variables influencing heart rate

Progress in Cardiovascular Diseases 52 (2009) 11–19www.progcardvascdis.com

Variables Inf luencing Heart RateMariaconsuelo Valentini, Gianfranco Parati⁎

Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milan, ItalyDepartment of Cardiology, S Luca Hospital, IRCCS, Istituto Auxologico Italiano, Milan, Italy

Abstract In both physiologic and pathological conditions, instantaneous heart rate value is the result of a

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Cardiology, S Luca HSpagnoletto, 3. 20149

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0033-0620/$ – see frodoi:10.1016/j.pcad.20

rather complex interplay. It constantly varies under the influence of a number of factors:nonmodifiable and modifiable ones. Pharmacologic blockade with β-adrenergic antagonistsand/or with parasympathetic antagonists such as atropine have permitted the identification ofthe mechanisms of autonomic nervous regulation of heart rate in a variety of physiologic andpathological conditions. The analysis of heart rate and blood pressure variability has yieldedadditional information on the autonomic control of the circulation, which has proven to havediagnostic and prognostic implications in a number of clinically relevant conditions such ashypertension, acute myocardial infarction, heart failure, and predisposition to sudden cardiacdeath. This article will summarize, based on available epidemiologic and clinical studies, thekey variables influencing heart rate and heart rate variability in view of the known associationbetween heart rate and cardiovascular disease. (Prog Cardiovasc Dis 2009;52:11-19)
© 2009 Elsevier Inc. All rights reserved.
Keywords: Heart rate; Heart rate variability; Physiology; Smoking; Alcohol

Heart rate in normal adults depends on the pacemakeractivity of the sinoatrial node cells and constantly variesunder the influence of a number of nonmodifiable andmodifiable factors. In both physiologic and pathologicalconditions, its value results from a rather complexinterplay. The sinoatrial node cells are innervated by theparasympathetic fibers of the vagus and by sympatheticnervous thoracic efferents, respectively, exerting a slowingand a speeding up influence on heart rate. Pharmacologicblockade with β-adrenergic antagonists such as proprano-lol and metoprolol and/or with parasympathetic antago-nists such as atropine has permitted the identification ofthe mechanisms of autonomic regulation of heart rate in avariety of physiologic and pathological conditions.Complete autonomic blockade, as with simultaneousadministration of sympathetic and parasympatheticantagonists, has also allowed investigation of the so-

lict of Interest: see page 17.requests to Gianfranco Parati, MD, Department oospital, IRCCS, Istituto Auxologico Italiano; Via. Milan, [email protected] (G. Parati).

nt matter © 2009 Elsevier Inc. All rights reserve09.05.004

f

d.

called intrinsic heart rate, that is, the basal firing rate ofpacemaker cells. Another approach to the assessment offactors involved in heart rate regulation is based on theanalysis of heart rate (and blood pressure) variability,which depends on control mechanisms operating with theaim of maintaining cardiovascular homeostasis.1 Theanalysis of heart rate and blood pressure variability, thatis, cardiovascular variability, has indeed been shown toprovide additional information on the autonomic controlof circulation both in normal and in a number of clinicallyrelevant pathological conditions such as hypertension,acute myocardial infarction, heart failure, and predisposi-tion to sudden cardiac death.2 Methods to estimate heartrate variability include both time domain and spectralmethods (the latter assessing heart rate changes in thefrequency domain). Spectral analysis has been frequentlyused to explore the patterns of cardiac autonomicmodulation. In humans, the power spectral density ofheart rate has usually been analyzed in 3 frequencyregions: very low frequency (LF) (below 0.04 Hz), LF(0.04-0.15 Hz), and high frequency (HF) (0.16-0.4 Hz),with most articles concentrating their interest on the LFand HF components. Variability of heart rate at HF mostly

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12 M. Valentini, G. Parati / Progress in Cardiovascular Diseases 52 (2009) 11–19

reflects parasympathetic cardiac modulation, whereasvariability of heart rate at LF reflects both sympatheticand parasympathetic modulation.

