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Resting Heart Rate and the Risk of Heart Failure in Healthy Adults: The Rotterdam Study Nanchen et al: Resting Heart Rate and Heart Failure David Nanchen, MD, MSc;1 Maarten J.G. Leening, MD, MSc;2,3 Isabella Locatelli, PhD;1 Jacques Cornuz, MD, MPH;1 Jan A. Kors, PhD;4 Jan Heeringa, MD, PhD;2 Jaap W. Deckers, MD, PhD;3 Albert Hofman, MD, PhD;2 Oscar H. Franco, MD, PhD;2 Bruno H.Ch. Stricker, MB, PhD;2,4,5,6 Jacqueline C.M. Witteman, PhD;2 Abbas Dehghan, MD, PhD2 Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 1 Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland 2 Department of Epidemiology, Erasmus Medical Center, Rotterdam, tterdam,, the Ne Net Netherlands 3 Department of Cardiology, Erasmus Medical Center, Rotterdam, rddaam, tthe he N Netherlands ethe ethe et herr 4 Department of Medical Informatics, Erasmus Medical Center, er, Rotterdam, Rott Ro tter tt erda er dam, da m tthe m, Netherlands 5 Department of IInternal nternal Me nt Medi Medicine, dici di cine ci ne,, Er ne Eras Erasmus asmu as muss Med mu Me Medical edica call Ce ca Cent Center, n err, Ro nt Rotterdam, ott tter erda er dam, da m, tthe h Netherlands he 6 Inspectorate off H Health e lth Ca ea Care, are, T The hee H Hague, agu gue, e,, the he N Netherlands ethe herl he rlaands rl dss Correspondencee tto: o: David Nanchen, M MD MD, D M MSc Sc Department of Ambulatory Care and Community Medicine University of Lausanne Rue du Bugnon 44 CH-1011 Lausanne, Switzerland Tel: + 41 21 314 60 53 Fax: +41 21 314 61 08 E-mail: [email protected] DOI: 10.1161/CIRCHEARTFAILURE.112.000171 Journal Subject Codes: Etiology:[8] Epidemiology, Heart failure:[110] Congestive 1 Abstract Background—An elevated resting heart rate is associated with re-hospitalization for heart failure and is a modifiable risk factor in heart failure patients. We aimed to examine the association between resting heart rate and incident heart failure in a population-based cohort study of healthy adults without pre-existing overt heart disease. Methods and Results—We studied 4,768 men and women aged 55 years or older from the population-based Rotterdam Study. We excluded participants with prevalent heart Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 failure, coronary heart disease, pacemaker, atrial fibrillation, atrio-ventricular block, and those using beta-blockers or calcium channel blockers. We used Cox-models sed extended C o allowing for time-dependent variation of resting heart rate along Over a ong ffollow-up. ollo ol l wlo w-up up.. O up median of 14.6 years The risk of yea yea ears of follow-up, foll fo llow ll ow-u ow -up, -u p, 656 656 participants parrti tici c pa pantss developed dev evel eloped elop el opped e heart hea eart rt failure. fai ailu lure lu re. T re heart failure wass higher high hi gher gh err in in men men with with higher hig i he herr resting rest re sttin ng heart hear he art rate. ar rate ra te. For te For ea each ch iincrement nccreem of 10 ncre beats per minute, multivariable ratios e th e, thee mu mult ltiv lt ivar iv aria ar iabl ia blee adjusted bl adju ad j st ju sted ed d hazard haz azar ardd ra ar rati tios ti os iin n me menn we were re 11.16 .16 16 ((95% confidence interval [CI], 1.05-1.28, p=0.005) in the time-fixed heart rate model and 1.13 (95% CI 1.02-1.25, p=0.017) in the time-dependent heart rate model. The association could not be demonstrated in women (p for interaction = 0.004). Censoring participants for incident coronary heart disease, or using time-dependent models to account for the use of beta-blockers or calcium channel blockers during follow-up did not alter the results. Conclusions—Baseline or persistent higher resting heart rate is an independent risk factor for the development of heart failure in healthy older men in the general population. Key Words: resting heart rate, heart failure, population-based, cardiovascular disease 2 Heart failure is a major public health problem that is associated with substantial mortality and morbidity.1 In the aging population of Western countries, the incidence of heart failure hospitalization is increasing despite the improvements in health care for heart failure patients.2 Therefore, it is important to develop strategies to detect adults at risk of heart failure in order to better tailor preventive measures and treatment. Resting heart rate is a very accessible biological parameter with potential predictive capacity for heart failure and cardiovascular disease.3 Among patients Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 suffering from heart failure, resting heart rate is a modifiable risk factor to prevent reassociation ion o between hospitalization for heart failure.4 However, studies examiningg the associati resting heart rate and heart failure have not included adults from rom th thee ge gene general nera ne rall ppopulation,5 ra or have included d aadults dults w with ithh ca it card cardiovascular rdio rd iova io vasc va scul sc u arr ddisease, ul isea easee,6 or or conduction cond co nduc nd u ti tion ion disorders dissor orde derss such as de n 7 oorr adults n, ad duulltss uusing sing si n aanti-arrhythmics ng ntint i-arrh irhyt rh ythm ythm yt hmic iccs orr bbeta-blockers. etaet a-bl abloc bl ocke oc kers ke rs.8 Th rs This iss rresearch e atrial fibrillation, question is important ort ort rtan antt to sstudy an tudy tu dy y iin n a pr pprospective ospe os p ct pe ctiv ivee ma iv mann manner nner nn er bbecause ecau ec ause au se iin n ca card cardiac rdia rd iacc pa ia pat patients, t a subclinical decompensated state might enhance a hemodynamic response that increases heart rate. This biological interaction between resting heart rate and subclinical heart failure may limit the interpretation of the role of heart rate in the etiology of heart failure, because of potential reverse causality. Thus, it is still uncertain whether the association between resting heart rate and heart failure can be extrapolated to healthy adults from the general population. We examined whether higher resting heart rate is independently associated with the development of heart failure among adults without pre-existing heart disease or heartrate modifying medication use in the general population. 