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The sixth sense is involved in noise-induced
stress responses and vascular inflammation:
evidence for heightened amygdalar activity
in response to transport noise in man
Thomas Mu¨nzel
1,2
*, Sebastian Steven
1,3
, Omar Hahad
1,2
, and
Andreas Daiber
1,2
1
Center for Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany;
2
German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz,
Germany; and
3
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
This editorial refers to ‘A neurobiological mechanism link-
ing transportation noise to cardiovascular disease in
humans’, by M.T. Osborne et al., doi:10.1093/eurheartj/
ehz820.
Noise: an important
cardiovascular risk factor
Risk factors in the physical as well as the psychosocial environment
are gaining more and more importance for the development and
pathogenesis of non-communicable disease, with a new research
topic termed the ‘exposome’ representing the totality all of environ-
mental exposures, internal changes of biochemical pathways, and the
associated health impacts.
1
This concept is strongly supported by
the report of the ‘Lancet Commission on pollution and health’ and
the WHO associating 9–12.6 million premature deaths worldwide
with all forms of pollution.
2
Air pollution [e.g. ambient particulate
matter with a diameter <2.5 lm(PM
2.5
)] is the leading physicochemi-
cal environmental risk factor and is responsible for 8.79 million pre-
mature deaths mostly due to cardiovascular and cerebrovascular
diseases.
3
Whereas the association between air pollution exposure
(in particular for PM
2.5
) and cardiovascular morbidity and mortality is
widely accepted and is accordingly discussed in the European
Guidelines for prevention of cardiovascular diease (CVD)
4
and for
the diagnosis and management of chronic coronary syndromes,
5
transportation noise is not mentioned in any of the guidelines of the
European Society of Cardiology or in the report ‘Health at a Glance
Europe 2018’. This is even more concerning since 100 million peo-
ple in the EU were estimated to be exposed to traffic noise levels and
70 million people to be exposed in the EU to road traffic noise
exceeding the L
den
and the L
night
indicator noise threshold of 55
dB(A) and since there is growing body of evidence linking traffic noise
to increased cardiovascular morbidity and mortality (for reviews, see
Mu¨nzel et al.
6,7
). The European Community estimates that the social
cost of noiseand air pollution is up to e1 trillion every year. The obvi-
ous gaps between insufficient noise research, an underestimated
noise health impact, and also insufficient legal protection were high-
lighted by the recent WHO environmental noise guidelines for the
European Region, urging for more mechanistic as well as large-scale
epidemiological studies on noise–health interactions.
8
Noise causes stress responses
According to the noise reaction model introduced by Babisch,
9
CVD
can be the result of an activation of a so-called ‘indirect pathway,’
where lower levels of noise disturb sleep, communication, and activ-
ities, with subsequent emotional and cognitive responses and annoy-
ance. The resulting initial acute psychosocial stress response is
characterized by the activation of the sympathetic nervous system,
causing the release of the catecholamine neurotransmitters adren-
aline and noradrenaline from the adrenal medulla and of noradren-
aline from sympathetic nerve terminals. Activation of the
hypothalamic–pituitary–adrenal (HPA) axis follows, with a delayed in-
crease in circulating cytokines, including interleukins IL-6 and IL-1b.
The HPA axis relies on three major hormones to influence the feed-
back reactions between the hypothalamus, pituitary gland, and the
adrenal glands: corticotropin-releasing factor (CRF or CRH), adreno-
corticotropic hormone (ACTH or corticotropin), and the major
glucocorticoid in humans, cortisol (with the bioactive fraction found
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. University Medical Center Mainz, Center for Cardiology, Cardiology I, Geb. 605, Langenbeckstr. 1, D-55131 Mainz, Germany. Tel: þ49 6131 175737,
Fax: þ49 6131 17 6615, Email: tmuenzel@uni-mainz.de
Published on behalf of the European Society of Cardiology. All rights reserved. V
CThe Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
European Heart Journal (2019) 0, 1–3 EDITORIAL
doi:10.1093/eurheartj/ehz867
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in saliva). Furthermore, chronic stress reactions in response to noise
may also generate cardiovascular risk factors on their own, including
increased blood pressure, glucose levels, blood viscosity and blood
lipids, and activation of blood coagulation, which may ultimately lead
to manifestation of CVD including myocardial infarction, chronic cor-
onary syndromes, heart failure, and stroke.
