Online Appendix
PubMed Search
For the purposes of this Review Topic of the Week, a PubMed search was performed using
several search terms, including sympathetic nerve activity, autonomic nervous system, tobacco
smoke, air pollution, electronic cigarettes, marijuana, hookah, heart rate variability, waterpipes,
TRPV1, lung afferents, baroreceptors, nicotine, nitric oxide, and others, in various combinations.
We also examined the references from these articles. We attempted to include articles most
relevant to the topic, although the number of articles far exceeded the space available for the
print version, so many are included in this appendix, by sub-topic.
Smoking as a Cardiac Risk Factor
Sandhu RK, Jimenez MC, Chiuve SE et al. Smoking, smoking cessation, and risk of sudden
cardiac death in women. Circulation Arrhythmia and Electrophysiology 2012;5:1091-7.
Gellert C, Schottker B, Muller H, Holleczek B, Brenner H. Impact of smoking and quitting on
cardiovascular outcomes and risk advancement periods among older adults. European Journal Of
Epidemiology 2013;28:649-58.
Merry AH, Boer JM, Schouten LJ et al. Smoking, alcohol consumption, physical activity, and
family history and the risks of acute myocardial infarction and unstable angina pectoris: a
prospective cohort study. BMC Cardiovascular Disorders 2011;11:13.
Mallaina P, Lionis C, Rol H et al. Smoking cessation and the risk of cardiovascular disease
outcomes predicted from established risk scores: results of the Cardiovascular Risk Assessment
among Smokers in Primary Care in Europe (CV-ASPIRE) study. BMC Public Health
2013;13:362.
Huxley RR, Woodward M. Cigarette smoking as a risk factor for coronary heart disease in
women compared with men: a systematic review and meta-analysis of prospective cohort
studies. Lancet 2011;378:1297-305.
Jha P. The 21st century benefits of smoking cessation in Europe. European Journal of
Epidemiology 2013;28:617-9.
Njolstad I, Arnesen E, Lund-Larsen PG. Smoking, serum lipids, blood pressure, and sex
differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation
1996;93:450-6.
Reviews of Potential Mechanism of Cardiac Risk from Cigarette Smoke
Barua RS, Ambrose JA. Mechanisms of coronary thrombosis in cigarette smoke exposure.
Arteriosclerosis, Thrombosis, and Vascular Biology 2013;33:1460-7.
Csordas A, Bernhard D. The biology behind the atherothrombotic effects of cigarette smoke.
Nature Reviews Cardiology 2013;10:219-30.
Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications
for treatment. Progress in Cardiovascular Diseases 2003;46:91-111.
Sympathetic nerve activity underlies increased cardiac risk in many cardiac conditions, and its
interruption forms a cornerstone in the treatment of many of these conditions.
Auerbach AD, Goldman L. beta-Blockers and reduction of cardiac events in noncardiac surgery:
scientific review. JAMA: the Journal of the American Medical Association 2002;287:1435-44.
Fonarow GC. Comprehensive adrenergic blockade post myocardial infarction left ventricular
dysfunction. Cardiology Clinics 2008;26:79-89, vii.
Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A. Plasma norepinephrine,
plasma renin activity, and congestive heart failure. Relations to survival and the effects of
therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87:VI408.
Kataoka M, Ito C, Sasaki H, Yamane K, Kohno N. Low heart rate variability is a risk factor for
sudden cardiac death in type 2 diabetes. Diabetes Research and Clinical Practice 2004;64:51-8.
Sympathetic Nerve Activity Increases Cardiac Risk in Many Cardiac Conditions
Auerbach AD, Goldman L. beta-Blockers and reduction of cardiac events in noncardiac surgery:
scientific review. JAMA : the Journal of the American Medical Association 2002;287:1435-44.
Fonarow GC. Comprehensive adrenergic blockade post myocardial infarction left ventricular
dysfunction. Cardiology Clinics 2008;26:79-89, vii.
Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A. Plasma norepinephrine,
plasma renin activity, and congestive heart failure. Relations to survival and the effects of
therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87:VI408.
