Short- and long-term effects of cigarette smoking on heart rate variability

MISCELLANEOUS

Short- and Long-Term Effects of Cigarette Smoking on Heart Rate Variability Junichiro Hayano, MD, Masami Yamada, MD, Yusaku Sakakibara, MD, Takao Fujinami, MD, Kiyoko Yokoyama, PhD, Yosaku Watanabe, PhD, and Kazuyuki Takata, PhD

The&H-andbng-tenneffectsofdgarette smdchgonaut-kcardiacregulathwere investigated by power spectrd analysis of heart rate vahbiHty uanler controfled respirath (lS/ min). lhe rhort-tem~ effects were examined in 9 smo&erswtthoutevhnceofcard~disorders after n ovemlght abdheme from smoking. Tbebeartmtespectd#nnponentratlecthgthe resphtory shus arrhythmii (02.5 Hz), a qumtitative index of vagal cardiac contrd, decreased 3 minutes after smddng 1 cigarette (p = 0.0081) and the ctmpomd refkcting Mayer wave sinus arvhythmia(O.tMto 0.15 Hz),whkhinchnkssym-

~lnediiactivity, -afte!r1oto 17mblutes (p = 0.0124). Thebmg-telmeffects were examined in 81 notmal subjects camprbinn 28 nonrmdcan, 31 moderate (1 to 24 cigarettes/ day) smdcers and 29 heavy (>W cigHes/day) smdcers after an ovemigbt abstinence. Althmgb tlbemagnitudeoftbeMayerwaveeomponccltwas maffected by the smoking status, the respiratory componentinthesqhepositionwassmalkrinthe young (130 years) beavy smokers than in the young IUMWJM&W or rndmte smokers (p =

0.0078).Ako,posturaldmngesb1tkeomponents, a&feaseinthrespiratorywmponentcndan increase in the Mayer wave cumponant with’-ing, were observed in the nonsmokersbutnotin tbekwysmo&efs.Tbeseresuttssuggestthat anaa4teandtransknthcreasein -WEvagd emRae cmtrd, and that heavy smddng hg-tefm re&ctkn in vagal cardiac control inyoungpeoplendbhtedportval~in autoununkcardiacregdatim. (Am J Cardid 1999;ssS4-88)

moking acutely increasessympatheticactivities and causesplasma catecholamine levelsto increase.l-5 This has been recognized as a major mechanism for increasedrisk of coronary artery diseasein smokers. However, the epidemiologic finding that smokershave a lower blood pressurebetween cigarettes than nonsmokers6Jsuggeststhat the sympathetic activities in smokers are not persistently increased. Many recent studies*-” have reported increased susceptibility to sudden coronary death and increased subsequent mortality after myocardial infarction in patients with decreasedvagal cardiac control assessedby heart rate variability. The decreasein vagal cardiac activities may be present in smokers and may be a reason for the association between smoking and cardiac death. In this study, we examined short- and long-term effects of smoking on autonomic cardiac control using spectral analysis of heart rate variability.‘2-17 The heart rate power spectral density contains 22 major frequency components,which reflect the activities of different divisions of the autonomic regulation system.‘2-15The respiratory componentI is a quantitative reflection of respiratory sinus arrhythmia,12 and the Mayer wave componentI (0.04 to 0.15 Hz) is derived from a blood pressure variability through the baroreflex mechanism.12The magnitudes of thesecomponentsrespectively provide a quantitative index of vagal cardiac control and an index of sympathetic cardiac control with vagal modulation.13-*5

S

METHODS Study I: Nine male volunteers, aged 24 to 30 years, with normal history, physical examination and laboratory tests, including complete blood count, blood chemistry, chest x-ray and electrocardiography, were selected from among the hospital staff and their relatives. None of them took any medication the week before the study. All were regular cigarette smokers,consuming 20 to 40 (mean 27 f 8) cigarettes/day. On the day before the study, they were instructed to refrain from smoking, or drinking beveragescontaining caffeine or alcohol, for >8 hours before the study and to take a light breakfast before 8:00 A.M. The study was performed between IO:00A.M. and 12:30P.M.After a supine resting period of >30 minutes, the subjects smoked 4 cm of 1 cigarette From the Third Department of Internal Medicine, Nagoya City Uni- containing 1.0 mg of nicotine during 2 minutes in the versity Medical School, Nagoya, Japan, and the Toyota College of supine position, inhaling the cigarette smoke deeply. Technology, Toyota, Aichi, Japan. Manuscript receivedJune 5, 1989; The autonomic function was tested before and 3, 10, 17 revisedmanuscript receivedand acceptedSeptember 1.1989. Addressfor reprints: Junichiro Hayano. MD, Third Department of and 24 minutes after the start of smoking. Study II: Eighty-one healthy male volunteers, aged Internal Medicine, Nagoya City University Medical School, I Kawasumi Mizuho-cho Mizuho-ku, Nagoya 467, Japan. 19 to 52 years, were enrolled, using the same selection 84

