Br HeartJ_ 1993;70:49-55

Heart rate, ischaemic heart disease, and suddencardiac death in middle-aged British men

A G Shaper, Goya Wannamethee, PW Macfarlane, Mary Walker

AbstractObjective-To examine the relationbetween resting heart rate and newmajor ischaemic heart disease events inmiddle aged men with and without pre-existing ischaemic heart disease.Design-Prospective study of a cohort ofmen with eight years follow up forcardiovascular morbidity and mortalityfor all men.Setting-General practices in 24 Britishtowns (the British Regional Heart study).Subjects-7735 men aged 40-59 yearsdrawn at random from the age-sex regis-ters of one general practice in each town.Main outcome measures-Major isch-aemic heart disease events such as sud-den cardiac death, other deathsattributed to ischaemic heart disease,and non-fatal myocardial infarction.Results-During the follow up period ofeight years, 488 men had a majorischaemic heart disease event (217 fataland 271 non-fatal). Of these, 117 wereclassified as sudden cardiac death (deathwithin one hour of the start of symp-toms) The relation between heart rateand risk of all major ischaemic heart dis-ease events, ischaemic heart diseasedeaths, and sudden cardiac death wasexamined separately in men with andwithout pre-existing ischaemic heart dis-ease. In men with no evidence ofischaemic heart disease, there was astrong positive association between rest-ing heart rate and age adjusted rates ofall major ischaemic heart disease events(fatal and non-fatal), ischaemic heartdisease deaths, and sudden cardiacdeath. This association remained signifi-cant even after adjustment for age, sys-tolic blood pressure, blood cholesterol,smoking, social class, heavy drinking,and physical activity, with particularlyhigh risk in those with heart rate > 90beatsimin. The increased risk seen inthose with increased heart rate waslargely due to a significantly increasedrisk of sudden cardiac death, which wasfive times higher than in those with heartrate < 60 beats/min. The effect of heartrate on sudden cardiac death was presentirrespective ofblood pressure or smokingstate. In men with pre-existing ischaemicheart disease a positive association wasseen between raised heart rate and riskof all major ischaemic heart diseaseevents, ischaemic heart disease death,

and sudden cardiac death, but the effectwas less noticeable than in men withoutpre-existing ischaemic heart disease.Conclusion-In this study of middle agedBritish men increased heart rate > 90beats/min) is a risk factor for fatalischaemic heart disease events but par-ticularly for sudden cardiac death. Theeffect is not dependent on the presence ofother established coronary risk factorsand is most clearly seen in men free ofpre-existing ischaemic heart disease atinitial examination.

(Br HeartJ' 1993;70:49-55)

A high resting heart rate is associated with anincreased risk of ischaemic heart disease'8and in some studies specifically with suddencardiac death.'-2 It is well established that anincreased resting heart rate is associated withhypertension9-"1 and that heart rate is stronglyinfluenced by smoking and physical activity,known risk factors for ischaemic heart dis-ease. Whereas some studies have found heartrate to be an independent risk factor forischaemic heart diseasel4 others have shownthe association to be dependent on confound-ing risk factors.57 We examined the relationbetween resting heart rate measured on anelectrocardiogram and risk of new majorischaemic heart disease events in middle agedBritish men, with a particular focus on mor-tality from ischaemic heart disease and onsudden cardiac death. The role of heart ratein influencing the risk of ischaemic heart dis-ease is examined primarily in men withoutevidence of pre-existing ischaemic heart dis-ease, with additional comment on those withpre-existing ischaemic heart disease.

Subjects and methodsThe British Regional Heart Study is aprospective study of cardiovascular disease of7735 men aged 40-59 selected from theage-sex registers of one group general prac-tice in each of 24 towns in England, Wales,and Scotland. The criteria for selecting thetown, the general practice, and the subjects aswell as the methods of data collection havebeen reported.'2 Research nurses gave eachman a standard questionnaire that includedquestions on smoking habits, alcohol intake,and medical history. Several physical mea-surements were made, and blood samples(non-fasting) were taken for measurement of