Kataoka M, Ito C, Sasaki H, Yamane K, Kohno N. Low heart rate variability is a risk factor for
sudden cardiac death in type 2 diabetes. Diabetes Research and Clinical Practice 2004;64:51-8.
Nicotine Metabolism
Benowitz NL, Porchet H, Sheiner L, Jacob P, 3rd. Nicotine absorption and cardiovascular effects
with smokeless tobacco use: comparison with cigarettes and nicotine gum. Clinical
Pharmacology and Therapeutics 1988;44:23-8.
Smoking is Not a Risk Factor for Hypertension
Green MS, Jucha E, Luz Y. Blood pressure in smokers and nonsmokers: epidemiologic findings.
American Heart Journal 1986;111:932-40.
Sympathetic Predominance Following Secondhand Smoke Exposure
Hausberg and colleagues studied 17 healthy never-smokers, and found that during acute
exposure to secondhand smoke but not vehicle, muscle SNA and nicotine levels increased, but
there was no detectable increase in blood pressure, heart rate or plasma catecholamine levels.
Similarly, secondhand smoke exposure leads to sympathetic predominance as estimated by
HRV. For example, healthy nonsmokers were intermittently exposed to secondhand smoke in a
commercial airport in smoking and nonsmoking areas at 2 hour intervals, while undergoing
ambulatory electrocardiogram recordings. Secondhand exposure was associated with a decrease
in heart rate variability as measured by both time domain and frequency domain analyses,
consistent with an acute, reversible shift in autonomic balance towards increased SNA during
secondhand smoke exposure
Hausberg M, Mark AL, Winniford MD, Brown RE, Somers VK. Sympathetic and vascular
effects of short-term passive smoke exposure in healthy nonsmokers. Circulation 1997;96:2827.43.
Pope CA, 3rd, Eatough DJ, Gold DR et al. Acute exposure to environmental tobacco smoke and
heart rate variability. Environmental Health Perspectives 2001;109:711-6.
Heart Rate Variability is Decreased in Most, But Not All Studies of Habitual Smokers
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. European Heart Journal 1996;17:354-81.
Cavallari JM, Fang SC, Eisen EA et al. Time course of heart rate variability decline following
particulate matter exposures in an occupational cohort. Inhalation toxicology 2008;20:415-22.
Penny WJ, Mir MA. Cardiorespiratory response to exercise before and after acute betaadrenoreceptor blockade in nonsmokers and chronic smokers. International Journal of
Cardiology 1986;11:293-304.
Levin FR, Levin HR, Nagoshi C. Autonomic functioning and cigarette smoking: heart rate
spectral analysis. Biological Psychiatry 1992;31:639-43.
Kupari M, Virolainen J, Koskinen P, Tikkanen MJ. Short-term heart rate variability and factors
modifying the risk of coronary artery disease in a population sample. The American Journal of
Cardiology 1993;72:897-903.
Eryonucu B, Bilge M, Guler N, Uzun K, Gencer M. Effects of cigarette smoking on the circadian
rhythm of heart rate variability. Acta Cardiologica 2000;55:301-5.
Alyan O, Kacmaz F, Ozdemir O et al. Effects of cigarette smoking on heart rate variability and
plasma N-terminal pro-B-type natriuretic peptide in healthy subjects: is there the relationship
between both markers? Annals of Noninvasive Electrocardiology: the official journal of the
International Society for Holter and Noninvasive Electrocardiology, Inc 2008;13:137-44.
Murata K, Landrigan PJ, Araki S. Effects of age, heart rate, gender, tobacco and alcohol
ingestion on R-R interval variability in human ECG. Journal of the Autonomic Nervous System
1992;37:199-206.
Kobayashi F, Watanabe T, Akamatsu Y et al. Acute effects of cigarette smoking on the heart rate
variability of taxi drivers during work. Scandinavian Journal of Work, Environment & Health
2005;31:360-6.
Minami J, Ishimitsu T, Matsuoka H. Effects of smoking cessation on blood pressure and heart
rate variability in habitual smokers. Hypertension 1999;33:586-90.