The accumulating data supporting the associationamong heart rate, heart rate variability, and cardiovasculardisease3 have refocused attention on this independent riskfactor and on its nonmodifiable and modifiable determi-nants. This article will summarize the key variablesinfluencing heart rate based on available epidemiologicand clinical studies. A comprehensive description of all ofthe factors potentially influencing heart rate is beyond thescope of this article, which will concentrate on mostclinically relevant determinants.

Nonmodifiable determinants of heart rate

Age

With advancing age, the variation shown by resting heartrate in healthy subjects remains a matter of controversy,whereas a decrease in maximal heart rate has beenrepeatedly reported.3 Resting heart rate has been shownby most of the studies to progressively decline withaging.3-7 Such change has been shown to be similar(0.13 beats/y) when the effects of several confounders wereremoved by multivariate analysis in data coming from acardiovascular survey,5 from the general population (theBelgian study), and from a hypertensive population (theHARVEST study). However, some reports found a positiveassociation between resting heart rate and advancing age.8,9

This was, for example, the case in a cohort of 4682 elderlysubjects with isolated systolic hypertension enrolled in theSystolic Hypertension in Europe Trial,8 in the Framinghampopulation,9 as well as in nearly 100,000 French subjectsexamined in a large population-based survey.10 Finally,some other studies11,12 have reported that heart rate isrelatively constant during the adult life span.

Maximal heart rate decreases with age independent ofother factors such as sex and habitual level of physicalactivity.13-15 The decrease in maximal heart rate observedwith age represents the key determinant of the progressivedecline in aerobic exercise capacity chiefly by means of areduction in maximal cardiac output.14,15 Although themechanisms involved in the reduction of maximal heartrate with age in healthy subjects is still a matter of debate,recent data16 suggest that such change is largely explainedby a decrease in both intrinsic heart rate and chronotropicβ-adrenergic responsiveness. A progressive decrease inintrinsic heart rate, that is, the heart rate observed in theabsence of autonomic influence as with dual autonomicblockade with atropine and propranolol, seems to be thegreatest contributor.

Advancing age seems to affect autonomic modulation,as suggested also by studies dealing with various measuresof short-term and long-term variability of heart rate.17,18

Sex

In healthy cohorts and among subjects evaluated in trialsfocusing also on other risk factors, women have consis-tently demonstrated a higher resting heart rate comparedwith men matched for age and other factors.3,9,10,19,20 Suchindependent sex-related difference, in the range of 3 to7 beats/min, is present in both developed and undevelopedcountries,3 operates at any age, and, according to some9 butnot all19 of the cohorts, tends to increase with age.

Race

In population surveys, racial differences in traditionalcardiovascular risk factors have been well profiled and havebeen attributed to varying hereditary, environmental, andcultural influences among races. Unlike age and sex, veryfew investigations have evaluated racial background as adeterminant of heart rate. In a US national survey,21 restingheart rate was slightly lower in blackmen than in white menin the age range of 18 to 34 and 65 to 74 years. In theCoronary Artery Risk Development in Young Adultsstudy,22 looking at the association between laboratorycardiovascular reactivity and subsequent 24-hour ambula-tory heart rate and blood pressure, blacks had overall higherheart rate and systolic and diastolic blood pressure thanwhites, with such differences being significant for all but thediastolic blood pressure and for morning heart rate. Blackshad similar 24-hour and daytime blood pressure and heartrate compared with nonblacks in the Dietary Approaches toStop Hypertension trial,23 but their nocturnal bloodpressure and heart rate decline were blunted with resultinghigher night time blood pressure and heart rate levels.

