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\begin{document}

\title{The ``brain-heart-gut'' axis and novel mechanisms of future
cardiovascular disease}



\author[1]{Chunsong Hu}%
\affil[1]{Nanchang University}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Cardiovascular disease (CVD) is a leading cause of morbidity and
mortality in the globe. Both established cardiovascular disease (eCVD)
and future CVD (fCVD) need to further explore the mechanisms. This
article briefly introduces current major studies on axis and CVD, which
were published in cardiovascular journals and non-cardiovascular
journals (Table 1 \& Table 2), and brings up and discusses the new
origins of fCVD linking to major risk factors in early life due to
unhealthy ``environment-sleep-emotion-exercise-diet'' intervention
{[}E(e)SEEDi{]} lifestyle referred as to a ``Golden Hoop Curse'', and
the ``brain-heart-gut'' axis---a fresh theory on novel mechanisms of
fCVD (Figure 1 \& Figure 2), which are mediated by E(e)SEEDi lifestyle
and microbiome. As a new theory, the ``brain-heart-gut'' axis will help
us to earlier and better prevent and control both eCVD and fCVD with
healthy E(e)SEEDi lifestyle.%
\end{abstract}%



\sloppy


REVIEW

\textbf{The ``brain-heart-gut'' axis and novel mechanisms of future
cardiovascular disease}

\textbf{Chunsong Hu}

Department of Cardiovascular Medicine, Nanchang University, Hospital of
Nanchang University, Jiangxi Academy of Medical Science, Nanchang
330006, Jiangxi, China

From: Department of Cardiovascular Medicine, Nanchang University,
Hospital of Nanchang University, Jiangxi Academy of Medical Science, No.
461 Bayi Ave, Nanchang 330006, Jiangxi, China. Tel: (+86) 189 70816800;
Email: cnhucs@ncu.edu.cn or cnhucs@163.com

Word count: 2,533 (Main text) + 135 (Abstract)

References: 122

Tables: 2

Figures: 2 Total pages: 28

\textbf{Corresponding Author} : Chunsong Hu, MD, PhD, Department of
Cardiovascular Medicine, Nanchang University, Hospital of Nanchang
University, Jiangxi Academy of Medical Science, No. 461 Bayi Ave,
Nanchang 330006, Jiangxi, China; e-mail, cnhucs@ncu.edu.cn or
cnhucs@163.com

Running Title: ``Brain-Heart-Gut'' Axis \& Future CVD

\textbf{ABSTRACT}

Cardiovascular disease (CVD) is a leading cause of morbidity and
mortality in the globe. Both established cardiovascular disease (eCVD)
and future CVD (fCVD) need to further explore the mechanisms. This
article briefly introduces current major studies on axis and CVD, which
were published in cardiovascular journals and non-cardiovascular
journals (Table 1 \& Table 2), and brings up and discusses the new
origins of fCVD linking to major risk factors in early life due to
unhealthy ``environment-sleep-emotion-exercise-diet'' intervention
{[}E(e)SEEDi{]} lifestyle referred as to a ``Golden Hoop Curse'', and
the ``brain-heart-gut'' axis---a fresh theory on novel mechanisms of
fCVD (Figure 1 \& Figure 2), which are mediated by E(e)SEEDi lifestyle
and microbiome. As a new theory, the ``brain-heart-gut'' axis will help
us to earlier and better prevent and control both eCVD and fCVD with
healthy E(e)SEEDi lifestyle.

\textbf{KEYWORDS:}

``brain-heart-gut'' axis, cardiovascular disease, COVID-19, E(e)SEEDi
lifestyle, mechanism

\textbf{INTRODUCTION}

As we all known, cardiovascular disease (CVD) is still a leading cause
of death in the globe. Currently, it is more and more common due to
aging and unhealthy lifestyle. With the rapid development of biomedical
technology, novel diagnostic and research tools, new insights into
mechanisms and therapeutic agents, and fresh evaluation and preventive
methods (e.g., a magic ``polypills'', that is,
``environment-sleep-emotion-exercise-diet'' intervention
{[}E(e)SEEDi{]}) (1) make a big change in its mortality and outcomes.