Yotsukura M, Koide Y, Fujii K et al. Heart rate variability during the first month of smoking
cessation. American Heart Journal 1998;135:1004-9.
Felber Dietrich D, Schwartz J, Schindler C et al. Effects of passive smoking on heart rate
variability, heart rate and blood pressure: an observational study. International Journal of
Epidemiology 2007;36:834-40.
Smoking Increases Oxidative Stress
Armani C, Landini L, Jr., Leone A. Molecular and biochemical changes of the cardiovascular
system due to smoking exposure. Current Pharmaceutical Design 2009;15:1038-53.
Burke A, Fitzgerald GA. Oxidative stress and smoking-induced vascular injury. Progress in
Cardiovascular Diseases 2003;46:79-90.
Lung Afferent Nerves
Canning BJ, Spina D. Sensory nerves and airway irritability. Handbook of experimental
pharmacology 2009:139-83.
Widdicombe J. Lung afferent activity: implications for respiratory sensation. Respiratory
Physiology & Neurobiology 2009;167:2-8.
Arterial Chemoreflex Sensitivity
Excitatory nicotine receptors are present on the glomus cells, cells located in the carotid and
aortic bodies that are similar to neurons but with a high metabolic rate and perfusion and thus
sensitive to changes in arterial blood gas tension. When activated, perhaps by nicotine in
cigarette smoke at nicotinic receptors, glomus cells activate the chemoreceptor nerve endings
leading to acute and/or chronic activation of the peripheral arterial chemoreflex, resulting in an
increase in efferent sympathetic excitation. In habitual smokers at baseline (room air), nicotine
increases blood pressure, heart rate, and muscle sympathetic nervous activity. During hypoxia, in
the presence compared to the absence of nicotine, there is no difference in the respiratory
response, refuting the hypothesis that in habitual smokers, acute nicotine exposure acutely
sensitizes the chemoreflex. Unfortunately, baseline, chronic arterial chemoreflex sensitivity has
not been compared between non-smokers and habitual smokers in these studies. However, the
observation that smokers do not have increased baseline respiratory rates compared to nonsmokers argues against a chronically activated arterial chemoreflex driving the persistent
increase in sympathetic nerve activity.
Carbon monoxide, present in tobacco smoke, may induce a mild hypoxia in susceptible
individuals, and so the impact of acute carbon monoxide on blood pressure, heart rate, muscle
sympathetic nervous activity and catecholamines in smokers and never smokers has been
investigated. Acute carbon monoxide administered under conditions mimicking smoking does
not have any effect on blood pressure, heart rate, or muscle sympathetic nervous activity,
suggesting that acute neural effects of smoking are not attributable to carbon monoxide.
Gerhardt U, Hans U, Hohage H. Influence of smoking on baroreceptor function: 24 h
measurements. Journal of Hypertension 1999;17:941-6.
Dinger B, Gonzalez C, Yoshizaki K, Fidone S. Localization and function of cat carotid body
nicotinic receptors. Brain Research 1985;339:295-304.
Anand A. Role of aortic chemoreceptors in the hypertensive response to cigarette smoke.
Respiration Physiology 1996;106:231-8.
Hausberg M, Somers VK. Neural circulatory responses to carbon monoxide in healthy humans.
Hypertension 1997;29:1114-8.
Zevin S, Saunders S, Gourlay SG, Jacob P, Benowitz NL. Cardiovascular effects of carbon
monoxide and cigarette smoking. Journal of the American College of Cardiology 2001;38:16338.
Marijuana
Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial
infarction by marijuana. Circulation 2001;103:2805-9.
Caldicott DG, Holmes J, Roberts-Thomson KC, Mahar L. Keep off the grass: marijuana use and
acute cardiovascular events. European Journal of Emergency Medicine : official journal of the
European Society for Emergency Medicine 2005;12:236-44.
Mukamal KJ, Maclure M, Muller JE, Mittleman MA. An exploratory prospective study of
marijuana use and mortality following acute myocardial infarction. American Heart Journal
2008;155:465-70.
Aronow WS, Cassidy J. Effect of marihuana and placebo-marihuana smoking on angina pectoris.