Department ofPublicHealth and PrimaryCare, Royal FreeHospital School ofMedicine, LondonA G ShaperG WannametheeM WalkerDepartment ofMedical Cardiology,Royal Infirmary,GlasgowW P MacfarlaneCorrespondence toProfessor A G Shaper,Department of PublicHealth and Primary Care,Royal Free Hospital Schoolof Medicine, Rowland HillSt, London NW3 2PF.Accepted for publication24 February 1993

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biochemical and haematological variables.Details of the measurement of serum lipidconcentrations have been described.'3 Themen were classified according to their currentsmoking state-namely, those who had neversmoked, ex-cigarette smokers, and currentsmokers. Those who had only ever smoked apipe or cigars are grouped as never smoked.Ex-cigarette smokers who are currently pipeor cigar smokers are classified as ex-cigarettesmokers. Alcohol consumption was recordedwith questions on frequency, quantity, andtype, similar to those used in the 1978General Household Survey. Heavy drinkerswere defined as those regularly drinking morethan six drinks daily. The longest held occu-pation of each man was recorded and thencoded in accordance with the RegistrarGeneral's occupational classification. Bodymass index calculated as weight/height2 wasused as an index of relative weight. Forcedexpiratory volume in one second (FEVI) wasmeasured with a Vitalograph spirometer(model J49-B2) with the subject seated. Twoconsecutive readings were made 15 secondsapart and the maximum of these two readingswas used. The FEV, values given in thispaper are height standardised to 1 73m, theaverage height of the men in this study. Themen were asked to indicate their usual pat-tern of physical activity, which included regu-lar walking or cycling, recreational activity,and sporting activity. A physical activity scorewas derived for each man based on frequencyand type of leisure activity.'4 The men weregrouped into six broad categories based ontheir total score: inactive, occasional, light,moderate, moderately/vigorous, and vigorous.Active men were those whose physical activitywas moderate or greater.

BREATHLESSNESSA modified version of the Medical ResearchCouncil questionnaire on respiratory symp-toms (1966 version) was given at the initialexamination. Each man was asked: (a) doyou get short of breath walking with peopleyour own age on level ground? (b) On walk-ing up hills or stairs do you get more breath-less than people your own age? (c) Do youever have to stop walking because of breath-lessness? Each affirmative answer scored 1giving a possible score of 0 to 3. Those whoscored > 2 were defined as those reportingmoderate to severe breathlessness.

PRE-EXISTING DISEASEThe men were asked to recall a doctor's diag-nosis of angina, myocardial infarction, dia-betes, and a number of other disorders listedon the questionnaire. The World HealthOrganisation (Rose) chest pain questionnairewas given to all men at the initial examina-tion.'5 A three orthogonal lead electrocardio-gram was recorded at rest with the subjectrecumbent and having been at rest at leasthalf an hour before the recording. The elec-trocardiogram preceded measurement oflung function and venepuncture for bloodsamples.

ISCHAEMIC HEART DISEASEThe men were separated into three groupsaccording to the evidence of ischaemic heartdisease present at screening. Group I had noevidence of ischaemic heart disease based onthe World Health Organisation chest painquestionnaire or electrocardiogram and norecall of a doctor's diagnosis of ischaemicheart disease. Group II were men with evi-dence suggesting ischaemic heart diseaseshort of a definite myocardial infarction. Thisgroup contained those with electrocardio-graphic evidence of possible or definitemyocardial ischaemia or possible myocardialinfarction, those with angina or a possiblemyocardial infarction according to the WorldHealth Organisation chest pain questionnaire,or with recall of a doctor's diagnosis ofangina. Group III were men with a previousdefinite myocardial infarction on electro-cardiogram or who recalled a doctor's diag-nosis of a myocardial infarction. In theanalyses, men with pre-existing evidence ofischaemic heart disease consist of men ingroups II and III.

HEART RATEHeart rate was determined at screening froma three lead orthogonal electrocardiogram. Allmen were supine, and before the recordingwere resting while answering the question-naire. On the basis of the eight secondrecording, the average RR interval (seconds)during that period was calculated: heart rate= 60/(average RR interval) beats. When aventricular extrasystole was included in theeight second recording (n = 209;2 7%), itwas used in an estimate of heart rate/min.Some patients were in atrial fibrillation (n =49, 0-06%); in such cases the occurrence ofan extrasystole would have little or no effecton the heart rate calculation. Heart rate wasnot available in 52 men because of difficultieswith electrocardiographic equipment. Themen were classified into five groups based onheart rate: < 60 = 1429 men (18-6%), 60-69= 2475 men (32 2%), 70-79 = 2101 men(27 3%), 80-89 = 1034 men (13-5%), and >90 = 644 men (8 4%).