As a front-line clinical doctor, the author has made giant efforts to
trace the origin and mechanisms of future CVD (fCVD). Luckily, five core
elements, ``environment-sleep-emotion-exercise-diet'' {[}E(e)SEED{]},
have been discovered and highly contribute to human cardiovascular
health. Based on this discovery, a novel classification of clinical risk
factors based on unhealthy E(e)SEED intervention {[}E(e)SEEDi{]}
lifestyle has been developed. In fact, many major risk factors related
to unhealthy E(e)SEEDi lifestyle could result in fCVD.

For example, as one's internal environment, on the one hand, a genetic
or family history is an important risk factor of fCVD; On the other
hand, as major non-communicable diseases, both established CVD (eCVD)
and fCVD highly link to acute or chronic infection, which leads to
abnormal status in one's internal environment. So far, the COVID-19
pandemics are still continuing due to the Omicron variant of SARS-CoV-2.
A recent study found that COVID-19 is a high risk factor of adverse
cardiovascular outcomes (2). It can be said that SARS-CoV-2 and its
variants are new origins of both eCVD and fCVD since there are more than
522.783 million confirmed cases and over 6.27 million deaths in the
globe (May 23, 2022) according to the report of the World Health
Organization.

\textbf{CURRENT MAJOR STUDIES ON AXIS AND CVD}

Since \emph{Laragh JH} reviewed the renin-aldosterone axis in
cardiovascular system in the \emph{New England Journal of Medicine} in
1985 (3), Bayes-Genis A, et al. reviewed the insulin-like growth factor
axis on atherosclerosis and restenosis in 2000 (4), and the cardiorenal
axis (Bush EW and McKinsey TA, 2010) (5) and the RAGE axis (6) (Yan SF,
et al. 2010) on cardiovascular mechanisms were also reviewed. So far,
there were many studies and some reviews on axis and CVD. It's really a
hot topic in life science and biomedicine. Here are summarized tables on
major studies of axis and eCVD or fCVD in cardiovascular journals (7-24)
and non-cardiovascular journals (25-42) (Table 1 \& Table 2). However,
exception of several reviews on ``Brain-Gut-Bone Marrow Axis''
(Santisteban MM, et al. 2016) (43) and ``Heart-Brain Axis''
(Tahsili-Fahadan P \& Geocadin RG, 2017) (44), which involved in
cardiovascular risk, the mechanisms and treatment, most of these
studies, and reviews or comments just only involved in targeting these
``branch axis'' of eCVD (atherosclerosis, hypertension, and others), for
example, the CCL2-CCR2 axis (Georgakis MK, et al. 2022; Crea F, 2022)
(45, 46). Although there was a new theory on the artery-brain circuit
(ABC) of atherosclerosis (Mohanta SK, et al. 202) (47), little is known
about the novel ``total axis'' on the brain, heart, and the gut.

\textbf{``BRAIN-HEART-GUT'' AXIS AND FUTURE CVD}

As we know, some risk factors associated with unhealthy E(e)SEEDi
lifestyle play a vital role in the development of fCVD. Due to the role
of parental genetic disposition, epigenetic modifications, inflammatory
cytokines, DNA methylation or mutation, endothelial dysfunction,
arteriosclerosis, chronic fetal hypoxia (48), and gut microbiota (49),
its mechanism may link to a novel theory of the ``brain-heart-gut'' axis
(Figure 1). Since there is ``prevention first, combination of prevention
and treatment'', tracing the origin and elaborating the mechanism of
fCVD is very valuable and meaningful. And the control and prevention of
fCVD highly links to less major adverse cardio-cerebrovascular events
(MACCE), healthy aging, and longevity.

