The prevalence and prognostic significance of electrocardiographic abnormalities

The Prevalence and Prognostic Significance of

Electrocardiographic Abnormalities

Euan Angus Ashley, MDVinod Kumar Raxwal , MD

Victor F. Froelicher, MD

Veterans AdministrationPalo Alto Health Care System

Palo Alto, California

Current Problems in

Cardiology®

Volume 25 Number 1 January 2000

2 Curr Probl Cardiol, January 2000

Current Problems in

Cardiology®

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Foreword 5

Introduction 7

Methods of Review and Analysis 8

The Studies 9The Framingham Heart Study 9The Seven Countries Study 10The US Pooling Project 11The Finnish Social Insurance Study 11The Manitoba Study 11The Busselton Health Studies, Busselton City, Australia 12Chicago, Illinois, Studies 12Copenhagen City Heart Study 12UK Studies 13Italian Risk Factors and Life Expectancy (RIFLE) Pooling Project 13The Tecumseh Community Health Study 14Belgian Interuniversity Research on Nutrition and Health 14The World Health Organization (WHO) European Study 15Multiple Risk Factor Intervention Trial (MRFIT) 15Studies of Participants with Different Racial Backgrounds 15Studies in the Elderly 17

Methodologic Issues 18Demographics 18Exclusions 22Random Sampling 22Epidemiologic Tools 23Length of Follow-up 29Endpoints 29

Curr Probl Cardiol, January 2000 3

Current Problems in

Cardiology®

Results and Discussion 33Left Ventricular Hypertrophy 34Q Waves 46ST Segment Abnormalities 48Bundle Branch Block 51Heart Rate, Atrial Fibrillation, and the Elder Population 53Pooled Categories and Other Races 55Sudden Cardiac Death 56Sensitivity and Specificity Estimates 58

Conclusions 59

References 61

Appendix 1: Search Terms 71

Appendix 2: The Rose Questionnaire 71

Appendix 3: A brief guide to the Minnesota Code 72


Foreword

The first Current Problems in Cardiology issue of the new millenniumis written by Drs Ashley, Raxwal, and Froelicher from the VeteransAdministration Palo Alto Health Care System and Stanford University.They provide a magnificent, awe-inspiring overview of the prevalent andprognostic significance of electrocardiographic abnormalities. Thismonograph is the most extensive review ever performed of the diagnos-tic significance of various findings on the resting electrocardiogram. DrFroelicher and his colleagues are to be congratulated on this extensiveeffort, which provides material that should be read by everyone involvedin electrocardiographic interpretations.

The editorial board of Current Problems in Cardiology could not haveselected a better first monograph for the year 2000.

Robert A. O’Rourke, MD, FACC, MACPEditor in Chief


Euan Angus Ashley, MD, qualified in physiology andmedicine from the University of Glasgow, Scotland,in 1996. He completed residency training in inter-nal medicine at the John Radcliffe Hospital,Oxford, England. In many ways similar to Buckaroo

Bonzai, he is also an internationally recognized saxophonist and a computerwizard. Since 1995 he has collaborated with Vic Froelicher on a number ofclinical and educational cardiology projects, including medical softwaredevelopment. He is currently the Wellcome Trust Cardiovascular ResearchFellow at the University of Oxford, England, maintaining an integrativeresearch program that includes the clinical effects of exercise stress on thecardiovascular system, and the role of nitric oxide in myocardial growth anddifferentiation.

Vinod Kumar Raxwal, MD, received his undergraduatedegree from The Air Force School, New Delhi, India. He wasthe recipient of a medical scholarship to State Medical Uni-

versity of Odessa, Ukraine, where he graduated with honors in 1996. He ispresently working as a research associate at Palo Alto Veterans Administra-tion Health Care System/Stanford University in the department of cardiology.He is actively involved in a variety of studies in exercise testing in patientswith coronary artery disease and a study on spinal cord injury patients. Heis the main researcher in Cardiokymography—a technique to study ventricu-lar wall motion abnormalities to diagnose coronary artery disease.

Victor F. Froelicher, MD, graduated from theUniversity of Pittsburgh Medical School in1967 and obtained his internal medicinetraining at Wilford Hall US Air Force Medical

Center, followed by fellowship in cardiology at the University of Alabama atBirmingham with T. J. Reeves. While at the US Air Force School of Aero-space Medicine, Dr Froelicher concentrated on exercise physiology andearly screening for coronary artery disease. In 1977 he joined the facultyat the University of California at San Diego and was the principal investi-gator of an NIH-funded randomized trial of cardiac rehabilitation. From1984 to 1992, Dr Froelicher was Chief of Cardiology at the Long BeachVeterans Affairs Medical Center and Assistant Chief at the University ofCalifornia, Irvine. He initiated follow-up of more than 3000 patients andperformed the largest outcomes study in the VA of coronary artery dis-ease. Since 1992, he has been Professor of Medicine at Stanford Uni-versity in the Cardiology Department and directs the ECG/Exercise Lab atthe Palo Alto Veterans Affairs Health Care System. Dr Froelicher has beeninterested particularly in computerized electrocardiography since being amember of the 10th Bethesda Conference on “Optimal Electrocardiogra-phy” in 1977. Educational resources for the ECG and a mobile channel forpalmtops are available on his web page: www.cardiology.org.


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Introduction

ince 1887,8,9 the electrocardiogram (ECG) has been used in the diagnosis of cardiovascular disease (CVD). It is objective, simple,rapidly obtained, painless, and largely independent of coopera-

tion or language differences. It remains the most important single diag-nostic indicator of acute myocardial infarction (MI). The ECG plays acrucial role through the exercise test in the appropriate application ofinvasive investigations, and has been used in the seminal epidemiologicstudies of the century. It has been stored on paper, microfilm, electro-magnetically,10 digitally,11 subjected to signal averaging and computeranalysis,12 and transmitted across the internet.13 Despite its ubiquity, thevalidity of using the resting 12-lead ECG as a screening test for CVD inasymptomatic patients has never been convincingly demonstrated.Indeed, notwithstanding the abundance of literature on the subject, therehave been few authors willing to draw conclusions, and they tend to dis-agree.10,14-18 This lack of accord implies the absence of a convincing syn-thesis of the existing data.

The value of any screening test depends critically on 4 key principles:its cost; the prevalence of the abnormalities detected in the populationassessed; the link of the abnormalities to morbidity and mortality; and thepossibility of reducing or avoiding future morbidity or mortality given theinformation provided by the test. In particular, to be worth the additionalexpense, the ECG must add significantly to the ability of standard riskfactors to identify asymptomatic persons with subclinical disease.

Literature review remains an important means of reaching consensus ontopics with a wide range of disparate research. There have been fewreviews attempting to reach consensus on this topic. Those available havebeen hindered by lack of key articles,15 or have been comprehensive with-out addressing the question of screening in detail.19 Furthermore, recentchanges in the pattern of CVD have altered the precepts of the question.Since the 1960s, the incidence of both coronary20,21 and hypertensive22

heart disease has been falling. Mosterd et al22 reported that the age-adjusted prevalence of systolic and diastolic high blood pressure declinedfrom 18.5% to 9.2% among men and from 28.0% to 7.7% among women


S

from 1950 to 1989. In an editorial, Levy20 reported that, over the past 30years, mortality from coronary heart disease (CHD) had declined by morethan 50%. Also, in the recent past we have for the first time clear evidenceof the benefit, both in mortality23 and economic24 terms, of primary pre-vention in CVD. The West of Scotland Coronary Prevention Trial demon-strated for the first time that treatment with an HMG-CoA reductaseinhibitor (“statin”) significantly reduced the incidence of MI and cardio-vascular death without adversely affecting noncardiovascular mortality inmen with moderate hypercholesterolemia and no history of MI. The ques-tion of screening also impacts on secondary prevention issues given theexistence of “silent” CVD. Similarly, recent data have emphasized thesuccess of secondary prevention.25

It is clear then, that a review of the epidemiologic studies that assess theprevalence and prognostic value of electrocardiographic abnormalities istimely and could direct both primary and secondary prevention practicein CVD.

Methods of Review and AnalysisUsing MEDLINE we reviewed the literature over a period of 33 years

from 1966 to 1999. The details of the search terms used are in Appendix1. We attempted to identify studies where a randomly selected populationof asymptomatic patients with no history of ischemic heart disease under-went resting 12-lead ECG before a follow-up of at least 5 years withrespect to mortality. We identified very few studies that exactly met ourcriteria, so we have included several studies where random sampling wasnot used, where symptomatic patients were not excluded, or where softendpoints such as MI were used. These articles are considered separately.All studies were critically assessed according to standard criteria26 and,wherever possible, the original articles describing the methods of thelarge epidemiologic trials were obtained. In large trials that produce manyarticles, authors often refer to earlier articles to avoid repeating method-ologic detail. In many cases, however, insufficient detail was found in thearticle to which we were referred, and it was necessary to gather severalother articles not directly relevant to this review to answer methodologicquestions. In one case,27 it was not possible to obtain details of method.

Prevalence data were assembled from the studies and classified in anextensive spreadsheet. In this article, box plots are used to illustrate thisdata. This simple visual technique, part of a family of “exploratory dataanalysis” tools, has been widely recommended as an effective means ofsummarizing large quantities of data within the medical literature.28 Thetop and bottom of the box represent the 75th and 25th percentiles, mak-


ing the length of the box the inter-quartile range (IQR). In this way, thebox represents the middle half of the data. The median (50th percentile)is marked on the box as a line. The T-shapes extending from each box arethe upper and lower adjacent values. The upper adjacent value is thelargest observation that is less than or equal to the 75th percentile plus 1.5times the IQR; the lower adjacent value is the smallest observation that isgreater than or equal to the 25th percentile minus 1.5 times the IQR. Val-ues outside this range are displayed as “outliers.”

Risk data were often available from studies. However, there was somevariation in the method of calculating risk. Many studies adjusted for anumber of confounding variables, including age, systolic blood pressure(SBP), cholesterol, smoking, and body mass index (Table 5). Most pre-sented adjusted risk ratios that resulted from the Cox analysis. Somedetermined risk relative to those with normal ECGs, and some calculatedrisk relative to those without the abnormality in question. In some cases,in which relative risk was not included in the article, we have calculateda figure from the raw data given.

Sensitivity and specificity estimates were calculated with standardmethods26 and are displayed in Table 17.

The Studies

The Framingham Heart Study6,29-42

The epidemiologic experiment started in Framingham, Mass, in 1948by T. R. Dawber represents one of the most famous medical studies in theworld. Its objective was to identify the common factors or characteristicsthat contribute to CVD by following its development over a long periodin a large group of participants who had not yet developed overt symp-toms of CVD or suffered a heart attack or stroke. The researchersrecruited 5209 men and women between the ages of 30 and 62 and car-ried out extensive physical examinations and lifestyle interviews that theywould later analyze for common patterns related to CVD development.The original study cohort consisted of respondents of a random sample oftwo thirds of the adults in the town. Since 1948, the subjects have con-tinued to return to the study every 2 years for a detailed medical history,physical examination, and laboratory tests. The study has produced sev-eral of the most important insights into human disease this century. Forexample, Framingham played a key role in defining the risk for CVD ofcigarette smoking, physical inactivity, cholesterol (including the protec-tive effect of HDL), and obesity. Framingham secured the link betweenhypertension and stroke. Framingham data analysis produced one of the


most important contributions to preventive cardiology: the Framinghamprognostic score (simple adding of risk factors, as recommended by somenational bodies,45 is not as accurate as using the logistic regression equa-tions developed from the Framingham data46). In an asymptomatic popu-lation, the score calculates an estimate of the 5-year or 10-year incidenceof cardiovascular events using age, smoking, diabetes, SBP, ECG-LVH,and the levels of HDL and total cholesterol.

In 1971, the study enrolled a second-generation group, 5124 of the orig-inal participants’ adult children and their spouses, to participate in similarexaminations. To date, approximately 1000 articles have been published inleading medical journals based on the data collected in Framingham.

The Seven Countries Study1

The Seven Countries Study was a landmark in epidemiology. AncelKeys and later, Henry Blackburn, were pioneers who pulled together forthe first time an international team of researchers to carry out separateepidemiologic studies in their own countries (Table 1) that would later beanalyzed together. This first study to examine systematically the relation-ship between lifestyle, diet, and the rates of MI and stroke in contrastingpopulations led to Keys’ hypothesis of the benefits of the “Mediterraneandiet and lifestyle.” Surveys were conducted from 1958 to 1970 in popu-lations of men aged 40 to 59, in 18 areas of 7 countries, with mortalityfollow-up in the cohorts up to the present day. Cohorts spanned Europe(Finland, Netherlands, Yugoslavia, Italy, Greece), Japan, and the UnitedStates (a sizeable sample of US railroad employees). Substantial reportswere produced at 5 years, and again at 10 years.


TABLE 1. Seven Countries Cohort.

Participation Total S-E Country Where When rate analyzed status

Italy Nicolera, Crevalcore, 1957-1962 85% 3126 RailwaymenMontegiorgio, Rome and rural

United Northwestern quadrant 1957-1959 66% 2102 Railroad States of US (Chicago, St Louis, employees

San Francisco, Canadian border)

Japan Ushibuka, Tanushimaru 1958-1960 100% 1013 RuralYugoslavia Dalmatia, Salvonia, 1958-1962 95% 2028 Rural

Velika KrsnaFinland East (Karelia) and 1959 98% 1677 Rural

West FinlandGreece Crete, Corfu 1960-1961 97% 1215 RuralThe Netherlands Zutphen 1960 84% 917 1/3

(commercial town) executives

The US Pooling Project47

The US Pooling Project was initiated on the basis of the hypothesis thatincreasing the pool of subjects analyzed would enable statistical tech-niques to better predict endpoints from commonly gathered subject data.It was hypothesized that pooling data from several studies would yieldresults on the relationship of key risk factors to CHD, and more precisequantitative estimates of their importance singly and in combination. In1964, the principal investigators of studies in middle-aged white men (theAlbany Civil Servant Cardiovascular Health Center Study, Chicago Peo-ples Gas Company Study, Chicago Western Electric Company Study,Framingham Heart Disease Epidemiology Study, Los Angeles HeartStudy, Tecumseh Community Studies, and Minnesota Business and Pro-fessional Men Study) collaborated to group their data and a pooling pro-ject was established. The committee on epidemiologic studies of theAmerican Heart Association assessed the comparability of methods ofmeasurement and criteria for defining disease. The main aim of the pro-ject was to refine predictive indices for various manifestations of CHD interms of risk factors in combination.

The Finnish Social Insurance Study48

To investigate the prevalence, risk factors, and incidence of CHD in mid-dle-aged Finnish men and women, the Social Insurance Institution of Finlandcarried out a Coronary Heart Disease Study as a part of a larger prospectiveMobile Clinic Health Survey. They were motivated by the fact that CHDmortality in Finnish middle-aged men was the highest in the world. The studywas carried out in 35 populations from 1966 to 1972 and consisted of 5738men and 5224 women, aged 30 to 59 years at entry, drawn from 12 cohortsfrom southwestern, western, central, and eastern Finland. The first examina-tion was conducted in 1966 and a reexamination was carried out after a fol-low-up of 5 years. The substantial report was published in 1983.