Physiologic determinants

Influence of circadian cycle

Neurohormonal factors, posture, and level of physicalactivity are mainly responsible for the circadian variations ofheart rate.3 Heart rate is generally lower during sleepcompared with waking periods,24 the difference, irrespectiveof age, being about 14 beats/min.25 Recently, in a cohort of3957 patients referred for ambulatory blood pressuremonitoring,24 heart rate value during sleep, and, in particular,the absence of sleep-related decrease in heart rate wererelated to all-cause mortality independent of blood pressuredipping and of other confounding factors. During daytime,heart rate shows substantial variations, showing highermorning readings in some,26 but not all, of the studies.27

Influence of posture

Adaptation from supine to erect posture28 is known toprompt in healthy young adults an immediate (first30 seconds) 30% to 35% increase in heart rate peaking

13M. Valentini, G. Parati / Progress in Cardiovascular Diseases 52 (2009) 11–19

in about 8 to 15 seconds and subsequently tapering down.To maintain adequate cerebral blood flow, stabilized(30 seconds to 20 minutes) heart rate responses of healthyadults to the head-up posture consist of a 15% to 30%increase associated with an increase of diastolic pressureby 10% to 15% and, in total, vascular resistance by 30% to40%. In elderly subjects (aged 60-69 years) compared withyounger ones, there are, with upright posture, lowerincrements of heart rate and diastolic pressure but nosignificant differences in cardiac output or total vascularresistance; in 14% to 20% of subjects 75 years and older,orthostatic hypotension is often observed partly related todefective autonomic function. In a large population-basedsample20 pooling data from 1200 subjects of 4 Europeancountries, RR interval and respiration were registered inthe supine and standing position. In this sample, togetherwith age and female sex, posture independently correlatedwith heart rate and measures of heart rate variabilityconsistent with a higher sympathetic tone.

Blood pressure

Resting heart rate has been consistently demonstratedto be associated to clinic blood pressure in bothepidemiologic and pathophysiologic studies.3-6,29-32 Inthe general population, the relationship between heart rateand blood pressure has been confirmed over the wholerange of blood pressure values and has been observed atany age.5,29,31,33

Heart rate progressively increases together with bothsystolic and diastolic blood pressure, although such directassociation is stronger for systolic than for diastolic valuesof blood pressure. This observation has been suggested inmore than 35,000 men and women of 25 to 64 years of ageincluded in the analysis of 4 Chicago epidemiologicsurveys29 and in approximately 5000 men and 4000women of a nationwide Belgian population study.32

In multiple linear regression analyses, the association ofheart and blood pressure was found to be significantindependent of a number of possible confounders such asage, sex, body mass index, smoking, alcohol intake,physical activity, and, when available, insulin data.3 Basedon these and other results, the positive association betweenheart rate and blood pressure appeared to be a linear one.3,5

That the relationship between heart rate and systolic bloodpressure is linear has been confirmed not only in adults butalso in children on the basis of a small number of studiesafter adjusting for several confounders.31,34

Finally, there has been some suggestions that therelationship between heart rate and blood pressure maybe affected by both socioeconomic factors and ethnicity. Infact, a few epidemiologic studies performed in primitivepopulations living in rural or in undeveloped areassuggested that, at least in men, heart rate was not associatedwith blood pressure unlike repeatedly described inWestern

populations.3 Similarly, such association was not observedin black boys and girls of the Bogalusa Heart Study3,31 andwas either absent or weaker in adult blacks compared withadult whites examined in the Chicago epidemiologicstudies.3,29 Taken altogether, these data suggest that restingclinic heart rate is closely associated with clinic bloodpressure, that such association tends to be linear andstronger inmen than in women at least in western countries.

Lifestyle factors

A number of modifiable lifestyle patterns are known tobe strictly related to cardiovascular events. Increased heartrate and decreased heart rate variability are among themechanisms by which unhealthy lifestyle habits nega-tively affect cardiovascular morbidity and mortality. As aconsequence, adopting correct lifestyle measures allows toimprove outcomes also through the recognized effect onheart rate and on its variability.

