Relation of Short-Term Heart Rate Variability to Incident Heart Failure (from the Multi-Ethnic Study of Atherosclerosis)

      Whether autonomic dysfunction predates the development of symptomatic heart failure (HF) or is simply a consequence of severe HF is unknown. We hypothesized that reduced heart rate variability (a marker of abnormal autonomic function) at baseline is associated with incident HF in subjects free of clinically recognized cardiovascular disease. In the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of subclinical cardiovascular disease in adults aged 45 to 84 years, we measured the heart rate variability using a standard 30-second, 12-lead electrocardiogram to measure the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences in RR intervals (RMSSD). During a median follow-up of 7.6 years, 95 participants developed HF (incidence rate 2.7/1,000 person-years). After adjusting for age, gender, and ethnicity, the hazard ratio for incident HF stratified by the RMSSD tertile was 2.4 (95% confidence interval 1.4 to 4.2) for the lowest tertile and 1.7 (95% confidence interval 1.0 to 3.2) for the middle tertile (highest tertile was the referent group; p for trend <0.001). The inverse association between the RMSSD and incident HF persisted after adjustment for additional covariates, including diabetes, systolic blood pressure, heart rate, subclinical atherosclerosis, left ventricular end-systolic volume, interim myocardial infarction, and high-sensitivity C-reactive protein (p for trend = 0.009). A similarly significant inverse association was also observed for SDNN. In conclusion, baseline autonomic dysfunction was a risk factor for the development of HF in a multiethnic cohort. These population-based findings implicate autonomic dysfunction in the pathogenesis of HF, and decreased short-term heart rate variability might be a novel form of stage B (asymptomatic) HF.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Palatini P.
        • Julius S.
        Relevance of heart rate as a risk factor in hypertension.
        Curr Hypertens Rep. 1999; 1: 219-224
        • Palatini P.
        Heart rate as a risk factor for atherosclerosis and cardiovascular mortality: the effect of antihypertensive drugs.
        Drugs. 1999; 57: 713-724
        • Bilchick K.C.
        • Fetics B.
        • Djoukeng R.
        • Fisher S.G.
        • Fletcher R.D.
        • Singh S.N.
        • Nevo E.
        • Berger R.D.
        Prognostic value of heart rate variability in chronic congestive heart failure (Veterans Affairs' Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure).
        Am J Cardiol. 2002; 90: 24-28
        • La Rovere M.T.
        • Pinna G.D.
        • Maestri R.
        • Mortara A.
        • Capomolla S.
        • Febo O.
        • Ferrari R.
        • Franchini M.
        • Gnemmi M.
        • Opasich C.
        • Riccardi P.G.
        • Traversi E.
        • Cobelli F.
        Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients.
        Circulation. 2003; 107: 565-570
        • Makikallio T.H.
        • Huikuri H.V.
        • Hintze U.
        • Videbaek J.
        • Mitrani R.D.
        • Castellanos A.
        • Myerburg R.J.
        • Moller M.
        Fractal analysis and time- and frequency-domain measures of heart rate variability as predictors of mortality in patients with heart failure.
        Am J Cardiol. 2001; 87: 178-182
        • Soejima K.
        • Akaishi M.
        • Meguro T.
        • Oyamada K.
        • Yoshikawa T.
        • Mitamura H.
        • Ogawa S.
        Age-adjusted heart rate variability as an index of the severity and prognosis of heart failure.
        Jpn Circ J. 2000; 64: 32-38
        • De Jong M.J.
        • Randall D.C.
        Heart rate variability analysis in the assessment of autonomic function in heart failure.
        J Cardiovasc Nurs. 2005; 20: 186-195
        • Jiang W.
        • Hathaway W.R.
        • McNulty S.
        • Larsen R.L.
        • Hansley K.L.
        • Zhang Y.
        • O'Connor C.M.
        Ability of heart rate variability to predict prognosis in patients with advanced congestive heart failure.
        Am J Cardiol. 1997; 80: 808-811
        • Aronson D.
        • Burger A.J.
        Gender-related differences in modulation of heart rate in patients with congestive heart failure.
        J Cardiovasc Electrophysiol. 2000; 11: 1071-1077
        • Ho K.K.
        • Pinsky J.L.
        • Kannel W.B.
        • Levy D.
        The epidemiology of heart failure: the Framingham study.
        J Am Coll Cardiol. 1993; 22: 6A-13A
        • Floras J.S.
        Sympathetic nervous system activation in human heart failure: clinical implications of an updated model.
        J Am Coll Cardiol. 2009; 54: 375-385
        • Bild D.E.
        • Bluemke D.A.
        • Burke G.L.
        • Detrano R.
        • Diez Roux A.V.
        • Folsom A.R.
        • Greenland P.
        • Jacob Jr., D.R.
        • Kronmal R.
        • Liu K.
        • Nelson J.C.
        • O'Leary D.
        • Saad M.F.
        • Shea S.
        • Szklo M.
        • Tracy R.P.
        Multi-ethnic study of atherosclerosis: objectives and design.
        Am J Epidemiol. 2002; 156: 871-881
        • Dekker J.M.
        • Schouten E.G.
        • Klootwijk P.
        • Pool J.
        • Swenne C.A.
        • Kromhout D.
        Heart rate variability from short electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men: the Zutphen Study.
        Am J Epidemiol. 1997; 145: 899-908
      1. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.
        Circulation. 1996; 93: 1043-1065
        • Curb J.D.