The Manitoba Study49,50

The University of Manitoba study was initiated in 1946. It was one ofthe first epidemiologic trials to address the natural history of human dis-ease by following a group of young men, initially known to be in goodhealth and free from clinical manifestations of CVD. As part of the study,a cohort of 3983 men initially employed by the Royal Canadian Air Forceand with a mean age at entry of 30 years, were followed with regularexaminations, including ECG, initially at 5 and later at 3 yearly intervals.The original stimulus was the study of the long-term predictive value ofECGs recorded on initially young and healthy persons.


The Busselton Health Studies, Busselton City, Australia51-53

The Busselton Health Studies form one of the longest running epidemi-ologic research programs in the world. The residents of the town of Bus-selton in the southwest of Western Australia have been involved in aseries of health surveys since 1966. In total, 3331 persons, comprising91% of the population of men and women aged 21 and over in Busselton,have undergone triennial mass health examinations. Measurementsincluded comprehensive medical examination and screening, collectionof sera and DNA samples, and compilation of information on family rela-tionships between survey participants. Using mortality and hospitaladmission rates, study organizers have conducted research into the epi-demiology of cardiovascular and respiratory disease, familial aggregationof chronic disease, and risk factors. This study has been the basis for morethan 150 articles published in the international research literature.

Chicago, Illinois, StudiesChicago Heart Association Detection Project in Industry.7 This was a

cross-sectional and prospective investigation of 39,753 young adult andmiddle-aged men and women. The baseline survey was carried out fromlate 1967 to early 1973 in 84 cooperating companies and organizations inthe Chicago area. In the article assessed in this review, the independentcontributions of baseline major and minor ECG abnormalities to subse-quent 11.5-year risk of death were explored among 9,643 white men and7,990 white women without definite prior CHD. The vital status of eachparticipant was ascertained every 5 years after baseline.

Chicago Western Electric Study.54 Chicago was also the base for thethis study, initiated in 1957 as a long-term prospective investigation ofCHD. A group of 2107 middle-aged men employed by the HawthorneWorks of the Western Electric Company underwent extensive baselineexaminations annually for 11 years. The data reported in this review isbased on the first 5 annual examinations (complete data on CHD risk fac-tors was available for substantially more men for this period).

Copenhagen City Heart Study55,56

The Copenhagen City Heart Study was designed to evaluate the inci-dence of CVD and its attendant risk factors in a Danish urban population.It was a prospective population study comprising a cohort of 9,384 menand 10,314 women, aged 20 or older at enrollment, who were followedfrom 1976. The participants were selected from 1 district of Copenhagenwith a total adult population of 87,172. The study has produced importantinsights into CVD, pulmonary disease, and stroke.57,58


UK StudiesWhite Hall Study.27 Geoffrey Rose, one of the pioneers of European

epidemiology, carried out the seminal White Hall Study in the early1970s. To assess the link between electrocardiographic abnormalities andmortality, 18,403 male civil servants aged 40 to 64 were followed for 5years. This was an important study that provided some of the earliest andmost influential data on prevalence and mortality in CVD. It also studiedone of the largest populations.

British Regional Heart Study.10 The British Regional Heart Studywas undertaken to explain the substantial variations in cardiovascularmortality detected across the United Kingdom, by assessing the role ofenvironmental, socioeconomic, and personal risk factors for CVD. Thestudy fell into 3 main phases: Phase I related cardiovascular mortalityin different regions to a wide range of environmental and socioeco-nomic data over 5 years in 253 towns of England, Wales, and Scotland.Phase II was a clinical survey of middle-aged men in 25 towns selectedfrom the broad database of phase I to represent the wide distribution ofcardiovascular mortality and water hardness. Phase III was a prospec-tive study of cardiovascular morbidity and mortality in the same groupof middle-aged men to determine which of the many personal risk fac-tors were most strongly related to cardiovascular events and to assesstheir behavior under differing environmental conditions. The selectedtowns represented all major geographic regions of the United King-dom. One group family practice was selected in each town. The crite-ria were that the town should have a population over 7500, two or morepractitioners, and represent the socioeconomic composition and char-acteristics of town. In the analysis presented in this article, a randomlyselected group of 7735 men aged 40 to 59 years were followed for 9.5years to examine the relation between resting ECG abnormalities andCHD.

Italian Risk Factors and Life Expectancy (RIFLE) Pooling Project59

The RIFLE Pooling Project was an epidemiologic observational study,the main objective of which was to produce multivariate models for theprediction of all-cause mortality, life expectancy, and selected causes ofdeath, as a function of some baseline characteristics. The study pooleddata from 9 Italian field studies covering more than 70,000 men andwomen aged 20 to 69 years, belonging to 52 population samples (50 ofdemographic nature and 2 occupational groups) distributed in 13 differentregions of the country. However, only 47 cohorts were finally consideredbecause a minimum follow-up could not be completed on the remaining 5


cohorts. The entry examinations of the population samples were performedbetween 1978 and 1987. The measurements were of risk factors and otherpersonal characteristics related to CVD and other chronic conditions. Theexamination included a large number of anthropometric, social, bio-chemical, biophysical, clinical, nutritional, and behavioral measurements.

The analysis reviewed in this article59 deals with 4 of the 9 studies, rep-resenting 23 cohorts of men (n = 12,180) and 22 cohorts of women (n =10,373) aged 30 to 69 years, where the electrocardiogram was recorded.Analyses were performed exclusively on subjects who had no clinicaldiagnosis of heart disease.

The Tecumseh Community Health Study This was a study of the entire population of an American community:

Tecumseh, Mich. The major object was to observe and identify collec-tions of etiologically significant factors associated with the maintenanceof health and the development of illness. They studied the effect of vari-ous risk factors (cholesterol, blood pressure, smoking, body weight, andblood sugar) on the prevalence of CHD. Tecumseh was selected becauseof its size (9500 inhabitants), its relative stability in terms of populationmobility, its variety of socioeconomic and occupational groups, and itsessentially urban, small-town setting. The area was divided into 5 regionson the basis of socioeconomic characteristics. Within each of theseregions, households were randomly selected and combined into 10 equalrepresentative samples of the study area. Medical examinations of thepopulation were conducted for 18 months during 1959 and 1960. A totalof 8641 participants were examined, comprising 85% of the adult popu-lation over 16 years of age in Tecumseh. Electrocardiograms wererecorded on 5129 people.

Belgian Interuniversity Research on Nutrition and Health63-66

In 1979, an interuniversity group was created to study the nutritionalpatterns in the Belgian male and female population, aged 25 to 74, withinthe framework of a cross-sectional survey. The study focused on the dis-tribution of cardiovascular risk factors and nutritional habits and theirrelation to total and cause-specific mortality. There were multiple objec-tives in this study of more than 11,000 people. In the analysis presentedin this review, the independent prognostic value of ischemic ECG find-ings for CVD mortality in 5,208 men and 4,746 women free of CHD atbaseline was assessed. Baseline measurements were made in the years1981 to 1984. The sample was then followed for at least 10 years, withrespect to cause-specific death.


The World Health Organization (WHO) European Study67

The WHO European study was a collaborative study of the prevalenceof ischemic heart disease in 6 samples of middle-aged male clerical workersdrawn from 5 European countries (Belgium, Denmark, Italy, The Nether-lands, and the USSR), including 4522 subjects. The participants were 40- to59-year-old men employed in clerical duties in government or other publicoffices. It was a restricted sample that was matched in regard to age, sex,urban residence, and occupation. The aim was to examine 2 problems: therelationship between national cardiovascular mortality and occupationalprevalence rates, and the feasibility of international cardiovascular compar-isons based on surveys conducted entirely by national teams of investiga-tors.

Multiple Risk Factor Intervention Trial (MRFIT)68-70

The MRFIT was designed to assess the efficacy of reducing risk factorsin persons at high risk of CHD. MRFIT is a randomized clinical trial, whichinvolves a total of 12,866 men, aged 35 to 57, free of CHD by history, phys-ical examination, or resting ECG at baseline, but at high risk of CHD byrisk factors. At the end of 3 screening examinations, participants were ran-domized into 2 groups: one group receiving special interventions and theother group receiving “usual care.” The selection criteria in MRFITincluded the use of a multiple logistic risk function, derived from the Fram-ingham data, to estimate each prospective participant’s 6-year risk of futureCHD death on the basis of serum cholesterol, diastolic blood pressure, andcigarette smoking. A total of 361,662 men, aged 35 to 57 years, werescreened during 1973 to 1976 to select those in the upper 10% risk, as pre-dicted by the Framingham risk score.

Studies of Participants with Different Racial BackgroundsThe Honolulu Heart Program. This was a prospective study of CHD

and stroke among men of Japanese ancestry who were born in the years1900 to 1919 and who lived on the island of Oahu, Hawaii, in 1965.Through the updated records of the World War II Selective Registrationprogram, 11,000 eligible men were identified and located. Of these, 8,006men aged 45 to 68 years participated in the initial examinations. Follow-up examinations were carried out on 7,682 men judged to be free of CHDat baseline 2 and 6 years after the baseline examination. In the analysisused for this review, the predictive value of ECG abnormalities at base-line for subsequent risk of fatal and total CHD was analyzed in a 12-yearfollow-up.

Evans County Study.4,74,75 A clinical observation that CHD appeared


less frequent in black than white patients, despite a higher prevalence andgreater severity of hypertension in blacks, prompted the Evans CountyHeart Study organizers to compare the epidemiology of CHD of blackand white residents of a southeastern US community. A community-basedclosed cohort study was initiated with a prevalence survey in 1960 to1962. In the primary analysis used in this review, a 20-year follow-upof 308 black and 511 white men is used to study the distribution ofECG abnormalities and their relationship with mortality and race.

Charleston Heart Study.3,76 The key aim of the Charleston HeartStudy was to determine racial differences in the prevalence of ECGfindings in black and white persons and to determine whether the pre-dictive power of these findings was different. The study began in 1960,based on a random sample of 1394 white and 787 black men andwomen in Charleston County, S. C. In the article considered for this


TABLE 2A. Demographics and follow-up of studies: Mortality studies.Total

Mortality Study duration Total Participationstudies Where When type of f/u approached rate Exclusions

Chicago industry Chicago 1967-1973 Prospective 18,218 ECG evidence of MICopenhagen City Copenhagen 1976-1978 Prospective 50 mo 19,698 69% (men), None

75% (women)Framingham Framingham 1948 Prospective “Low level of diagnosis of established

CHD” via full MD examinationWhitehall Study UK 1970s Prospective 18,403 Symptomatic and asymptomatic

analyzed separatelyBIRNH 1981-1984 Prospective 10 y 30,000 36% Rose questionnaire, no Q waves

on ECGHonolulu Oahu 1965-1968 12 y 8,006 ECG evidence of old MI, h/o chest pain

compatible with MI, coronary insufficiency or AP

British Regional Scotland, England, 1969-1973 then Prospective 9.5 y 9,917 NA Rose questionnaire + history then Wales 1978-1980 symptomatic and asymptomatic

analyzed separatelyItalian RIFLE North, South, and 1978-1987 Prospective 6 y NS 65%-70% Rose questionnaire then MD history

Central Italy excluded d. of CHD, h/o MI, h/oother c/v disease

Busselton Perth, Australia 1966-1972 Prospective 5 y 3,611 NAPooling Project US 1964-1972 Prospective 8 y 78% h/o AP/MI and ECG evidence of MI

regardless of historyMRFIT 22 US 1973-1976 Prospective 16 y NA NA excluded if “definite evidence of CHD”

centers + ECG exclusions Qs, BBBs , WPW, av block af/aflut, parox lachyarrhyth,

idioventr rythymFinnish social 12 areas of 1966-1972 Prospective 5-11 y 6,533 (men) 90% None

Finland 1973-1976 5,806 (women)Charleston Charleston 1960-1990 Prospective 30 y 84% None

County, USA

European Belgium, Denmark, Prospective 86%-95%Italy, Holland, USSR

Reykjavik study Reykjavik 1967 4-24 y 9,139 71% 2 groups analyzed: silent ST change(no AP b Rose questionnaire/MD exam, hosp records, no ECG

Manitoba Mostly Canadian 1946 Prospective 30 y evidence of MI) vs no CHDTunstall-Pedoe UK 1971-1973 4 y History of AP/MI, Rose questionnaireEvans County Evans County, Ga 1960-1980 Prospective 20 y NA 92% No major or mod Qs (MC 1.1,1.2),

no h/o AP/MISeven Countries Italy, USA,Japan, 1959-1989 Prospective 5 y 13,737 96% None

Yugoslavia, Finland, The Netherlands, Greece

Tervahauta Finland 1984-1989 Prospective 716NHANES 1 Representative 1971-1975 Retrospective 5-12 y None

samples of USRajala et al Tampere, Finland 1977-1983 Prospective 674 NoneCASTEL North Italy Prospective 7 y 3,088 73% None

NA, Not available; Y, yes; N, no.

review, a 30-year follow-up of the long-term association of ECG find-ings with disease endpoints was studied in a biracial cohort of blackand white men ages 35 to 74.

Studies in the ElderlyThe Cardiovascular Health Study.77 The Cardiovascular Health Study

is a population-based, longitudinal study of CHD and stroke in adultsaged 65 years and older. The objective was to identify factors related tothe onset and course of CHD and stroke in a population of older adults.More specifically, it aimed to confirm the importance of conventionalCVD risk factors in this age group, and to identify new risk factors, withspecial regard to those that may be protective and modifiable. The studyenrolled 1250 men and women in each of 4 communities situated in NorthCarolina, California, Maryland, and Pennsylvania, who were recruited


Totalanalyzed Male Female Random Age S-E status Race

17,633 9,643 7,990 N 40-64 Company employee White14,211 6,475 7,736 Y 20-80+ Middle class >99% white

5,209 2,336 2,873 N 30-62 NA “Primarily white”

18,403 18,403 N 40-64 Civil servants NA

11,302 5,208 4,746 Y 25-74 NA NA

7,682 7,682 N 45-68 NA Japanese ancestry

7,735 7,735 Y 40-59 Deliberate NAvariation

22,553 12,180 10,373 N 30-69 NA NA

3,611 1,715 1,896 N 21-70+ Rural NA12,381 N 30-59 Variation Variation

12,866 12,855 Y 35-57 NA NA

10,962 5,738 5,224 Some 30-59 Predominately subgroups industry workers

2,181 (data from 986 333 black/ 741 white/ Y 35-74 Black mainly low Black and white men presented only 653 white 454 black analyzed separately

4,522 N 40-59 Clerical workers

8,340 8,340 N 33-60 NA NA

3,983 3,983 15-64 Air Force8,228 8,228 40-59 Employed in industry

819 819 (308 black/ N 40-64 Black and white511 white) analyzed separately

12,078 12,078 Mostly not 40-59 Variable

697 697 0 Rural3,950 1,807 2,143 NA 25-74 Representative of

(1,609 white) (1,884 white) US pop559 99 460 N

2,254 818 1,436 N

from random samples of the Health Care Financing AdministrationMedicare eligibility lists. Extensive physical and laboratory evaluationswere performed at baseline to identify the presence and severity of CVDrisk factors. The first of two examination cycles began in June 1989.