Physical activity

The autonomic nervous system is chiefly involved inregulating resting heart rate and the transient heart ratechanges accompanying and after physical activity.35 Regularphysical activity affects heart rate at rest and atsubmaximal exercise intensity, aswell as during the recoveryafter exercise.35 From rest through increasing intensities ofexercise, heart rate shows a gradual increase up to a peakvalue. Several studies using pharmacologic blockade haveshown that such increase is primarily due to parasympatheticwithdrawal,35-37 whereas at greater workloads, morepronounced increases of heart rate result from the combina-tion of parasympathetic withdrawal and sympatheticactivation,35-37 althoughevenat veryhigh-intensity exercise,the parasympathetic withdrawal is never total.35,38

Regular physical activity training elicits a reduction ofheart rate at rest31,35,39,40,41,42 and at submaximal exercise,whereas maximum heart rate slightly decreases or remainsunchanged with chronic training.35 A number ofstudies1,35,39,41,42 with heterogeneous protocols in termsof follow-up duration, frequency, and duration of exercisesessions suggest that regular endurance training, besidesincreasing exercise tolerance and endurance, decreasesresting heart rate. A decrease in intrinsic rhythmicity, amore predominant parasympathetic activity, and a slightdecrease in the sympathetic contribution42 have beensuggested to mediate such change. The cross-sectionalnature of most of the studies reporting the effects ofphysical activity on resting heart rate in trained subjects ascompared with untrained ones, as well as the possibleconfounding effect of environmental factors,5,42,43 has ledsome authors to recommend the use of minimum heartrate during sleep to assess the training status.44 However,there is a substantial variation in sleeping minimum heartrate (5 beats/min), thus, giving support to the discrepancy


observed among studies reporting the effects of regularphysical activity on awake resting heart rate.

Although many reports agree in demonstrating adecrease in heart rate at submaximal load,35,41,45 most ofthe evidence suggests that maximal heart rate shows anegligible change with regular endurance training. Over-all, maximal heart rate has shown to either remainunchanged or slightly decrease by 5 to 13 beats/min.35,46-48 The data available so far on the effects ofendurance training on indices of heart rate variabilityeither in the time or in the frequency domain remaininconclusive.35 This discrepancy has largely been attrib-uted to the different exercise protocols that have been usedor to methodological differences between studies in theassessment of heart rate variability.

Mental stress

Epidemiologic, clinical, and laboratory studies haverepeatedly demonstrated a relationship between emotional,cognitive, and physical stress and cardiovascular disease (ie,hypertension, acute myocardial infarction, and suddencardiac death).49,50 The activation of the sympatheticnervous system seems to be crucial in mediating suchrelationships. Acute mental stress triggers a rather consistentincrease in plasma catecholamines, heart rate, and bloodpressure51 despite a rather inconsistent variation in sympa-thetic neural outflow.50 Although mental stress has mostlybeen reported to increase in muscle sympathetic nerveactivity (MSNA),52-54 there are some reports suggesting adecrease55 or no change.56 In a recent study reporting on alarge human sample (82 subjects), variousMSNA responses(ie, positive, negative, unchanged) were observed to mentalstress; surprisingly, MSNA responses were disassociatedfrom heart rate and blood pressure responses.51 Significantheart rate and blood pressure responses to acute stress havebeen demonstrated both in the laboratory environment andin real-life situations. A number of tests have beendeveloped in the attempt to reproduce, under controlledexperimental conditions, the effects of real-life stress. Themaneuvers, aimed at qualitatively and quantitatively defin-ing the heart rate and blood pressure responses to discretestressors, roughly belong to the broad categories of mentaland physical stressors.57 Mental stressors engage thesubjects emotionally by confronting them with mathema-tical, organizational, or technical problems. Themost widelyrecognized mental stressors include the mental arithmetictest (in which subjects are asked to compute subtractionsunder time constraint), memory tasks, or complex psycho-motor tasks such as the mirror drawing test (in whichsubjects are requested to reproduce a geometric drawinglooking at their writing hand only as reflected in a mirror),the Stroop color-word test (in which they are asked to pointto a colored object being influenced by conflicting

auscultatory and visual inputs), and public speaking,which, carrying strong social features, triggers a potentβ-adrenergic stimulation and more evident cardiovascularresponses than the previous laboratory mental stress tests.58