FOLLOW UPAll men, whether or not they showed evi-dence of ischaemic heart disease at initialexamination were followed up for all causemortality and cardiovascular morbidity.Information on death was collected throughthe established "tagging" procedures provid-ed by the NHS registers in Southport (forEngland and Wales) and Edinburgh (forScotland). All cause mortality and majorischaemic heart disease events (fatal and non-fatal) are based on eight years of follow up foreach man. A non-fatal myocardial infarctionwas diagnosed according to World HealthOrganisation criteria. Fatal events weredefined as those with death from ischaemicheart disease (International Classification ofDiseases (ICD) 9th revision codes 410-4) asthe underlying cause. They comprised anischaemic heart disease death in an individual

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<60 60- 70- 80- o90 <60 60- 70- 80- o90

Sudden cardiac death

12

14 6

<60 60- 70- 80- ¢90

Heart rate (beats/min)

Figure 1 Age adjusted rates for major ischaemic heart disease (IHD) events, mortalityfrom (IHD), and sudden cardiac death in men without pre-existing ischaemic heartdisease in thefive heart rate (beatslmin) groups. < 60 = 1088 men, 60-69 = 1870 men,

70-79 = 1619 men, 80-89 = 747 men, > 90 = 445 men. Absolute numbers of eventsare indicated.

subject during the eight year follow up irre-spective of a previous non-fatal event duringthat period. The certifying doctor was askedto complete an enquiry form that asked theduration from the start of symptoms todeath-namely, < 1 hour, 1-24 hours or > 24hours. Sudden cardiac death was defined as

an event in which death occurred within one

hour of the start of symptoms. Only those forwhom clear information was available regard-ing death within one hour were included as

sudden cardiac death. Case fatality is definedas the proportion of the major ischaemicheart disease events in which death occurredduring the first event during follow up andwithin 28 days of the start of symptoms, andin which the death certificate recordedischaemic heart disease (ICD codes 410-4).

STATISTICAL METHODS

Multiple logistic regression was used toobtain the relative risk for the five heart rategroups adjusted for age, social class, smoking,heavy drinking, physical activity, systolicblood pressure, blood cholesterol, and bloodglucose. Age, systolic blood pressure, bloodcholesterol, and blood glucose were fitted as

continuous variables, heart rate as fourdummy variables (for the five groups), physi-cal activity as five dummy variables (for thesix physical activity groups), smoking as fourdummy variables (never, ex, light, moderateand heavy), social class as two dummy vari-ables (manual, non-manual, and armedforces) and heavy drinking as a 0 or 1 vari-able. Tests for trend were assessed by fittingheart rate as a continuous variable.

ResultsDuring the follow up of eight years there were

488 major ischaemic heart disease events(217 fatal, 271 non-fatal) of which 117 were

classified as sudden cardiac death. Data onheart rate were not available in 52 men ofwhom five had a major ischaemic heart dis-

ease event. The mean resting heart rate atscreening was 70 7 beats/min (SD 12-8) in7683 men for whom heart rate was available.At initial examination, 25% of the men hadevidence of ischaemic heart disease; 19-5%had ischaemic heart disease short of a definitemyocardial infarction (group II), and 5-5%had definite previous myocardial infarction(group III). The mean resting heart rate inthese two groups (II and III) and group I(men free of pre-existing heart disease) were71-7 beats/min and 70 4 beats/min respec-tively. The percentage of men with evidenceof ischaemic heart disease was significantlyhigher in those with heart rate > 80/min thanthose with lower heart rate (p < 0-0001). Thepercentages of men with pre-existingischaemic heart disease by the five heart rategroups were 24%, 24%, 23%, 28%, and 31%(test for difference between the five groups; p< 0-0001). Because of the effect that the pres-ence of ischaemic heart disease has on heartrate we have examined the relation betweenheart rate and risk of ischaemic heart diseaseseparately in men with and without evidenceof pre-existing ischaemic heart disease.