The ECG and Survival in the Very Old.2,78 This study is one of the fewto look specifically at ECG abnormalities and their associated prognosticvalue in the very old. The ECGs of 559 persons, 83% of the total popula-tion 85 years of age or over in the city of Tampere, Finland, were evalu-ated according to the classification of the modified Minnesota code. A 5-year follow-up study evaluated the relative risks of the abnormalitiesdescribed. The importance of the study is emphasized by the finding thatmore than 96% of the subjects had ECG abnormalities.

Methodologic Issues

Demographics Summary demographic information on the major studies in this article

are summarized in Tables 2A, 2B, and 2C. As illustrated, the majority ofsubjects for whom ECG and prognostic data are available are male. Thisis partly due to two very large prevalence studies that screened young, fitmen in the US Air Force, accounting for 189,418 participants.79,80 Thesetwo studies have not been included in the box-plotted data to avoid bias-


TABLE 2B. Demographics and follow-up of studies: Morbidity studies.Morbidity Study Total Participationstudies Where When type approached rate Exclusions

Jamaica Lawrence Tavern, 1962-1967 Prospective 1,200 89% Rose questionnaire assessed Kingston “no exclusions for CV disease”

Cardiovascular North Carolina, Prevalence 5,201 Institutionalized, wheelchair-Health North California, only bound, Rx for cancer, 49 with

Maryland, Pittsburgh pacemakers, "no exclusions for CV disease"

Scottish Heart 22 Scottish districts 1984-1986

UF aircrew and ATCs UK 1977-1979 14,000


TABLE 2C. Demographics and follow-up of studies: Prevalence studies.Total

Prevalence Study duration Total Participationstudies Where When type of f/u approached rate Exclusions

Michigan Tecumseh, Mich 1959-1960 Observation 8,641 NA No exclusions for CV diseaseREBUS Stockholm 1969-1971 90%Rajala et al Tampere, Finland 1977-1983 Prospective 674 NoneStrong Heart Arizona, Dakota 1989-1992 71%, 54%,

Chicago Gas 1958 20 y 62%Chicago Electric 1957


ing the estimates with a heavy weighting from populations prescreened tobe eligible for military service.

�

D. McCall: The authors have provided an excellent resume of the many diverse epi-demiologic studies of cardiovascular disease in which ECGs were recorded. Clearly,these studies cover wide-ranging population bases and many nationalities. The authorsalso provide a concise description of these various epidemiologic studies, some ofwhich are known to us by name only. The explanation of these various studies com-bined in this way is extremely useful. It is clear that from the combined populations ofthese studies there is a huge database which defines not only the prevalence of ECGabnormalities in widely ranging population bases but also the prognostic significanceof electrocardiographic findings in the long-term follow-up of these studies.

�

With some exceptions,3,4,49,71 the ongoing epidemiologic trials now allinclude women in their cohorts. Although most studies included a wideage range of participants, most information is available about subjects inthe 40- to 60-year age bracket. Some studies stratified according toage.10,52,55,65,81,82 A small number of studies focused particularly on theelder population.77,78,83 One study took a young, fit population and fol-lowed them for more than 35 years.49 However, the largest portion ofdata available on young people are the prevalence data from US AirForce screening programs.79,80


Totalanalyzed Male Female Random Age S-E status Race

1,067 526 541 Y 35-64 Rural Predominately Jamaican

2,210 2,940 Y 65+ 94.7% white, 4.7% African-American

Y 40-59

14,000 14,000 0 N

Totalanalyzed Male Female Random S-E status Race

5,129 2,449 2,680 N NA NA2,458 1,197 1,261 Y

559 99 460 N4,544 1,845 2,699 N American Indian

As with much of the current literature, the data on ECG abnormalitiesis heavily biased toward a white population. In some studies, it was diffi-cult to obtain detailed information on the ethnicity of the participant pop-ulation. Fortunately, however, a small number of studies have focused ongroups with different racial backgrounds. The Strong Heart Study84

looked at American Indians, whereas the Evans County Study4 and the


TABLE 3. Details of ECG methods and coding of the major studies considered in this article.

12-lead Coding

Mortality studiesChicago industry Varied over years, MC/PP

mostly 12-leadCopenhagen city Y MC/PPFramingham 13-lead MC

Whitehall Study Limb leads only MCBIRNH Y MC/PPHonolulu 13-lead (V3R) MC/PP except LVH

British Regional 3-lead orthogonal Bespoke system with computer analysis related to MC(12-lead if problems)

Italian RIFLE Y MCBusselton NA (presumed) MCPooling Project Y Major/minor

MRFIT 12-lead + Frank X,Y, Z MC revised for serial ECG change

Finnish social Y MC

Charleston 8-lead MC/PPEuropean Y MC/rev MC

Reykjavik study Y MCManitoba YTunstall-Pedoe Y but only limb leads coded MCEvans County Y MC/PPSeven Countries Y MC

Tervahauta MCNHANES 1 YRajala et al Y Computer Novacoding and

Scandinavian modificationsCASTEL Y MC

Morbidity studiesJamaica Y Revised MCCardiovascular Health Y Major/minor acc to MCScottish Heart Y MC/PPUK aircrew and ATCs Y NAPrevalance studiesMichigan Y MCREBUS 11-lead Scandinavian modified MCRejala et al Y MC and Scandinavian

modificationsStrong Heart Y MC

Chicago GasChicago ElectricHiss and Lamb62

Averill and Lamb60 Y


Charleston Study3 compared abnormalities in black and white personsliving in the United States. The Jamaican Study85 assessed prevalenceamong blacks in Jamaica. Those of Japanese ancestry were examinedboth in Hawaii (the Honolulu Heart program71) and in Japan.1 Two stud-ies included pan-European cohorts.1,27 It is clear that, although the racial


By whom Independent assessment Categories

1 cardiologist N Major/minor PP

2 nurses/lab techs Y Major/minor PPLead author 400 were cross-hatched N

by H. Blackburn2 technicians Y N1 physician NA Major/minor PP

Univ of Minnesota By Honolulu Heart Major/minor PPProgram physicians

Computer Only if technical Nproblems

3 trained coders Y 5 categories (see text)5 trained coders Y No evidence IHD,

Physicians/technicians trained Variable suspect IHD, probable IHDby Henry Blackburn Major/minor/no abnormality

3 trained coders Y Evolving Q, evolving ST

2 technicians Y Major/minor PP merged into “major”: cardiologist identified

4 specific diagnoses (LAD, LVH, early repol, NS ST/T)

1 cardiologist NANA for individual countries Y

All ECGs recoded by 5 centralNA NA MC only

2 coders YSingle coder N Major/minor PP

2-3 medical readers at Univ of Minnesota

1 MD author and 1 coder Y

2 internists Y Major and minor (not Pooling Project criteria)

Single “expert” NA

1 coder NA N

2 coders Y Major/minor PP3 physicians NA NA

NA N N

2 internists Y Major and minor (not Pooling Project criteria)

Staff cardiologist, 3 other cardiologists,

Univ of Minn coding center

backgrounds of participants heavily favors white persons, there is at leastsome information from each of the five continents.

The socioeconomic status of participants was not always well docu-mented. Several studies recruited from particular sections of industry,7

business,67 or even the British civil service.27 Some articles specifiedwhether the community was predominantly rural.81,86 However, manystudies provided very little information at all.

ExclusionsIn assessing the value of the baseline ECG as a screening test, we were

particularly interested in studies that excluded or analyzed separatelypatients with a known history of CVD, or a current history of undiagnoseddisease. There were a number of different approaches to this. Some studiesmade no exclusions.3,77,78,83,85 The Manitoba Study87 followed an initiallyyoung and fit population over many years as CVD developed in them. Somestudies made exclusions on the basis of ECG findings alone (evidence ofMI7). The pooling project excluded all those with major Q waves.47 How-ever, many more excluded participants on the basis of more than 1 criterion,including physician history of MI or angina pectoris, medical examination,and ECG. Many studies used the Rose questionnaire (discussed below) toassess current symptoms. Three studies analyzed symptomatic and asymp-tomatic participants separately,10,52,67 although one did not present the sepa-rate data.52 Certainly cohorts, including subjects with symptomatic heart dis-ease, would have a higher prevalence of ECG abnormalities than cohortswho were excluded, and the exclusion criteria would alter these differences.

Random SamplingThe technique of random sampling is necessary to draw conclusions

based on probability estimates from a sampled population to the whole pop-ulation. Only certain studies in this article used random sampling.10,55,64

Two points are relevant here. First, at the time when many of the large stud-ies were initiated, the importance of random sampling was not yet fullyunderstood and the practice was not routine in clinical and epidemiologictrials. Second, in many studies it was not the intention of the study orga-nizers to “sample” a population to extrapolate to the rest of that population,but rather to describe the whole of one representative population to extrap-olate to surrounding (similar) populations. This feature makes analysis ofthe populations under scrutiny particularly important. Specifically, it raisesquestions over the demographic make-up of the study participants and theoverall participation rates for the studies. For many studies, the participa-tion rate is not stated explicitly, but can be calculated or inferred from the


text. Most of the participation rates were greater than 70%, with the excep-tion of the Strong Heart Study84 (54% to 71%), the Belgian Study64 (36%)and the Italian pooling project.59 In some studies, participation rate wasgreater than 90%.4,88

Epidemiologic ToolsTable 3 details the methods used for obtaining ECGs and the subsequent

coding applied for the main studies considered in this article.ECG classification systems. The “Minnesota code” was developed by

the pioneering cardiovascular epidemiologists of the 1960s89 as a tool toaid consistency and comparison in the use of the ECG in large clinicalstudies. The rules for its application were more closely defined in 1968,90

but it was criticized by one of its originators91 and a modified version waspublished in 1982. Despite the initial shortcomings, it rapidly became thede facto standard for the accurate and reproducible measurement of ECGabnormalities in epidemiologic trials. Indeed, it was used in some form inmost of the major studies in this article.

Perhaps the biggest contribution of the Minnesota code to mainstreamcardiology was its clarity and definitive guidance for ECG wave labelingand measurement. The classification itself (Appendix 2) is hierarchicallybased and represented by 3 numbers separated by dashes. The first num-ber refers to the broad grouping (eg, Q waves = 1-x-x), and the secondand third numbers indicate severity. To be coded, the abnormality has tobe present in the majority of complexes. Originally, there were 4 levels of


TABLE 4. The Pooling Project classification. Note the absence of major Q waves from the Majorclassification. Subjects with abnormality were excluded because they were assumed to have heart disease.

ECG findings (Minnesota code)

Major abnormalities • Complete or second-degree atrioventricular block (6.1-6.2)• Complete left or right bundle branch block, or intraventricular

block (7.1, 7.2, 7.4)• Complete left or right bundle branch block or intraventricular block

(7.1, 7.2, 7.4)• Atrial fibrillation, atrial flutter (8.3)• Frequent premature beats (8.1)• Significant ST segment depression (4.1-4.2)• T wave deep inversion (5.1-5.2)

Minor abnormalities • Q waves, borderline (1.3)• ST segment depression, borderline (4.3)• Moderate T wave inversion (5.3)• First-degree AV block (6.3)• QRS, high voltage (3.1, 3.2)• Axis deviation (2.1, 2.2)


TABLE 5. Details of statistical techniques and endpoints for the major studies considered in this article.Male/

All-cause CHD CV Non-CV Sudden femalemortality mortality mortality mortality death Morbidity separate? By age group?

Mortality StudiesChicago industry Y Y Y Y Y Not presented

Copenhagen City Y Y Not presentedFramingham Y Y Noncoronary Y Y Not presentedWhitehall Study Y Male only Not presentedBIRNH Y Y Y Y Not presented

Honolulu Y Nonfatal MI, AP, Male only Not presentedtotal CHD

British Regional Y Total CHD

Italian RIFLE Y Y Y All CV disease, CHD

Busselton N Y YPooling Project AP, non fatal/fatal NA Y

CVA, intermittentclaudication

MRFIT Y Y Y N NA N

Finnish social Y Y Y

Charleston Y Y NA N

European YReykjavik study Y AP, MI (acc to NA N

- criteria of MONICA project)

Manitoba Y Y N

Tunstall-Pedoe Sudden CHD

Evans County Y Y Y N NA

Seven Countries Y Y Y Y

Tervahauta Y Nonfatal MI

NHANES I Y

Rajala et al Y Y NCASTEL Y Y Y N

Morbidity StudiesJamaicaThe Cardiovascular Hypertension, CHD, Y Y

Health Study small artery disease, cardiomyopathy

Scottish Heart As left Y N

UK aircrew & ATCs


Concludes that ECG Adjusted for Origin of morbidity/ is a worthwhile

Analysis used covariables mortality figures screening tool?

Cox regression model Age, DBP, chol, cig/day, Blindly from death Independent prognostic dm, anti-BP meds certificates indicator in those

Log rank Not calculated Population register with heart diseaseRRs and SMRs N Hospital records Y

NA Age Registrar General’s office NACox regression model Age and any other Death certificates/ Better than risk factors

abnormality other than family doctorthe one studied

Chi square (incidence Age Panel of doctors looked NAof CHD men with at hospital records,× men without autopsy reports, and × men with normal ECG) death certificates

Multiple regression Age, other ECG abnor- Registrar General’s office Only in those with for RR Chi square for malities and sympto- symptomatic CHDprevalence in face of ECG matic coronary diseaseabnormality and without

Multiple regression for RR Age, SBP, chol, cigs, BMI Single trained coderentered as covariates

RRs onlyLogistic regression BP, smoking, chol, wt Variable

Cox Mantel statistic + Interim clinical MI, age Death certificatesproportion hazards chol, DBP, cigsregression correlation, Central statistical office Maentel-Haentzel, F test of Finland (8th ICD)

Cox proportional hazards Age, race (multivariate ICD VIII-IXanalysis included age,

SBP, chol, BMI, dm

Cox regression >14 cofactors listed Death certificates Silent ST changes are in article and autopsy reports predictors of reduced

(all of the latter were survivalreviewed-55% of cases)

When any study participanthad a clinical event, the attending physician wasasked for a detailed report

“Local sources” and AgainstRegistry Office

Cox regression Age, SBP,chol, current Death certificate ICDand past smoking, Quetelet’s index

Chi square, logistic Hospital records reviewed for regression and all who reported MI, and for all correlation coefficient whose d/c code suggested it.