The most frequent physical stressors include the coldpressure test (hand immersion in ice-cold water for60 seconds) and the handgrip test (hand isometric exerciseapplied for 90 seconds at 30% of subject's maximalstrength). Laboratory assessment of heart rate and bloodpressure, that is, of cardiovascular reactivity, to stress is notfree from limitations in spite of the controlling quality andduration of the stressor, the environmental conditions, andthe continuous follow-up of the hemodynamic responsesbefore, during, and after the stressful stimulation.59 Evenwith attention to methodological testing characteristics,within-subject reproducibility of heart rate and bloodpressure responses results are rather poor, having a variationcoefficient in the range of 15% to 33%.60 In our experience,average heart rate and blood pressure responses to coldpressure test and handgrip test, repeated 6 times in a rowwith 15-minute intervals between repetitions in 20 essentialhypertensives (after 7- to 10-day pharmacologic washout)and in 19 normotensives, showed a marked variabilityamong subjects and within subjects. In the whole popula-tion, the coefficient of variation of heart rate (SD×100/meanresponse) to the cold pressure test and to the handgrip testwas 24.6% (11.9%-49.1%) and 44% (18.1%-158.1%),respectively, whereas the coefficient of variation of bloodpressure was 22.2% (12.8%-32.3%) and 17.2% (8.2%-34.7%). An additional problem limiting our ability to test thecardiovascular responses to stress in the laboratory lies in thepoor consistency of responses elicited by different tests.59,61

In 22 subjects with untreated mild hypertension,61 the intra-arterial blood pressure and heart rate responses to mentalchallenges (mental arithmetic and mirror drawing test) werecompared with those observed in response to physicalstressors (handgrip and cold pressure test). Heart rateresponses to mental arithmetic was significantly correlatedto those triggered by mirror drawing test, although nocorrelation was observed in heart rate responses betweenphysical stressors and between physical stressors andmentalchallenges. Different patterns have been observed for bloodpressure responses secondary to mental and physical formsof laboratory stressors. Other investigations have addressedthe issue of stability of cardiovascular responses acrosslaboratory tests,62 and they have all come to the sameconclusion: subjects cannot be unequivocally classified ashyper-, hypo-, or normoreactors based on application of asingle laboratory stressor. A final limitation pertains to thefact that, with most traditional tests, heart rate and bloodpressure responses to discrete stressors are taken at theirpeak without considering the anticipation and the recoveryphase. This may underestimate the overall engagement ofthe cardiovascular system especially by sustained and

Ambulatory Blood Pressure Data

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Fig 1. Heart rate and blood pressure effects of an earthquake: evidence by ambulatory blood pressure monitoring (reproduced with permission fromreference 63).


articulated responses as those most frequently observedoutside the laboratory environment in real-life stressfulsituations. Recently, devices allowing continuous noninva-sive beat-to-beat heart rate and blood pressure monitoring orintermittent ambulatory heart rate and blood pressuremonitoring have permitted better definition of heart rate

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Fig 2. Correlation of the heart rate response to the speech test and to thedoctor's visit in hypertensive subjects (reproduced with permission fromreference 58).

and blood pressure responses related to challenges meticu-lously standardized in the laboratory setting, to challengesfaced during routine daily activities (such as undergoing adoctor's visit, taking school examinations, giving a speechin public, driving a car), or to challenges during highlystressful situations (such as an earthquake)63 (Fig 1). Inparticular, data collected by these techniques have suggestedthat heart rate (and blood pressure) response to physical oremotional stress in subjects' usual life, for example, thealerting reaction induced by a doctor's visit, displays limitedor no correlation with each other58 and with most laboratorystressful stimulations.62 In another investigation,58 on theother hand, in hypertensive subjects, public speakingtriggered an important and sustained heart rate and systolicblood pressure response, which was closely associated withthe alerting reaction to the doctor's visit (Fig 2), suggesting ageneralized reactivity to psychosocial stress at least inthis population.

Smoking

Acute and chronic effects of smoking on heart rate aswell as on heart rate variability and on baroreflexresponses have been described.

