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Volume 9 | Issue 1 | 1
Cardio Open, 2024
Research Article
How a Plant-Based Diet (PBD) Reduces In-Stent Restenosis (ISR) and Stent
rombosis (ST)
Dasaad Mulijono1,2,3*, Albert M Hutapea2,4, I Nyoman E Lister2,5
Department of Cardiology, Bethsaida Hospital,
Tangerang-Indonesia
Indonesia College of Lifestyle Medicine, Indonesia
Department of Cardiology, Faculty of Medicine, Prima
University, Medan-Indonesia
Department of Pharmacy, Faculty of Life Sciences, Advent
University, Bandung-Indonesia
Department of Biomolecular and Physiology, Faculty of
Medicine, Prima University, Medan-Indonesia
Department of Epidemiology, Faculty of Public Health,
University of Indonesia, Jakarta-Indonesia
Department of Community Nutrition, Faculty of Dentistry,
Yarsi University, Jakarta-Indonesia
Citation: Mulijono, D., Hutapea, A. M., Lister, I. N. E., Sudaryo, M. K., Umniyati, H. (2024). How a Plant-Based Diet
(PBD) Reduces In-Stent Restenosis (ISR) and Stent Thrombosis (ST). Cardio Open, 9(1) , 01-15.
Abstract
Despite the advances in stent design, coating drugs, polymers, the use of intravascular imaging, special devices (such as
intravascular lithotripsy, ultra-high-pressure non-compliant balloons, and drug-coated balloons), and improved operator
skills and techniques, the problem of in-stent restenosis (ISR) and stent thrombosis (ST) remains a challenge for interventional
overcome biological and epigenetic problems in managing ISR and ST similarly to reversing atherosclerosis. Our team is
PBD in decreasing the incidence of ISR and ST.
Plant-Based, Supplements, In-Stent Restenosis, Stent Thrombosis
1. Introduction
The American Heart Association reports that roughly 600,000
coronary stent procedures are conducted annually in the United
States [1], with more than three million stents utilized globally.
Despite progress in cardiovascular health and interventional
cardiology, coronary ISR and ST continue to present a
challenge to interventional cardiologists. Despite the signicant
advancements in interventional techniques and intracoronary
imaging, there is no universally accepted approach to managing
either condition. The lack of a denitive strategy is a testament
to the underlying mechanisms' complexity [2].
Balloon dilation and stent implantation may result in vascular
injury, which can lead to restenosis. Mechanical stretch,
endothelial denudation, and subintimal hemorrhage may
trigger an inammatory response, which subsequently induces
a proliferative process. The activation of vascular smooth
muscle cells (VSMC), including proliferation, migration, and
dierentiation, as well as matrix metalloproteinase activation,
DNA, and extracellular matrix synthesis, can all contribute to
neointimal hyperplasia formation [3,4]. Drug-eluting stents
(DES) have anti-inammatory, immunomodulatory, and
antiproliferative properties, which help the coronary vessel heal
properly. Nonetheless, if the suitable dose of the medication
does not elute at the appropriate moment, in cases of drug
resistance or if persistent systemic inammation exists, or if the
patient exhibits an allergy to the stent platform, stent polymer,
or in the formation of neoatherosclerosis, all of these factors can
contribute to the development of ISR and ST.
*Corresponding Author
Prof. Dasaad Mulijono, Department of Cardiology, Bethsaida Hospital,
Tangerang-Indonesia; Indonesia College of Lifestyle Medicine, Indonesia;
Department of Cardiology, Faculty of Medicine, Prima University, Medan-
Indonesia.