MONICA criteria used, interim check-up in the field once or twice yearly.

Chi square and Death certificates and In the elderly a reliable logistic regression hospital records history may be less likely

and that the ECG could bea useful indicator of silentdisease

ANCOVA, Cox Death certificatesproportional hazards

Sex, age NACox proportional hazard Sex Hospital files, Registrar’s office

NA

Patient's self-reporting of physician diagnosis for MI, angina, hypertension,

CABG, PTCA

severity (eg, 3-1 to 3-4), although later the ST group was extended to 6.The system provided much needed standardization and solved severalproblems particularly in relation to the consistency of measurementsexacerbated by variations in tracing thickness. Rautaharju has dealt com-prehensively with the issues surrounding coding reproducibility.

One criticism of the Minnesota code was its limited ability to deal withserial changes. It was clear that small changes in serial ECGs could resultin falsely large code changes in independently coded tracings. Someaccount was taken of this in the 1982 Minnesota code revision, and morerecently, some researchers, in collaboration with one of the original Min-nesota code authors, have suggested a further modification to address thisproblem.69

Computerization has solved many of the problems that the Minnesotacode was designed to address.92 Although the early systems were con-fronted with lack of correlation with human coding prevalence rates(related, among other things to “tracing width” issues), modern systemsthrough their pervasiveness can make accurate and reproducible mea-surements without such problems. Early systems made use of the 3orthogonal lead ECG system (also known as “Frank XYZ”) for computeranalysis. This system makes use of signals from only 3 leads to constructa 3-dimensional electrical image that has been shown to be equivalent tothe 12-lead system.10,93,94 Each can be calculated from the other, althoughthe algorithms for the 12-lead to XYZ conversion are more accurate.Despite the benefits of the more straightforward Frank system for epi-demiologic trials, current practice, in tandem with clinical practice,focuses on the 12-lead ECG (with the notable exception of the BritishRegional Study10).

The most commonly used computer coding system in epidemiologictrials has been the NOVACODE system. NOVACODE is a hierarchicalclassification system in which algorithms for visual and computer cod-ing of serial ECGs quantify changes in critical waveform patterns on acontinuous scale by determining, for each ECG coded, a Q-QS score,ST depression score, ST elevation score, and T-wave score, each rang-ing from 0 to 50. Rautaharju has listed the current epidemiologic stud-ies making use of this tool.19 The Minnesota Code itself has also beenimplemented in a computer system. The MEANS system from TheNetherlands operates on a standard personal computer under the Win-dows operating system.95,96

The pooling project categories. The US pooling project categorizedECG findings into major and minor groupings (Table 4). Because someauthors have found this useful in achieving statistical significance


where the individual ECG abnormalities fail to do so, it has intuitiveappeal for epidemiology. However, the clinical use of this simpledichotomization is uncertain and, remarkably, the final report of thepooling project47 does not make it clear why these particular abnormal-ities were chosen, or indeed why they opted to categorize at all. Despitethis, the categorization proved popular and was adopted in numerouslarge scale trials.3,4,7,55,63,97 It is important to note that in the pooling pro-ject, the presence of major Q waves on the ECG was an exclusion crite-rion, meaning that those studies, which used the pooling project catego-rization (with the exception of the Cardiovascular Health Study that useda modified version), did not consider major Q waves in their analyses.

The Rose questionnaire.98 The Rose questionnaire, created by Geof-frey Rose at the London School of Hygiene in 1962, answered a needfor a standard, unbiased assessment of chest pain that could be used inepidemiological trials (Appendix 2). It has been widely used and wellvalidated. The Evans county study99 reported on the variability ofresponse to questionnaires administered 1 year apart and concluded thatthe variability was largely due to the natural history of the disease. Thequestionnaire was found to have 81% sensitivity and 97% specificitycompared with clinical judgement. Another study100 found that 50%more cases of angina were identified by physicians than by the ques-


Fig 1. Prevalence of LVH defined using high R wave (Minnesota code 3.1) criterion. Displays are boxplots representing interquartile range and nearest upper and lower adjacent values. Horizontal line inmiddle of box is median. Note wide range extending to include high values in young age group, whichreduces to minimum at age range 40 to 49 before increasing again. This may represent the young andfit becoming inactive before disease increases ventricle again. Outliers are Moscow cohort of Europeanstudy, and 2 Finnish groups.

tionnaire. However, in this population of over 3700 postinfarctionpatients, neither method was significantly predictive of recurrent nonfa-tal MI over 25 months of follow-up. The only study to suggest cautionin the use of the questionnaire was presented by Wilcosky.101 In thisstudy, major and minor resting ECG abnormalities and self-reported his-tory of a heart attack were not significantly associated with Rose anginaamong young participants of either gender. They did, however, show pos-itive associations among older participants.

�

D. McCall: The Rose questionnaire has been widely used in many epidemiologicstudies to provide an objective assessment of chest pain. It has been well vali-dated and, as the authors point out, it has a high sensitivity and specificity for thediagnosis of angina pectoris. It can, however, be misleading. Approximately 5years ago, a physician was seen at our institution who had the history of exer-tional left-arm pain. For the preceding 2 years he had repeatedly administered theRose questionnaire to himself. Since the questionnaire deals only with chest pain,he had convinced himself that he did not have ischemic heart disease. In thiscase, although it must be remembered that the Rose questionnaire was neverdesigned for self-administration, the physician was able to maintain his denial ofhis symptoms. He was subsequently found to have 3-vessel coronary artery dis-


Fig 2. Risk of mortality after ST depression inclusive–LVH compared with mortality after overt CHD in formof MI or angina. Framingham subjects were aged 30 to 62. Adapted from Kannel et al.6

ease that required aortocoronary bypass surgery. Therefore, although this ques-tionnaire is an extremely useful tool in epidemiologic studies, care must be takenin its application and clinical judgment must be used.

�

Length of Follow-upThere was some variation in the length of follow-up. This is illustrated

in Table 2. Of course, many studies are on-going, and continue to presentfindings. Some studies undertook screening, then followed up with nomore than a vital status (alive or dead) check. It should be noted that vitalstatus has been determined in many different ways ranging from directlycontacting participants to using national death registries. In many waysthese studies have most relevance for our primary question. Other stud-ies, however, such as Framingham and Manitoba, saw patients more reg-ularly (eg, every 2 years). These studies give more complete informationin relation to the incidence and natural history of CVD.

Endpoints Although we attached the most significance to studies that use random

sampling and hard endpoints, we could not present a complete picturewere we to discount several studies that did not meet our stringent crite-


Fig 3. Prevalence of major and minor (where marked) Q waves in various white populations. Displaysare box plots representing interquartile range and nearest upper and lower adjacent values. Horizontalline in middle of box is median. Prevalence clearly rises with age in both sexes but note that female val-ues seem to lag approximately 10 years behind male values in line with current views on epidemiologyof heart disease in these populations.

ria but that, nevertheless, provide important information with regard toprevalence and morbidity. Of the studies that used hard endpoints, severalused all cause mortality.3,4,7,10,49,55,59,65,69,72,78,83,102,103 Others looked atCHD mortality instead of27,67,82 or in addition3,4,7,59,69,102 to this. Most of


Fig 5. Prevalence of ST elevation in various white populations. Displays are box plots representinginterquartile range and nearest upper and lower adjacent values. Horizontal line in middle of box ismedian. Note wide range and higher prevalence in younger population. This may relate to early repo-larization secondary to physical fitness.

Fig 4. Prevalence of major and minor ST depression in various populations. Displays are box plots rep-resenting interquartile range and nearest upper and lower adjacent values. Horizontal line in middle ofbox is median. Again, prevalence clearly rises with age.

the studies used standard International Classification of Disease (ICD)criteria for defining death, and many researched hospital notes andautopsy reports as well. Some studies used the broader classification ofcardiovascular mortality.4,7,52,59,65,69,83 Some looked specifically at sudden


Fig 6. Prevalence of LBBB in various populations. Displays are box plots representing interquartilerange and nearest upper and lower adjacent values. Horizontal line in middle of box is median.Note prevalence of <0.01 in youngest groups. Explanation for high prevalence in females >70 yearsis unexplained.

Fig 7. Prevalence of RBBB in various populations. Displays are box plots representing interquartile rangeand nearest upper and lower adjacent values. Horizontal line in middle of box is median. Note overalllow prevalences and reverse pattern male-female compared with LBBB group.

death.14,31,47,62,104 However, it should be noted that the definitions of “sud-den” within these articles vary greatly. For example, in the Framinghamstudy,31,33 sudden CHD death was defined as “death in a matter of min-utes . . .attributed to no other causes by the physician who completed thedeath certificate,” whereas in the UK Heart Disease Prevention Project


Fig 8. Prevalence of AF in various populations. Displays are box plots representing interquartile rangeand nearest upper and lower adjacent values. Horizontal line in middle of box is median. Note large risein 70+ population.

Fig 9. Box plots of various ECG abnormalities in age range 50 to 59 to demonstrate comparative preva-lence. Boxes represent interquartile range and nearest upper and lower adjacent values. Horizontal line inmiddle of box is median. Wide variation in prevalence of different abnormalities is noted.

data, analyzed by Tunstall-Pedoe,14 the definition was “death attributedto coronary heart disease occurring definitely or possibly within 24 hoursof the onset of acute symptoms.” The US Pooling Project47 defined sud-den death as “when a man in apparent good health was observed to diewithin 3 hours of onset of symptoms with no history that violence or acci-dent played any role in the fatal outcome.” It is clear that the results fromthese studies cannot be directly compared.

In addition to mortality studies, we have considered a smaller numberof morbidity studies where these were of particular significance.77,97,105

To further inform the prevalence data, we have included several observa-tional studies.79,80,84,88

Results and DiscussionAs suggested previously, a critical factor in the adoption of any screen-

ing test is the prevalence of the detectable abnormality in the asympto-matic, apparently healthy population. There were few studies that fullypresented data on asymptomatic participants.4,10,14,47,59,64,67 In addition,there was some variation in the exclusion criteria for cardiac disease(symptoms, etc) in those studies that did. However, despite the wideinterpopulation variation in prevalence, and despite some studiesfinding no intrapopulation difference in prevalence of ECG abnor-


Fig 10. Prevalence of major ECG abnormalities as defined by Pooling Project in those studies that pre-sented age-pooled data. Figure clearly demonstrates higher prevalence of ECG abnormalities in blackpopulations. Higher value for major abnormalities in Chicago study women is a finding neither we norstudy authors can explain.

malities between those with a diagnosis of heart disease and thosewithout,7 findings from 18,403 British men in the Whitehall Studysuggest caution in the combination of these 2 groups for analyticalpurposes. Figures 1 and 3 to 11 illustrate the variation in prevalence byage for the common ECG abnormalities for all major studies in thisreview (including those with limited or no exclusion policies), whereasTable 8 shows actual prevalences and weighted means for only those withstringent exclusion criteria for those with previous cardiac disease. Dataon relative risk are included in Tables 9 through 14.

Left Ventricular HypertrophyElectrocardiographic left ventricular hypertrophy (LVH) has been rec-

ognized as a risk factor for cardiac death for some time. Most of the sem-inal data comes from the Framingham study, but as these researchers havepointed out, assessment of the actual impact of LVH has been confoundedby the use of different definitions.


Fig 11. Prevalence of minor ECG abnormalities as defined by Pooling Project in those studies thatpresented age-pooled data.

Definitions. There are essentially 3 modalities widely available for theestimation of LVH. Radiologic techniques have been used for sometime,107 either to determine cardiothoracic ratio or in more sophisticatedestimation of heart volume. However, despite an association withincreased risk for cardiac death,108,109 these variables poorly correlatewith LVH determined by other means.108,110

Historically, the most commonly used electrocardiographic definitionsof LVH have been the voltage criteria of Sokolow and Lyon,111 that ofGubner and Ungerleider,112 and that of Casale et al113 (Table 6). Computersystems have made use of the point score of Romhilt and Estes.114,115

However, epidemiologic trials have demonstrated that these criteria aredependent on the prevalence and severity of LVH in the population in


TABLE 6. Definitions of left ventricular hypertrophy referred to in the text

Minnesota code 3.1Minnesota code 3.3Sokolow-Lyon voltage SV1 + RV5/6 ≥3.5 mVCornell voltage RavL + SV3 ≥2.8 mV (male) ≥2.0 (female)Gubner and Ungerleider RI + SIIICornell product (RavL + SV3) × QRS durationDe Vries equation LV mass = –137.5 –13.1*sex) + (1.1*age) + (101.4*BSA) +

(0.43*PV1dur) + (28.7*SV1) + (26.5*SV4)Wolf equation R (aVL), T (V6), and S (V1) for men and R (aVL), T (V6), and

S (I) for womenPerugia score Positivity of at least 1 of the following: 1) Sv3 + RaVL >2.4 mV (men)

or >2.0 mV (women); 2) a typical strain pattern; 3) a Romhilt-Estes point score ≥5

Framingham score R in lead I + S lead II >2.5 mV orS in V1/2 + R in V5/6 >3.5 mV orS in V1-3 >2.5mV + R in V4-6 >2.5 mV and>0.1 mV ST segment depression + T inversion in V2-6

Romhilt- Estes point score • Amplitude of QRS(3), ST-T strain pattern (3), LAE(3), LAD(2),QRS duration >0.09 (1), intrinsicoid QRS deflection of >0.05 s in V5 or V6 (1).

• ≥5 points – definite LVH• ≥4 points – probable LVH

TABLE 7. Comparison of sensitivity and specificity of the Perugia score and the Wolf multivariate equa-tion for prediction of echocardiographic LVH

Sensitivity Specificity

Men Women Men Women

Perugia score128 39% 29% 94% 93%Wolf equation121 54% 63% 95% 93%

which they developed, suggesting limited portability to other popula-tions.116

More recent studies have begun to make use of echocardiographicestimates of LV mass117 and these measurements have been thought bymany to be the “gold standard” noninvasive measurement.118 As such,there have been many attempts at improving the predictive value of theECG by relating the 12-lead ECG to echocardiographic estimates of LVmass.108,118,119 Casale and colleagues118 found that augmenting the Cornellcriterion with information from the T wave in V1 improved the perfor-mance of the ECG in estimation of LV mass. Okin119,120 has suggested theuse of a time-voltage criterion for identification of LVH. However, takingaccount of sex, age, body surface area, the duration of the terminal P in V1,and the S voltage in V1 and V4 has been demonstrated to explain more ofthe variance than this model,121 than a linear regression model of Wolf,122

and significantly more than standard criteria. Rautaharju has made thepoint that dichotomized measurements of LVH (present/not) will by defi-nition only identify those at the extreme end of the spectrum of cardiacenlargement and limit the extrapolation of risk estimates made on this lowprevalence population to the more general population.108 In its place, he


TABLE 8. Prevalence estimates classified by age for only those studies that excluded symptomatic patientsand those with a history of CHD. The Framingham data are used in the Pooling Project.