The New England Journal of Medicine 1974;291:65-7.
Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet
2009;374:1383-91.
Electronic-Cigarettes
Abrams DB. Promise and peril of e-cigarettes: can disruptive technology make cigarettes
obsolete? JAMA : the Journal of the American Medical Association 2014;311:135-6.
Sutfin EL, McCoy TP, Morrell HE, Hoeppner BB, Wolfson M. Electronic cigarette use by
college students. Drug and Alcohol Dependence 2013;131:214-21.
Vansickel AR, Eissenberg T. Electronic cigarettes: effective nicotine delivery after acute
administration. Nicotine & Tobacco Research: official journal of the Society for Research on
Nicotine and Tobacco 2013;15:267-70.
Fuoco FC, Buonanno G, Stabile L, Vigo P. Influential parameters on particle concentration and
size distribution in the mainstream of e-cigarettes. Environ Pollut 2014;184:523-9.
Goniewicz ML, Hajek P, McRobbie H. Nicotine content of electronic cigarettes, its release in
vapour and its consistency across batches: regulatory implications. Addiction 2014;109:500-7.
Czogala J, Goniewicz ML, Fidelus B, Zielinska-Danch W, Travers MJ, Sobczak A. Secondhand
Exposure to Vapors From Electronic Cigarettes. Nicotine & Tobacco Research : official journal
of the Society for Research on Nicotine and Tobacco 2013.
Cahn Z, Siegel M. Electronic cigarettes as a harm reduction strategy for tobacco control: a step
forward or a repeat of past mistakes? Journal of Public Health Policy 2011;32:16-31.
Montharu J, Le Guellec S, Kittel B et al. Evaluation of lung tolerance of ethanol, propylene
glycol, and sorbitan monooleate as solvents in medical aerosols. Journal of Aerosol Medicine
and Pulmonary Drug Delivery 2010;23:41-6.
Werley MS, McDonald P, Lilly P et al. Non-clinical safety and pharmacokinetic evaluations of
propylene glycol aerosol in Sprague-Dawley rats and Beagle dogs. Toxicology 2011;287:76-90.
Wang T, Noonberg S, Steigerwalt R et al. Preclinical safety evaluation of inhaled cyclosporine in
propylene glycol. Journal of Aerosol Medicine : the official journal of the International Society
for Aerosols in Medicine 2007;20:417-28.
Nicotine Tob Res. 2014 May 15. pii: ntu078. [Epub ahead of print]
Sandhu RK, Jimenez MC, Chiuve SE et al. Smoking, smoking cessation, and risk of sudden
cardiac death in women. Circulation Arrhythmia and Electrophysiology 2012;5:1091-7.
Gellert C, Schottker B, Muller H, Holleczek B, Brenner H. Impact of smoking and quitting on
cardiovascular outcomes and risk advancement periods among older adults. European Journal of
Epidemiology 2013;28:649-58.
Merry AH, Boer JM, Schouten LJ et al. Smoking, alcohol consumption, physical activity, and
family history and the risks of acute myocardial infarction and unstable angina pectoris: a
prospective cohort study. BMC Cardiovascular Disorders 2011;11:13.
Mallaina P, Lionis C, Rol H et al. Smoking cessation and the risk of cardiovascular disease
outcomes predicted from established risk scores: results of the Cardiovascular Risk Assessment
among Smokers in Primary Care in Europe (CV-ASPIRE) study. BMC Public Health
2013;13:362.
Huxley RR, Woodward M. Cigarette smoking as a risk factor for coronary heart disease in
women compared with men: a systematic review and meta-analysis of prospective cohort
studies. Lancet 2011;378:1297-305.
Jha P. The 21st century benefits of smoking cessation in Europe. European Journal of
Epidemiology 2013;28:617-9.
Njolstad I, Arnesen E, Lund-Larsen PG. Smoking, serum lipids, blood pressure, and sex
differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation
1996;93:450-6.
Waterpipes (hookahs)
Roskin J, Aveyard P. Canadian and English students' beliefs about waterpipe smoking: a
qualitative study. BMC Public Health 2009;9:10.