MEN WITHOUT PRE-EXISTING ISCHAEMICHEART DISEASEFigure 1 shows the age adjusted rate(1000/year) for all major ischaemic heart dis-ease events (fatal and non-fatal), ischaemicheart disease mortality, and sudden cardiacdeath in men without pre-existing ischaemicheart disease by the five heart rate groups.There was a strong positive association withall these outcomes (p < 0-0001), with ratesincreasing progressively with increasing heartrate. Rates for mortality from ischaemic heartdisease and in particular for sudden cardiacdeath, were considerably higher in those withheart rate > 90 beats/minute than in thosewith lower heart rates. Case fatality (firstevent that resulted in death within 28 days)increased significantly with increasing heartrate (18%, 27%, 24%, 32%, and 53% for thefive heart rate groups respectively)-that is,those with raised heart rate were less likely tosurvive a major ischaemic heart disease eventwhen it occurred.

Heart rate and cardiovascular risk factorsSeveral studies have shown strong associa-tions between heart rate and cardiovascularrisk factors that could influence the correla-tion between heart rate and major ischaemicheart disease events, notably blood pressureand smoking. The relations between heartrate and cardiovascular risk factors wereexamined for the five heart rate groups inmen without pre-existing ischaemic heart dis-ease (table available on request). Those withhigher heart rate tended to be older (p <0.01) and heavier (p < 0 01) and systolic anddiastolic blood pressure, and blood choles-terol, blood glucose, and triglyceride concen-trations increased significantly with increasingheart rate (p < 0-0001). There was little dif-ference in mean high density lipoprotein cho-lesterol between the five heart rate groups.

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Table 1 Relative risk (95% CI) of major ischaemic heart disease (IHD) events, mortality from IHD, and suddencardiac death according to heart rate in men without pre-existing IHD

Major IHD events (n = 243) IHD mortality (n = 89) Sudden cardiac death (n = 44)Heart No ofrate men (A) (B) (A) (B) (A) (B)

<60 (1088) 1 0 1.0 1.0 1.0 1.0 1 060-69 (1870) 1-1 (0-7 to 1-6) 1 0 (0-6 to 1-5) 1-5 (0 7 to 3 4) 1-4 (0-6 to 3-0) 1-7 (0 5 to 6 4) 1-6 (0 4 to 5-8)70-79 (1619) 1-6 (1 0 to 2 4) 1-3 (0-8 to 1-9) 2-3 (1 1 to 5 2) 1-8 (0-8 to 4-0) 3-2 (0 9 to 11-1) 2-6 (0-7 to 8 6)80-89 (747) 1-6 (1 0 to 2 6) 1 1 (0 7 to 1-8) 2-5 (1 0 to 6-0) 1-7 (0 7 to 4- 1) 2-8 (0-7 to 11-4) 1-9 (0-5 to 7 4)> 90 (445) 2-2 (1-3 to 3 6) 1-2 (0-8 to 1-3) 5-5 (2-3 to 12-9) 3-3 (1-4 to 7 8) 9 5 (2-6 to 34.8) 5-2 (1-4 to 18-7)Testfortrend p<001 NS p<0001 p<001 p<0001 p<001

(A) adjusted for age; and (B) adjusted for age, social class, smoking, heavy drinking, physical activity, systolic blood pressure,blood cholesterol and blood glucose.

The proportion of current smokers and heavydrinkers increased significantly with increas-ing heart rate. The proportion of active mendecreased progressively with increasing heartrate. Social class was not significantly associ-ated with heart rate although there was a ten-dency for the percentage of manual workersto increase with increasing heart rate.Although blood glucose was strongly associat-ed with heart rate, a doctor's diagnosis of dia-betes was not significantly associated withheart rate.