Major risk factors associated with early unhealthy E(e)SEEDi lifestyle
play a pivotal role in the development of fCVD by disruption~of the
``brain-heart-gut'' axis. And early unhealthy E(e)SEEDi lifestyle is
like a ``Golden Hoop Curse'', it may restrict and control one's physical
and mental health. Like the ``Tang Monk'', each of us should manage the
``Golden Hoop Curse'' with healthy E(e)SEEDi lifestyle by ourselves,
make it relax and maintain the health of brain, heart, and gut, and
control and prevent hypertension, ischemic heart disease or coronary
artery disease (stable or unstable angina, acute myocardial infarction),
arrhythmia (atrial fibrillation, premature beat or tachycardia),
congenital heart disease, infectious disease due to reduction of human
immunity, cardiac injury, cardiomyopathy, heart failure, type 2
diabetes, stroke, sudden cardiac death, mental disease (anxiety or
depression, schizophrenia), neurodegenerative diseases (Parkinson's
disease, cognitive aging or declines, dementia, and~Alzheimer's
disease), and cancer.

\textbf{MECHANISMS MEDIATED BY E(e)SEEDi LIFESTYLE AND MICROBIOME}

\textbf{Mechanisms mediated by environment and microbiome}

Currently, environment is still the No. 1 element of health. It highly
associates with one's cardiovascular health and CVD, and other mNCDs,
such as diabetes and cancer. First, socioeconomic environment or
vulnerabilities (50, 51), which includes ethnic differences, educational
attainment, employment, occupational class, income, and
personal~relationships may affect individual health. For example, as a
proxy phenotype, there is an obvious link between educational attainment
and cognitive function (52-54). Second, natural (neighborhoods or built)
environment and air quality (55) are important factors of
cardiocerebrovascular health. ``Water-Air-Radiation-Sound (WARS)''
pollutions (e.g., e-noise) (56-58) greatly increase the hazard of fCVD
(acute myocardial infarction, stroke).

Third, internal environment with a genetic or family history, new or
traditional modifiable risk factors (59), is a~critical~variable, such
as maternal adverse pregnancy outcomes (preterm birth, low birth weight)
(60, 61) as well as acute or chronic infection, e.g., COVID-19 (2),
abnormal blood pressure, diabetes, dyslipidemia, hyperuricemia, and
obesity. A recent study found that a genetic factor (ABO genotype) can
alter the composition of the gut microbiota (62), and this is a strong
evidence for internal environment associated with human health. Herein,
the gut microbiota\textsuperscript{4} may play a crucial role in the
development and progression of eCVD and fCVD. Sometimes positive
intracellular environmental stress in the cardiac cells can help the
heart repair (63). However, changes in the concentrations of
intracellular sodium, calcium, potassium, and ATP/ADP may link to
arrhythmias (64, 65). In addition, in a murine inflammation resolution
model of atherosclerotic plaque, reshaping of the gut~microbiome~has a
therapeutic effect (66).

Several known risk factors such as age, genetic variants, Y chromosome
(ChrY) structural aberrations and environmental stressors, link to
mosaic loss of ChrY (LOY) in human somatic cells (67), and as the most
commonly acquired mutation, it is associated with mNCDs including
cancer, Alzheimer's disease, and fCVD. Maternal risk factors in
pregnancy (68) such as advanced age and a suboptimal in utero
environment (fetal growth restriction, preterm birth, and/or
preeclampsia) link to an increased risk of fCVD in adulthood for both
the mother and offspring. Sudden cardiac death in younger patients is
associated with isolated congenital coronary artery anomalies (69).
Acute coronary syndrome have distinct serum metabolome and gut microbial
profiling, which link to an increased risk of coronary artery disease
(CAD) (70).

\textbf{Mechanisms mediated by sleep and microbiome}

A clinical study found that night shift exposure may increase incident
atrial fibrillation and the risk of CAD (71).
Self-reported~sleep~quality (insufficient sleep or loss of sleep) is
associated with cardiometabolic diseases, such as obesity and diabetes,
CVD, and neurological and cognitive impairments, due to shifts in gut
microbiome composition (72, 73). Disrupted sleep may lead to
cardiovascular pathology since there are associations between sleep
fragmentation, mean arterial pressure, and the gut/fecal metabolome
(74). And the acute circadian rhythm disturbance caused by sleep-wake
shifts affect the human gut microbiota (75), especially the functional
profiles of gut microbes and interactions among them. Thus, the gut
microbiome is a potential target for reducing the impact of chronic
insomnia on cardiometabolic health (76). Due to a causal relationship
between the gut microbiome and hypertension (77), the former may be a
target for treatment of OSA-related and other typical hypertension.