Martinasek MP, McDermott RJ, Martini L. Waterpipe (hookah) tobacco smoking among youth.
Current Problems in Pediatric and Adolescent Health Care 2011;41:34-57.
Maziak W, Ward KD, Afifi Soweid RA, Eissenberg T. Tobacco smoking using a waterpipe: a reemerging strain in a global epidemic. Tobacco Control 2004;13:327-33.
Air Pollution
Araujo JA, Barajas B, Kleinman M et al. Ambient particulate pollutants in the ultrafine range
promote early atherosclerosis and systemic oxidative stress. Circulation Research 2008;102:58996.
Araujo JA, Nel AE. Particulate matter and atherosclerosis: role of particle size, composition and
oxidative stress. Particle and Fibre Toxicology 2009;6:24.
Yin F, Lawal A, Ricks J et al. Diesel exhaust induces systemic lipid peroxidation and
development of dysfunctional pro-oxidant and pro-inflammatory high-density lipoprotein.
Arteriosclerosis, Thrombosis, and Vascular Biology 2013;33:1153-61.
Miller MR, McLean SG, Duffin R et al. Diesel exhaust particulate increases the size and
complexity of lesions in atherosclerotic mice. Particle and Fibre Toxicology 2013;10:61.
Blunted Baroreflex Sensitivity Increases Cardiac Risk
Grassi G, Seravalle G, Dell'Oro R, Facchini A, Ilardo V, Mancia G. Sympathetic and baroreflex
function in hypertensive or heart failure patients with ventricular arrhythmias. Journal of
Hypertension 2004;22:1747-53.
Farrell TG, Odemuyiwa O, Bashir Y et al. Prognostic value of baroreflex sensitivity testing after
acute myocardial infarction. British Heart Journal 1992;67:129-37.
La Rovere MT, Bigger JT, Jr., Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and
heart-rate variability in prediction of total cardiac mortality after myocardial infarction.
ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet
1998;351:478-84.
Direct and Indirect (via nitric oxide synthase) Sympathomimetic Effects of Nicotine.
In animal studies, nicotine receptors have been identified in the rostral ventrolateral medulla.
Activation of these receptors in a rat model causes an increase in renal sympathetic nerve
activity, as well as an increase in blood pressure and heart rate. This pressor response is greatest
in spontaneously hypertensive rats, and is blocked by prazosin. Nitric oxide acts as a
neurotransmitter in the central nervous system to inhibit central neural sympathetic outflow. In
humans, cigarette tobacco smoke inhibits endothelial nitric oxide synthase in the vasculature.
Data are emerging in animal studies that nicotine also uncouples neuronal nitric oxide synthase
centrally. Inhibition of nitric oxide synthase with intravenous L-NG- monomethyl-L-arginine
leads to an increase in sympathetic nerve activity in humans.
Tseng CJ, Ger LP, Lin HC, Tung CS. The pressor effect of nicotine in the rostral ventrolateral
medulla of rats. The Chinese Journal of Physiology 1994;37:83-7.
Tseng CJ, Appalsamy M, Robertson D, Mosqueda-Garcia R. Effects of nicotine on brain stem
mechanisms of cardiovascular control. The Journal of Pharmacology and Experimental
Therapeutics 1993;265:1511-8.
Harada S, Tokunaga S, Momohara M et al. Inhibition of nitric oxide formation in the nucleus
tractus solitarius increases renal sympathetic nerve activity in rabbits. Circulation Research
1993;72:511-6.
Zanzinger J, Czachurski J, Seller H. Inhibition of sympathetic vasoconstriction is a major
principle of vasodilation by nitric oxide in vivo. Circulation Research 1994;75:1073-7.
Arrick DM, Mayhan WG. Acute infusion of nicotine impairs nNOS-dependent reactivity of
cerebral arterioles via an increase in oxidative stress. J Appl Physiol (1985) 2007;103:2062-7.
Owlya R, Vollenweider L, Trueb L et al. Cardiovascular and sympathetic effects of nitric oxide
inhibition at rest and during static exercise in humans. Circulation 1997;96:3897-903.