9
The amygdala provides the link
between noise stimulus and
adverse cardiovascular effects
So far we have been missing the ‘cerebral link’ between the noise
stimulus and the subsequent stress reactions. The study by Osborne
et al. in this issue of the European Heart Journal
10
provides evidence
that the amygdala, a limbic centre involved in stress perception and
emotional control, participates in the stress responses to noise. It is
important to note that higher amygdalar metabolic activity has al-
ready been demonstrated to be associated with increased CVD risk
through a mechanism involving heightened arterial inflammation.
11,12
To test whether this may also be the case in response to transporta-
tion noise stress, 498 adults without CVD or active cancer under-
went clinical [
18
F]fluorodeoxyglucose positron emission tomo-
graphy/computed tomography ([
18
F]FDGPET/CT) imaging. The
results indicate that over a median of 4.06 years, 40 individuals expe-
rienced major adverse cardiovascular events (MACE). Higher noise
exposure [per 5 dB(A) increase] predicted MACE and remained ro-
bust to multivariable adjustments. Higher noise exposure was associ-
ated with increased amygdalar activity and arterial inflammation (Take
home figure). Mediation analysis suggested that higher noise exposure
associates with MACE via a serial mechanism involving heightened
amygdala activity and arterial inflammation that accounts for 12–26%
of this relationship. These findings clearly indicate that noise expos-
ure associates with MACE via a mechanism that begins with increased
stress-associated limbic (amygdalar) activity and eventually leads to
heightened arterial inflammation and therefore atherosclerosis.
10
The presented results showing increased stress responses and ad-
verse haemodynamic and vascular effects induced by transportation
noise are in agreement with results from epidemiological studies (for
reviews, see Mu¨nzel et al.
13,14
) and from human field studies where
healthy subjects, but also patients with established coronary artery
disease, were exposed to simulated aircraft noise leading to impaired
endothelial function (measured by flow-mediated dilation, FMD) that
was improved by the antioxidant vitamin C, being compatible with
increased oxidative stress in the vascular tissue.
15,16
Subsequent ani-
mal studies revealed that aircraft noise but not white noise increased
oxidative stress produced by the phagocytic NADPH oxidase
(NOX-2) and an uncoupled endothelial nitric oxide synthase
(eNOS) and neuronal NOS (nNOS) along with heightened inflamma-
tion of the vasculature and the brain (Take home figure).
17,18
Importantly, neurohormonal stress responses, blood pressure
increases, oxidative stress, inflammation, and endothelial dysfunction
were eliminated in Nox2 knockout animals, indicating a crucial role
for reactive oxygen species (ROS)-producing inflammatory cells such
as granulocytes and macrophages in mediating the cardiovascular
side effects in response to noise stress.
17,18
Further studies revealed
that night-time but not daytime noise is most responsible for the
noise-induced cardiovascular side effects, indicating that too short
sleep and the fragmentation of sleep may lead to more pronounced
stress responses.
17
Despite the exciting observation of increased activation of this
part of the limbic system,
10
the study has several limitations which in-
clude (i) the retrospective nature of the study; (ii) the very specific
Take home figure Mechanistic data on noise-induced neuroactivation of the endocrine systems, neuroinflammation, and cerebral oxidative
stress leading to dysregulated circadian and vascular gene expression, highblood pressure, vascular inflammation and oxidative stress, and endothelial
dysfunction, representing major triggers of cardiometabolic disease as revealed by studies in mice.
17,18
Proof-of-concept translational study in man of
noise-induced adverse key processes such as cerebral (amygdalar) activation and arterial inflammation increasing MACE.
10
Images are modified from
Kroller-Schon et al.
17
and Osborne et al.
