Heart Disease. Vital Statistics-Special Reports, 49, no. 35, 1959. U. S. Public Health Service. 34. PAUL, .J. R. The Epidemiology of Rheumatic New York, 1957. American Heart Fever. Association. 35. STAMLER, R. and STAMLER, J. Mortality due to rheumatic fever-rheumatic heart disease in Chicago. In preparation. 36. \,'kITE,P. D. Heart Disease, ed. 4. New York, 1956. Macmillan Company. 37. SAGEN, 0. K. and WATERHOUSE, A. M. Cardiovascular data obtainable from health examinations in the U. S. national health survey. Am. J. Puh. H&h, 51 : 386,1961. 38. Sr~.ce~., A. C., JOI~NSON, E. E.. and STOLLERMAN, G. H. Controlled studies on streptococcal pharyngitis in a pediatric population. I. Factors related to the attack rate of rheumatic fever. ?VPWE&and J. Med., 265: 559, 1961. 39. GROSSMAN, B. and STAMLER, J. Preventability of first attacks of acute rheumatic fever. In preparation. 40. LATIMER, .4. D., SIEGEI., A. C. and DECELLES, .J. Evaluation of the recovery of beta hemolytic streptococci from two mail-in methods. Am. J. Pub. Health. In press. 41. SIEGEL, A. C. Recognition of streptococcal infections in the prevention of rheumatic fever and acute glomerulonephritis. Illinois M. .I., 110 : 113,1956. 42. BREESE, B. B. and DISNEY, F. .A. The accuracy of diagnosis of beta streptococcal infections on clinical grounds. J. Pediat., 44: 670, 1954. 43. POWERS, G. F. and BOISVERT, P. L. Age as a factor in streptococcosis. J. Pfdiat., 25 : 481,1944. 44. RANTZ, L. A., BOISVERT, P. J. and SPINK, W. W.

Stamler

338 Hcmolytic streptococcal diwases of the respiratory 45.

46.

47.

48.

49.

50.

51.

and tract.

nonstrcptococcal .-lrr,h. Int. .Med.:

78 : 369,1946. C:ATANIARO, 1:..I., STETSON., (J..L\., MORRIS, :\. .I., CIIAMOVI~.~, R., hMMEI.KAMP, <.:. H., .JK., Sro~.ZER, B. I,. and PERRY, bv. D. Thr role of the streptococcus in the pathogenesis of rhrumatic ff?\w-. .4m. ./. .%r$., 17: 749, 1954. Rccommrndations of (:ornmittrr on Prewntion of Rheumatic Fever and Bacterial Endocarditis, 1960, Council on Rheumatic and rwiscd, Congenital Heart Diseasr. N~cw York. 1960. American Heart Association. of the Heart Diseasr SIAMLER. .I. :\nnual Report C:hicaqo, 1960. Control Program for 1959. PrivateI)- printed. of Five Yrars’ Experience STAMLER, .r. :\ Rrvirw of the Hrar-t Disease Control Program. Chicago Board of Health. Proccc-dings of thv Srminar on Cardiovascular Disczrs. In press. Annual Report of thr Heart Disease (:ontrol Program, Chicago Board of Health for 1961. In prrparation. STAMLER, .I. Interrelationships bctwt.en thv two diseases, hypertension and atherosclerosis. .‘frn. J Cardiol.. 9 : 743, 1962. Experimental KATZ, I,. N. and STAIILER, J. Spring&Id, 1953. C:harles <: Atherosclerosis.