3 Methods Study sample This study was performed within the framework of the Rotterdam Study, a prospective population-based cohort study designed to evaluate the determinants and consequences of chronic diseases in the elderly. Details regarding the objectives and methods of the Rotterdam Study have been reported previously.9 Briefly, all inhabitants aged 55 and over of a well-defined suburb in the city of Rotterdam, the Netherlands, were invited to Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 participate and 7,983 (78%) were enrolled. The Medical Ethics Committee of the inf n Erasmus Medical Center approved the study and participants gave written informed m ttheir heir he irr ttreating reat re atin at i consent to participate in the study and to obtain information from rate ra t ly. From F om 1990 Fr 199 9900 until unti un till 1993, ti 119993 9 , baseline baseeli ba line ne data dat a a were w ree collected we col olle lect le ect cted ed using uss physicians, separately. memee-in inte in teerrvvieews and andd established an e ta es tabllis ishe hedd cardiovascular he card ca rd dio iova vasc va scul sc ular ul a risk ar rissk factors fact fa ctor orss were w we standardized home-interviews ses esse sedd at the se the research res esea earc ea rchh center. rc cent ce nter nt er. er subsequently assessed Of the 7,129 individuals in the Rotterdam Study who visited the research center at baseline, heart rate measurement was available for 6,966 participants. To account for endogenous heart rate variation only, we further excluded 873 participants using betablockers and 173 using calcium channel blockers. Because we aimed to examine the association between heart rate and the development of heart failure in participants free of heart disease, we also excluded participants with a pacemaker, second or third degree atrio-ventricular block on the baseline electrocardiogram (ECG), a history of heart failure, atrial fibrillation, and those with known coronary heart disease (CHD) defined as a history of myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention.10 The final sample for analysis comprised 4,768 participants. 4 Measurement of heart rate In all participants, baseline resting pulse was measured for 30 seconds at the right radial artery between two consecutive blood pressure measurements at the research center, with the subject in a sitting position. To obtain heart rate in beats per minute (bpm), the obtained pulse count was multiplied by two. Repeated examinations of heart rate were performed every 3-4 years and were available for 3 additional follow-up visits, from 1993 to 1995, from 1997 to 1999, and from 2002 to 2004. For sensitivity analysis, resting heart Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 rate was further measured from a 10 seconds 12-lead ECG at baseline in 4,127 participants. Repeated measurements of ECG were available for all 3 addit additional tio followup visits. All ECGs were recorded with an ACTA Gnosis IV ECG CG G rrecorder ecor ec orde or derr ((Esaote de Biomedica, Florence, Italy) All enc nce, Ita aly y) att a sampling sam ampl plin pl ingg frequency in frreq e ue uenc nccy of 500 500 0 Hz H aand nd sstored tore to ore redd di ddigitally. g 11 ECGs were processed using the validated modular ECG system c se cesse sedd us usin ingg th in he va ali l da datted m odul od ular ul ar E CG aanalysis n ly na lysi s s sy si syst stem ((MEANS). st stem ME ME MEANS locates th thee QR QRS S co comp complexes mp ple lexe xess an xe andd de dete determines term te rmin rm ines in es a sstable tabl ta blee re bl refe reference fere fe renc re ncee po nc poin point intt in each in complex. The QRS detector of MEANS operates on multiple simultaneously recorded leads, which are transformed to a detection function that brings out the QRS complexes among the other parts of the signal. RR intervals are taken as the intervals between the reference points in adjacent QRS complexes. The median RR interval was computed, after exclusion of RR intervals that immediately precede and follow any premature ventricular complex. Heart failure assessment Prevalent and incident heart failure was determined as defined previously.1, 10, 12 For prevalent cases, a validated score was used based on the heart failure definition of the 5 European Society of Cardiology.13 This score was based on the presence of at least two signs or symptoms suggestive of heart failure or use of medication for the indication of heart failure.10 Cases of incident heart failure were obtained by continuously monitoring participants during follow-up through automated linkage with files from general practitioners. All available data on heart failure, such as hospital discharge