Minor Q waves Tall

Follow-up (MC 1.3) R waves

Study No. (y) 40-49 50-59 40-49 50-59

Albany 2,394 8 1.2 0.6 3.6 1.2Chicago People Gas 1,264 8 1.4 1.0 0.2 1.3Chicago Western Electric 1,981 8 1.5 0.5 0.9 0.8LA Heart 755 8 0.5 0.3 2.4 3.1Minneapolis 284 8 1.2 0.0 3.6 5.1US railroad 2,425 8 0.4 1.3 1.8 3.3Framingham 1,375 8 0.1 0.3 1.4 3.4Italian RIFLE 7,846 6 2.3 6.1Michigan 691 8 0.2 0.4 3.4 3.9Whitehall Study 16,016 5 1.1 1.4 0.7 0.6Weighted mean 1.0 1.1 1.5 2.5British Regional‡ 7,727 9.5 1.1 2.8Evans County‡ 511 20 12.0 7.4BIRNH‡ 5,208 10 — 0.8†Tunstall-Pedoe‡ 8,228 4 1.02 2.5*

*All Q waves coded together.†High R waves + ST abnormality.‡Studies provided only combined data for 40 to 59 years.

suggests a continuous scale based on echocardiographic LV mass esti-mates. This technique also results in an improved relation to mortality.

The importance of stratifying ECG estimates has been emphasized byCasale.123 As previously suggested, when stratified by age and sex, thesensitivity and specificity of predictions derived from echocardiographicLV mass improves. Other studies have demonstrated the importance ofobesity. Okin et al124 examined the test accuracy of the criteria for LVHin relation to the body mass index (BMI) in 250 patients and confirmedthe need to consider BMI in LVH estimates. This was reinforced by find-ings from the Framingham study where incorporation of obesity and ageinto ECG algorithms consistently improved their performance in the detectionof hypertrophy.125 More recently, Rautaharju, using data from the thirdNational Health and Nutrition Survey, and the Atherosclerosis Research inCommunities Study, demonstrated that Sokolow-Lyon voltages decreased andCornell voltages increased significantly with increasing breast tissue.126 How-ever, the overall conclusion was that these effects were small, and that whenentered into a multivariate equation, chest size was the dominant variable.

One study found a poor correlation overall with ECG and echocardio-graphic criteria. Crow et al127 studied the association between 8 ECG crite-ria and echocardiographic LV mass estimates in men and women with mild


LBBB RBBB Atrial fibrillation ST depression

40-49 50-59 40-49 50-59 40-49 50-59 40-49 50-59

0.2 0.1 0.3 0.1 0.1 0.0 0.8 0.90.2 0.3 0.3 1.3 0.0 0.7 1.0 2.50.1 0.7 0.5 0.8 0.1 0.4 0.6 1.30.3 0.5 0.3 0.8 0.0 1.0 1.3 2.41.2 0.9 0.0 0.0 0.0 0.0 0.0 2.60.1 0.4 0.2 1.4 0.0 0.6 0.5 3.40.4 0.3 0.4 0.5 0.5 0.7 1.3 3.4

0.2 1.1 0.0 0.4 0.0 0.0 2.9 2.81.0 1.6 0.2 1.5 0.6 1.80.6 1.2 0.3 0.8 0.1 1.1 0.7 2.0

0.2 0.8 0.7 —0.7 1.8 0.4 2.9— — — 1.60.5 0.9 0.3 2.3

hypertension. ECGs and echocardiograms were recorded at baseline, 3months, and annually for 4 years. The ECGs were computer processed todefine 8 different criteria, and the researchers found a poor correlationbetween ECG and the echocardiogram. However, this result may have beenconfounded by poorly reproducible echocardiographic measurements.

Although the use of echocardiographic LV mass as a gold standard torefine ECG estimates is valid, perhaps the more important relation forECG measurements is that with prognosis. In a recent prognostic study,128

the value of ECG criteria for LVH in patients with essential hypertensionwas evaluated. Six methods were compared. A total of 1717 white hyper-tensive subjects were prospectively followed for a mean of 3.3 years. Atentry, the prevalence of LVH was highest with the Perugia score129 (18%)and lowest with the Framingham score (4%). During follow-up, there were159 major cardiovascular events (33 fatal). The event rate was higher inthe subjects with than in those without LVH. The Perugia score best pre-dicted cardiovascular events, accounting for 16% of all cases, whereas theothers only accounted for 7%. LVH diagnosed by the Perugia score wasalso associated with an increased risk of cardiovascular mortality (4×) andoutperformed the classic LVH criteria. Notably, the Perugia score exhibitslower sensitivity ratings when related to echocardiographic LV mass com-pared with at least 1 multivariate continuous model (Table 7).

Despite these more recent improvements in the classification of LVHfrom the ECG, most of the studies reported in this article, antedating thesemodifications, used either the simple high R wave criterion of MinnesotaCode 3.1, or the more inclusive criterion that includes ST depression(code 4.1-4.4).


TABLE 9. Risk ratios from studies assessing the prognostic impact of ECG-LVH defined either with Min-nesota Code 3.1 (high R wave LVH) or with the ST depression inclusive criterion. Note that risk ratios arehigher for the latter group.

High R waves LVH + ST-T

Follow-up(MC 3.1) abnormality

Study No. (y) AC CHD CVD SD AC CHD CVD SD

Italian RIFLE 12,180 6 1.3 1.8 2.0 3.4 6.5 6.3Copenhagen 6,475 4.2 1.2Manitoba 3,983 30 1.3 4.0British Regional 7,735 9.5 2.7BIRNH 11,302 10 1.5 1.5 2.6Honolulu Heart 7,682 12 2.8 11.4Charleston 653 30 5.5 5.6Tunstall-Pedoe 8,228 4 1.6Tervahauta 697 5 1.4Framingham 2,336 20 12.7 4.4 12.2 3.4

Prevalence of ECG LVH. The prevalence estimates of ECG LVH fromthe studies considered in this article demonstrate a wide variation. Boxplots demonstrating the median, interquartile range, and upper and loweradjacent values for LVH defined as Minnesota Code 3.1 (high R wave)are displayed in Figure 1. All studies showed increases in prevalence ofECG LVH with increasing age. The wider variation with extension tohigh values that is seen in the younger men can be readily explained byphysical fitness. We could hypothesize that older men are less physicallyactive and have correspondingly lower voltage R waves. Then, with fur-ther increasing age in both men and women, pathologic processes set in,and the amplitude of the R wave increases again. In fact, recent studies inboth humans and animals have emphasized gender differences in theresponse to pressure overload. Although degree of hypertrophy seems tobe similar,130,131 male animals exhibit earlier transition to heart failure,with cavity dilatation, loss of concentric remodeling, and diastolic dys-function. This falls into line with human echocardiography studies, whichshow that for obesity and hypertension, relative increase in left ventricu-lar mass is similar132 among men and women, but that overall, other fac-tors, including risk,133 are not.134

The most startling finding from these studies is the high prevalencein the Finnish populations assessed both as part of the Finnish cohortof the Seven Countries Study and the Finnish Social Insurance Insti-tution Study (outliers). For the 50 to 59 year old men, the Finnishcohort of the Seven Countries Study had a mean prevalence of LVH(MC 3-1) of 19%; the Finnish Social Insurance Study measured aneven larger 27.3%; and this relative high prevalence even extended tofemales (mean 13.5%). The figure demonstrates how far these pointsoutlie. Of all the other countries drawing on predominant white popu-


TABLE 10. Risk ratios from studies assessing the prognostic impact of Q waves (major and minor). Notethe wide variation in calculated risk.

Follow-up All Q waves

Study No. (y) AC CHD CVD SD

Finnish Social 5,738 5-11 19.5Framingham 2,336 6 1.8 3.7 5.3Italian RIFLE 12,180 6 1.8 1.6 2.8Copenhagen 6,475 4.2 2.5Busselton 2,119 13 3.7British Regional 7,735 9.5 6.8Tunstall-Pedoe 8,228 4 4Tervahauta 697 5 1.5

AC, All cases; SD, sudden death.

lation, only Copenhagen55 (12%) and the Moscow cohort of the Euro-pean study (18.7%) came close to these estimates. Estimates were alsohigh in the black population, both from the Jamaica study (29.9% inthe 40 to 49 age group) and 19.8% in Evans county. (One study hasdemonstrated a similar predictive value of the ECG for estimation ofechocardiography-LV mass in blacks as for whites76.) The wide vari-ation is demonstrated by studies such as the Whitehall study, whichfound a prevalence of 0.63% in British civil servants aged 50 to 59,and the age-pooled, white male cohort of the Charleston Study3 (0.3%).These wide variations require some explanation that is not apparent at thistime.

A clearer pattern is the lower prevalence of ECG-LVH when the crite-ria requires ST depression. The Belgian study found the age pooledprevalence of LVH by this definition to be 0.8% male and 0.5% female.64

The Honolulu Heart Program found the prevalence of high R wave-LVHto be 5.4% compared with the prevalence of 0.6% when both high Rwaves and ST-T depression is used.71 Although the Charleston Studyfound a low prevalence of ST depression inclusive LVH (0.9%) in theirage-pooled, male-only sample, they in fact found LVH by high R wavecriterion to be only 0.3%. This contrasted with the findings in the blackpopulation in which they found the prevalence of LVH by these criteriato be 7.8%. This was mirrored in the high R wave criteria of the Evanscounty study4 that found the prevalence in blacks to be more than doublethat in whites (19.8% compared with 7.4%).

In conclusion, it is not entirely clear why there has been such a widevariety of LVH prevalence estimates from ECGs carried out in different


TABLE 11. Risk ratios for studies assessing the prognostic impact of ST depression. Those studies thatconsidered major and minor ST depression separately are also displayed.

Major ST Minor ST Pooled STdepression depression depression

Follow-up(MC 4.1-4.2) (MC 4.3) (MC 4.1-4.3)

Study No. (y) AC CHD CVD ACCHD CVD AC CHD CVD SD

Finnish Social 5,738 5 11.4 6Framingham 2,336 6 2.3Copenhagen City Heart 6,475 4.2 1.9Busselton 2,119 13 2.1BIRNH 11,302 10 2.6 4.0 4.6Honolulu Heart 7,682 12 6.2 3.1Tunstall-Pedoe 8,228 4 3.5Tervahauta 697 5 2.7 1.9

Major ST depression relates to Minnesota Code 4-1, 4-2. Minor ST depression relates to MinnesotaCode 4-3, 4-4.

populations using the same quite stringent criteria. Many studies wererigorous in their training of coders and use of independent assessments.In particular, the Finnish Social Insurance Study used 2 independentcoders, and all ECGs from the Seven Countries participating centers wereread by 2 or 3 independent medical readers at the University of Min-nesota. Some important points can be made. First, it seems likely that atleast some of the differences noted are real. It would not seem unreason-able to conclude on the basis of this and previously mentioned data thatblack populations and the Finnish population have a truly higher mean Rwave amplitude than many others. As discussed previously, this may notnecessarily imply a greater prevalence of echocardiographic LVH,although comparison of the relative weight and skin fold thickness mea-surements from the Seven Countries Study suggests no differencebetween the Finnish population and the others (Finnish relative weight:92.5%, others: 92%; Finnish skin fold: 15, others: 17.7). In addition, Fin-land did not have the highest rates of hypertension, although the CHDdeath rate was higher than all other countries. No definitive conclusioncan be drawn. It may be that adoption of some of the new criteria detailedin the Definitions section may lead to more consistent coding in thefuture, but the important point will be the link between definitions andmortality.

Although these studies provide cross-sectional prevalence estimates,studies such as Framingham are able to provide incidence data. Accord-ing to these figures, ECG LVH increases with age with a slight male pre-dominance, and 1 in 10 persons aged 30 to 62 can expect it to developwithin 12 years.102 At any age, cardiac enlargement by radiograph is twiceas prevalent as ECG LVH, and in only 16% of those with x-ray evidenceof cardiac enlargement, does ECG LVH subsequently develop.

Prediction of risk with ECG LVH. The important point in relation tothe question of screening must be the relationship of the finding of LVH


TABLE 12. Risk ratio of LBBB, RBBB and atrial fibrillation.

Atrial

Follow-upLBBB RBBB fibrillation

Study No. (y) AC CHD CVD SD AC CHD CVD AC CVD

Finnish social 5738 5 2.7 4.1 1.6Copenhagen 6475 4.2 4.4 1.5Manitoba 3983 30 1.5 3.8 10.0 1.0 2.6 1.5 4.8British Regional 7735 9.5 4.5 0.5 4.7Tervahauta 697 5 1.3 1.8 1.8Framingham 2336 18-40 3.0 2.4

AC, All cases.

to mortality, and the possibility of reversing the risk with appropriateintervention. In these terms, the Framingham study has provided the sem-inal data.36-38,106 Many factors are known to contribute to LVH, includingage, hypertension, obesity, stature, and glucose intolerance.38 It has beenclear for some time that ECG ST depression inclusive–LVH has a signif-icantly higher risk than high R wave LVH alone. The Framingham datasuggests that the 5-year mortality for the former condition is 33% for menand 21% for women. Further, the risk of sudden death is comparable tothat of CHD or cardiac failure. To put this in perspective, the mortalityrisk of ST depression inclusive-LVH is higher than that after overt CHDin the form of MI or angina106 (see Fig 2). In comparison, when adjustedfor hypertension, the risk associated with high R wave–LVH is virtuallynil.106 In one sense, this is not surprising, because resting ST depressionhas been associated with latent CHD in asymptomatic men.135

An important point in relation to the appeal of Rautaharju to expressLVH estimates as a continuous variable is that, in the Framingham data,cardiovascular events occurred incrementally in relation to left ventricu-lar mass.36 Furthermore, anatomic LVH (determined either by echocar-diography or chest radiograph) was shown to contribute independently to


TABLE 13. Prevalence data for the very old expressed as a percentage.

Geneva166 Tecumseh59 Copenhagen54 Tampere2 Paris165 Buffalo164

Age >80 y >80 y >80 y >85 y >90 y >90 y(n) (208) (69) (128) (559) (110) (100)

Q-QS 3 6 6 21 38High R waves 14 19 16 26 44LBBB 7 4 5 4 11 7RBBB 5 4 7 7 6 7AF 10 3 2 17 11 16

*Adapted from Rajala et al.2

TABLE 14. Risk ratios for the categories defined by the Pooling Project. Major abnormalities are asso-ciated with greater risk than minor, however, there is a wide variation and some overlap.

Major ECG Minor ECG

Follow-upabnormality abnormality

Study No. (y) AC CHD CVD AC CHD CVD

Chicago Industry 9,643 11.5 2.4 3.7 3.4 1.7 2.1 2.1BIRNH 11,302 10 1.7 2.1 3.0 1.0 1.2 1.2Evans County 511 20 2.2 1.8 2.2 0.9 1.3 0.9Honolulu Heart 7,682 12 2.9 2.2Charleston 653 30 2.1 2.7 1.3 1.3

Note: The major classification does not include major Q waves.

the risk of CVD. The combination of anatomic and ECG LVH conferreda greater risk than having either alone.