‘Thomas. BERKSON, 11. M.. STAMmR, .I.,IJNUBBKG, H. A., MILLER. W. and HALI., Y. Socioeconomic correlates of atherosclerotic and hypertrnsivr discase. &K. .\;w I;?& ,4cad. SC., 84: 835, 1960. Approaches to the prewntion 53. STAMLER, .I.et d. of coronary heart disease-- recent studies and rpidcmiological foundations. .r. .-iv. I)lP/CI. .4. ( 40: 407, 1762. 54. STAMIXR. .I..bWBERC, H. A., B~KKSUN, 1). h’f., SHAI+I;R, A., MII.I.ER, W. and POINDEXTEK, A. wsith thr assistance ~~COI.C\.ELI., hl. and H.u.I., Y. l’rcvalcncc and incidence of coronary hrart disease in strata of the labor force of a CXicago in.r. C/won. Dif.. 11. 405, dustrial corporation. 1960. 55. STAMI.ER .J. ()n the natural history of hypvrtrnsion and hypcrtcnsivr disrasc. In : The Pathogenesis of Essential Hypertrnsion, Procrrdings of thv Prague Symposium, p. 67. Editrd by C:or-t. J. H., Fend, V., Hrjl, %. and Jirka, .J. Prague, 1960. State Medical Publishing House. of hyperten56. STAMLER, J. On the epidemiology sive disrasc. In : The Pathogenesis of Essential Hypertension, Procredings of the Prague Symposium, p. 107. Edited by Cart. J. H., Fmcl, V., Hejl, %. and Jirka, J. 1960. Stat? Medical Publishing Houw. 57. LASSER, R. P. and MASER, A. M. Observation of frequency distribution curves of blood pressure in persons aged 20 to 106 years. Ccrtoirirt. 14: 345, 1957. 52.

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59.

C:OMSTOCK, G. W. An epidemiologic study of blood prcssurr fcvcls in a biracial community in the Southern United States. Ani. .f. Hyo.. .y 65: 271, 1957. PHILLIPS, J. H., .JR. and BUKCH, G. I:,. cardiovascular diseases in the whit? races. ,%frd~inr. 39 : 241. 1960.

.2 revirw of and Nrgro

G(I. Build and Chicago,

Blood 1959.

Prrssure Study, lO5U: \‘ol. 1. Socirty of Actuaries. 6 I HUXXINSON, J. J. Clinical implications of an ertensive actuarial study of build and blood prcssure. .4wz. Z/z/..Zlpd.. 54: 90, 1961. 62. Heart Conditions and High Blood Pressure Rcported in Interviews; Ijnited Statrs, July 1957-m June. 1958. Health Statistics from the L;. S. National Health Survey, LJ. S. Dept. of Hralth, Iiducation and Wrlfarr, Public Hralth Service, 1960. 63. SI.AUI.EK, J., 12~~~~~~~, H. A., BERKSOS, D. M., SIIAI:~EK. 11.. MIXER, W. and P~INDEXTER, A. with the assistanct of Cor.wpr.r., hf. and HALL; Y. Lpicicmiological analysis of hypertension and hypertensive disease in the labor force of a Chicago utility company. In: Hypertension, Volumr vu, Drllg .4ction, Epidemiology and Hemodynamics, p. 23. Edited by Skelton, F. R. I’roccedinqs of tht C:ounril for Hiqh Blood Pressure Rrscarch. .\merican Heart .Association, 1958. New York, 1959. .\merican Heart Association. 64. ‘l‘i~ows, C:. B., cat al. ‘l‘br Precursors of 1;ssential Hyprrtcnsion and Coronary Artery Disease, Vol. 1. 1948%1959Collected Papers. Baltimore, Xfd.. 1959. ‘1‘hc Johns Hopkins School of hfvdicirw. 65. WAMLER. J., KJEI.SBERG, M., H.u.I.. Y. and SCoTCrr, N. Epidemiologic studies on cardiovascular-renal diseases. I. =\nalysis of mortality by age-race-sex-occupation. ./. Ch,on. 1);s.. 12: 440. 1960. 66. KJELSHERG, hl. and S.~.~~%LEK: J. b:pidemiologic studies on cardiovascular-renal diseases. II. .jnalysis of mortality by age-race-sex-place of wsidrncr. including urban-rural comparison. J. C//,-o,/.I);.<., 12: 456, 1960. 67. S.I..WIXR. J., KJL:LSRERC, hf., H-41.1. Y. and Sco~rr:tc. N. Epidemiologic stud& on cardiovascular-renal diseases. 111. hnalysis of mortality by aqr-srr-nationality. J. Chrm~. I)is., 12: 464, 1960. 68. l’rocwdinqs of the Joint W.H.<>.-C:zrchoslovak C:ardiological Socirty Symposium on the Pathoqencsis of Essential Hyprrtension. Edited by (Zort, .I. H., Fencl, V., He.jl, Z. and Jirka, J. Prague, 1961. State Medical Publishing House. 69. PICI(I:RINC,(i. W. High Blood Pressure. New York. 1955. Grunt PC Stratton. 70. hAI.1.. K. Essential hypertension-inridenw, coursr and htrrdity. :lnn. I,,/. .Wed., 55 : 1. 1961. 71. hfoRRISoN, s. 1..and .h'foR~~s, .r.N. Epidemiological observations on high blood pressure without cvidcnt cause. L~nc-r~, 2: 864. 1959. 72. MCKIISIC~~ V. A. Editorial---Genrtics and the naturc’ of rsscntial hypertension. Circ&lion, 22 :