letters and notes from general practitioners, were copied from the medical records. Heart failure was adjudicated in accordance with the criteria of the European Society of Cardiology13 based Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 on the combination of signs and symptoms, and objective evidence of cardiac y. Two indep pen end research dysfunction, including chest radiographs or echocardiography. independent disa s gr sa gree eeme ee m the physicians adjudicated all potential heart failure cases. In casee off di disagreement ard ard rdiiologiistt was was sought sou ough ghtt and gh and considered c nssid co der ered red ddecisive. ecis ec isiv is ive.10 O iv Only n y de nl defi definite finii and fi judgment of a cardiologist o heart hear he a t failure ar fail fa illur uree were weree included inc nclu ude dedd inn the the analyses. ana naly lyse ly ses. se s Th Thee date date of of incident inci in ci probable cases of heart failure was the fi first irs rstt oc occu occurrence curr cu rren rr ence en ce of ssymptoms y pt ym p om omss su sugg suggestive gges gg esti es tive ti ve ooff he hear heart artt fa ar fail failure, ilur il uree, oorr th ur the h day of receipt of a first prescription of a loop diuretic or an angiotensin-converting enzyme inhibitor for heart failure. For the present analysis, incident heart failure was adjudicated until 1st January, 2009. Covariables Hypertension was defined as a systolic blood pressure 140 mmHg or a diastolic blood pressure 90 mmHg or use of blood pressure lowering drugs with the indication of hypertension. Diabetes mellitus was defined as a random or post-load blood glucose measurement exceeding 11.0 mmol/L, or the use of anti-diabetic drugs. Body mass index was calculated by dividing measured weight by height squared. Assessment of incident 6 fatal and non-fatal CHD has been previously described.10 For the present analysis, incident CHD events, including myocardial infarction and myocardial revascularization procedures have been adjudicated until 1st January, 2009. For all medication use from 1st January 1991 onwards, eight fully automated pharmacies in the research area provided data on use, dosage, duration of use, and date of first prescription, using a single computer network to register all prescriptions, as previously described.9, 10 Moreover, data on medication use were collected during the baseline home interview. Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 Statistical analysis es. This Thi hiss was was done donn separately do Resting heart rate values at baseline were grouped into tertiles. for men and women, m n, because men me beccau ause s women wom omen en are are known kno n wnn too have no have a hhigher igheer re ig rest resting s in ng he hear heart r rate than ANO NOVA VA and and Ȥ2 tes tests ests es tss orr th thee Kr Krus Kruskal-Wallis uska us kalka l-Wa lWall Wa llis ll is rank ran a k test tesst were te wer eree used u for men.14 One-way ANOVA baseline comparisons iso sons ns bbetween etwe et ween we en ttertiles. erti er tile less. W Wee ccalculated alcu al cula cu late tedd in te inci incidence cide denc ncee ra nc rate rates tess pe te pperr 11,000 ,00 00 0 personyears of follow-up in participants categorized according to their resting heart rate and constructed Kaplan-Meier cumulative incidence curves. The associations between baseline resting heart rate and heart failure were examined in a time-fixed analysis using multivariable Cox proportional hazard models. A quadratic mixed-effect model was used to estimate change in average heart rate per year of follow-up. Among different polynomial models, we chose the quadratic one which minimized the BIC criterion. Moreover, we used an extension of the Cox model allowing for introduction of repeated measurements of heart rate over time in a time-dependent analysis.15 With this version of the Cox model, the risk of event at any time t depends upon the last available measure of heart rate before time t. 7 P for trend across categories was obtained by entering heart rate tertiles as a continuous variable. In the first model, we only adjusted for age. In the second model, we entered traditional cardiovascular risk factors, including age, smoking status, systolic blood pressure, antihypertensive treatment, diabetes mellitus, body mass index, total cholesterol, and high-density lipoprotein cholesterol.16 Among participants, 302 (6.3%) had missing values for one or more covariables. The multivariable adjusted analysis was restricted to those participants with complete information on cardiovascular risk factors at Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 baseline. Participants were followed until the occurrence of heart failure, death, or the etween heart rrate a and at end of the study period. In order to evaluate the association between nally ly y ccensored e so en sore redd pparticipants at re incident heart failure not mediated through CHD, we additionally of nnon-fatal on-faataal CH HD D..17 F Furthermore, urth ur th herrmo m ree, we cconducted ondu on d ct du cted e ttime-dependent imeim e de depe pend pe n analyses the occurrence of CHD. oci oci ciat atio at i n between io betw be tw wee eenn heart hear he arrt rate raate and and incident inci in cide ci dent de nt heart hea e rt rt ffailure ailu ai lure lu re nnot o m ot ed to assess the association mediated by the use of heart rate influencing infl in flue fl uenc ue ncin nc ingg medication, in medi me dica di cati