Other large epidemiologic trials have assessed the risk associated withECG LVH, and these serve to reinforce the findings of the Framinghamstudy (Table 9). As with the prevalence data, there is a wide variation in riskdocumented. However, in line with the Framingham data, a clear pattern ofincreased risk is shown to be associated with ST depression inclusive–LVH.The Italian RIFLE study was one of the few to present the risk of both forms,and this data from 22,553 Italians corresponds reasonably well with theFramingham data. Both suggest that the risk associated with ST depressioninclusive–LVH is double that of high R wave–LVH. The maximum relativerisk among all the studies assessed in this article for high R wave–LVH is 2.8,whereas several studies found the risk of ST depression inclusive–LVH to begreater than 5.3,59,71 Kannel,38 who has been forthright in his pleas for clini-cians to take ST depression inclusive–LVH seriously, suggests a pathologicmechanism, namely, that high R wave–LVH represents duration and severity


TABLE 15. Prevalence data for selected ECG variables in black and white men.

Black White

Evans County Charleston Evans County Charleston(n = 308) (n = 307) (n = 511) (n = 584)

ST depression 3.9 1 2.7 0.6High R waves 19.8 9 7.4 2T wave inversion 12.7 8.2 3.1 1.9RBBB 0.3 0 1.8 0LBBB 0 0 0.8 0

From the Charleston3 and Evans County4 studies. Charleston: men 35-74 y; Evans County: men 40-64 y.

TABLE 16. Long- and short-term risks associated with sudden cardiac death (SCD) and selected ECGcharacteristics based on 2011 men and 2534 women from the Framingham Study (values rounded tonearest decimal place).

Risk of SCD Long-term risk Short-term risk

Men Ventricular rate 1× 1.2×Intraventricular block 1.7× 4.1×ST depression inclusive–LVH 2.1× 5.0×ST-T abnormality 1.3× 2.4×

Women Ventricular rate 0.8× 1×Intraventricular block 3.1× 7.3×ST depression inclusive–LVH 1.5× 0.6×ST-T abnormality 2.1× 3×

Short-term risk is expressed as an odds ratio and represents the 2-y age adjusted risk for SCD.Long-term risk relates to 28 y of follow-up. Note that for all figures the long-term risk is lower than the short-term risk.Adapted from Cupples et al.5

of hypertension, whereas ST depression inclusive–LVH indicates concomi-tant coronary disease and myocardial damage.106

It has recently become known that echocardiographic LVH carries agreater impact on survival in women than in men. Liao et al133 studied436 black men and women free of angiographic coronary artery diseaseand found that adjusting for age, hypertension, and ejection fraction, therelative risk of total and cardiac death for LVH was 2.0 and 1.3 in menand 14.3 and 7.5 in women, respectively. The mechanism for this is notentirely clear, although animal studies suggest that there is a potential forestrogen signaling through the adult myocyte estrogen receptor in bothmales and females.131

Effect of treatment. A central issue to the question of screening is thepossibility of averting morbidity or mortality with early and appropriateintervention. In relation to this, the Framingham study has again beencentral. Several risk factors for LVH are known, and these include age,hypertension, obesity, and glucose intolerance. Furthermore, the risk ofLVH is not uniform but varies widely depending on the presence of theseassociated features.36 This suggests that there may be much to be gainedfrom reducing these risk factors. Data from the UK Prospective DiabetesStudy has clearly demonstrated that tight blood pressure control inpatients with hypertension and type 2 diabetes achieves a clinicallyimportant reduction in the risk of deaths related to diabetes,136 emphasiz-ing the link between these conditions. Although these authors found thatintensive blood-glucose control by either sulphonylureas or insulin sub-stantially decreased the risk of microvascular complications in patientswith type 2 diabetes, macrovascular disease was resistant.137

It is now apparent from several trials, meta-analyses,138 and 1 meta-analysis review139 that there is a strong relationship between changes inblood pressure and LVH regression. The overall ranking of antihyperten-


TABLE 17. Sensitivity and specificity estimates for certain ECG abnormalities as predictors of CHD mortality calculated from the original articles (with the exception of the British Regional Study where all-cause mortality was used). Note the low sensitivities. Major and minor are the categories from the Pooling Project.

Q wave ST depression BBB

Study Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity

Framingham 18.9 98.4 17.7 97.8BIRNH 11.5 98.3 5.2 98.5Tunstall-Pedoe 3.9 98.9 7.8 97.6British Regional* 21 95.6 4.7 98.2Chicago industries

*Sensitivity and specificity of ECG abnormalities as predictors of all-cause mortality.BBB, Combined right and left bundle branch block.

sives according to Jennings and Wong139 was angiotensin-convertingenzyme (ACE) inhibitors and calcium antagonists, diuretics, alpha-blockers, beta-blockers, and lifestyle change. Percentage reductionsin left ventricular mass were typically 12% for ACE inhibitors, 11%for calcium channel blockers, 5% for beta-blockers, and 8% fordiuretics (there is currently not enough data for figures on AT-recep-tor antagonists).

Evidence of LVH regression with antihypertensive treatment alsocomes from population data. Mosterd et al22 presented data from 10,333participants who were 45 to 74 years of age at entry. From 1950 to 1989,the rate of use of antihypertensive medications increased from 2.3% to24.6% among men and from 5.7% to 27.7% among women, while theage-adjusted prevalence of a systolic blood pressure above 160 mmHg ordiastolic blood pressure above 100 mmHg declined from 18.5% to 9.2%among men and from 28.0% to 7.7% among women. They report that thisdecline was accompanied by reductions in the prevalence of LVH(defined strictly by Cornell criteria plus repolarization abnormality) from4.5% to 2.5% in men and from 3.6% to 1.1% in women. In fact, the Fram-ingham investigators removed LVH from the most recent version of theirprognostic score (previously the most important factor in the score)because its prevalence has declined, probably as a result of the improvedtreatment of hypertension.43

Some important data from the Framingham study has shown that reduc-tion of ECG LVH is associated with a decrease in risk. Levy140 studied 274men (mean age, 60 years) and 250 women (mean age, 64 years) who werefree of overt CVD but manifested ECG evidence of LVH. Logistic regres-sion analyses of pooled biennial examinations were used to determine riskfor CVD as a function of baseline voltage (sum of R wave in aVL plus Swave in V3) and repolarization abnormality. Subjects with a serial decline


Atrial fibrillation Minor abnormality Major abnormality LVH with strain

Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity

24 64.9 36.8 9425.2 85.5 15.7 96

3.3 99.3 2 99.711.6 88.5 31.9 87.1

in voltage were at lower risk for CVD; those with a serial rise were atgreater risk. An improvement in ST depression was associated with a mar-ginally significant reduction in cardiovascular risk in men only. Worseningof ST depression was associated with increased risk for CVD in both sexes.

Although high R wave LVH may simply be a marker of physiologicresponse to hypertension, ST depression inclusive–LVH is associated withup to a 15-fold increase in the risk of cardiac death, making it a more potentrisk factor than any other, and suggesting that clinicians take seriously itsdetection and reversal. Of the cross-sectional studies that presented data onpersons with no history of CVD, only the Belgian study provided an esti-mation of the prevalence of ST depression inclusive–LVH, that is, the num-ber of people with unrecognized ST depression inclusive–LVH, whichmight be picked up by screening asymptomatic persons. From this data, itwould appear to occur in less than 1% of the healthy population.

�D. McCall: Clearly, many of the epidemiologic studies cited by the authors pointstrongly to the fact that ECG evidence of left ventricular hypertrophy, particularlythat associated with ST-segment depression, is associated with a significantincrease in cardiac death compared to those who are free of this observation. Thisis true not only of the epidemiologic studies cited, but there is, in addition, datato support the fact that ECG evidence of left ventricular hypertrophy carries with itan immediate short-term risk of increased cardiovascular events in patients under-going noncardiac surgery. Since most left ventricular hypertrophy is associatedwith hypertension, and since that hypertension per se is a major risk factor forcoronary artery disease, it is likely that the two coexist even in the absence of ST-segment depression. It can be concluded, therefore, that the presence of left ven-tricular hypertrophy on the resting ECG should alert the physician to the possibil-ity of concomitant coronary artery disease, which most probably contributes to theincreased risk of adverse cardiovascular events. It is well established that appro-priate antihypertensive therapy, particularly with ACE-inhibitors and calcium chan-nel blockers, results in regression of hypertrophy and a decrease in left ventricu-lar mass as measured by echocardiography. Only one small subset from theFramingham study shows regression of hypertrophy to be associated with adecrease in cardiovascular risk. Obviously, this is because many of the epidemio-logic studies have not considered evaluating the effect of regression of left ven-tricular hypertrophy on subsequent cardiac risk, but it is an important point asshown by the data from the Framingham study.

�

Q WavesTable 8 demonstrates that the prevalence of both major and minor Q

waves is low in the asymptomatic population, and of the order of 1%. Fig-ure 3 shows the age stratified data for all populations. What is clear, as


with LVH, is the obvious relation to increasing age. In fact, in middle age,where the increase in prevalence is most marked, our data offer supportfor the observation that women lag approximately 10 years behind menin their prevalence of CVD.141 At all ages, women have a lower preva-lence than men.

Q waves in screening ECGs are important as markers for latent CVD.In fact, the syndrome of painless MI has been recognized for sometime.142 Estimates vary as to the proportion of actual infarctions that gounrecognized, but the average seems to be around 30%.143 There alsoseems to be an increase with age. The mechanism for this is uncertain,although several suggestions have been put forward. The most commontheory suggests that the defect is in the pain pathway, and that elderly sub-jects have a defective “ischemia warning system.”144 Glazier145 studiedthe responses to painful stimuli in 12 patients with predominantly pain-less, and 15 patients with predominantly painful ischemic episodes. Thepatients with predominantly painful episodes had a significantly lowerthreshold and tolerance for forearm ischemia, cold, and electrical skinstimulation, leading the authors to suggest that a generalized defectiveperception of painful stimuli plays an important role in many patientswith predominantly painless myocardial ischemia.

Despite the wide variation, data from Table 10 clearly shows that thereis significant risk associated with the presence of Q waves on the ECG.Again, the Finnish study risks outlie. According to the abstract of thisstudy, men with ECG findings compatible with old infarction had a 19.5-fold increased risk of CHD mortality. In fact, the article itself details risksof 13.4 for major Q waves and 3 for minor Q waves. We cannot be cer-tain why these values are so much greater than the equivalent values forother populations. Certainly, the Finns display very high overall mortal-ity from CHD compared with other populations, but this should not causethe risk from pathologic ECG change to be higher. If the prevalence wasto be equivalent to other populations, then a greater mortality would beassociated with increased relative risk. However, the prevalence valuesfor the Finnish Social Insurance Study (and the Moscow cohort of theEuropean study) are correspondingly disproportionately high (on theorder of 5% to 7%). Interestingly, the Finnish cohort of the Seven Coun-tries Study had a prevalence in line with the other populations (1% to2%). Alternatively, given that these risk ratios were not, as far as we cantell, adjusted for other risk factors or confounding variables, it may bethat this population starts from a position of higher overall risk and this ismerely reflected in the higher risk ratios for individual ECG findings (theRR for ST depression is also disproportionately high).


Of 708 MI among the 5127 participants in the Framingham study,34

more than 25% were recognized only at screening ECG (half of thesewere truly silent and half were associated with atypical symptoms—afinding consistent with the Israel Study146). Risk estimate comparisonsbetween recognized and unrecognized MI suggested that unrecognizedinfarctions were as likely as recognized to cause death, heart failure, orstroke. This finding corresponds with data from the Honolulu HeartStudy73 that analyzed the incidence of clinically unrecognized MIsamong 7331 Japanese-American men in Hawaii, aged 45 to 68 years atentry. The proportion of asymptomatic MI after a 6-year follow-upaccounted for 33% of Q wave infarctions. The 10-year prognosis ofunrecognized infarction was in fact (nonsignificantly) worse than recog-nized with relative risks of all cause, CHD, and cardiovascular mortalityon the order of 1.5 to 1.7. The Reykjavik study also looked at this.147

These researchers studied 9141 men residing in the Reykjavik area whowere born between 1907 and 1934. Prevalence was strongly influencedby age. Nearly undetectable in the youngest age group, incidence wasalmost zero up to age 40, then increased steeply to more than 300 casesper year per 100,000 persons at age 60, and decreased with age after age65. Ten- and 15-year survival probabilities were 51% and 45%, respec-tively, and similar to those for patients with recognized MI. Interestingly,although those with unrecognized MI were less likely than those with rec-ognized MI to have a history of angina pectoris, the risk ratios for recog-nized and unrecognized MI were higher in those patients with angina.

Given the relation of silent MI with age, particularly interesting datacomes from the Bronx aging study143 that assessed unrecognized MI inparticipants 75 years and older in an 8-year prospective investigation.They found no difference in mortality and morbidity among subjects withrecognized and unrecognized MI. In fact, the mortality rate per 100 per-son years was 7.1 for ECG diagnosis and 8.4 for ECG and history diag-nosis. The only study to find a lower risk for unrecognized MI was theIsrael Study146,148 (where the risk was about half in 5-year follow-up of10,000 participants).

In summary, unrecognized MI is a common and high-risk condition.Secondary prevention measures for recognized infarction are widely rec-ommended and often represent significant life changes for persons whocan drastically cut their risk factor profiles. From the studies discussedpreviously in this article, the long-term risk of infarction is likely to besimilar whether recognized or not. It may be that clinicians should bemaking more efforts to detect those with silent infarcts to provide them


secondary prevention as well. For the age group 40 to 59, we can expectto pick up 1 silent MI per 100 patients from routine screening.

ST Segment AbnormalitiesIt is apparent that ST depression is a negative prognostic marker for

CVD from all the studies in which this feature was related to mortality. Inthe Framingham Study,29 the prevalence of nonspecific ECG abnormalitydefined as “greater than 1 mm ST depression and/or T wave flattening orinversion where this should not occur,” among a population aged 44 to 74years over 30 years was 8.5% for men and 7.7% for women. It was relatedto age and closely linked to elevated blood pressure. The age-adjustedCHD morbidity and mortality occurred at about twice the rate in thosewith this abnormality. It is worth noting the stringency of this criterion forST depression. The Minnesota code allows for a lesser degree of ST seg-ment depression in code 4-2 (0.5 mm). Other studies such as the ChicagoWestern Electric Study54 allowed downsloping ST depression less than0.5 mm at the J point, as long as the nadir of the segment or the T wavewas greater than 0.5 mm below the PR isoelectric line. This study alsofound an association with increased risk. Schouten et al149 followed mor-tality over 28 years in relation to variations in ST segment depressiongreater than 0.25 mm in a cohort of 1953 apparently healthy, civil ser-vants (aged 40 to 65). They also showed that this was associated withincreased risk (1.9 for CVD mortality and 2.2 for CHD mortality).