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

criteria as in study 1. According to the smoking status, they were divided into 3 groups: 25 nonsmokers, 31 moderate smokers (1 to 24 cigarettes/day) and 25 heavy smokers(>25 cigarettes/day). Mean habit durations in the moderate and heavy smokerswere 11.6 and 12.4 years, respectively. They were instructed as in study I, and the autonomic function was tested between lo:00 A.M. and 12:30 P.M. after a supine resting period of >30 minutes without smoking. Autammk hnetion tesk Electrocardiogram (CM5 lead) and respiratory waveforms (nose-tip thermistor) were continuously stored on a frequency modulated tape recorder (TEAC MR-30). Data were collected for 5 minutes in the supine position. Also, 5-minute data while standing were collected in study II. During the test the subjects breathed quietly to the metronome signal at 15 beats/min (0.25 Hz), to obtain a stationary respiratory sinus arrhythmia without frequency change or phasedrift.15-” Blood pressurewas measuredat the end of the autonomic function tests in each position. Data mrlsr The electrocardiogram was digitized at 1,000 samples/s/channel with a Canopus Electronics A/D converter (ADX-98E), and ail RR intervals were measured with a fast peak detection algorithm at an accuracy of 1 ms on an NEC microcomputer (PC9801VX). Only the time series comprising 250 to 300 normal sinus RR intervals during which the subjects faithfully matched all breaths to the metronome were included in the final analysis. We calculated the power spectral density of RR interval variability by an autoregressive algorithm that computed the autoregressivecoefficients by the Marple method.‘” The model order was chosenas the one that minimized Akaike’s final prediction error figure of merit.iy The program computed individual power and cen-

ter frequency of each spectral component (Figure l).‘O We defined the componentsat 0.04 to 0.15 Hz as the Mayer wave*’ component and those at the respiration frequency (0.25 Hz) as the respiratory component. In considering the RR interval variation attributable to each single component, we representedthe magnitudes of individual componentsby the parameter we termed the coefficient of componentvariance, which is calculated as 100. (power of a component)‘/2/(mean RR interVd) (%T).‘~-‘~ StatirUeal analysis: We used 2-way (time after smoking and subject) analysis of variance followed by the Bonferroni test to compare data after smoking with the control value in study 1. We compared the spectral variables among the 3 groups in study I1 after adjusting for the effect of age using analysis of covariance for general linear models (least square means method) by meansof the Statistical Analysis System. We usedStudent I tests for paired samplesto evaluate the effects of posture. A p value <0.05 was consideredsignificant. RESULTS Study I: The mean RR interval decreased after smoking 1 cigarette (p
SPECTRAL COMPONENTS

AUTOREGRESSIVE POWER SPECTRUM c 40 0 *

RSA ,

> ?I2 E b : x .5

RSA n MWSA Frequency = 0.12Hz sq = 670ms. Power

5 2.0-

Mean R-R

Maan heart rala

= 73.3bom 73.3bpm

ii b

Srqma A-R Sroma A -II

= 45.9ms

AR order AA

=9

Frequency = 0.25H2 Eq

= 300

Power

= 1003ms’

ccv

= 3.66%

u

MWSA

interval

i

= 820ms

‘i ;

= 3.150

ccv RSA

I

0.0

0.0

0.2

0.1

0.3

0.4

r

I

I

I

I

0.0

0.1

0.2

0.3

0.4

I

0.3

c/b r

0.5 Hz eq

0.4

1

I

I

I

I

0.0

0.1

0.2

0.3

0.4

c/b I

,

0.5 Hz eq

TABLE I Basic Hemodynamic

530 years (n) Age Ws)

subjects (>30 years old). In both age groups, the magnitude of the respiratory component decreased with standing in the nonsmokersand moderate smokers (p
Parameters After