Heart rate and outcome of ischaemic heart diseaseNot all the factors associated with restingheart rate are independently predictive of newmajor ischaemic heart disease events.Therefore they need not be included in a

multivariate analysis to find whether heartrate is independently associated with morbid-ity and mortality from ischaemic heart dis-ease. Body mass index is not an independentpredictor once blood cholesterol and bloodpressures are taken into account.'6 Tri-glyceride concentration is not an independentpredictor of mortality from ischaemic heartdisease once blood cholesterol is taken intoaccount.'7 Heavy drinking has been shown tobe positively associated with sudden cardiacdeath.'8 The relation between heart rate andmorbidity and mortality from ischaemic heartdisease has therefore been examined withadjustment for age, social class, smoking,heavy drinking, physical activity, systolicblood pressure, blood cholesterol, and bloodglucose (table 1). Adjustment for all of thesefactors (column B) diminished the strongpositive association seen with all majorischaemic heart disease events when only agewas adjusted for (colunm A), and the associa-tion was no longer significant. There was,however, still a significant positive associationbetween heart rate and mortality fromischaemic heart disease and sudden cardiac

death. In particular the risk of mortality fromischaemic heart disease was substantiallyincreased at heart rates of 90 beats/min andabove, largely due to a noticeably increasedrisk of sudden cardiac death. Indeed, the pro-

portion of sudden deaths from ischaemicheart disease was highest in those with highheart rate (63%) and lowest in those with low(< 60 beats/min) heart rate (38%).

Table 2 shows the relative risk of majorischaemic heart disease events, mortality fromischaemic heart disease, and sudden cardiacdeath in men with a raised heart rate () 90beats/min) compared with all other men

adjusted for age, social class, smoking, heavydrinking, physical activity, systolic bloodpressure, blood cholesterol, and blood glu-cose, separately for men with and without evi-dence of pre-existing ischaemic heart disease.In those without pre-existing ischaemic heartdisease, after adjustment, increased heart ratewas not associated with an increased risk ofmajor ischaemic heart disease events but was

significantly associated with an increased riskof mortality from ischaemic heart diseaselargely due to a significant increase in the riskof sudden cardiac death.

Heart rate and hypertensionBecause of the strong association betweenheart rate and hypertension we have exam-

ined the relation between a high heart rateand mortality from ischaemic heart diseaseand sudden cardiac death in the presence or

absence of hypertension in men with no pre-existing ischaemic heart disease (fig 2).Hypertension was defined as men with mea-

sured systolic blood pressure > 160 mm Hgor diastolic blood pressure > 90 or on regu-lar antihypertensive treatment. Eleven percent of hypertensive men had a high heartrate compared with 6% in normotensive men.

A raised heart rate was associated with over

a twofold increase in relative risk (RR) of

Table 2 Relative risk (95% CI) of major ischaemic heart disease (IHD) events, mortalityfrom IHD and suddencardiac death in men with raised heart rate (> 90 beatslmin) compared with all other men, in those with and withoutpre-existing IHD

Men with no evidence ofIHD (n = 5769) Men with evidence ofpre-existing IHD (n = 1914)

No of No. ofMajor IHD Major IHDevents (A) (B) events (A) (B)

IHD events 243 1-7 (1-1 to 2-5)** 1-1 (0-7 to 1-7)NS 240 1-5 (1 0 to 2-2)* 1-4 (0-9 to 2-1)NSIHD mortality 89 3-2 (1-9 to 5 5)*** 2-0 (1-2 to 3-6)** 126 2-1 (1-3 to 3-3)** 2-0 (1-2 to 4-9)*Sudden death 44 4-4 (2-2 to 8-7)*** 2-7 (1-3 to 5-4)** 71 1-6 (0-8 to 3-4)NS 1-5 (0-8 to 3-0)NS

(A) adjusted for age; (B) adjusted for social class, smoking, heavy drinking, physical activity, systolic blood pressure, blood cho-lesterol, and blood glucose.* p < 0-05; ** p < 0-001;*** p < 0-0001.