10
2Editorial
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subject population; (ii) the uncontrolled follow-up; (iv) noise expos-
ure data from a period after the study was finished; (v) not having all
relevant confounders available on the individual level; and (vi) not
providing fully adjusted models. Future studies should address in par-
ticular whether night-time noise has more pronounced stimulatory
effects on amygdalar activity than daytime noise, which may explain
why the cardiovascular side effects of noise are substantially more
pronounced when there is too short or fractionated sleep.
What are the consequences for
legislation?
Thus, results from epidemiological studies, more recent noise re-
search data, and the new WHO noise guidelines contain a message
that is loud and clear. This should be the catalyst for revised policies
and actions to ensure that there is an equitable balance between eco-
nomic benefit from transportation and the adverse side effects of
transportation noise for health and well-being. The cost and long-
term consequences of inaction will be considerable.
19
Acknowledgements
The present work was supported by a vascular biology research
grant from the Boehringer Ingelheim Foundation for the collaborative
research group ‘Novel and neglected cardiovascular risk factors: mo-
lecular mechanisms and therapeutic implications’ to study the effects
of environmental risk factors on vascular function and oxidative stress
(A.D., S.S., and T.M.). The authors also acknowledge the continuous
support by the Foundation Heart of Mainz and the DZHK (German
Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz,
Germany.
Conflict of interest: none declared.
References
1. Wild CP. Complementing the genome with an ‘exposome’: the outstanding chal-
lenge of environmental exposure measurement in molecular epidemiology.
Cancer Epidemiol Biomarkers Prev 2005;14:1847–1850.
2. Landrigan PJ, Fuller R, Acosta NJR, Adeyi O, Arnold R, Basu NN, Balde AB,
Bertollini R, Bose-O’Reilly S, Boufford JI, Breysse PN, Chiles T, Mahidol C, Coll-
Seck AM, Cropper ML, Fobil J, Fuster V, Greenstone M, Haines A, Hanrahan D,
Hunter D, Khare M, Krupnick A, Lanphear B, Lohani B, Martin K, Mathiasen KV,
McTeer MA, Murray CJL, Ndahimananjara JD, Perera F, Potocnik J, Preker AS,
Ramesh J, Rockstrom J, Salinas C, Samson LD, Sandilya K, Sly PD, Smith KR,
Steiner A, Stewart RB, Suk WA, van Schayck OCP, Yadama GN, Yumkella K,
Zhong M. The Lancet Commission on pollution and health. Lancet 2018;391:
462–512.
3. Lelieveld J, Klingmuller K, Pozzer A, Poschl U, Fnais M, Daiber A, Munzel T.
Cardiovascular disease burden from ambient air pollution in Europe reassessed
using novel hazard ratio functions. Eur Heart J 2019;40:1590–1596.
4. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney
MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML,
Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N,
Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM, Binno S,
ESC Scientific Document Group. 2016 European Guidelines on cardiovascular
disease prevention in clinical practice: The Sixth Joint Task Force of the
European Society of Cardiology and Other Societies on Cardiovascular Disease
Prevention in Clinical Practice (constituted by representatives of 10 societies and
by invited experts). Developed with the special contribution of the European
Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J
2016;37:2315–2381.
5. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C,
Prescott E, Storey RF, Deaton C, Cuisset T, Agewall S, Dickstein K, Edvardsen T,
Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip J,
Muneretto C, Valgimigli M, Achenbach S, Bax JJ, ESC Scientific Document Group.
2019 ESC Guidelines for the diagnosis and management of chronic coronary syn-
dromes. Eur Heart J 2019;doi: 10.1093/eurheartj/ehz425.
6. Mu¨nzel T, Gori T, Babisch W, Basner M. Cardiovascular effects of environmental
noise exposure. Eur Heart J 2014;35:829–836.
7. Mu¨nzel T, Schmidt FP, Steven S, Herzog J, Daiber A, Sorensen M. Environmental
noise and the cardiovascular system. J Am Coll Cardiol 2018;71:688–697.