Many reports have shown that cigarette smoking acutelyaffects the cardiovascular system. Acute effects of smokinginclude an increase in heart rate and blood pressure.64-68 Thechronotropic and pressor effects of smoking are at least in


part mediated by a generalized stimulation of peripheraladrenergic receptors as the result of increased concentrationsof plasma catecholamines.64,65 In one report, smoking afiltered cigarette markedly decreased, in healthy normoten-sive subjects, MSNA.69 Such decreased MSNA, which wasinversely related to the pressor response, was most probablysecondary to baroreflex activation. This was confirmed inother studies inwhich cigarette smoking increasedMSNA inhealthy subjects whose baroreflex responses where bluntedby nitroprusside70 and in habitual smokers with coronaryartery disease and impaired baroreflex function.71 The acutehemodynamic and neurohumoral changes seem to persist atleast for 30 minutes after smoking and occur again onsmoking a second cigarette.67,69 Additional effects ofsmoking on the cardiovascular system extend to thebaroreflex. Some reports suggest that smoking impairs thebaroreflex modulation of heart rate72,69 when the baror-eceptor activity assessment results from spontaneous bloodpressure fluctuations and not when reflex changes in heartrate depend on laboratory stimuli such as carotid mechanicalstimulation by a neck suction device. The impairment ofbaroreflex sensitivity associated with smoking, as detectedby a 1-hour continuous beat-by-beat blood pressurerecordings in the laboratory with Finapres (OhmedaInc),72 was confirmed more precisely in another investiga-tion in which 24-hour beat-to-beat monitoring69 withPortapres (TNO-TPD Biomedical Instrumentation, Amster-dam, the Netherlands) was performed in daily life insmoking individuals. This study showed that smoking notonly impairs baroreflex responses but also exerts long-termeffects. In fact, smokers exhibited significantly higherambulatory heart rate and blood pressures than nonsmokers.This observation was confirmed in a large population studyassessing the determinants of resting heart rate in a Belgiannationwide survey involving more than 5000 men and 4000women aged 25 to 74 years.32 In male subjects, cigarette

bpm

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Fig 3. Acute hemodynamic effects of red wine, ethanol, and water. One drink (Podrinks (Post-2) of either alcohols elicited a marked positive chronotropic responreference 83).

smoking was the second strongest determinant of restingheart rate after blood pressure (r = 0.150, P b .05); such anassociation, still present, was rather weaker in femalesubjects. In another study completed in 1175 hypertensivewomen and men aged 35 to 64 years, resting heart rate washigher in active smokers compared with ex-smokers ornonsmokers (P b .05).73 Finally, also second-hand smokeposes a significant threat to the cardiovascular system,among other mechanisms, through changes in autonomicfunction as indexed by heart rate variability.74-76 Pope et al74

first demonstrated, by means of electrocardiogram signalsrecorded in subjects moving at 2-hour intervals between thesmoking and the nonsmoking area of an airport, that short-term exposure to second-hand smoke was associated with amarked decrease in all measures of heart rate variability. Inagreement with the above findings, Dietrich et al,75 bymeans of 24-hour Holter electrocardiogram recordings,demonstrated in nonsmokers that exposure to second-hand smoke either at home or at work for longer than2 hours a day was associated with a higher heart rate and alower heart rate variability.

Alcohol

The presence of a J-shaped relationship between alcoholintake and a variety of health outcomes has been repeatedlysuggested.77-82 Such relationship extends from total mor-tality to a variety of cardiovascular and noncardiovascularoutcomes such as hypertension, coronary heart disease,congestive heart failure, diabetes, stroke, and dementia.According to the J-shaped relationship, regular light-to-moderate alcohol intake (1 drink/d in women and1-2 drinks/d in men) clearly confers substantial cardiopro-tection. Although some studies have suggested thatred wine, because of high polyphenol content, mayhave some additional protective advantage over other