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* <90 beats/min

] :90 beats/min

IHD mortality

8

i1 |~~~3Norm

11

Hyp

Sudden cardiac death7

14

3728 239 1640 206

5

Norm

3728 239

18

1yp1 640 206

Figure 2 Relative risk of mortality from ischaemic heart disease (IHD) and suddencardiac death by heart rate (< 90 and > 90 beatslmin) by presence or absence ofhypertension in men without pre-existing ischaemic heart disease adjustedfor age, socialclass, smoking, heavy drinking, physical activity, systolic blood pressure, blood cholesterol,and blood glucose. Absolute numbers of events are indicated. Norm, normotensive;hyp, hypertensive.

sudden cardiac death in both normotensive(RR = 4 0) and hypertensive (RR = 2 6) meneven after adjustment for age, social class,smoking, heavy drinking, physical activity,blood cholesterol, and blood glucose.Hypertension itself was associated with a

more than twofold increase in risk of suddencardiac death (RR = 2-4, 95% confidenceinterval (CI) 1 2 to 4-9), but hypertensionaccompanied by an increased heart rate was

associated with more than a sixfold increasein risk of sudden cardiac death comparedwith normotensive subjects with heart rate <

90 beats/min (RR = 6-0, 95% CI 2-4 to 15-2(fig 2).

Heart rate and smokingThe relation between heart rate andischaemic heart disease was also examinedseparately with reference to current smokingstatus in men without pre-existing ischaemicheart disease adjusting for age, social class,heavy drinking, physical activity, systolicblood pressure, blood cholesterol, and bloodglucose. The higher risk of mortality and sud-den death from ischaemic heart disease inthose with raised heart rate was apparent inboth non-smokers (never smokers and ex-cig-arette smokers) and in current cigarettesmokers. A high heart rate was associatedwith over a twofold increase in the risk ofsudden cardiac death in both smokers andnon-smokers.

Heart rate and lungfunctionWe have previously reported on the role ofdecreased lung function and breathlessness as

independent indicators of increased risk of a

major ischaemic heart disease event in men

free of pre-existing ischaemic heart disease.19It was suggested that this phenomenon mightindicate early heart failure due to impairedmyocardial function not detected by electro-cardiography or the World Health Organiza-tion chest pain questionnaire. As an increased

Table 3 Heart rate and measures oflungfunction

Heart rate FEV, Breathlessness(beatslmin) (mean (SE)) (% moderate to severe)

< 60 346-9 (2-2) 3-460-69 343-1 (1-7) 3-870-79 338-5 (1-7) 4-480-89 329-5 (2-8) 6-5> 90 321-3 (4-0) 8-1

resting heart rate might indicate a similarlyimpaired myocardial function, we have exam-ined the relation between heart rate and lungfunction (breathlessness and FEV,) in menwithout evidence of pre-existing ischaemicheart disease (table 3).

There is a strong inverse associationbetween resting heart rate and FEV, (p <0 0001) and a strong positive associationbetween resting heart rate and the proportionof men reporting moderate or severe breath-lessness (p < 00001). Additional adjustmentfor FEV, or breathlessness of the data inTable 2 made little difference to the strongpositive association between resting heart rateand sudden cardiac death in men free frompre-existing ischaemic heart disease.

Heart rate and antihypertensive treatmentIn the 5769 men -with no pre-existingischaemic heart disease, only 155 men wereon antihypertensive treatment of whom eighthad a raised heart rate. The men on treat-ment had a lower mean heart rate (66-7beats/min) than those not on antihypertensivetreatment (705 beats/min). We have there-fore examined the relation between raisedheart rate and risk of sudden cardiac deathexcluding all the 155 men on antihyperten-sive treatment. The strong associationbetween raised heart rate and sudden cardiacdeath remained (RR = 2-8, 95% CI 1-4 to5 8).

MEN WITH PRE-EXISTING ISCHAEMIC HEARTDISEASEFigure 3 and table 4 show the age adjustedrates/1000/year for all major ischaemic heartdisease events, mortality from ischaemic heartdisease, and sudden cardiac death in menwith evidence of ischaemic heart disease(groups II and III) according to resting heartrate. The risk of major ischaemic heart dis-ease events, and in particular of mortalityfrom ischaemic heart disease was increased inthose with raised heart rate (> 90 beats/min).Case fatality rate was also highest in thosewith a raised heart rate (43%, 44%, 38%,36%, and 50% for the five heart rate groups).Table 2 shows the age adjusted relative risk ofmen with a raised heart rate compared withthose with a heart rate below 90 beats/min.The increased risk of major ischaemic heartdisease events and mortality from ischaemicheart disease seen in those with raised heartrate was significant after adjusting for age(table 2; column A). Sudden cardiac deathwas also increased in those with raised heartrate although the difference was not signifi-cant or as noticeable as that seen in thosewith no evidence of ischaemic heart disease