In the Manitoba study,104 the prevalence of ECG abnormalities pre-empting sudden death was 71.4% and among these, the frequency ofmajor ST-T abnormalities was 31.4%—greater than any other ECGabnormality.

Our data also demonstrate that, in line with all abnormalities (with theexception of ST elevation) the prevalence of ST segment depressionincreases with increasing age. The Reykjavik study82 found the preva-lence of silent ST-T changes among men without overt CHD to bestrongly influenced by age, increasing from 2% at 40 years to 30% at 80years. The former value corresponds with our pooled data (Fig 4),although the latter is higher suggesting that the trend for increasing preva-lence with age continues past 70 years of age. Inconsistently, althoughsimilar median prevalence values are seen in the youngest age groups, inboth the 40 to 49 and 50 to 59 age groups, prevalence of ST depressionwas lower for men than for women. (The outliers are the Japanese cohortof the Seven Countries Study, and the Whitehall Study.) This is not easyto explain, and the pattern is inconsistent with virtually all other abnor-malities. It may be that it relates to the loss of the protective effect of


estrogen. Estrogen is known to prevent the accumulation of low-densitylipoprotein and increase high-density lipoprotein, have vasodilating andantioxidant properties,150 and may even modulate cardiac natriuretic pep-tides through the renin-angiotensin system.151 It is possible that interplaybetween the loss of these effects on a population scale, and the younger-age mortality from CVD in men, contributes to ST depression. Notably,Q wave prevalence does not display this pattern.

Many studies have reported that ST-T abnormalities are not a stablephenomenon. Only 50% of Framingham study subjects with nonspecificECG abnormality on their initial ECG (defined previously) still had theabnormality at follow-up. In the Reykjavik study more than 36% of menwith silent ST-T changes did not display these changes at the next stageof the study. In this study also, the changes demonstrated a close relationto hypertension. The frequency of appearance of these changes was fur-ther investigated in the recently reported analysis of the Chicago Electriccompany data.54 In this assessment, the prognostic importance (29-yearfollow-up) of the number of times minor ST-T abnormalities (definedpreviously) were observed on annual screening ECGs over 5 baselineyears was determined. There were 1673 men aged 40 to 55 years at entry,with no evidence of CHD, and no major ECG abnormalities followed.For men with ST-T abnormalities noted on 3 or more occasions, the rela-tive risks were 2.4 for CHD death and 1.6 for all-cause mortality. Therewas a graded relationship between frequency of occurrence and mortal-ity.

One reason for the inconsistent appearance of ST segment depression isits association with other conditions than CHD. This pattern is known tobe associated with digitalis, hyperventilation, electrolyte abnormalities,and even recent food ingestion.152 Despite this, the abnormality is evi-dently associated with considerable risk (Table 11). The Finnish socialstudy calculated an outlying risk ratio of 11.4 for all-cause mortality asso-ciated with ST depression, whereas the Honolulu study calculated risk at6.2. The high-risk ratios of the Finnish study are discussed previously.The Honolulu study also calculated a disproportionately high-risk ratiofor LVH. The Framingham study provides long- and short-term risks forsudden death for the presence of ST depression in the range 1.3 to 3,whereas the Reykjavik study calculates a risk of 2 for silent ST-T change.Furthermore, in this study, ST-T changes were markers for other risk fac-tors: men with ST-T changes were older, had higher serum triglyceridelevels, higher blood pressure, and poorer glucose tolerance than menwithout such changes.

As discussed previously in relation to MI, ischemic changes can often


be silent. The asymptomatic data in Table 8 suggests that 2% of the malepopulation aged 50 to 59 would be expected to exhibit ST depression ona screening ECG. Although the pathophysiologic basis of resting STdepression remains speculative, particularly in regard to the relativeimportance of hypertrophy and ischemia, a fascinating retrospectiveanalysis demonstrated that patients undergoing coronary artery bypasssurgery who had ST depression were more likely to have an improvementin ventricular function after revascularization.153 This suggests that STdepression is associated with resting ischemia. Despite a lack of speci-ficity for CHD, the association of ST segment depression with poor car-diovascular prognosis is stable, reproducible, related to the frequencywith which the abnormality is present, found in both men and women,65

and demonstrated by both mortality and morbidity105 data, including thevery old.78

Schouten et al149 assessed ST depression as previously discussed, butnotably, they demonstrated that the risks for slight ST elevation at 80 mspast the J point (compared with isoelectric ST segment) were 0.5 and 0.4,respectively (all associations were weaker for women). That is, curved,upward sloping ST segments were associated with a lower risk than theisoelectric flat ST segment. This data helps to clarify the decreasingprevalence of ST elevation in men with increasing age, and the lack ofany clear pattern in women, that is shown in Figure 5.

Normal ST elevation or “early repolarization” is a phenomenonrecently reviewed by Mehta.154 The review confirms the association ofthis electrocardiographic pattern with bradycardia, the male gender, andyouth (most patients exhibiting the pattern are younger than 50 years ofage). The incidence of 1% to 2% is found equally common in all races. Inline with our pooled data, Mehta reports that the degree and incidence ofST elevation decreases with advancing age. The mechanism of earlyrepolarization is uncertain, but the observation that ST segments can nor-malize on exercise (or with isoproterenol administration) leads to thethought that vagotonia, sympathetic stimulation, or early repolarization ofthe subepicardium may be responsible. The reciprocal change in preva-lence between ST depression and elevation with increasing age shown inour pooled data links nicely with these changes in risk profile (some stud-ies found a “protective” effect of elevation10).

The low prevalence of ST elevation in the elderly has relevance for thedifficult diagnosis of pericarditis. In fact, the data suggest that a lowerindex of suspicion for this diagnosis in older people would be appropri-ate when ST elevation is present on the ECG (they are less likely to haveearly repolarization).


Bundle Branch Block

As Table 8 demonstrates, the prevalence of these abnormalities in theasymptomatic population is lower than the abnormalities previously dis-cussed and this makes their value in screening more dependent on asso-ciated risk. Figures 6 and 7 show the pooled prevalence data. As before,the abnormalities increase in prevalence with increasing age. For rightbundle branch block (RBBB), men have a higher prevalence than womenat all ages, whereas the reverse is true for left bundle branch block (LBBB).The reason for this is not entirely clear. RBBB may relate to smoking andlung disease, and certainly, at the time these studies were carried out, menhad higher smoking rates than women. Less easy to explain is why womenshould display higher rates of LBBB. Certainly, the pattern is most markedfor the oldest age group, and we might speculate that the lesser longevityand higher CHD mortality of men might reduce the pool of those men withLBBB, leaving the prevalence of cardiomyopathy and its associatedLBBB155,156 to increase with age (LBBB is in fact an independent prognos-tic indicator for idiopathic dilated cardiomyopathy157). Reinforcing thispossibility is the Framingham data that suggest a trend for higher mortalityin left rather than right bundle, which is more apparent in men.158

There is, in fact, some debate over whether RBBB exerts a negativeprognostic effect. Some studies found no effect,10,67,71 whereas othersfound the reverse. The Framingham study39 showed an excess of CVDmortality, related primarily to the high prevalence of associated cardio-vascular abnormalities, in all 70 people who developed complete RBBBduring 18 years of follow-up. Although the initial appearance of RBBBwas usually unaccompanied by overt clinical events, the subsequent inci-dence of CHD was 2.5 times greater than that in matched control subjects.A QRS duration of greater than or equal to 130 ms and a QRS axisbetween –45 and –90 degrees identified those most likely to have associ-ated cardiovascular abnormalities. Data from the Finnish population16,48

also suggests an increase in risk in those manifesting RBBB. The Mani-toba study found an increase in cardiovascular mortality but no increasein the relatively diluted all-cause mortality variable. Some insight intocause can be gained from the angiography study135 of 325 air crewmenwith the US Air Force. In the 41 who manifest RBBB (mean age 41), only8 were found to have significant coronary artery disease on angiography.

It is apparent from a number of studies that LBBB is associated with asignificant increase in risk.10,16,48,49,55,67 Of the 55 people who developedLBBB over 18 years of observation in the Framingham Study, most hadantecedent hypertension, cardiac enlargement, or CHD. The appearance


of LBBB was an independent contributor to increased risk of CVD mor-tality. The British Regional Study10 and the Copenhagen Heart Study55

both calculated relative risks for all-cause mortality above 4. The Mani-toba study reported 29 cases of LBBB without clinical evidence ofischemic heart disease in their cohort of 3983 men.159 The most frequentcardiovascular event observed after development of the block was suddendeath and they report a 5-year incidence for sudden death defined as “thefirst manifestation of heart disease” that is 10 times greater for those withLBBB than those without it.

Again, insight into the pathophysiologic basis for LBBB comes fromthe US Air Force.135 Angiography performed on 34 asymptomatic aircrewmen with LBBB demonstrated only 8 cases of significant coronaryartery disease, emphasizing that the cause of the conduction abnormalitywill relate to the populations in which it is found.

The increasing prevalence of LBBB with age makes the prognosticcharacter of the abnormality in the elderly population of interest. Rajala78

found no increased risk of death associated with either LBBB or RBBBin a population of 559 people over the age of 85 years—a finding thatconfirms the earlier finding of Kitchin and Milne160 but contradicts thefindings of Caird and colleagues.161

These results serve to illustrate a concept first delineated by the medievalmonk Bayes, namely, that the pretest probability of disease is cruciallyimportant to the predictive value of a test. As detailed previously, popu-lation data suggest that LBBB is associated with an extremely poor prog-nosis. However, in the follow-up study of USAF crewmen, Rotman andTriebwasser162 reported a very low mortality over a period of 15 years. Infact, only 9 of 125 subjects with LBBB and 14 of 394 subjects withRBBB died during this period.

Heart Rate, Atrial Fibrillation, and the Elder PopulationRecent studies have led to a realization of the importance of heart rate

as a prognostic marker in the elderly population. Surprisingly, the normalrange for resting heart rate is relatively constant over age after the rela-tive tachycardia of infancy and early childhood.163 A clear finding is thatwomen have a rate between 5 and 10 beats/min higher than men in bothblack and white populations, although these values converge around mid-dle age before separating again. The CASTEL study83 examined the asso-ciation between heart rate and 12-year incidence rates of total and car-diovascular death in a cohort of 763 men and 1175 women aged 65 yearsor older. Subjects were divided into quintiles of heart rate ranging fromless than 64 beats/min to greater than 80 beats/min. In the men, the cardio-


vascular mortality was significantly increased in those in the top quintileof heart rate (crude RR 1.55) but decreased in those in the bottom quintile(crude RR 0.65). Although similar relationships were found in women,the associations did not reach statistical significance and, after adjustmentfor a number of confounding variables, the risk ratios showed the sametrend but the confidence intervals included one. However, in the Coxanalysis, heart rate came out as a strong and significant predictor of timeto cardiovascular death. These findings have recently been corroboratedin a younger population by Benetos et al164 who assessed the effects ofhigh heart rate on mortality in a French population of 12,123 men and7,263 women aged 40 to 69 years. Heart rate measured by ECG was clas-sified into 4 groups and follow-up for mortality continued for 20 years. Inboth sexes, heart rate was a significant predictor of noncardiovascularmortality. In men, the adjusted relative risk for cardiovascular death inthose with a resting heart rate of >60 beats/min was between 1.35 and2.18. Further, the risk was higher in the higher heart rate groups. Inwomen, heart rate did not influence cardiovascular mortality. The associ-ation of heart rate with overall cardiovascular mortality in men wasaccounted for by a strong relation to CHD mortality and not cerebrovas-cular mortality. The effect was independent of age and hypertension, andwas influenced by the level of pulse pressure, such that patients with highpulse pressure (>65 mm Hg) did not have an increased risk associated withtheir accelerated heart rate. These fascinating findings are as yet unex-plained but demonstrate the prognostic power of the simplest of clinicalmeasurements.

The prevalence of atrial fibrillation (AF) is known to increase in theelderly. Figure 8 displays the pooled prevalence data for AF. In compari-son with LVH, Q waves and ST depression, the prevalence values for theyounger population are low. Further, it can be seen that the prevalenceremains fairly low in both men and women until 70 years of age when itincreases markedly. Some studies have demonstrated that this steep risecontinues. Rajala2 reported a prevalence as high as 19.2% and 17% inmen and women over the age of 85, whereas other studies165-167 alsofound values above 10% (Table 13). The pathophysiologic mechanismfor the increase in prevalence of AF with age is not entirely certain. The“classical” causes such as rheumatic heart disease and thyrotoxicosis, infact, account for an increasingly small number of cases (due to thedeclining incidence of the former). Most cases seem to be related tocoronary or hypertensive heart disease, whereas in about 15% of cases,no cause is found.168 Table 13 also demonstrates the prevalence of otherECG abnormalities in the very elderly population. In all cases, it can be


seen that the trend for increasing prevalence of ECG abnormalities seenin our pooled data up to the age of 70 to 80 continues beyond this. Thedata of Rajala78 suggests that risk ratios for the younger population maynot apply. However, all studies in this age group are confounded by thesmaller numbers.

Because of its association with stroke, the negative prognostic value ofAF (rheumatic or ischemic), is well known41,169,170; however, it is onlymore recently that a mortality risk independent from that of its associatedcardiovascular conditions has been demonstrated.42 Of the 5209 Fram-ingham subjects in whom AF developed over 40 years of follow-up, andafter adjustment for a number of confounding variables, AF was associ-ated with an odds ratio for death of 1.5 in men and 1.9 in women. AF alsodiminished the female advantage in survival.

The Manitoba study50 assessed the natural history of AF over 44 years.Of the 3,983 study members, AF developed in 299 (7.5%) during 154,131person-years of observation. The incidence rose with age from less than0.5 per 1,000 person-years before age 50 to 9.7 per 1,000 person-yearsafter age 70. Clinical cardiac abnormalities, particularly recent ischemicheart disease and hypertension, were strongly associated with increasedrisk for AF. Further, AF independently increased the risk for stroke (RR2.07), congestive heart failure (RR 2.98), all-cause mortality rate (RR1.31), and cardiovascular mortality, including fatal stroke (RR 1.41).

The Italian Acute Stroke Study Group171 have demonstrated a poorerprognosis in the setting of acute stroke for those patients with AF—a find-ing not entirely explained by cerebral embolism alone. In participantsover the age of 85, Rajala78 found that of all ECG abnormalities, AF mostclearly predicted mortality, a finding consistent with that of earlier inves-tigators.160

As with these abnormalities, the critical question from the point of viewof screening is what proportion of AF goes unrecognized? There is clearlymuch to be gained from anticoagulation172 in stroke and possibly demen-tia173 prevention. The prevalence in asymptomatic persons would appearto be low, but it is unknown what percentage of the higher numbers ofpeople suffering with increasing age goes unrecognized. Although ourpooled data demonstrates a prevalence of approximately 1% in the 50- to59-year-old asymptomatic population, we know that this prevalenceincreases with age.