Submitted: 2024, Mar 29; Accepted: 2024, Apr 23 ; Published: 2024, Apr 29
ISSN: 2476-230X
Cardiology: Open Access
https://doi.org/10.33140/COA.09.01.05
Volume 9 | Issue 1 | 2
Cardio Open, 2024
Various factors may be implicated in the development of DES
restenosis, including patient factors, lesion factors, procedural
factors, biological, genetic (epi-genetic), mechanical, and
technical elements. In the context of this paper, we will focus on the
patient, biological, and epigenetic factors that can be eectively
managed with the help of a PBD. The biological mechanisms
that could play a role in the emergence of ISR and ST involve
inammatory/ immunity processes, heightened sensitivity, drug
resistance, the development of neoatherosclerosis, and defective
re-endothelialization within the coronary artery where the stent
was placed [5] (Please refer to Figure 1). Consequently, either
the vessel wall heals or neointimal hyperplasia and/or neo-
atherosclerosis develops. Identifying the core molecular and
signaling pathways responsible for inammatory, immune,
hypersensitivity, vascular healing, and thrombotic processes is
crucial for developing eective therapeutic approaches aimed at
overcoming the primary challenge to the success of percutaneous
coronary intervention (PCI). This is necessary to prevent the
occurrence of ISR and ST as eectively as possible [6-8].
*Red highlights are the ones that PBD has a role
Figure 1: Risk Factors and Mechanisms of DES ISR
Numerous studies have underscored the critical signicance of
PBDs in managing chronic inammatory diseases, including
atherosclerosis, hyperlipidemia, obesity, non-insulin-dependent
diabetes mellitus (NIDDM), and hypertension. It has been
widely acknowledged that PBD may not only contribute to the
prevention of atherosclerosis but may also cause regression of
coronary plaques that have occurred [9-15]. To our knowledge,
no published work has explored the role of PBDs in mitigating
ISR and ST. The role of PBDs as an anti-inammatory,
immunomodulatory, and assisting vascular healing has been
recognized and published as benecial in chronic inammatory
diseases, especially atherosclerosis. Consuming PBD in
conjunction with anti-platelet drugs may aid in the mitigation of
thrombosis processes, ultimately reducing the risk of developing
acute coronary syndrome (ACS) and subacute thrombosis [16-
22].
Atherosclerosis is a systemic disease resulting from metabolic
dysfunction and persistent inammation rather than a localized
process. Consequently, it is classied as a metabolic chronic
condition. Patients who have experienced
coronary obstruction due to the atherosclerosis process have
typically exhibited a state of metabolic disorder and systemic
inammation for a prolonged period. Cardiologists who
exclusively employ interventions such as stent implantation to
manage systemic diseases are likely to be disappointed if they do
not address these systemic issues. Following stent implantation,
the artery is disturbed locally by the balloon, and foreign body
implantation (stent) will undergo a healing process for the local
injury. Nevertheless, the systemic environment will signicantly
inuence the local healing process. At the very least, the
atherosclerosis process, which is a systemic process, will still
be developing. Even if patients do not experience ISR or ST,
there may still be an atherosclerosis process occurring that could
cause coronary stenosis in new vessels dierent from the vessels
that have been treated with coronary interventions. Therefore, it
is not judicious to manage ISR and ST solely by addressing the
local vessel issue.
Our cardiac center, Bethsaida Hospital in Indonesia, conducted
interventional studies on approximately 1000 cardiology
patients. These patients implemented PBDs months before they
underwent their PCI procedures using various second and third-
generation DES. Our research has been ongoing for nearly ve
3
*Red highlights are the ones that PBD has a role
Fig. 1. Risk factors and mechanisms of DES ISR
Numerous studies have underscored the critical significance of PBDs in managing chronic
inflammatory diseases, including atherosclerosis, hyperlipidemia, obesity, non-insulin-dependent
diabetes mellitus (NIDDM), and hypertension. It has been widely acknowledged that PBD may not only
contribute to the prevention of atherosclerosis but may also cause regression of coronary plaques that
have occurred [9-15]. To our knowledge, no published work has explored the role of PBDs in mitigating
ISR and ST. The role of PBDs as an anti-inflammatory, immunomodulatory, and assisting vascular healing
has been recognized and published as beneficial in chronic inflammatory diseases, especially
atherosclerosis. Consuming PBD in conjunction with anti-platelet drugs may aid in the mitigation of
thrombosis processes, ultimately reducing the risk of developing acute coronary syndrome (ACS) and
subacute thrombosis [16-22].