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MajorIHD events IHD mortality

34

68

'Ii 32

Sudden cardiac death

23

1i1

23 19 1

711<60 60- 70- 80- 90+ <60 60- 70- 80- 90+ <60 60- 70- 80- 90+

Heart rate (beats/min)

Figure 3 Age adjusted rates (1000year) for major ischaemic heart disease (IHD) events,

mortality from IHD, and sudden cardiac death in men with pre-existing ischaemic heartdisease in the five heart rate (beatslmin) groups: < 60. = 341 men, 60-69 = 605 men,

70-79 = 482 men, 80-89 = 287, men, > 90 = 199 men. Absolute numbers of events are

indicated.

Table 4 Age adjusted rate (1000/year) for major events, mortality from ischaemic heartdisease (IHD) sudden death, and IHD case fatality (%) in men with pre-existing IHD(groups II and III)

Age adjusted ratesIlOOO/year

Heart rate Major IHD Sudden Case(beats/min) IHD events mortality death fatality(%)

< 60 (341) 13-0 (37) 6-1 (18) 2-4 (7) 43 (16)60-69 (605) 15-4 (73) 8-0 (36) 4-9 (23) 44 (32)70-79 (482) 17-9 (68) 8-6 (32) 5-0 (19) 38 (26)80-89 (287) 12-0 (28) 6-3 (15) 4-6 (11) 36 (10)> 90 (199) 21-3 (34) 14-4 (23) 6-8 (11) 50 (17)

(table 2). Table 2 column B also shows theRR of a raised heart rate (.> 90 beats/min)for ischaemic heart disease events, mortality,and sudden cardiac death adjusted for age,social class, smoking, heavy drinking, systolicblood pressure, blood cholesterol, and bloodglucose. In those with pre-existing ischaemicheart disease, a raised heart rate was associat-ed with a small but non-significant increase inrisk of a major ischaemic heart disease eventafter these adjustments. Risk of mortalityfrom ischaemic heart disease was significantlyincreased in those with an increased heartrate, similar to those without pre-existingischaemic heart disease. The increase in riskof sudden cardiac death in those with raisedheart rate was present but not as noticeable as

that seen in those with no ischaemic heartdisease. A test for interaction did not show a

significant difference in the relation betweenraised heart rate and risk of sudden death inmen with and without pre-existing ischaemicheart disease.

DiscussionIn this study of middle aged men a raisedheart rate (>,90 beats/min) in men with no

evidence of pre-existing ischaemic heart dis-ease was strongly associated with an increasedrisk of major ischaemic heart disease events,mortality from ischaemic heart disease andsudden cardiac death. The increased death

rate from ischaemic heart disease was largelydue to a significant increase in the risk of sud-den cardiac death. This positive associationbetween resting heart rate and death fromischaemic heart disease, and sudden cardiacdeath in particular, has been reported in sev-eral prospective studies. 1-8

OTHER STUDIESIt is well established that a raised heart rate isassociated with hypertension and is stronglyinfluenced by smoking, physical activity, andbody weight, factors associated with risk ofischaemic heart disease. Some studies havefound strong associations between heart rateand blood glucose and blood lipids,911 rela-tions also seen in this study. In some studies,heart rate has been shown to be independent-ly associated with ischaemic heart diseasewhereas others have shown the relation to bedependent on the presence of coronary riskfactors. In the three Chicago studies-Chicago People's Gas Company, the ChicagoHeart Association, and the Western ElectricCompany-all of which excluded men withdefinite ischaemic heart disease, raised heartrate was associated with an increase in risk ofmortality from cardiovascular and ischaemicheart disease and sudden cardiac death. Afteradjustment for age, blood pressure, smoking,blood cholesterol, and body weight, however,the relation with sudden cardiac death onlyremained significant in two of the three stud-ies.' A positive association was still present inthe Western Electric Study but the trend wasnot significant.' In the Kaiser PermanenteStudy a positive association was found withsudden cardiac death but this was largelyaccounted for by the presence of other coro-nary risk factors.7 In the Israeli study thestrong positive association seen between heartrate and five year incidence of myocardialinfarction was also diminished after adjust-ment for the established coronary riskfactors.5 In the NHANES study a significantpositive association was seen with mortalityfrom corojiary heart disease in black meneven after adjustment for the risk factors, butan independent association was not seen inwhite men.4 In the Framingham study, how-ever, raised heart rate remained significantlyassociated with mortality from cardiovascularischaemic heart disease and sudden deatheven after adjustment for the establishedcoronary risk factors.2