\textbf{Mechanisms mediated by emotion and microbiome}

Since psychological or emotional stress links to cardiovascular health
(78), current available literatures have showed the health benefits of
meditation (79-81), which is like ``keeping the pubic region
(Dantian)''. In fact, mindfulness-based meditation may reduce not only
cardiovascular risk factors but also both eCVD (atherosclerosis,
hypertension, and hear failure) (82) and fCVD by lowering psychological
stress, improvement of psychological health and human gut microbiota
(83). More basic studies found that there are some associations (84-86)
among animal behaviors and emotional phenotypes (e.g., anxiety-like
behavior), the gut mycobiota, and host-protective immunity, since the
gut microbiota can regulate central activity by different G proteins and
changes in cellular calcium levels (87). In addition, a new study showed
that high chronic social and psychosocial stressors link to immune aging
and poor health (88) due to changes in na\selectlanguage{ngerman}ïve and terminally
differentiated T cells and the ratio of
CD4\textsuperscript{+}:CD8\textsuperscript{+}.

\textbf{Mechanisms mediated by exercise and microbiome}

At the same time, positive and effective physical activity or exercise
in children and adolescents (89) can prevent fCVD in adult. Animal
experiments showed that physical activity or exercise results in a
persistent decrease in systolic blood pressure in the spontaneously
hypertensive rats (SHRs) since it can reshape gut microbiota and improve
impaired gut-brain axis (90). As a non-medical treatment, when
combination of vitamin C intake, it can modify the composition of gut
microflora and improve the inflammatory state, therefore, alleviate the
blood pressure in the SHRs (91). The gut~microbiome~also mediates the
protective effects of~moderate-intensity exercise~on cardiac function in
myocardial infarction mice by its metabolites 3-Hydroxyphenylacetic acid
(3-HPA) and 4-Hydroxybenzoic acid (4-HBA) (92, 93).

There are the associations between the gut microbiota and
cardiometabolic phenotypes, however, short-term endurance exercise has
little effect on gut microbiota in elderly individuals (94). Regular
physical activity or endurance exercise can reduce a Western diet
-induced atherosclerosis through the amelioration of obesity,
inflammation, and chemotaxis signaling, which are modulated by the
microbiota and its metabolites (95). Particularly, the molecular and
cellular mechanisms on the metabolic benefits of physical activity has
been accurately disclosed in a recent study since an
exercise-inducible~metabolite~can control food intake and prevent
cardiometabolic diseases (96), such as obesity, T2D and fCVD.

\textbf{Mechanisms mediated by diet and microbiome}

As we known, medicine and food are homology. The composition of
the~gut~microbiota following early-life antibiotic exposure affects host
health and~longevity (97) due to an impaired immunity, increased insulin
resistance and inflammaging in later life. But metformin increases
lifespan by altering the~gut~microbiota and methionine metabolism (98).
As a part of diet, a high-throughput screening platform found that
host-microbe-drug-nutrient interactions improve health and longevity
through targeted the gut microbiome therapies (99). For example, the
interactions between the gut microbiome and vitamin D are associated
with better human health (100). In fact, microbiome~interactions can
shape host fitness (such as development, fecundity, and lifespan) (101).

There are also interactions between the gut and the brain in
inflammation-associated diseases and their molecular and cellular
mechanisms link to sensing and communicating the levels of diet- and
microbiome-derived essential amino acids (EAAs) (102, 103). High dietary
fiber intake may improve maternal obesity-induced cognitive and social
dysfunctions (104) since microbiome associations with some traits (105),
such as age, dietary intake, and the specific gut microbiome can affect
social behaviours through discrete neuronal circuits that mediate stress
responses in the brain (106). These studies further confirm the novel
``brain-heart-gut'' axis theory. Herein, healthy E(e)SEEDi lifestyle can
be adopted for the secondary prevention of eCVD and the primary
prevention of fCVD.