ca tion ti on,, as the on the indication indi in dica di cati ca tion ti on for for the the pr pprescription escr es crip cr ipti ip tion ti onn of betablockers or calcium channel blockers might be associated with the risk of heart failure and these medications affect resting heart rate measurements. This was done by changing the exposure of the participants whenever they filled-out a prescription of beta-blockers or calcium channel blockers during follow-up.18 In the sensitivity analyses, we repeated all analyses using time-fixed and time-dependent resting heart rate measured by ECG, since ECG-derived heart rate is more accurate.19 We report estimates with 95% confidence intervals (CIs). All hypothesis tests are two-sided and the significance level set at 5%. Statistical analyses were performed using STATA statistical software® (Version 12, STATA Corp, College Station, Tex) and R (Version 2.15.2, http://www.rproject.org). 8 Results Gender-specific baseline characteristics with respect to resting heart rate categories are presented in Table 1. Mean age of the participants was 68.5 years and 62% were females. In men, heart rate was 68 bpm or less for the first tertile, 69 to 78 bpm for the second tertile, and 79 bpm or more for the third tertile. In women, these rates were 72 bpm or less, 73 to 80 bpm, and 81 bpm or more, respectively. Participants in the highest heart rate tertile were more likely to smoke, and to have elevated blood pressure, and diabetes Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 mellitus. No differences in the use of anti-hypertensive drugs was found across heart rate categories, but a higher heart rate was more frequently noted in male userss of o antiasthmatics and female users of oral corticosteroids. Average resti resting tiing hheart eart ea rt rrate at decreased similarly in both during tended h ge genderss du duri ing ffollow-up, olllo low w-u up, bbut ut ten en nde dedd to o sstabilize taabi b lize ze oover verr ti ve time me me (Supplemental Figu Figure). F ure re). ) ). During a m median edia ed iann (i ia ((interquartile nter nt erqu er q ar qu arti tile ti le range) rangge) 14.6 14.66 (7.6) (7.6) 6) years y ar ye arss of follow-up, fol ollo lowlo w-up wup, 656 up 6 participants developed incident heart failure. Crude incidence rates of heart failure were higher in men with higher heart rate than in men with lower heart rate, with 13.7 versus 9.9 per 1,000 person-years. In women, crude incidence rates of heart failure were similar across heart rate categories, except when heart rate was measured with ECG (Figure). Accordingly, there were remarkable differences in adjusted hazard ratios (HRs) between men and women. The multiplicative interaction term between heart rate as a continuous variable and gender was significant both in the age- and gender adjusted model (p=0.011) and in the multivariable adjusted model (p=0.004). For each increment of 10 beats per minute, the multivariable adjusted HRs in men were 1.16 (95% confidence interval [CI], 1.05-1.28) in the time-fixed heart rate model and 1.13 (95% CI 1.02-1.25) in the time- 9 dependent heart rate model (Table 2). Further adjustment for use of anti-asthmatic drugs and corticosteroids use did not change the estimates. In women, resting heart rate was not associated with a higher heart failure risk (Table 2). To assess the heart failure risk not mediated by CHD, we additionally censored 328 participants at the occurrence of non-fatal CHD during follow-up. This yielded similar results (Table 3). We also examined the risk of heart failure taking into account follow-up time until the first prescription of common heart rate lowering drugs. This Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 represented 1,700 first prescriptions, including 248 prescriptions prior to the diagnosis of heart failure. In this analysis, men with a heart rate in the upper compared to those per tertile comp mpaa mp with a heart rate in the lower tertile had a higher risk of heart failu failure with multivariable lu ure w ithh a m it adjusted HR of 1.4 CII 11. 1.08 11.47, .477, 95% .4 %C .08 tto o 2.01 2.01 2. 01. Re Relative R lati tive vee risk risk issk estimates esti es tima ti matees were ma we e not not significant sii and omen ((Table om Tabl Ta ble 33) ). unchanged in women 3). Sensitivity analysis (heart rate measured with ECG) Using resting heart rate measured by ECG instead of pulse measurement, baseline heart rate was generally somewhat lower resulting in 62 bpm or less for the first tertile, 63 to 73 bpm for the second tertile, and 74 bpm or more for the third tertile in men, and 69 bpm or less, 69 to 76 bpm, and 77 bpm or more in women, respectively (Supplemental Table). However, for each increment of 10 bpm in men, we still found a significant 13% higher heart failure rate for the time-fixed heart rate model and 18% higher rate for the timedependent heart rate model (Table 4). In women, the association did not reach statistical significance in the multivariable models. Further excluding 10 men and 7 women with a resting heart rate lower than 50 bpm, e.g. with bradycardia, yielded similar results. 