JACC VOL. 68, NO.

4, 2016 Letters 431

JULY 26, 2016:426–33

Anil K. Pareek, MD
*Franz H. Messerli, MD
The Networks Between
Nitin B. Chandurkar, MPharma the Sympathetic Nervous
*Division of Cardiology System and Immune
Mount Sinai Health Medical Center
Icahn School of Medicine System in Atherosclerosis
1 Gustave L. Levy Place
New York, New York 10029
Recently, we read with great interest a review by
E-mail: messerli.f@gmail.com
Libby et al. (1). In this review, they demonstrated that
http://dx.doi.org/10.1016/j.jacc.2016.05.014
leukocytes act as prostaglandins in atherosclerosis
Please note: Dr. Messerli is a consultant for or has consultant/advisory re-
lationships with Daiichi-Sankyo, Pfizer, Takeda, Abbott, AbbVie, Servier, Med- and build up important neuroimmune networks.
tronic, Ipca Laboratories, and Menarini. Dr. Pareek and Mr. Chandurkar are However, there are some concerns about how the
employees of Ipca Laboratories Limited, Mumbai, India.
sympathetic nervous system (SNS) interacts with the
REFERENCE
immune response in atherosclerosis.
The SNS exerts complex control over inflammation
1. Pareek AK, Messerli FH, Chandurkar NB, et al. Efficacy of low-
dose chlorthalidone and hydrochlorothiazide as assessed by 24-h ambula-
in atherosclerosis both on a systemic scale and at the
tory blood pressure monitoring. J Am Coll Cardiol 2016;67:379–89. regional level (Figure 1). SNS fibers innervate the

F I G U R E 1 The Circle Between the SNS and Atherosclerosis

CNS

Vagal Nerve

Sensory Nerve

SNS

Local Level
IL-1
Thymus Bone Marrow Spleen Lymph Node Atherosclerosis IL=6
TNF-α

Immune Cells

Inflammatory
Cytokines

Systemic Scale

CNS ¼ central nervous system; IL ¼ interleukin; SNS ¼ sympathetic nervous system; TNF ¼ tumor necrosis factor.
432 Letters
primary and second lymphoid organs (bone marrow,
thymus, spleen, lymph nodes) involved in immune
modulation. The SNS contributes to the differentia-
tion, maturation, recruitment, and regulation of im-
mune cells via lymphoid organs. The SNS is also a
modulator in thymus, spleen, and lymph node and can
modulate the recognition, proliferation, and effector
phases of the immune response. It influences immune
cell migration and alters cytokine production (2,3).
What’s more, the SNS directly innervates the
target lesion and plays a proinflammatory role in
immune cells. First, norepinephrine released from
sympathetic nerve endings binds to a - or b -adrenergic
receptors expressed on immune cells (T cells, B cells,
natural killer cells, and macrophages). This response
gives rise to a cascade of events, including the pro-
duction of proinflammatory cytokines and recruit-
ment of leukocytes (4). Second, the SNS releases
neuropeptide Y, which increases the adhesion of hu-
man leukocytes to endothelial cells. Third, the SNS
might also exert an influence on vascular and
lymphatic smooth muscle regulating the blood flow or
lymph flow and thereby lymphocyte delivery (5).
Furthermore, peripherally secreted
matory cytokines, such as interleukin-1, interleukin-
6, and tumor necrosis factor- a , can signal to the brain
via the circulation or through afferent fibers, which in
turn leads to activation of the SNS (2). This might
form a vicious circle between SNS activity and in-
flammatory disease (atherosclerosis).
Mingxian Chen, MD
Qiming Liu, MD
*Shenghua Zhou, MD
*Department of Cardiology
The Second Xiangya Hospital of Central South University
No. 139 Middle Renmin Road
Furong District
Changsha City
Hunan Province 410011
China
E-mail: xyzhoushenghua@126.com
http://dx.doi.org/10.1016/j.jacc.2016.04.049
Please note: This work was supported by grants from the National Natural
Science Foundation of China (No. 81270257). The authors have reported that
they have no relationships relevant to the contents of this paper to disclose.
REFERENCES
1. Libby P, Nahrendorf M, Swirski FK. Leukocytes link local and systemic
inflammation in ischemic cardiovascular disease: an expanded “cardiovascular
continuum.” J Am Coll Cardiol 2016;67:1091–103.
2. Kenney MJ, Ganta CK. Autonomic nervous system and immune system in-
teractions. Compr Physiol 2014;4:1177–200.
3. Dutta P, Courties G, Wei Y, et al. Myocardial infarction accelerates
atherosclerosis. Nature 2012;487:325–9.
JACC VOL. 68, NO. 4, 2016
JULY 26, 2016:426–33
4. Sundman E, Olofsson PS. Neural control of the immune system. Adv Physiol
Educ 2014;38:135–9.
5. Pongratz G, Straub RH. The sympathetic nervous response in inflammation.
Arthritis Res Ther 2014;16:504.
REPLY: The Networks Between the
Sympathetic Nervous System and Immune
System in Atherosclerosis
We thank Dr. Chen and colleagues for their interest
in our recent paper (1). We agree completely with
the importance of the sympathetic nervous system
as a modulator of leukocyte functions and hemato-
poiesis. Indeed, similar to the diagram that they pro-
vide, the central Figure of our publication depicts
explicitly the links between the central nervous sys-
tem, sympathetic outflow, and beta3-adrenergic sig-
naling as a stimulator of overproduction of leukocytes
under stress conditions such as acute myocardial
infarction. We described this pathway in the paper by
Dutta et al. (2) cited in their letter. We thank these
readers for their appreciation of this important point.
*Peter Libby, MD
Matthias Nahrendorf, MD
proinflam-
Filip K. Swirski, PhD
*Division of Cardiovascular Medicine
Department of Medicine
Brigham and Women’s Hospital
Harvard Medical School
77 Avenue Louis Pasteur
Boston, Massachusetts 02115
E-mail: plibby@bwh.harvard.edu
http://dx.doi.org/10.1016/j.jacc.2016.05.017
Please note: Dr. Libby is involved in consulting in clinical trials; receives
sponsored research support from Novartis; and receives funding from the
National Heart, Lung, and Blood Institute (R01 HL080472). All other authors
have reported that they have no relationships relevant to the contents of this
paper to disclose.
REFERENCES
1. Libby P, Nahrendorf M, Swirski FK. Leukocytes link local and systemic
inflammation in ischemic cardiovascular disease: an expanded “cardiovascular
continuum.” J Am Coll Cardiol 2016;67:1091–103.
2. Dutta P, Courties G, Wei Y, et al. Myocardial infarction accelerates
atherosclerosis. Nature 2012;487:325–9.
Percutaneous Coronary
Intervention After
Transcatheter Aortic
Valve Replacement:
Approach and Challenges
We read with great interest the paper by Chakravarty
et al. (1) regarding percutaneous coronary interven-
tion (PCI) of the left main coronary artery (LM) in