Atherosclerosis is a systemic disease resulting from metabolic dysfunction and persistent
inflammation rather than a localized process. Consequently, it is classified as a metabolic chronic
inflammatory condition. Patients who have experienced coronary obstruction due to the atherosclerosis
process have typically exhibited a state of metabolic disorder and systemic inflammation for a prolonged
period. Cardiologists who exclusively employ interventions such as stent implantation to manage
systemic diseases are likely to be disappointed if they do not address these systemic issues. Following
stent implantation, the artery is disturbed locally by the balloon, and foreign body implantation (stent)
will undergo a healing process for the local injury. Nevertheless, the systemic environment will
significantly influence the local healing process. At the very least, the atherosclerosis process, which is a
Volume 9 | Issue 1 | 3
Cardio Open, 2024
years, making our center the only one in Indonesia to pioneer
PBDs for patients who receive PCI procedures. Our data
suggests that only a small percentage of individuals who adhere
to PBD experience ISR in their subsequent annual coronary
angiography follow-up. Our research ndings suggest that the
occurrence of ISR is signicantly lower in patients who adhere
to our PBD interventions, at approximately 2-3%, as compared
to those who do not follow our interventions, the omnivorous
patients, who have an ISR rate of 10-20%; similar with the
results of other studies [23,24]. We did not observe any early ST
among the participants in our PBD intervention within the rst
year following their stent implantations. In contrast, the rate of
ST in the NPBD group was 1% [25].
It would undoubtedly be more prudent to initiate anti-
atherosclerosis, anti-ISR, and anti-ST management as early as
feasible in relation to the development of ISR and ST. It is the
responsibility of the interventionalist to manage the patient's
metabolic and inammatory condition well in advance of their
scheduled intervention. In the acute setting, for instance, when
performing an intervention on patients with acute coronary
syndrome, similar issues arise. Sadly, interventionists often
underestimate the importance of managing the patient's
metabolic and chronic inammatory condition post-intervention
to minimize the occurrence of ISR and ST in the long run.
This paper emphasizes the signicance of launching metabolic
interventions as soon as feasible, with the aim of rectifying
metabolic abnormalities, restoring endothelial function,
reducing systemic inammation, preventing allergic reactions,
enhancing the availability of nitric oxide (NO), fostering a
healthy microbiota, correcting mitochondrial dysfunction, and
improving telomere as part of epigenetic adjustments. By doing
so, a solid foundation can be established prior to the occurrence
of injuries resulting from coronary interventions.
Given the promising outcomes that our cardiac center has
achieved, additional research is warranted to assess the ecacy
of PBDs in reducing the incidence of ISR and ST before the
broader application of this intervention in the cardiology
community, particularly among interventional cardiologists.
This would ultimately benet numerous patients in the future
and elevate the reputation of the interventional cardiology
society as a pioneer in promoting PBDs, thereby surpassing
other methods (optimal medical therapy (OMT) and bypass
surgery) in achieving optimal coronary intervention results.
2. Mechanism PBD in Reducing ISR and ST
the Risk of Atherosclerosis, ISR, and ST
The key mechanism by which a healthy PBD can reduce the
probability of atherosclerosis, ISR, and ST is by changing one's
diet to PBD, thereby eliminating the consumption of foods that
contribute to coronary heart disease in the rst place. Adhering to
an omnivorous diet and consuming foods such as sugary products,
processed meat, processed snacks, red meats, poultry, dairy
products, and eggs signicantly increases the risk of developing
atherosclerosis and the likelihood of ISR and ST. These
unhealthy eating behaviors have been linked to dyslipidemia,
insulin resistance, hypertension, glucose intolerance, endothelial
dysfunction, chronic systemic inammation, increased oxidative
stress, elevated trimethylamine N-oxide (TMAO), low NO,
gut dysbiosis, mitochondrial damage, and shortened telomeres
(accelerating the aging process) [26-30]. All of these are widely
accepted as risk factors for the development of atherosclerosis.