10 Discussion In a large population-based cohort study of healthy adults, higher resting heart rate measured with pulse palpation (and alternatively by ECG) was independently associated with incident heart failure in men during follow-up, and this association was not mediated through overt CHD. The association was found significant in men both with single and repeated heart rate measurement over time. In women, the association could not be Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 demonstrated. Our study highlights the importance of resting heart rate as an independent marker of future heart failure in middle-aged and older healthy hy men from tthe h general he population. Previous sstudies reported that rate tu udies hhave ave re av repo porrte po tedd th hat a hheart e rt rat ea atte is a prognostic p og pr ogno ost stic icc and nd potentially pot oe modifiable marker k r in patients ker pat atie ient ie ntss suffering nt suufffer erin ingg from in from heart hea eart rt failure fai ailu lure lu re or or CHD. CHD CH D.3 IIn n a co convenient onv sample of patients nts w with ithh CH it CHD, D, D Diaz iazz an ia andd co coll colleagues lleeag ll gue uess de demo demonstrated mons mo nstr ns trat tr ated at ed tthat hatt he ha hear heart artt ra ar rate a was associated with incident heart failure hospitalization.5 However, both the basic hemodynamic response to a decompensated state and the excessive neuroendocrine activation cause tachycardia in patients with subclinical heart failure.20 Thus, the etiologic nature of the association between heart rate and incident heart failure can only be examined in subjects without pre-existing overt cardiac disease at baseline. In line with our results, investigators from the EPIC-Norfolk study recently reported on a positive association between a single heart rate measurement and heart failure in middleaged adults from the general population.7 In addition to the EPIC-Norfolk study, we could demonstrate that the association was not influenced by variation of resting heart rate over time or by the measurement method used to assess heart rate. Furthermore, 11 participants of the EPIC-Norfolk study may still have had subclinical heart disease, because they relied on use of medication only to define prevalent heart failure cases, as well as self-reported CHD, and they did not exclude adults with pre-existing atrial fibrillation or other conduction disorders based on ECG. Finally, the EPIC-Norfolk study examined only incident heart failure hospitalization, without including diagnoses of heart failure made by general practitioners or nursing home physicians as in our study. As confirmed in our data, resting heart rate is higher in women than in men.14 Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 Gender differences have also been proposed in heart failure etiology: in men CHD is en hypertension on plays a more considered the most important determinant, whereas in women owed ed d a stronger sttro stro rong nger ng e association predominant role.21 In our study sample, resting heart rate showed in men than in women wom wom omen for orr the the development dev evel elop el opme op mennt of me o heart heart rtt failure, fai ailu uree, but b t hy bu hype hypertension pertten pe ensi sion si on was associated with inci iincident cide ci dent de nt hheart eart ea r ffailure rt a lu ai ure r bo bboth th iin n me menn an andd wo wome women menn wi me with without thou th outt a si ou significant ign gnii gender differencee (p ffor or iinteraction nter nt erac er acti ac tion ti on 00.77). .77) 77)). Re Rest Resting stin st ingg he in hear heart artt ra ar rate te iin n wo wome women menn ma me mayy bbe less precise due to more important endogenous variations and previous experiences with cardiac volume overload during pregnancy. Indeed, the healthy female heart might have an advantage to adapt to elevated heart rate and volume overload related to pregnancy, offering protection against heart failure.22 Our results are in line with those from the EPIC-Norfolk study examining adults from the general population, in which the investigators could not find a statistically significant association between heart rate and heart failure in women not taking heart rate lowering drugs, with a p for trend of 0.055 across heart rate categories.7 We could further demonstrate that higher heart rate was an independent marker of heart failure that was not preceded by CHD, or by the use of beta-blockers or calcium 12 channel blockers during follow-up. Through mechanisms linked to oscillatory shear stress in the coronary arteries, an elevated heart rate might promote coronary atherosclerosis.3 In our study, it seems unlikely that the higher incidence of heart failure that we observed in adults with a higher heart rate was mediated by CHD. Current guidelines for the prevention of heart failure classify heart rate as a minor clinical risk factor, probably because the pathophysiological pathways between heart rate and heart failure remain speculative.23 Recently, two clinical trials reported the additional benefit of Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 a specific heart rate lowering drug on outcomes in patients with heart failure and heart men seemed too derive d equal rate above 75 bpm.24, 25 Interestingly, in the SHIFT trail, women benefit than men from the heart rate lowering drug to avoid re-hospitalization e-ho ospi pita taali liza zati za tion ti o for heart failure.25 Specific ic hheart ic eart ra rate tee red reducing educ ed ucin uc ng th ther therapy e ap er py sh should hould ld bbee co cconsidered ons nsid ns sid i erred ffor orr eevaluation valu va l a in ithh elevated elev el ev evat vated ted heart hea eart r rate rat atee to to prevent prev pr even ev en nt or ppostpone ostp os tpon tp onee th on thee