Nonsmokers

(l-24/day)

(>25/day)

15

13

11 26f3

24f3

25 f 3

1,015 f 154

937 f 132 118k8

supine RR interval (ms) Systolic BP (mm Diastolic BP (mm Standing RR interval (ms) Systolic BP (mm Diastolic BP (mm >30 years (n) Age Ws) Supine RR interval (ms) Systolic BP (mm Diastdic BP (mm Standing RR interval (ms) Systolic BP (mm Diastolic BP (mm

114f9 68f8

Hg) Hg)

Hg) Hg)

885f139 118f8 72 f 7

67 f 7

777 f 86’ 111flO 83f8* 10 39f6

756 f 68* 119f9 82 f 10’ 18 4Of6

747 f 968 116f7 85f6’ 14 37 f 5

878f 118 116f5 73f8

918 f 109

Hg) Hg)

117fll 76f9

875f 150 115f 10 70f9

Hg) Hg)

756 f 94’ 116f6 84f79

770 f 97* 113f 10 84f8*

740f 130. 112f9 79*9*

l p
Values are mem

f standard

ckvlal~on.

the decline has been shown to be greatly reduced after 30 years. Thus, the subjects in study II were divided into 2 groups by age: 130 years and >30 years (Table 1). Although the magnitude of the Mayer wave component was unaffected by the smoking status in either age group, it increased with standing only in the young (130 years old) nonsmokers(p <0.05), but not in the moderate or heavy smokers (Figure 3). On the other hand, the magnitude of the respiratory component in the young subjects was significantly lower in the heavy smokersthan in the nonsmokersand moderate smokers (p = 0.0078), but no difference was found in the older

I

120-

E

z ;

z

:

I

I

3.5 &.&

6060

THE AMERICAN

JOURNAL

;:i

D

I

I

p=O.O061

*

1:s I*

f

1

CONTROL 3

10

17

SMOIII’NG

88

I

I

I

B

loo-

E E 0

I

DISCUSSION We found that cigarette smoking causesacute and transient changesin the heart rate spectral components, and that even after an overnight abstinencethe supine respiratory component in the subjects 130 years of age is decreasedin the heavy smokers. Also, the postural responsesof the componentswere blunted over the long term in the heavy smokers.These results suggest that smoking causesnot only short- but also long-term alterations in autonomic cardiac control. Spectral cmnpom& of herrt rate variability: The magnitude of the respiratory component has been acceptedas an index of vagal cardiac control.‘3J7 Intravenous atropine abolishesthis component, but propranolol has no effect on it.‘*J3 Moreover, a recent study** on the transfer function of autonomic regulation showed that the heart rate fluctuation at the usual respiration frequency (0.1545 Hz) is only vagally but not sympathetically mediated. Also, we have previously reported that the coefficient of componentvariance for the respiratory component correlates linearly with the vagal cardiac control defined as (HRp+* - HR p)/HRp+*, where HRp is the heart rate after propranolol (0.2 mg/ kg) and HRP+A is that after additional atropine (0.04 mg/W.15 Although the respiratory component shows a decrease while standing, the Mayer wave component shows a &adrenergically mediated increase.‘)-I7 The Mayer wave component is thought to be derived from the fluctuation in the vasomotor activity at about 0.1 Hz through the baroreflex mechanism,‘* in which the cardiac efferent is both vagally and sympathetically me diated.