8. Kempen EV, Casas M, Pershagen G, Foraster M. WHO Environmental Noise
Guidelines for the European Region: a systematic review on environmental noise
and cardiovascular and metabolic effects: a summary. Int J Environ Res Public
Health 2018;15:379.
9. Babisch W. Stress hormones in the research on cardiovascular effects of noise.
Noise Health 2003;5:1–11.
10. Osborne MT, Radfar A, Hassan MZO, Abohashem S, Oberfeld B, Patrich T,
Tung B, Wang Y, Ishai A, Scott JA, Shin LM, Fayad ZA, Koenen KC, Rajagopalan
S, Pitman RK, Tawakol A. A neurobiological mechanism linking transportation
noise to cardiovascular disease in humans. Eur Heart J 2019;doi:
10.1093/eurheartj/ehz820.
11. Dar T, Radfar A, Abohashem S, Pitman RK, Tawakol A, Osborne MT.
Psychosocial stress and cardiovascular disease. Curr Treat Options Cardiovasc Med
2019;21:23.
12. Tawakol A, Ishai A, Takx RA, Figueroa AL, Ali A, Kaiser Y, Truong QA, Solomon
CJ, Calcagno C, Mani V, Tang CY, Mulder WJ, Murrough JW, Hoffmann U,
Nahrendorf M, Shin LM, Fayad ZA, Pitman RK. Relation between resting amygda-
lar activity and cardiovascular events: a longitudinal and cohort study. Lancet
2017;389:834–845.
13. Mu¨nzel T, Sørensen M, Gori T, Schmidt FP, Rao X, Brook J, Chen LC, Brook RD,
Rajagopalan S. Environmental stressors and cardio-metabolic disease: part I—epi-
demiologic evidence supporting a role for noise and air pollution and effects of
mitigation strategies. Eur Heart J 2017;38:550–556.
14. Mu¨nzel T, Sørensen M, Gori T, Schmidt FP, Rao X, Brook FR, Chen LC, Brook
RD, Rajagopalan S. Environmental stressors and cardio-metabolic disease: part
II—mechanistic insights. Eur Heart J 2017;38:557–564.
15. Schmidt F, Kolle K, Kreuder K, Schnorbus B, Wild P, Hechtner M, Binder H, Gori
T, Munzel T. Nighttime aircraft noise impairs endothelial function and increases
blood pressure in patients with or at high risk for coronary artery disease. Clin
Res Cardiol 2015;104:23–30.
16. Schmidt FP, Basner M, Kroger G, Weck S, Schnorbus B, Muttray A, Sariyar M,
Binder H, Gori T, Warnholtz A, Munzel T. Effect of nighttime aircraft noise ex-
posure on endothelial function and stress hormone release in healthy adults. Eur
Heart J 2013;34:3508–3514.
17. Kroller-Schon S, Daiber A, Steven S, Oelze M, Frenis K, Kalinovic S, Heimann A,
Schmidt FP, Pinto A, Kvandova M, Vujacic-Mirski K, Filippou K, Dudek M,
Bosmann M, Klein M, Bopp T, Hahad O, Wild PS, Frauenknecht K, Methner A,
Schmidt ER, Rapp S, Mollnau H, Munzel T. Crucial role for Nox2 and sleep de-
privation in aircraft noise-induced vascular and cerebral oxidative stress, inflam-
mation, and gene regulation. Eur Heart J 2018;39:3528–3539.
18. Munzel T, Daiber A, Steven S, Tran LP, Ullmann E, Kos smann S, Schmidt FP,
Oelze M, Xia N, Li H, Pinto A, Wild P, Pies K, Schmidt ER, Rapp S, Kroller -
Schon S. Effects of noise on vascular function, oxidative stress, and inflamma-
tion: mechanist ic insight from studies in mice. E ur Heart J 2017;38:
2838–2849.
19. Banatvala J, Peachey M, Mu¨nzel T. The harms to health caused by aviation noise
require urgent action. BMJ 2019;366:l5329.
Editorial 3
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