development deve de velo lopm pm pmen men of heart healthy adults with failure. Strengths of our study include the large sample size in a population-based setting with a long follow-up, the repeated measurement of resting heart rate over time, the concurrent assessment of resting heart rate by means of both arterial pulse and ECG recording, as well as the large number of heart failure cases adjudicated using standardized definitions. The detection of heart failure relied not only on hospitalization, but also included diagnoses of heart failure made by general practitioners and nursing home physicians. This systematic approach potentially reduced selection of severe cases only. Previous studies have evaluated risk factors for incident heart failure based on ECG measurement.6, 8 The ECG provides important clinical information other than heart rate, such as presence of left ventricular hypertrophy, bundle branch blocks, or ST-T 13 abnormalities that might together improve cardiovascular risk prediction.26 In our study, we showed that a single or repeated assessment of heart rate based on arterial pulse was sufficient to identify men at higher risk of developing heart failure. However, our study also has some limitations. The association between heart rate and heart failure in our population of healthy older adults suggests that heart rate is not merely a surrogate marker of an underlying process leading to heart failure. However, even with a comprehensive assessment of traditional cardiovascular risk factors, we cannot rule out Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 residual confounding. For example, we could not account for the circadian variation of iation of heartt rrate a is small resting heart rate in our analyses. However, the circadian variation ults.27 S Similarly im mil ilar arly ar ly to previous between 10 AM and 6 PM, and tends to diminish in older adults. reports,6, 8 we were ere also unable ere un nab a le to to account accco coun untt for un forr the fo th he degree degr de gree gr ee of of physical physsic ph ical al activity act ctiv ivit iv ityy performed it a t, and ant andd therefore there heere r fo fore r the the h associations asssoci ciat atio at io ons n found fou ound nd with wiitth heart hear he artt rate ar rraate t may may y be by each participant, confounded by ph pphysical phys ysic ys ical ic al ffitness. itne it ness ne ss. Fi ss Fina Finally, nall na lly, ll y we ccould y, ould ou ld nnot ot aassess sses ss esss ca es card cardiac rdia rd iacc ch ia chan changes ange an gess or ge differentiate between echocardiographic systolic and diastolic dysfunction in our study. Therefore, further studies should better characterize healthy men and women with elevated heart rate, for instance using echocardiography or B-type natriuretic peptide measurements. In conclusion, in our population-based study of adults free of heart disease, both single and repeated measurements of resting heart rate based on pulse palpation or alternatively ECG identifies men at higher risk of developing heart failure, beyond other cardiovascular risk factors. Whether healthy older individuals with higher resting heart rate might benefit from preventive therapy that specifically reduces heart rate remains to be explored. 14 Acknowledgements The dedication, commitment, and contribution of inhabitants, general practitioners, and pharmacists of the Ommoord district to the Rotterdam Study are gratefully acknowledged. Sources of Funding This research was supported by the Swiss National Science Foundation [grant number Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 PBLAP3-132943 to DN], the Netherlands Organization for Scientific Research (NWO) and the Netherlands Organization for Health Research and Development (ZonMw) [Vici evelopment (Z Zo grant number 918-76-619; Veni grant number 916-12-154; ZonMw 80onM Mw grant gran gr antt number an n m nu 82500-98-10208]. 8]. 8]. ] The Rotterdam erdam erda dam da m Study Stud St udyy is ud is funded funnde dedd by Erasmus Era rasm sm muss Medical Med edic ical ic aall Center Cen nte terr and an nd Erasmus Erraass Eras University Rotterdam; erd rdam am;; The am The Netherlands Neth Ne ther th erla er land la ndss Organization nd Orga Or gani ga niza ni zati za tion ti on for for the the Health Hea ealt lthh Research lt Rese Re sear se arch ar ch h and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. None of the funders had any role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Disclosures None. 15 References 1. 2. Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 3. 4. 5. 6. 7. 8. 9. 10. 11. Bleumink GS, Knetsch AM, Sturkenboom MCJM, Straus SMJM, Hofman A, Deckers JW, Witteman JCM, Stricker BHCh. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. Eur Heart J. 2004;25:1614-1619. 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An Analysis time-varying HChh, S HC tijn ti j en T jn Anal alys al ysis ys is of iindividual ndiv nd ivid iv idua id uall dr ua drug ugg uuse se aass a ti time me-v me -v v determinant studies. antt of eexposure an xpos xp osur uree in i pprospective rosp ro spec ecttiv i e population-based popu po pula l ti la tion on-b -b bas ased ed d ccohort oh hor ortt st studi stud udii Eur J ud Epidemiol. 2010;25:245-251. Palatini P, Benetos A, Grassi G, Julius S, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G, Pessina AC, Ruilope LM, Zanchetti A. Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting. J Hypertens. 2006;24:603-610. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-823. Lam CS, Carson PE, Anand IS, Rector TS, Kuskowski M, Komajda M, McKelvie RS, McMurray JJ, Zile MR, Massie BM, Kitzman DW. Sex differences in clinical characteristics and outcomes in elderly patients with heart failure and preserved ejection fraction: the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial. Circ Heart Fail. 2012;5:571-578. Martínez-Sellés M. What Do Women Have In Their Hearts? Rev Esp Cardiol. 2007;60:1118-1121. Schocken DD, Benjamin EJ, Fonarow GC, Krumholz HM, Levy D, Mensah GA, Narula J, Shor ES, Young JB, Hong Y. Prevention of Heart Failure. Circulation. 2008;117:2544-2565. 17 24. 25. 26. 27. Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807-816. 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Baseline characteristics by gender-specific resting heart rate Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 Men (n=1,829) First Second Third tertile tertile tertile (n=571) (n=1,221) (n=837) (n=881) 74 (69-78) 86 (79-128) 68 (40-72) 76 (74-80) 88 (81-128) 67.4 (8.1) 67.6 (8.1) 67.2 (8.3) 0.62 0.662 69.3 6 (9.7) 69 68.9 (9.4) 69.1 (9.4) 0.61 Never 60 (8.7) 47 (8.6) (8.66) (8 47 (8. 8 6) 48 (8.6) <0.0001 <0 <0.001 640 (53.8) 640 417 (51.8) 450 (52.9) 0.38 Former 452 (65.5)) 3335 3 ((61.4) 35 61.4 61.44) 287 28 87 (5 ((51.3) 1. 1.3) 343 343 (28.8) 238 (29.6) 209 (24.6) Current 181 (26.1) 164 (30.0) 224 (40.1) 206 (17.3) 149 (18.5) 191 (22.5) 289 (40.9) 257 (46.6) 293 (51.4) 0.001 599 (49.1) 386 (46.2) 493 (56.0) <0.001 37 (5.3) 51 (9.3) 60 (10.5) 0.001 86 (7.1) 65 (7.9) 105 (12.0) <0.001 Resting heart rate, median bpm (range) First Second Third tertile tertile tertile (n=706) (n=552) 64 (40-68) Women (n=2,939) P-value P-value Demographics Age, years Smoking status, No. (%) Comorbidities Hypertension, No. (%)1 Diabetes mellitus, No. (%)2 19 Objective measures Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 Systolic blood pressure, mmHg 136 (21) 138 (21) 140 (22) 0.009 137 (23) 137 (22) 141 (22) <0.001 Diastolic blood pressure, mmHg 73 (11) 75 (12) 76 (12) <0.001 72 (11) 72 (11) 74 (12) 0.052 Body mass index, kg/m2 25.5 (2.9) 25.6 (3.0) 25.2 (3.0) 0.044 26.5 (3.8) 26.3 (4.0) 26.5 (3.9) 0.37 Total cholesterol, mmol/L 6.3 (1.1) 6.3 (1.3) 6.3 (1.2) 0.70 6.8 (1.2) 6.9 (1.2) 6.9 (1.3) 0.47 HDL-cholesterol, mmol/L 1.3 (0.3) 1.2 (0.3) 1.2 (0.3) 0.144 1.5 (0.4) 1.5 (0.4) 1.5 (0.4) 0.37 88(14) 88 (15) 89 (22) 0.16 77 (14) 76 (14) 76 (13) 0.81 Anti-hypertensive drugs, No. (%) 57 (8.1) 52 (9.4) 52 (9.1) 0.67 0.67 221 22 (18.1) 124 (14.8) 151 (17.4) 0.139 Anti-asthmatics, No. (%) 39 (5.5) 30 (5.4) (5.4) 64 (11.2) (111.2) 00.002 0. 002 40 (3.3) 29 (3.5) 46 (5.2) 0.184 Corticosteroids, No. (%) 11 (1.6) 10 (1.8) ( .88) (1 177 (3.0) (3. 3 0) 0.45 0.4 .45 10 1 (0.8) 8 (1.0) 31 (3.5) <0.001 Thyroid therapy, No. (%) 1 (0.1) 3 (0.5) 2 (0.4) (0. 0.4) 4) 0.63 477 (3.8) 28 (3.3) 32 (3.6) 0.76 Creatinine, μmol/L Medication use Data are given as mean (standard deviation) unless unl nles esss otherwise otthe herw rwis rw isee indicated. is iindicated in ndi dica c te ca tedd 1 Defined as a systolic blood pressure 140 mmHg or diastolic blood pressure 90 mmHg or use of blood pressure lowering drugs for the indication of hypertension. 2 Defined as a random or post-load blood glucose measurement of 11.1 mmol/L or the use of anti-diabetic drugs. Abbreviations: bpm, beats per minute; HDL, high-density lipoprotein. 20 Table 2. Heart failure risk for each increment of 10 bpm for time-fixed versus time-dependent heart rate measurement during followDownloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 up Men (n= 1,829) Women (n=2,939) N events HR 95% CI P-value N events HR 95% CI P-value 261 1.14 1.16 1.14 (1.04 ; 1.26) (1.05 ; 1.28) (1.03 ; 1.27) 0.008 0.005 .005 0.012 .01 0112 395 0.97 0.95 0.94 (0.89 ; 1.05) (0.87 ; 1.04) (0.86 ; 1.03) 0.45 0.27 0.21 2611 1.15 1.1 . 5 1.13 1.11 1. .11 (1.0 (1 (1.04 .044 ; 1.27) .0 1 27 1. 27)) (1.02 (1. 1 02 0 ; 11.25) .225) 5 (1.00 (1. 1.00 0 ; 11.22) 00 . 2)) .2 0.005 0.00 0. .00 005 00.017 0. 017 0.05 0. 05 395 3 1.04 0.98 0.98 (0.95 ; 1.13) (0.90 ; 1.07) (0.89 ; 1.07) 0.41 0.72 0.58 Baseline heart rate Age adjusted Multivariable adjusted1 Additionally adjusted for treatment2 Time-dependent heart rate Age adjusted Multivariable adjusted1 Additionally adjusted for treatment2 1 Adjusted for age, smoking status, systolic blood pressure, diabetes, body mass index, total cholesterol, high-density lipoprotein cholesterol, and antihypertensive treatment. 2 Additionally adjusted for systemic corticoid and anti-asthmatic treatment. Abbreviations: N, number; HR, hazard ratio; CI, confidence interval; 21 Table 3. Hazard ratios for developing heart failure, with respect to gender-specific baseline resting heart rate tertile, and after Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 considering heart rate modifying medication during follow-up, or censoring at the occurrence of myocardial infarction Men (n=1,829) Women (n=2,939) First tertile Second tertile Third tertile First tertile Second tertile Third tertile Heart rate Heart rate Heart rate Heart rate Heart rate Heart rate <69 bpm 69-78 bpm 79 bpm <73 bpm 73-80 bpm 81 bpm Number of events 84 89 88 17 172 110 113 Incidence rate, per 1,000 9.9 13.6 13.7 111.0 1 10.4 10.8 Age adjusted HR 1.00 1.36 1. 1.36 3 1.48 1. .48 1.00 1.0 1. 0 1.00 1.00 (95% CI) (ref) (1.01 01 ; 1. 1.83 1.83) 83)) 83 (1 (1.10 1.1 10 ; 2. 