Pooled Categories and Other RacesAs detailed previously, the Pooling Project divided ECG abnormalities

into 2 groups, major and minor (Table 4). The prevalence values for these


2 groups for 40- to 59-year-old men is displayed in Figures 10 and 11. Asexpected, the values for minor abnormalities display a higher prevalenceand, reflecting the previous discussions, both major and minor havehigher prevalence in the older of the 2 age groups. It is important toremember that major Q waves are not included in the major category, asthis was an exclusion criterion for the Pooling Project. The 2 other whitepredominant populations displayed in the table included women in theircohorts. Inexplicably, the Chicago Industry study7 found a higher preva-lence of major abnormalities in women, which was not reproduced in theminor category. The authors discuss an observation made by Reunanen48

that although many studies found a similar prevalence for ECG abnor-malities in men as women, the prevalence of CHD in the same popula-tions was in fact lower for women. With the advantage of pooled data inthis article, there are clear differences between the sexes in relation toECG abnormalities. It may be that the absence of Q waves (in whichwomen seem to have lower prevalence, unlike LBBB and ST depression)from the major categorization contributes to this phenomenon. The Bel-gian study found a marginally lower prevalence for major abnormalitiesin women over men. In the minor category, women had lower prevalencein all the studies.

The effect of race on the ECG is an important consideration. Two stud-ies in this article compared ECG findings in black and white populations.Both categorized abnormalities into major and minor (Figs 10 and 11).The prevalence findings for individual ECG abnormalities are displayedin Table 15, which serves to enforce the common observation that blacksdisplay higher levels of QRS voltage, ST segment abnormalities, and Twave inversion than whites. Importantly, other data from the Evanscounty study showed that T wave abnormalities are not predictive ofCHD in the black population.174 In the Charleston study, there was no dif-ference in all-cause mortality between black and white persons with Twave inversion, although less died from CHD.3 ST segment abnormali-ties, however, were shown to be associated with equal increased risk(approximately double) in both populations supporting the findings dis-cussed in the ST Segment Abnormalities section. The Evans Countystudy did not report separate risk ratios for individual ECG abnormalitiesbut rather reported risk for major and minor categories. These were foundto be equal in white and black persons (2.2 and 1.7 for all-cause mortal-ity, respectively). Pooled data from these studies show that black men dis-play significantly less coronary disease mortality than white.175 It isapparent that more data is need to confirm these findings in black women.


Sudden Cardiac DeathSudden cardiac death (SCD) is not so much a separate endpoint as a

subset of each of the 3 main endpoints assessed in this article. It is clearfrom the literature that the risk factors for SCD are largely the same asthose for generalized CHD. This has led some to suggest that there is noway of identifying those specifically at risk from SCD, and that ourefforts should be directed in the conventional direction against CHD.176

However, what marks SCD out as an important subset is our helplessnessin treating it. Whereas we have an opportunity with chronic heart failure,non-sudden death MI, or even cardiogenic shock, to do something clini-cally, with sudden death we have not. This makes predisposing factors ofparticular interest. The most important information on sudden deathcomes from Framingham,5,30,31 Manitoba,104 and the UK.14,177,178 Tunstall-Pedoe14 studied 3 groups of men from the UK heart disease preventionproject: postinfarct patients, employed symptomatic men, and employedasymptomatic men (only the data from the symptomless group isincluded in Table 8). He correlated the sudden death rates of these groupswith common findings classified by Minnesota code on the resting ECG.Over 4 years, the unadjusted relative risk (relative to subjects without thefinding in question) was 4 for Q waves, 1.6 for high-amplitude R wave(HR)–LVH, and 3.5 for ST depression. However, it should be noted thatthe definition of sudden used in this study included deaths up to 24 hoursafter an acute event (this was the WHO definition179). The Manitoba arti-cle also used this definition and reported a 30-year follow-up. In theircohort, the prevalence of ECG abnormalities before sudden death was71.4%. The most commonly occurring precursor (as previously noted)was major ST segment and T wave abnormality (31.4%), followed byventricular extra systoles (12.9%), HRW-LVH (7.1%), and completeLBBB (5.7%).

More recent studies have used a narrower definition of SCD thatincludes deaths up to 1 hour after the acute event. Data from the Britishregional heart study was used to identify independent risk factors for SCDin 7735 middle-aged men who were followed up for 8 years.177 Factorsthat emerged as independent risk factors for SCD after adjustment for awide range of possible confounders were as follows: age, preexistingCHD (RR up to 8.3), arrhythmia—defined as anything that was not sinusrhythm or sinus arrhythmia in an 8 second recording (ie, inclusive of ven-tricular ectopics [RR: 3.2], systolic blood pressure [RR: 2.2], blood cho-lesterol [RR: 3.3], elevated heart rate [≥90 bpm—RR: 4.8], and physicalinactivity [RR: 0.4 for moderately vigorous/vigorous exercise comparedwith none/occasional]). Interestingly, diabetes was not found to be asso-


ciated with SCD, and neither was FEV1 nor body mass index. Whenexamined in relation to non-sudden CHD deaths and nonfatal MI, ele-vated heart rate, heavy drinking, and arrhythmia emerged as factors spe-cific for SCD.

The Framingham investigators compared the long- and short-term risksfor SCD (≤1 hour).5 They averaged the risk factor measurements over thefirst 4 biennial examinations and then assessed short-term risk by relatingthese risk factors at each examination to the ensuing 2-year incidence ofSCD. They concluded that most of the modifiable or constitutional riskfactors, including glucose intolerance, systolic blood pressure, body massindex, and cigarette smoking, had a greater effect on long-term SCD thanshort-term, an effect less apparent in women. ECG abnormalities (Table15) such as LVH, intraventricular conduction block, and nonspecificrepolarization abnormality were better short-term predictors.

We have not specifically considered ventricular premature beats in thisdiscussion as our focus is on the resting 12-lead ECG and not Holter mon-itoring. Early studies suggested a link between ventricular ectopydetected on routine ECG and SCD.62,180 In fact, the more recent literaturedoes not support the often quoted strong relationship between ventricularectopy and SCD but rather suggests an increased risk of CHD death overseveral years of follow-up.30,181,182

Half of those who suffer sudden death have no antecedent overtCHD.183 Although there is little evidence that altering known risk factorsfor CHD will prevent SCD as a subgroup of cardiac mortality, it is rea-sonable to suggest that this might be the case. Taken together, these stud-ies suggest that ECG abnormalities represent an important risk marker forfuture SCD.

Sensitivity and Specificity EstimatesAny test considered as a screening test should be considered in terms of its

sensitivity and specificity. Most screening tests are compared with a “goldstandard” (such as angiographic disease in the case of tests for coronaryartery disease). To assess the prognostic value of a screening ECG, we needto determine how well the test predicts the ultimate endpoint: mortality. By acareful reexamination of the articles, we were able to extract the data for theappropriate 2 × 2 tables from only a few. These calculations are displayed inTable 17. As is clearly seen, the sensitivity estimates of individual ECGabnormalities are very low. We know that attributable risk is dependent on theprevalence of the abnormality in the population, and that low prevalence willresult in low sensitivity. This is what seems to be happening here. The dataare calculated only from those studies with stringent exclusion criteria, so we


could be certain of assessing the true screening qualities of the test. The sen-sitivity values seem to be highest for LVH, and this almost certainly relates tothe higher prevalence of this abnormality and (at least when defined by theFramingham investigators using ST depression inclusive criteria) greater risk.

We may, however, be underestimating the value of the ECG if we con-sider only individual abnormalities in isolation. After all, the clinician car-rying out the screening test will do 1 ECG and consider several abnor-malities. From this point of view, the pooling project classification ishelpful. Accordingly, we have included estimates based on this data. Asillustrated, the sensitivity values are higher when abnormalities arepooled but still do not reach levels where we might consider the ECG use-ful as a screening tool (for the ultimate “gold standard” of mortality).

The only other authors to carry out data analysis in the consideration ofthe ECG as a screening test were Whincup and colleagues.10 In this study, 2important ECG abnormalities (definite myocardial ischemia and definiteMI) were analyzed separately in the presence or absence of symptomaticcoronary disease. They note that the prevalence of these abnormalities waslow in their asymptomatic population, especially below 50 years of age, andthat these abnormalities in combination had only about 10% sensitivity formajor CHD events in a 10-year follow-up. Finally, they note that the rate ofmajor coronary disease events occurring in men identified by the test waslow and on the order of 14/1000 per year. The fact that these 2 ECG abnor-malities were able to identify only 10% of major events over 10 years agreeswith our sensitivity estimates. However, the point made previously in rela-tion to individual ECG abnormality estimates is important. Although theseauthors have considered the 2 highest risk abnormalities (which would pre-sumably include the very high risk ST depression inclusive–LVH), clinicianswould consider more than 2 abnormalities on a screening ECG. In particu-lar, we have noted the high risk for heart rate in the elder population, and sig-nificant risk associated with LBBB.

ConclusionsIn light of recent changes in the approach to primary prevention in car-

diovascular medicine,23 we have comprehensively reviewed the availabledata on the ECG and its use in screening asymptomatic persons for futureCHD. In so doing, we have considered the seminal epidemiologic studies(indeed some were set up with the initial intention of following ECG abnor-malities in an asymptomatic population49). This has led us to retrace the stepsof some of the pioneers of western medicine.184-186 Our review has confirmedthat all ECG abnormalities increase with age and that some are more preva-lent in men (Q waves, RBBB), whereas some are more prevalent in women


(ST depression, LBBB). We have identified several ECG abnormalities thatare associated with significant risk. A striking finding is that ST depressioninclusive–LVH has a 33% 5-year mortality in men and a 21% 5-year mor-tality in women.6 Also, unrecognized Q wave infarction is associated withthe same risk as recognized symptomatic infarction.34 Studies have shownthat ST depression is a poorly reproducible phenomenon, yet increasing riskis associated with the frequency of its occurrence.54 Our review emphasizesthat chronic ST elevation is benign149,187 and that the predictive value of bun-dle branch block depends on the population in which it appears.40,162 Theprevalence of AF rises exponentially with age, probably continues to rise inthe very elderly, and is associated with a higher risk than any other ECGabnormality the elderly.78 We have confirmed the often quoted observationthat T wave inversion and high voltage QRS are more common in black thanin white persons, but in general, do not predict CHD to the same extent.3 Wehave also noted that elevated heart rates, but not ventricular premature beats,are independent risk markers specific for SCD.177

Finally, we have assessed the use of the ECG as a screening tool by cal-culating sensitivity and specificity values from some of the studies thatused stringent exclusion criteria. We found that, for individual ECG abnor-malities as well as for pooled categories of abnormalities, the sensitivity ofthe ECG for future death was too low for it to have much practical value inscreening asymptomatic populations. This finding almost certainly relatesto the low prevalence of these abnormalities in the populations considered.The attributable risk of the ECG abnormalities is low because of their lowprevalence.

However, all ECG abnormalities increase with age and their attributablerisk increases. Therefore, the threshold for performing ECG should decreasein our elder patients because it should be more helpful than in youngerpersons. There is clearly much to be gained from the use of statins, alter-ation of other risk factors in the secondary prevention of those who havehad a silent MI, anticoagulation for unrecognized AF, and aggressivereduction of hypertension in the presence of ST segment inclusive–LVH.The cost of the ECG is minimal and likely to decrease further as stand-alone machines are replaced by integration of ECG hardware and soft-ware into personal computers as part of medical databases. Althoughdiagnostic criteria have been standardized and improved by computeranalysis, the interpretation programs can be improved by the newer stud-ies as previously described.

Many epidemiologists are recommending multivariate equations toidentify those who would benefit from additional therapy or health pro-motion.10 We conclude that in those who are already symptomatic with


ischemic heart disease or congestive heart failure, the ECG can identifya subset at particularly high risk. We hypothesize that this would extendto those at high risk from diabetes, hypertension, and those with highrisk scores from other causes. The Framingham data suggest that,although conventional risk factors relate to long-term risk, ECG abnor-malities better predict risk in the short-term.5 This places the ECG at apivotal point in the identification of those most in need—and in all prob-ability with most to gain, from diagnostic and therapeutic intervention.Increased awareness of the prognostic implications of ECG abnormali-ties in selected populations should allow us to optimize one of the mostuseful medical tools in this new millennium.

�

D. McCall: This is a truly unique monograph. Drs Ashley, Kumar, and Froelicher are tobe congratulated for putting together this extremely useful review. I know of nowhereelse in the cardiology literature where a complete review of the many epidemiologicstudies that have served to define both the prevalence, and more particularly, the prog-nostic significance of the resting ECG, can be found. This is, therefore, a “must read”monograph for cardiologists, cardiology fellows, and internists. It is clear that importantprognostic information can be gleaned from a simple 12-lead resting ECG. Too often inthis day of high-tech procedures, the value of simple tests gets lost; this monographserves to highlight, particularly to the more junior cardiologists, the importance of care-fully evaluating basic clinical assessment including an ECG before proceeding to morecostly high-tech approaches. The monograph is well written and makes fascinating read-ing. It is a valuable reference source not only on the ECG and its prognostic significance,but on the multiple and varied epidemiologic studies on which the authors’ conclusionsare based. This is a truly important contribution to current cardiologic literature.

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Appendix 1: Search Terms

Search terms used for MEDLINE search (All Fields, using PUBMED—the US National Library of Medicine’s online server): electrocardiogra*,ECG, EKG, screen*, prognosis, prevalence, morbidity, mortality, epidemiol*.

Appendix 2: The Rose Questionnaire

The Rose Questionnaire was developed for epidemiologic studiesbut the many studies of its validity make it a useful diagnostic tool. Thediagnosis of angina pectoris using the London School of Hygiene Car-diovascular Questionnaire requires the patient to answer these questions:

1. Have you every had any pain or discomfort in your chest?Yes No

2. Do you get it when you walk uphill or hurry?Yes No Never hurry

3. Do you get it when you walk at an ordinary pace on the level?Yes No

4. What do you do if you get it while you are walking?Stop or slow down Carry on

5. If you stand still, what happens to it?Relieved Not relieved

6. How soon?10 min or less More than 10 min

7. Will you show me where it was?Sternum (upper or middle) Sternum (lower)Left anterior chest Left arm Other

8. Do you feel it anywhere else?Yes No

9. Did you see a doctor because of this pain (or discomfort)?Yes No

10. If yes, what did he say it was?

Responses for diagnosis of angina pectoris to questions 1 through 61, 2, or 3. Yes; 4. Stop or slow down; 5. Relieved; 6. 10 min or less.

Appendix 3: A brief guide to the Minnesota Code188

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The prevalence and prognostic significance of electrocardiographic abnormalities

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