\textbf{UNHEALTHY LIFESTYLE, GUT MICROBIOME, AND FCVD}

Clinical studies showed that the gut microbiota play a pivotal role in
human vascular physiology, and they may be potential therapeutic and
preventive targets for CVD, such as atherosclerosis (107), heart failure
with preserved ejection fraction (HFpEF) (108). Morevover, gut-related
metabolites, L-carnitine, acetyl-L-carnitine, and Trimethylamine N-oxide
(TMAO), show associations with adverse short-term and long-term outcomes
in acute HF (109), respectively. And the gut microbiome is a vital
mediator of age-related arterial endothelial dysfunction, arterial
stiffening, vascular oxidative stress and inflammation (110), therefore
may be a promising therapeutic target for preserving arterial function
with ageing and reducing the risk of CVD.

As we known, the gut microbiome is associated with human diseases. A
recent study found that lifestyle (socioeconomic factors, genetics,
current exposome, diet and medication), particular early life shape the
microbiome in health and disease due to significant association with
microbiome function and composition (111). Risk factors related to
unhealthy lifestyle may disrupt the ``brain-heart-gut'' axis by negative
regulations of the gut microbiome and induce fCVD, but a healthy
lifestyle intervention (brain and physical activities and diet) among
older adults is effective in preventing MACCE (112). And current the
microbiome-based ``brain-heart-gut'' axis explains the vital mechanisms
of fCVD (Figure 2), since the microbiome contributes to many
cardiometabolic traits by modulating human inflammation and metabolism
(113). Herein, healthy E(e)SEEDi lifestyle plays a vital role in the
``brain-heart-gut'' axis and novel mechanisms of fCVD.

All in all, there is indeed a direct association between the gut
microbiota and host aging, diseases, and health by changes in
mitochondrial dynamics (114). And currently, fecal microbiota
transplantation is a novel method and an effective strategy against
age-related human diseases (115, 116). And there is also a definite
association between major risk factors in early life (117) and fCVD.
Developments in artificial intelligence and big data will help us to
setup a population-based risk algorithm (118, 119) or a scoring
algorithm linking to unhealthy E(e)SEEDi lifestyle for evaluation,
prediction, and prevention of fCVD.

With the development of cellular and molecular biology in brain and
cardiovascular system and new tools of biomedicine (120-122), the
scientist will further disclose the mechanisms of eCVD and fCVD under
the help of this novel theory of ``brain-heart-gut axis''. And it is
believed that with the further understanding of new origins and novel
mechanisms, there will be better prospects in healthy aging and
longevity due to better protection of brain and cardiovascular system.
Here, wish everyone health, peace and happiness when the World Heart Day
in this September is coming.

\textbf{CONCLUSIONS}

Since unhealthy E(e)SEEDi lifestyle links to the new origins and novel
mechanisms of fCVD, the author setup a fresh theory, that is, the
``brain-heart-gut'' axis. The novel mechanisms of fCVD are mediated by
the role of ``environment-sleep-emotion-exercise-diet'' and the gut
microbiota in early life, which is like a ``Golden Hoop Curse''. On the
one hand, the ``brain-heart-gut'' axis provides a theoretical basis not
only for the cardiovascular health benefits of ``keeping the pubic
region'' advocated by traditional Chinese medicine, but also for the
control and prevention of both eCVD and fCVD; On the other hand,
``keeping the pubic region'' is the best example on the fresh theory of
``brain-heart-gut'' axis. As a new theory, the ``brain-heart-gut'' axis
will help us to earlier and better prevent and control both eCVD and
fCVD with healthy E(e)SEEDi lifestyle.

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\textbf{ACKNOWLEDGMENTS}

The reviewers and editors are gratefully acknowledged for critical
review.

\textbf{AUTHOR CONTRIBUTIONS}

C.H. did conception and design, drafting of the article, critical
revision of the article for important intellectual content, and final
approval of the article.