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st-1) of either red wine or ethanol did not affect heart rate andMSNA. Twose and a significant increase in MSNA (reproduced with permission from


alcoholic beverages, other studies have shown that thecardioprotective effect is conferred by ethanol itself and notby other specific components.77,78 To explore this issue, in arecently published study, we assessed acute dose-relatedeffects of red wine, as compared with those of ethanol, withrespect to heart rate, blood pressure, sympathetic nerveactivity, and conduit artery diameter in healthy subjects.83

Thirteen volunteers, for 3morning sessions 3weeks apart, ina randomized single-blind water-controlled protocol, dranka first drink of wine, ethanol, or water, followed by a secondone, while under heart rate and MSNA continuousrecording.83 Red wine and ethanol achieved comparableblood alcohol concentrations both with low (one drink) andmoderate (2 drinks) ingestion. One standard dose of eitheralcoholic beverages did not affect heart rate and MSNA,whereas 2 doses increased both heart rate and MSNA by5.7 ± 1.6 beats/min and by 9 to 10 burst/min (P b .001),respectively. Blood pressure never changed, whereasbrachial artery diameter increased after both 1 and2 alcoholic beverages (Fig 3).83 Taken altogether, theseresults suggest that the presence of polyphenols in red winedoes not confer any additional acute effect to ethanol; thatone standard drink of ethanol or of red wine does not elicitany sympathoexcitatory effect; and that 2 drinks, that is,higher doses of ethanol, are needed to increase sympatheticnerve firing rate and heart rate. Blood pressure did notacutely increase in this study likely because of the counter-vailing vasodilatation. These latter results are in line withthose of previous studies evaluating the acute effects ofgreater doses of ethanol in the intoxicating range.84,85 Astimulation of the sympathetic nervous system activity wasassociated with dilation of the conduit arteries, and with anincrease in heart rate and blood pressure, the latter persistingfor hours after vasodilation had subsided. Based on theseobservations, it has been speculated that repeated sympathe-tically mediated increases in heart rate and blood pressurecould possibly account for the sustained elevation of heartrate and blood pressure observed when more than 2 drinksare chronically consumed.77,83,86

In conclusion, the overall association between alcoholand heart rate seems to be dose dependent. With moderatedaily alcohol intake, the effect on heart rate is negligible,and, on the cardiovascular system, the cardioprotectiveeffects mediated by an improvement on endothelialfunction, inflammation markers, and high-density lipo-protein cholesterol levels predominate.77,78 With heavieralcohol consumption, the abovementioned cardioprotec-tive affects are lost and the sustained increase in heart rateand blood pressure take the lead in causing detrimentalcardiovascular effects.

Excess body weight

An association among heart rate, body weight, andblood pressure has been repeatedly reported in cross-

sectional investigations.6,87 In subjects with excess bodyweight, sympathetic activation has been demonstrated bymeans of various methods. In a cohort of healthy subjectsfollowed up for 10 years88,89 subjects with greater entryheart rate and signs of sympathetic activation developedover time greater blood pressure values and heavierbody weight. Long-standing increased sympathetic tonemay elicit a down-regulation of β-adrenergic metabolicand energy expenditure responsiveness predisposing toweight gain.87,90

Genetic determinants

A large body of evidence ranging from epidemiologicstudies to genomewide linkage studies suggests that somefeatures of heart rate and heart rate variability can be trans-mitted over generations because of the influence of geneticfactors.91-93 In addition, some data suggest that chromo-somes containing genetic loci related to heart rate variabilitycontain candidate genes relevant for the autonomic nervoussystem and for the cholinergic receptors.94

Conclusions

The available evidence clearly indicates that factorsaffecting heart rate are multifold, a major role being playedby neural influences, either central or reflex in nature. Theautonomic neural control of heart rate is of complexinterpretation, which does not permit considering heartrate itself a precise marker of sympathetic activity.Nevertheless, because of its easy quantification and to itssensitivity to changes in neural cardiovascular control,heart rate assessment remains a valuable, although notalways specific, tool to gauge neural cardiovascularmodulation, with obvious diagnostic, prognostic, andtherapeutic implications also for daily practice.

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

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