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'I'HEi\Mt.RI(:.~N ,JOIIRNAI.OF C.ARDIOL.OIT:Y

Cardiovascular

Diseases

76. Proceedings of the Conference on Basic Mechanisms of Arterial Hypertension. Edited by Hoobler, S. W. Circulation, 17: 641, 1358. 77. GOLDLBATT, H. The Renal Origin of Hypertension. Springlicld, 1948. Charles C Thomas. 78. Hvprrtrnsion, Vol. TX. Chemical and Hormonal Factors. Proceedings, Council for High Blood Pressure Research, .4m. Heart A., Nov., 1960. New York, 1961. American Heart Association. 79. ST~MI.ER, ,I., PICK, R. and KATZ, I.. N. Expericnces in assessing estrogen antiatherogenesis in the chick, the rabbit, and man. iInn. n’~zo )hrk .4md. Sc., 64: 596. 1956. 80. STAMLER,.J., et al. Effectiveness of estrogens for for the long-term therapy of middle aged men with a history of myocardial infarction. In: Proceedings of the Hahnemann Symposium on Coronary Heart Disease, 1962. In press. 8l.!K.brz, L. N., STAMLER..J. and PICK, R. Nutrition and .%theros&rosis. Philadelphia, 1958. I.ea & Febiger. 82.: SIGLER, I.. H. The mortality from arteriosclerotic and hyprrtensive heart diseases in the United States. II. Possible relation to industry. Am. .I. Cordial., 3: 605. 1959. 83. LNTXRLINE,P. E., RIKLI, A. E., SAWER, H. I. and HYMAN, M. Death ratrs for coronary heart disease in metropolitan and other areas. Pub. Heal/h Rq., 75: 759, 1960. 84. PEL.I..S. and D’ALONZO, C. A. Myocardial infarction in a one-year industrial study. J.A.M.A., 166: 332,195s. 85. l’~1.1.. S. and D’ALONZO, C. .4. A three-year study of myocardial infarction in a large employed population. J.A.M..4., 175: 139, 1961. 86. %UKEL,W. J. et al. .4 short-term community study of the epidemiology of coronary heart disease. :IIII. J. Pub. Health, 49: 1630, 1959. 87. B.\RROW, .J. G., QUINLAN. C. B., EDMONDS, R. E., WHITNER, V. S. and GOODI.OE,M. H. R. Comparison by gas-chromatography of the fatty acid content of adipose tissue with dietary intake of fat in vegetarian and non-vegetarian males. Cmulation,22: 673, 1960. 88. &‘YNDER, E. I,., LEMON, F. R. and BROSS, I. J. Cancer and coronary artery disease among Seventh-day Adventists. &lcer, 12: 1016, 1959. 89. I)AM.BER, T. R., MOORE, F. E. and MANN, G. V. Coronary heart disease in the Framingham study. Am. J. Pub. Health, 47, no. 4, part 2, 4, 1957. 90. Doyr.~, J. T., HESLIN A. S., HILI.EBOE,H. E., FORMEL,P. F. and KORNS, R. F. A prospective study of degenerative cardiovascular disease in Albany : report of three-years’ experience. I. Ischemic heart disease. Am. J. Pub. Hwdth, 47, no. 4, part_ 2, 25, 1957. 91. <:IIAPMAN, J. M., GOERKE, L. S., DIXON, W., LoveI.AND,D. B. and PHILLIPS,E. The clinical status of a population group in Los Angeles underobservation from two to three years. Am. .I. Pub. Health, 47, no. 4, part 2, 33,1957. 92. Measuring the risk of coronary heart disease in adult population groups. A symposium. Am. .I. Pub. Hmlth, 47, no. 4, part 2, 1957. 93. Prevention and control of heart disease. A SEPTEMBER1962

in the United

94.

95.

96.

97.

98.

39.

100.

101.

102.

103.

104.

105.

106.

107.

108. 109.

110.

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