\textbf{DECLARATION OF INTERESTS}

The author declares no competing interests.

\emph{Figure 1}\textbf{.}

\textbf{The ``brain-heart-gut'' axis and novel mechanisms of future
cardiovascular disease (fCVD).}

The new origins and novel mechanisms of fCVD link to the
``brain-heart-gut'' axis disrupted by early unhealthy E(e)SEEDi
lifestyle, which is like a ``Golden Hoop Curse''. In the
``brain-heart-gut'' axis, the brain is the decision system, the heart is
the power system, the gut is the execution system. The three closely
cooperate and interact with each other to form the new mechanisms of
fCVD. Here, E: environment (external); e: environment (internal); S:
sleep; Em: emotion; Ex: exercise; D: diet. E(e)SEEDi:
``environment-sleep-emotion-exercise-diet'' intervention. Green :
positive biofeedback by healthy E(e)SEEDi lifestyle; Grey : negative
disruption by unhealthy E(e)SEEDi lifestyle.

\emph{Figure 2} \textbf{}

\textbf{Unhealthy E(e)SEEDi Lifestyle, Gut Microbiome, and fCVD.}

According to the novel theory of the ``brain-heart-gut'' axis, since the
E(e)SEEDi highly links to the brain, heart, and cardiovascular system,
unhealthy E(e)SEEDi lifestyle will result in fCVD and its major
cerebrocardiovascular events (MCCVE) by playing a role in the gut
microbiome and its metabolites. In contrast, healthy E(e)SEEDi lifestyle
will prolong brain and cardiac aging and promote human longevity due to
beneficial effects on the gut microbiome. Here, E: environment
(external); e: environment (internal); S: sleep; E: emotion; E:
exercise; D: diet; i: intervention. E(e)SEEDi:
``environment-sleep-emotion-exercise-diet'' intervention. fCVD: future
cardiovascular disease. \$/\#/\&: gut microbiota; o/*/\selectlanguage{english}>: metabolites.