        • McTiernan A.
        • Heckbert S.R.
        • Kooperberg C.
        • Stanford J.
        • Nevitt M.
        • Johnson K.C.
        • Proulx-Burns L.
        • Pastore L.
        • Criqui M.
        • Daugherty S.
        Outcomes ascertainment and adjudication methods in the Women's Health Initiative.
        Ann Epidemiol. 2003; 13: S122-S128
        • Schellenbaum G.D.
        • Heckbert S.R.
        • Smith N.L.
        • Rea T.D.
        • Lumley T.
        • Kitzman D.W.
        • Roger V.L.
        • Taylor H.A.
        • Psaty B.M.
        Congestive heart failure incidence and prognosis: case identification using central adjudication versus hospital discharge diagnoses.
        Ann Epidemiol. 2006; 16: 115-122
        • Schellenbaum G.D.
        • Rea T.D.
        • Heckbert S.R.
        • Smith N.L.
        • Lumley T.
        • Roger V.L.
        • Kitzman D.W.
        • Taylor H.A.
        • Levy D.
        • Psaty B.M.
        Survival associated with two sets of diagnostic criteria for congestive heart failure.
        Am J Epidemiol. 2004; 160: 628-635
        • Sacks D.B.
        • Arnold M.
        • Bakris G.L.
        • Bruns D.E.
        • Horvath A.R.
        • Kirkman M.S.
        • Lernmark A.
        • Metzger B.E.
        • Nathan D.M.
        Position statement executive summary: guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus.
        Diabetes Care. 2011; 34: 1419-1423
        • McClelland R.L.
        • Chung H.
        • Detrano R.
        • Post W.
        • Kronmal R.A.
        Distribution of coronary artery calcium by race, gender, and age: results from the Multi-Ethnic Study of Atherosclerosis (MESA).
        Circulation. 2006; 113: 30-37
        • Natori S.
        • Lai S.
        • Finn J.P.
        • Gomes A.S.
        • Hundley W.G.
        • Jerosch-Herold M.
        • Pearson G.
        • Sinha S.
        • Arai A.
        • Lima J.A.
        • Bluemke D.A.
        Cardiovascular function in Multi-Ethnic Study of Atherosclerosis: normal values by age, sex, and ethnicity.
        AJR Am J Roentgenol. 2006; 186: S357-S365
        • Bahrami H.
        • Bluemke D.A.
        • Kronmal R.
        • Bertoni A.G.
        • Lloyd-Jones D.M.
        • Shahar E.
        • Szklo M.
        • Lima J.A.
        Novel metabolic risk factors for incident heart failure and their relationship with obesity: the MESA (Multi-Ethnic Study of Atherosclerosis) study.
        J Am Coll Cardiol. 2008; 51: 1775-1783
        • Goldberg L.R.
        • Jessup M.
        Stage B heart failure: management of asymptomatic left ventricular systolic dysfunction.
        Circulation. 2006; 113: 2851-2860
        • Triposkiadis F.
        • Karayannis G.
        • Giamouzis G.
        • Skoularigis J.
        • Louridas G.
        • Butler J.
        The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.
        J Am Coll Cardiol. 2009; 54: 1747-1762
        • Makikallio T.H.
        • Tapanainen J.M.
        • Tulppo M.P.
        • Huikuri H.V.
        Clinical applicability of heart rate variability analysis by methods based on nonlinear dynamics.
        Card Electrophysiol Rev. 2002; 6: 250-255
        • Lahiri M.K.
        • Kannankeril P.J.
        • Goldberger J.J.
        Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications.
        J Am Coll Cardiol. 2008; 51: 1725-1733
        • Bleasdale R.A.
        • Frenneaux M.P.
        Cardiac resynchronisation therapy: when the drugs don't work.
        Heart. 2004; 90: vi2-vi4
        • Carnethon M.R.
        • Prineas R.J.
        • Temprosa M.
        • Zhang Z.M.
        • Uwaifo G.
        • Molitch M.E.
        The association among autonomic nervous system function, incident diabetes, and intervention arm in the Diabetes Prevention Program.
        Diabetes Care. 2006; 29: 914-919
        • Tacoy G.
        • Acikgoz K.
        • Kocaman S.A.
        • Ozdemir M.
        • Cengel A.
        Is there a relationship between obesity, heart rate variability and inflammatory parameters in heart failure?.
        J Cardiovasc Med (Hagerstown). 2010; 11: 118-124
        • Araujo F.
        • Antelmi I.
        • Pereira A.C.
        • Latorre Mdo R.
        • Grupi C.J.
        • Krieger J.E.
        • Mansur A.J.
        Lower heart rate variability is associated with higher serum high-sensitivity C-reactive protein concentration in healthy individuals aged 46 years or more.
        Int J Cardiol. 2006; 107: 333-337
        • Lanza G.A.
        • Sgueglia G.A.
        • Cianflone D.
        • Rebuzzi A.G.
        • Angeloni G.
        • Sestito A.
        • Infusino F.
        • Crea F.
        • Maseri A.
        Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris.
        Am J Cardiol. 2006; 97: 1702-1706
        • Tarkiainen T.H.
        • Timonen K.L.
        • Tiittanen P.
        • Hartikainen J.E.
        • Pekkanen J.
        • Hoek G.
        • Ibald-Mulli A.
        • Vanninen E.J.
        Stability over time of short-term heart rate variability.
        Clin Auton Res. 2005; 15: 394-399