2.2. Mechanism of Nitric Oxide (NO) in Reducing
Atherosclerosis, ISR, and ST
The endothelium exhibits anti-atherosclerotic properties, which
can be ascribed to the presence of NO. NO prevents monocytes
and leukocytes from adhering to the endothelium, inhibits
platelet-vessel wall interactions, and suppresses the proliferation
of VSMC, which are important processes in developing ISR and
ST. Additionally, NO promotes coronary dilation and increases
coronary blood ow [31]. Furthermore, NO plays a vital role in
endothelial regeneration, which is crucial for the healing of the
coronary artery after stent placement [5].
Conditions such as obesity, hypertension, hyperlipidemia, insulin
resistance, and glucose intolerance, which are associated with
atherosclerosis risk factors, can decrease NO release into the
coronary wall due to impaired synthesis or excessive degradation
[32]. PBD has been found to improve chronic inammatory
diseases, including obesity, hypertension, hyperlipidemia, insulin
resistance, and elevated glucose levels, and it may also reverse
atherosclerosis [8-15]. Notably, NO production decreases with
age, which is signicant since atherosclerosis primarily aects
older populations [33]. To measure NO, we may use a salivary
strip, which has a 96% accuracy rate [34].
We can enhance our patients' NO availability by altering their
diet and lifestyle. The process of converting nitrate-rich foods,
such as green leafy vegetables, into NO is illustrated in Figure
2. Please note that it is crucial to consider that certain vegetables
that are high in nitrates can have their nitrate levels reduced
through cooking. Food preparation is also a signicant factor
in determining the eectiveness or benecial eects of the food
[35]. Many studies of PBDs have not given much consideration
to the quality of the food consumed by their participants,
including the selection, quantity, and processing of the food.
This lack of attention may fail to maximize the benets of PBDs.
Another important factor is the potential
vitamins, minerals, and micronutrients often present in PBD.
Therefore, it is crucial to ensure that these important nutrients
are adequately supplemented, as a deciency in these nutrients
may not only decrease the ecacy of a PBD but can also be
potentially harmful [36,37].
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Cardio Open, 2024
Figure 2: The Entero-Salivary Circulation of Nitrate in Human
Recent progress has been made in applying NO coatings on stents,
demonstrating the potential for preventing ISR and ST [38,39].
NO strategies promote normal endothelial cell growth, prevent
neointimal hyperplasia formation, inhibit the proliferation of
VSMCs, increase vasodilation, and decrease platelet activation
and aggregation. This research should enlighten those who
advocate for administering PBD to their patients, as PBD can
potentially increase circulating levels of NO, which may be
more eective than local NO administration. This is because the
pathogenesis of atherosclerosis and the occurrence of ISR and
ST are driven by systemic processes rather than a local reaction
post-coronary intervention.
Crucial Factor in Repairing Endothelial Dysfunction
In 1998, a small randomized controlled trial known as the
Lifestyle Heart Trial was conducted by Ornish et al. The study
demonstrated that intensive lifestyle changes with PBD could
reverse coronary atherosclerosis. The most important mechanism
of this process is repairing endothelial dysfunction [40]. In 2014,
Esselstyn et al. presented a famous image, as depicted in Figure
3, which illustrated that strict PBD (without oil) can regress
coronary stenosis [41].
7
Figure 3. Reversal of coronary artery disease
It has been a decade since the remarkable research studies on atherosclerosis have garnered
significant praise and acceptance within the PBD community and among practitioners who recommend
PBD. Despite this, the widespread adoption of recommending PBD to patients has not been extensively
embraced within the interventional cardiology community. As an interventional cardiologist myself, I
initially had reservations about these findings. However, after being diagnosed with coronary stenosis
on my coronary multi-slice CT angiography, I decided to follow the advice of these PBD experts. To my
surprise, after three years, my LAD stenosis of 50% had regressed to 20%, and my CT calcium reading
had decreased by 30%. Moreover, I found that this method effectively regressed atherosclerosis and
reduced the incidence of my patient’s ISR and ST.