\textbf{Table 1} Current major studies on axis and CVD in cardiovascular
journals.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Axis}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Chemicals, Gene, or Molecule}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Targets}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{CVD}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CaMKII/Na\textsubscript{v}1.5 axis (7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Ca\textsuperscript{2+}/calmodulin-dependent kinase II (CaMKII),
PP2A-B56\selectlanguage{greek}α\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PP2A regulates Na\textsubscript{v}1.5 activity in cardiomyocytes, B56\selectlanguage{greek}α
\selectlanguage{english}as a novel target\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Congenital and acquired human arrhythmia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cardiosplenic axis (8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Proinflammatory leukocytes\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Splenic activation after ACS, leukocyte proinflammatory remodeling\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Acute coronary syndrome (ACS)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cardiosplenic~axis (9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Mononuclear phagocytes, antigen processing in the spleen\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Splenocytes immune-mediated injurious responses \& the spleen to cardiac
remodeling\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
chronic heart failure (CHF)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
CXCL1-CXCR2~axis (10)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Angiotensin II-induced infiltration of monocytes CXCL1-CXCR2
signalling\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Inhibition of CXCL1 and/or CXCR2 \& cardiac remodeling\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Hypertensive heart diseases (cardiac remodeling)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CXCL12/CXCR4 chemokine ligand/receptor axis (11)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Arterial CXCR4 (atheroprotective role)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Arterial integrity, endothelial barrier function, and a normal
contractile SMC phenotype\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Atherosclerosis\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CXCR4/SDF-1~axis (12)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
The thrombin inhibitor bivalirudin did not interfere with BMC homing or
SDF-1/CXCR4 signaling\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Bivalirudin but not heparin recommended as an anticoagulant for
intracoronary infusion of BMCs for cell therapy\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Acute or chronic myocardial ischemia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
KLF10-IL-9 signaling~axis (13)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Ang II (angiotensin II) promoting CD4+ T-cell activation via
upregulation of interleukins (IL)-9\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Kruppel like factor 10 (KLF10 or Klf10) or IL-9 in T cells (novel
therapeutic targets)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Perivascular Fibrosis \& vascular disease\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Leucopoietic-arterial~axis (14)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Higher air pollution exposure \& socioeconomics, traffic noise, and risk
factors\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Higher leucopoietic tissue activity and arterial inflammation
(ArtI)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CVD \& major adverse cardiovascular events (MACE)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Lipoprotein(a)-lipoprotein-associated phospholipase A2-oxidized
phospholipid~axis (Lp-PLA2 axis) (15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Ysophosphatidylcholine\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Valve interstitial cells\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Calcific aortic valve stenosis (CAVS), acquired valvular heart
disease\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
miR-208-Mef2~axis (Mef2-microRNAs axis) (16)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Myocyte enhancer factor 2 (Mef2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Mef2 regulates microRNAs for cardiac development and disease\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Pulmonary hypertension \& Right ventricular failure\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
miR-223/PDGFR\selectlanguage{greek}β \selectlanguage{english}VSMC~Axis (17)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Platelet miR-223 or VSMC PDGFR\selectlanguage{greek}β\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Lack of miR-223 \& VSMC dedifferentiation and medial damage\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Coronary artery pathology in Kawasaki~Disease (acute vasculitis of early
childhood)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
NFATc3/miR-204 axis (18)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Macrophage NFATc3, a negative regulator of atherogenesis\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Up-regulation of NFATc3 in macrophages, up-regulates miR-204 to reduce
SR-A and CD36 levels\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Atherosclerosis (preventing foam cell formation)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Nuclear Ca\textsuperscript{2+}-CaMKII\selectlanguage{greek}δ\selectlanguage{english}C axis (19)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
CaMKII (Ca\textsuperscript{2+}-Calmodulin dependent protein kinase)
\selectlanguage{greek}δ\selectlanguage{english}C\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Early transaortic constriction perinuclear CaMKII\selectlanguage{greek}δ\selectlanguage{english}C activation, myocyte
Ca\textsuperscript{2+}~transients and nuclear transcriptional
responses\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Eccentric hypertrophy and heart failure (HF)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p38\selectlanguage{greek}α-\selectlanguage{english}CREB-OGDH axis (20)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Plasma succinate concentrations\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Macrophages\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aortic aneurysm and dissection (AAD)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
p-Erk1/2-MMP axis (21)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Lower serum uric acid (SUA) levels\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Smooth muscle cell (SMC)-elastin contractile units (degradation of
elastin)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Recurrent intracerebral hemorrhage (R-ICH)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sirt1/p53/p21~axis (22)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Metoprolol\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Arginine vasopressin (AVP)-Induced Cellular Senescence in H9C2
Cardiomyocytes \& the AVP-induced expression of acetylated p53 and
p21\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Ischemia injury in cardiovascular system\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
SR-A1-c-Myc~axis (23)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Tissue-resident and monocyte-derived cardiac macrophage\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Endothelial progenitor cells differentiation \& neovascularization\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Doxorubicin-Induced Cardiomyopathy (DiCM)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Vegfc-Emilin2a-Cxcl8a Signaling~axis~(24)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Vegfc, emilin2a~and~cxcl8a~ for coronary revascularization \& Cardiac