OF CARDIOLOGY

VOLUME

24 min

65

1.0

CONTROL3 10 SMoKiNG

17

24 min

Short-term effects of sand&g: Most of the acute effects of smoking on nemocardiovascular regulation can be explained as the effects of nicotine.s The mechanisms of the effects of nicotine include both stimulation and blocking of the autonomic ganglia, direct liberation of catecholaminestoresin the heart, liberation of adrenomedullary epinephrine, stimulation of carotid body chemoreceptorsand aortic baroreceptorsand direct action in the central nervous system.3*4.2)-z5 Our observation of the transient decreasein the respiratory component after 3 minutes of smoking suggests that smoking acutely suppressesvagal cardiac control. Nadeau and James24have shown that, although the direct perfusion of nicotine (IO pg) to the sinoatrial node in the dog causesa cholinergically mediated brief slowing of the heart within the initial 10 seconds,it also causesa nonreaction of the heart to electrical stimulations of the cervical vagus for >5 minutes. The latter correspondsto the ganglionic blocking effect of nicotine, and our observation may indicate that this effect of nicotine is manifested even by cigarette smoking in humans. The short-term increase in the Mayer wave component with smoking may be the result of either or both liberation of catecholamines or stimulation of baroreceptors. It is well establishedthat plasma catecholamine levelsincreasewithin 1 minute after smoking or an infusion of nicotine.t.2 Although absenceof the increase in the Mayer wave component after 3 minutes of smoking appears inconsistent with the reported changes in plasma catecholamine levels, this may be attributable to the

concomitant decreasein vagal cardiac control at this time. The increasein this component after 17 minutes, on the other hand, can be explained as the result of the stimulation of baroreceptorsrather than the liberation of catecholamines,becausethe RR interval and blood pressuresat this time had already returned to the control levels (Figure 2). Lag-tenn effects of smoking: Our observation of long-term reduction in the supine respiratory component in the young heavy smokers suggeststhat heavy smoking causes long-term reduction in vagal cardiac control in young people. This finding is consistent with the epidemiologic findings that smokers,between cigarettes, show a higher heart rate than nonsmokers.“.’ The absenceof postural changes in the heart rate spectral components in heavy smokers suggests that heavy smoking causes blunted postural responsesin autonomic cardiac regulation. Despite the fact that smoking acutely increases blood pressure,4the blood pressure in long-term smokers, between cigarettes, is less than the average blood pressure in nonsmokersh.’ In most epidemiologic studies blood pressure is measured in the sitting position,’ such that the blunted postural responsesmay contribute to a decreasein blood pressurein this position. We cannot explain the mechanismfor the long-term alterations in autonomic function in heavy smokers. Smoking possibly has an effect on various parts in the neurocardiovascular regulation system, which includes the heart, lung. blood vessels,the afferent and efferent division of the autonomic nervous system and the cen-

STANDING POSITION

SUPINEPOSITION

Age S 30 yr 0

Nonsmokers

q

Age 5 30 yr

Age > 30 yr Moderate Smokers (l -24/0ay)

a

Age > 30 yr

Heavy Smokers(over

25/Day)

THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 1. 1990

87

tral nervous system.3*23Also, the differences in other factors, such as exercise level, between smokers and nonsmokersmay be related to our results. Further studies (including animal investigations) are required to establish the pathogenesisof our findings. Wed impiications: Population studies26-28have shown an increased rate of cardiac death in cigarette smokers, and several mechanismshave been known to contribute to the association betweensmoking and cardiac death.)v4Our findings of short- and long-term reduction in vagal cardiac control may add 1 more mechanism to this association, becausemany recent studies have shown that patients with decreasedvagal cardiac control assessedby heart rate variability have increased susceptibility to sudden coronary death,” increasedsub sequent mortality after acute myocardial infarction9 or increased late mortality after coronary angiography.‘O REFERENCES 1. Crycr PE. Haymond MW, Santiago JV. Shah SD. Norepinephrine release and adrenergic mediation of smoking-associated hemcdynamic and metabolic events.

N Engl J Med 1976:295:S73-577. 2. Hill P, Wynder EL. Smoking and cardiovascular disease. Effect of nicotine on the serum epinephrine and corticoids. Am Hem1 J 1974;87:49/-496. 3. Rober1son D, Tseng CJ, Appabamy M. Smoking and mechanisms of cardioAm Heorr J 1988:ll5:258-263. vascular control. 4. Trap-Jensen J. Effects of smoking on the hear1 and peripheral circulation. Am

10. Rich MW. Saini JS. Kleigcr RE. Carney RM, teVelde A, Freedland KE. Correlation of heart rate variability with clinical and angiographic variablea and Am J Cardiol /988,62;7/4-717. late mortality after coronary angiography. 11. Myers GA. Martin GJ, Magid NM. Barnett PS, Schaad JW, Weiss JS. Lesch M. Singer DH. Power spectral analysis of heart rate variability in sudden cardiac death: comparison IO other methods. IEEE Traaw Biomed Eng 1986: BME 33:f 149-1156. 12. Akselrod Ilemodynamic

S, Gordon D, Madwed JB. Snidmdn NC, Shannon regulation: investigation by spectral analysis.