THE BRUIISH REGIONAL HEART STUDYOur findings are similar to those found in theFramingham study, which excluded men withovert evidence of ischaemic heart disease atscreening.2 A strong positive association wasseen between raised heart rate and ischaemicheart disease mortality and sudden deatheven after adjustment for age, social class,smoking, heavy drinking, physical activity,systolic blood pressure, blood cholesterol,and blood glucose. The increased risk of mor-tality from ischaemic heart disease was largelydue to an increased risk of sudden cardiacdeath. The positive association with all major

25

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Heart rate, ischaemic heart disease, and sudden cardiac death in middle aged British men

ischaemic heart disease events diminishedafter adjustment, indicating that resting heartrate is more associated with fatal than withnon-fatal events. This was also found in theFramingham study, in which those withraised heart rate were less likely to survive amyocardial infarction and were at greater riskof having a sudden death. In the Chicagostudies raised heart rate was shown to beindependently associated with sudden death.It seems from this study and the Chicago andFramingham studies that raised heart rate isparticularly associated with an increased riskof sudden cardiac death. This is likely toexplain the lack of independent associationseen in several studies where the overall inci-dence of myocardial infarction (fatal andnon-fatal) was used after adjustment for coro-nary risk factors, as we have found in theBritish Regional Heart study. In theGothenburg study, Tibblin et al showed nodifference in heart rate between non-fatalcases and men free of disease, but they notedthat fatal cases had the highest mean heartrate.20

PRE-EXISTING ISCHAEMIC HEART DISEASEIt is well established that heart rate is stronglyassociated with the presence of ischaemicheart disease, and an increased heart rate maybe a reflection of underlying myocardial dam-age. Inclusion of men with evidence ofischaemic heart disease may thus obscure therole of heart rate in the risk of majorischaemic heart disease events. In our studyincreased heart rate was also associated withan increase in risk of mortality fromischaemic heart disease and sudden cardiacdeath in men with pre-existing ischaemicheart disease but the positive relationbetween heart rate and sudden cardiac deathwas less noticeable (table 2). The increasedrisk of fatal attacks may to some degreereflect the severity of the underlying myocar-dial damage.

HEART RATE AND SUDDEN CARDIAC DEATHThe mechanisms by which raised heart ratemight predispose to sudden cardiac death areunclear.2 It has been suggested that the rela-tion may be associated with lack of physicalfitness, lipoprotein profile, and previous car-diovascular health. The strong associationwith sudden cardiac death found in thisstudy, however, remained after excludingmen with evidence of pre-existing ischaemicheart disease and taking account of physicalactivity and blood lipids. Heart rate is oftenassociated with hypertension but in men withno ischaemic heart disease in this study,raised heart rate was associated with anincreased risk in both normotensive andhypertensive subjects. Exclusion of the smallnumber of men on antihypertensive treatmentdid not affect the outcome. The Framinghamstudy suggests that "tachycardia may indicatesubclinical loss of cardiac reserve as a resultof impaired myocardial function leading tohigh fatality rate and increased propensity to

sudden death." The independence of thecorrelation between heart rate and suddencardiac death, and breathlessness and lungfunction in this study suggests that the under-lying mechanism is not a diminished myo-cardial function with early cardiacdecompensation. Neither breathlessness nordiminished FEV1 are adequate measures ofleft ventricular function, and this issueremains to be explored.

In this study of middle aged British men,raised heart rate (> 90 beats/min) is a riskfactor for fatal ischaemic heart disease eventsbut particularly for sudden cardiac death.The effect is not dependent on the presenceof other established coronary risk factors andis most clearly seen in men free of pre-exist-ing ischaemic heart disease at initial examina-tion.

The British Regional Heart study is a British HeartFoundation Research Group and is also supported by theDepartment of Health and the Stroke Association.

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