Regeneration\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Coronary endothelial cells upregulate~vegfc, vegfc signaling upregulates
epicardial~emilin2a~and~cxcl8a~expression\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Ischemic heart disease\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2} Current major studies on axis and CVD in
non-cardiovascular journals.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Axis}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Chemicals, Gene, or Molecule}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Targets}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{CVD}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Autophagy-apoptosis~axis (25)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Melatonin\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Vascular endothelial~cell~damage and apoptosis mediated by
macrophages\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Kawasaki disease (KD)-associated vasculitis\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
BCAA-BCKA axis Branched-chain amino acid (BCAA)-Branched-chain keto acid
(BCKA) axis (26)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Telmisartan (anti-hypertension drug)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Significantly represses Bcat2 activity via direct binding \& enhanced
white adipose tissue (WAT) browning and reduced adiposity\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Obesity \& metabolic syndrome\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Circ\_ROBO2/miR-149~axis (27)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CircRNAs (circ\_ROBO2 \& miR-149)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Activating NF-\selectlanguage{greek}κ\selectlanguage{english}B Signaling, aortic smooth muscle cells\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Atherosclerosis \& coronary artery disease (CAD)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Microbiome-brain-\selectlanguage{greek}β-\selectlanguage{english}cell~axis (28)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Acetate\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
A nutrient-gut microbiota interaction \& activation of the
parasympathetic nervous system\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Obesity, insulin resistance \& metabolic syndrome\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-1277-5p/KLF5~axis (29)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LINC01123\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Vascular smooth muscle cells (VSMCs)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Carotid atherosclerosis (CAS)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-149-5p/MMP9~axis (30)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Circular RNAs (circRNAs): circDHCR24 \& miR-149-5p \& MMP9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Human aortic vascular smooth muscle cells (HA-VSMCs) proliferation,
migration and phenotypic switching\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Atherosclerosis and CAD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-185-5p/PAK2~axis (31)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Long noncoding RNA (lncRNA) FGF9-associated factor (FAF)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hypoxia/ischaemia-induced pyroptosis in cardiomyocytes, a potential
therapeutic target of AMI\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Various CVDs \& acute myocardial infarction (AMI)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-206/216b-Atg13~axis (32)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Serum histamine, Histidine decarboxylase (HDC)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Histamine regulating myocardial autophagy and apoptosis in
cardiomyocytes\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hypoxia and AMI\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-344b-5p/FAIM3~axis (33)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Long noncoding RNA (lncRNA) XR\_596701\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Proliferation and apoptosis of intermittent hypoxia (IH)-induced H9c2
cells\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Obstructive sleep apnea (OSA), IH -induced myocardial injury\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-577/COBLL1 axis (34)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Fibrosis and apoptosis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Long non-coding RNA (lncRNAs) NORAD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
AMI\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
miR-6873-3p/MyD88/NF-\selectlanguage{greek}κ\selectlanguage{english}B~axis (35)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Circular RNAs (circRNAs) \& circ-RELL1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Endothelial cells, the expression of ICAM1 and VCAM1 in ox-LDL induced
endothelium inflammation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Atherosclerotic CVD (ASCVD)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
OTUD7B/KLF4/NMHC IIA axis (36)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Bioactive components of~Salvia miltiorrhiza\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sal-miR-1 and 3 inhibition of VSMC migration and monocyte adhesion to
VSMCs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Vascular remodeling\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p62/Nrf2/ARE axis (37)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Autophagy\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
The pyroptosis of macrophages\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Atherosclerosis\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PTEN/AKT/mTOR~axis (38)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
A plant-derived flavone tangeretin\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Myocardial autophagy, a novel cardioprotective therapeutic target\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sepsis-Induced Myocardial Dysfunction\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
RAC1-MEK-ERK-CHD4~axis (39)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Harmine (a natural compound)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Chromodomain helicase DNA binding protein 4 (CHD4), a negative modulator
of Ucp1 \& harmine-mediated ERK activation in adipocytes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Obesity\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ROR\selectlanguage{greek}α-\selectlanguage{english}erythropoietin-AMPK~axis (40)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Bavachalcone, a natural~bioactive compound or a promising angiogenesis
agent\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Endothelial progenitor cells (EPCs) differentiation \&
neovascularization\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Angiogenesis and tissue repair in CVD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
T helper 17 (T\textsubscript{H}17)~axis (41)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
High salt intake\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
The effects of salt on the gut microbiome (a potential therapeutic
target) \& autoimmunity related to T\textsubscript{H}17 cells\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Salt-sensitive hypertension \& CVD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
TNF\selectlanguage{greek}α-\selectlanguage{english}NLRP3 signalling~axis (42)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aconitine, the natural product extracted from Aconitum species\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
A TNF\selectlanguage{greek}α \selectlanguage{english}inhibitor and BNIP3-mediated mitophagy.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aconitine-induced cardiotoxicity and neurotoxicity\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2.

\selectlanguage{english}
\FloatBarrier
\end{document}