I985;249tH867-H875.

13.

Pomeranz B, Macaulay RJB. Caudill MA. Kutz 1. Adam D. Gordon D. Kilborn KM, Barger AC. Shannon DC, Cohen RJ, Benson H. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol

1985;248:HlSI-HI53.

14.

Pagani M. Lombardi F, Guzzetti S. Rimoldi 0, Furlan R, Pitinelli P. Sandrone G. Malfatto G, Dell’Orto S. Piccaluga E, Turiel M. Baaseli G, Cerutti S, Malliani A. Power spectral analysis of heart rate and arterial pressure variabilities as a marker ofsympatho-vagal interaction in man and conscious dog. Circ Res

1986;59:178--193.

IS.

Hayan Autonomic

J. Yamada M, Fujinami T. Yokoyama K, Watanabe Y, Takata K. nervous function and spectral components of heart rate variability.

Biophysics 1988:28:32-36.

16. Hayano J. Quantitative assessment of autonomic functions by autoregressive spectral analysis of heart rate variability: effect of posture, respiratory frequency, I988;25:334-344. and age. Jiritsushinkei 17. Shannon DC, Carley DW, Benson H. Aging of modulation of heart rate. Am J Physiol 1987:253:H874-H877. 18.

Marple

L. A new autoregressive

spectrum

19.

Akaike

H.

Firting

autoregressive

models

20. with

Zettcrbcrg application

21.

Penaz

J. Mayer

waves:

history

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

for prediction.

and methodology.

22. Berger RD. Saul JP. Cohen RJ. Transfer regulation. I. Canine atrial rate response. Am

88

IEEE

Tray

Ann Star Math

LH. Estimation of parameters for a linear difference Marh Biosci /%9;5;227-275. IO EEG analysis.

5. Aronow WS, Dendinger J, Rokaw SN. Heart rate and carbon monoxide level after smoking high-, low-. and non-nicoline cigarettes. A study in male patients with angina pectoris. Ann Intern Med 1971;74:697-702. 6. Goldbourt U. Medalie JH. Characteristics of smokers, non-smokers and exsmokers among 10,000 adult males in Israel. II. Physiologic, biochemical and genetic characteristics. Am J Epidemiol 1977;105:78-86. 7. Green MS, Jucha E, Luz Y. Blood pressure in smokers and nonsmokers: epidemiologic findings. Am Hearr J I986;l I/:932. 940. 9. Martin GJ. Magid SM. Myers G. Barnet PS, Schaad JW, Weiss JS. Leach M. Singer DH. Heart rate variability and sudden death secondary IO coronary artery disease during ambulatory electrocardiographic monitoring. Am J Cardiol

262.

algorithm.

1969;21:234-247.

141.

1987.60:86-89.

analysis

Acoust Speech Signal Processing I98O;ASSP-28:441-455.

Heart J I988;l I5:263-267.

9. Kleiger RE, Miller JP. Bigger JT Jr, Moss AJ. the Multicemer Post-Infarction Research Group. Decreased heart rate variability and its association with increased mortality after acute myocardial infarclion. Am J Cardiol /987;59:256-

DC, Cohen RJ. Am J Physio/

function

Automedica analysis

equation

1978;2:135of autonomic

J Physiol 1989;256:HI42-HI52.

23. Benowitz NL. Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med 1988;319tl318-1330. 24. Nadeau RA, James TN. Effects of nicotine on heart rate studied by direct perfusion of sinus node. Am J Physiol 1967;212:9/1-916. 25. Mandel WJ. L&s M, Hayakawa H, Obayashi K. McCullen A. Cardiowscular effects of nicotine in the conscious dog. Modification by changs in autonomic tone. Am J Cardiol 1973;32:947-955. 26. Hallstrom AP, Cobb LA, Ray R. Smoking as a risk factor for recurrence of sudden cardiac arrest. N Engl J Med 1986;314:271-275. 27. Kannel WB. McGee DL. Castelli WP. Latst Perspective on cigarettesmoking and cardiovascular disease: the Framingham study. J Cardiac Rchabif

1984;4:267-277. 29. Wilhelmsen vention studies

L. Coronary of smoking.

heart

disease:

epidemiology

of smoking

Am Heart J 1988;115:242-249.

and inter-