Eating poor-quality food that is high in sugar (refined carbohydrate), devoid of fiber-phytonutrients,
highly processed, and contains saturated and trans fats, cholesterol, and chemicals that promote chronic
inflammation is a major contributor to the development of atherosclerosis. The consumption of these
unhealthy foods has been demonstrated to increase levels of LDL cholesterol, triglycerides,
apolipoprotein (a), apolipoprotein (b), C-reactive protein (CRP), pro-inflammatory mediators, pro-
inflammatory chemokines/ cytokines, Trimethylamine N-oxide (TMAO), persistent organic pollutants
(POPs), oxidative stress, tumor promotion, and cell proliferation, among other factors. All of these
factors play significant role in the development of atherosclerosis, ISR, and ST [42,43]. On the contrary,
eating healthy PBD with adequate supplementations such as vitamins B12 and D and minerals will
enhance our body to fight against inflammation. Healthy foods such as vegetables, fruits, and legumes
contain carotenoids, isoflavones, phytoestrogens, and phytosterols, which have been shown to prevent
atherosclerosis. These polyphenols and phytochemicals' role in molecular signaling are anti-
inflammatory, antiplatelet aggregation, inhibitor to VSMCs proliferation and migration, and safeguard
for lipid oxidation (ox-LDL) [44,45]. Oxidized LDL, in addition to its infamous role in causing
atherosclerosis, also plays a significant part in the progression of ISR [46]. Healthy PBD will also help to
restore endothelial function and enhance the process of endothelialization post-traumatic balloon
inflation and stent insertion during coronary intervention.
Figure 3: Reversal of coronary artery disease
Volume 9 | Issue 1 | 5
Cardio Open, 2024
It has been a decade since the remarkable research studies on
atherosclerosis have garnered signicant praise and acceptance
within the PBD community and among practitioners who
recommend PBD. Despite this, the widespread adoption of
recommending PBD to patients has not been extensively
embraced within the interventional cardiology community. As
an interventional cardiologist myself, I initially had reservations
about these ndings. However, after being diagnosed with
coronary stenosis on my coronary multi-slice CT angiography,
I decided to follow the advice of these PBD experts. To my
surprise, after three years, my LAD stenosis of 50% had
regressed to 30%, and my CT calcium reading had decreased by
30%. Moreover, I found that this method eectively regressed
atherosclerosis and reduced the incidence of my patient’s ISR
and ST.
Eating poor-quality food that is high in sugar (rened
carbohydrate), devoid of ber-phytonutrients, highly processed,
and contains saturated and trans fats, cholesterol, and chemicals
that promote chronic inammation is a major contributor to
the development of atherosclerosis. The consumption of these
unhealthy foods has been demonstrated to increase levels of LDL
cholesterol, triglycerides, apolipoprotein (a), apolipoprotein (b),
C-reactive protein (CRP), pro-inammatory mediators, pro-
inammatory chemokines/ cytokines, Trimethylamine N-oxide
(TMAO), persistent organic pollutants (POPs), oxidative stress,
tumor promotion, and cell proliferation, among other factors.
All of these factors play signicant role in the development of
atherosclerosis, ISR, and ST [42,43]. On the contrary, eating
healthy PBD with adequate supplementations such as vitamins
B12 and D and minerals will enhance our body to ght against
inammation. Healthy foods such as vegetables, fruits, and
legumes contain carotenoids, isoavones, phytoestrogens, and
phytosterols, which have been shown to prevent atherosclerosis.
These polyphenols and phytochemicals' role in molecular
signaling are anti-inammatory, antiplatelet aggregation,
inhibitor to VSMCs proliferation and migration, and safeguard
for lipid oxidation (ox-LDL) [44,45]. Oxidized LDL, in addition
to its infamous role in causing atherosclerosis, also plays a
signicant part in the progression of ISR [46]. Healthy PBD will
also help to restore endothelial function and enhance the process
of endothelialization post-traumatic balloon ination and stent
insertion during coronary intervention.
Paclitaxel and sirolimus, which are used in the coating of DES,
possess therapeutic properties that can reduce intimal hyperplasia
and promote re-endothelialization, thereby decreasing the
incidence of ISR in bare-metal stents from 30-50% to 10-20%
in DES.