22.00) 00 0) (re (r (ref) e (0.78 ; 1.26) (0.79 ; 1.26) Multivariable adjusted HR 1.00 1.35 1.51 1.00 0.99 0.98 (95% CI)1 (ref) (0.99 ; 1.84) (1.11 ; 2.07) (ref) (0.77 ; 1.27) (0.76 ; 1.26) 1.00 1.34 1.48 1.00 0.99 0.99 (ref) (0.98 ; 1.83) (1.09 ; 2.03) (ref) (0.77 ; 1.28) (0.77 ; 1.27) 1.00 0.99 1.00 (ref) (0.78-1.26) (0.79-1.27) 1.00 0.98 0.99 (ref) (0.76-1.26) (0.77-1.27) P for trend P for trend person-years Additionally adjusted for 2 treatment HR (95% CI) 0.009 0.00 0. 0099 00 0.009 0.013 0.97 0.86 0.92 Using the prescription of beta-blockers and calcium channel blockers as time-dependent variables Age- adjusted HR 1.00 1.31 1.41 (95% CI) (ref) (0.97-1.77) (1.05-1.91) Multivariable adjusted HR 1.00 1.32 1.47 (95% CI)1 (ref) (0.97-1.80) (1.08-2.01) Censoring participants at the occurrence of coronary heart disease 22 0.022 0.014 0.98 0.93 Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 Number of events 74 76 76 Age adjusted HR 1.00 1.31 1.46 (95% CI) (ref) (0.95-1.81) (1.06-2.00) 1.00 (ref) 1.33 1.56 (0.95-1.86) (1.12-2.19) Multivariable adjusted HR 1 (95% CI) 1 0.020 0.009 103 105 1.00 (ref) 0.99 0.98 (0.77-1.26) (0.77-1.25) 0.97 0.96 (0.75-1.27) (0.74-1.25) 1.00 (ref) Adjusted for age, smoking status, systolic blood pressure, diabetes mellitus, body mass index, total cholesterol, high-density lipoprotein cholesterol, and antihypertensive treatment. 2 162 Additionally adjusted for systemic corticoid and anti-asthmatic treatment. Abbreviations: HR, hazard ratio; CI, confidence nce cee iinterval; nter nt erva er v l; bpm, beats per p r minute. pe minuutee. 23 0.86 0.76 Table 4. Heart failure risk for each increment of 10 bpm for time-fixed versus time-dependent heart rate measurement during followDownloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 up, as measured by ECG (n=4,127) Men (n= 1,574) Women (n=2,553) N events HR 95% CI P-value N events HR 95% CI P-value 219 1.17 1.13 11.12 1. 12 (1.05 ; 1.30) (1.01 ( ; 1.26)) ((1.00 1.00 1. 00 ; 11.25) .25)) .2 0.004 4 0.030 0 00.053 .0 .053 053 33 338 1.07 1.01 1.00 (0.97 ; 1.17) (0.91 ; 1.11) (0.90 ; 1.10) 0.165 0.91 0.93 219 1.21 1.21 21 11.18 18 1.16 (1.10 (1.110 ; 1.34) (1 1 34 1. 34)) (1.06 ((11 06 ; 11.31) 331) 1) (1.05 ; 1.29) <0 <0.001 0.0 .001 001 00.002 0022 00 0.005 338 33 3 1.09 1.02 1.01 (1.00 ; 1.19) (0.93 ; 1.12) (0.92 ;1.11) 0.047 0.72 0.86 Baseline heart rate Age adjusted Multivariable adjusted1 Additionally adjusted for treatment2 Time-dependent heart rate Age adjusted Multivariable adjusted1 Additionally adjusted for treatment2 1 Adjusted for age, smoking status, systolic blood pressure, diabetes, body mass index, total cholesterol, high-density lipoprotein cholesterol, and antihypertensive treatment. 2 Additionally adjusted for systemic corticoid and anti-asthmatic treatment. Abbreviations: N, number; HR, hazard ratio; CI, confidence interval. 24 Figure Legend Figure Cumulative incidence of heart failure according to tertile of baseline heart rate, by gender a) Heart rate measured at the radial artery for 30 seconds (n=4,768) b) Heart rate measured from a 10 second ECG (n=4,127) Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 25 Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 Resting Heart Rate and the Risk of Heart Failure in Healthy Adults: The Rotterdam Study David Nanchen, Maarten J.G. Leening, Isabella Locatelli, Jacques Cornuz, Jan A. Kors, Jan Heeringa, Jaap W. Deckers, Albert Hofman, Oscar H. Franco, Bruno H.Ch. Stricker, Jacqueline C.M. Witteman and Abbas Dehghan Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 6, 2017 Circ Heart Fail. published online April 18, 2013; Circulation: Heart Failure is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-3289. Online ISSN: 1941-3297 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circheartfailure.ahajournals.org/content/early/2013/04/18/CIRCHEARTFAILURE.112.000171 Data Supplement (unedited) at: http://circheartfailure.ahajournals.org/content/suppl/2013/04/18/CIRCHEARTFAILURE.112.000171.DC1 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Heart Failure can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. 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Incidence rates and hazard ratios for developing heart failure, with respect to gender-specific resting heart rate tertile, as measured by baseline ECG (n=4,127) First tertile Men (n=1,574) Third tertile Heart rate <63 bpm Heart rate 63-73 bpm Heart rate ≥74 bpm 60 66 93 Incidence rate, per 1,000 person-years 8.9 10.3 16.3 Age adjusted HR (95% CI) 1.00 (ref) 1.12 (0.79-1.59) 1.66 (1.20-2.29) 0.002 Multivariable adjusted HR (95% CI)1 1.00 (ref) 1.07 (0.74-1.54) 1.50 (1.07-2.11) 0.015 Additionally adjusted for treatment2 1.00 (ref) 1.07 (0.74-1.54) 1.46 (1.04-2.06) 0.023 Heart rate <69 bpm Heart rate 69-76 bpm Heart rate ≥77 bpm Number of events 104 110 124 Incidence rate, per 1,000 person-years 8.5 10.4 12.4 Age adjusted HR (95% CI) 1.00 (ref) 1.08 (0.82-1.41) 1.20 (0.93-1.56) 0.166 Multivariable adjusted HR (95% CI)1 1.00 (ref) 0.98 (0.74-1.30) 1.05 (0.80-1.39) 0.69 Additionally adjusted for treatment2 1.00 (ref) 0.98 (0.74-1.30) 1.05 (0.80-1.39) 0.70 Adjusted for age, smoking status, systolic blood pressure, diabetes, body mass index, total cholesterol, high-density lipoprotein cholesterol and antihypertensive treatment. 2 P for trend Number of events Women (n=2,553) 1 Second tertile Additionally adjusted for systemic corticoid and anti-asthmatics treatment. Abbreviations: HR, hazard ratio; CI, confidence interval, ECG, electrocardiograph; bpm, beat per minute.