The formation of an excessive amount of reactive oxygen species
(ROS) results in oxidative stress, a signicant contributing
factor to the emergence and progression of atherosclerosis
[47]. Robust evidence indicates that ROS, through their pro-
atherogenic eects, play a crucial role in several pathological
processes, including inammation, endothelial dysfunction,
and dysregulated lipid metabolism. Moreover, ROS has been
demonstrated to impair mitochondrial function, which is critical
to ensure eective healing following coronary interventions.
Tissue damage resulting from coronary intervention and stent
implantation triggers increased production of ROS, which plays
a role in the initial proliferation, migration, and apoptosis of
VSMC, contributing to the development of ISR [48]. Vascular
damage during coronary intervention often results in the
overproduction of ROS, leading to platelet dysfunction and
subsequent abnormal activation and aggregation, which can
contribute to the formation of blood clots and ST [49].
Carotenoids, prominently present in foods like pumpkin, carrots,
tomatoes, green leafy vegetables, broccoli, and bell peppers, are
lipophilic antioxidants that can mitigate the detrimental eects
of ROS. Citrus fruits, bell peppers, strawberries, kiwis, broccoli,
green leafy vegetables, grains, and legumes are rich in vitamin
C and the B-complex group. Both vitamins function as potent
antioxidants, helping combat ROS's negative eects. Adopting
healthy dietary habits in conjunction with PBD can not only
guard against the onset of atherosclerosis but can also protect
against the potential complications of coronary interventions
such as ISR or ST. It is important to note that individuals who
have adopted healthy and correct PBDs may never need coronary
intervention in their lifetimes. Consuming foods that elevate
the dietary inammatory index (DII) is advisable to counteract
the inammation and ROS implications in the progression of
atherosclerosis and the development of ISR and ST, as depicted
in Table 1.
Table 1: List of foods that Reduce and Increase DII
Foods that reduce DII Foods that increase DII
Red meat (steak and hamburgers)
Animal products (including eggs and dairy products)
Processed meat
Commercial baked goods
White our (bread and noodles), white rice
Deep-fried foods
Sugary products
Products with trans-fats
Saturated fats (especially animal fats)
Cholesterol (red meats, processed meats, eggs, fried
foods and dairy products)
Plant-based proteins (beans, lentils, chickpeas, edamame,
hemp seeds, tofu, tempeh, and nuts)
Whole grains (oatmeal, buckwheat, quinoa, pigmented rice)
Starchy vegetables (sweet potatoes and beets)
Seeds (axseeds and chia seeds)
Green leafy vegetables (raw)
Colorful vegetables (raw)
Fruits (berries, apples, grapes, oranges, peaches, gs,
bananas, and kiwi)
Spices and herbs (turmeric, ginger, cumin, peppermint,
cinnamon, chili, parsley, bay leaf, and basil)
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Cardio Open, 2024
2.4. PBD Decreases Systemic Allergic Reactions and May
Prevent Stent Hypersensitivity/ Allergic Reaction
In contrast to the omnivorous diet, which contains many pro-
inammatory nutrients. PBDs are enriched with micronutrients
and dietary avonoids that are associated with not only anti-
inammatory but also anti-allergy eects.
There have been suggestions that ISR and ST may be linked to
allergies or hypersensitivity to stent materials, including metal,
polymer, and eluting drugs. Identifying whether individuals who
experience ISR or ST are allergic to these materials is a complex
challenge, and it has only recently been raised as a potential
cause. In certain circumstances, an allergic patch test may be
administered; however, even if the test returns a negative result,
the likelihood of the patient being allergic to the stent materials
cannot be entirely eliminated. The most common allergic
reaction to stent materials is type 4 hypersensitivity, which is
T-helper cell-mediated [50]. This type of allergic reaction can
be inhibited by avonoids, which are found in abundance in
PBDs. Flavonoids can inhibit the activation of T cells, reduce
the production of inammatory biomarkers, decrease IgE
production and binding, and prevent degranulation of mast cells
that release histamine, IL-4, IL-5, IL-6, IL-13, and MCP-1 [51].
Given that it is challenging to predict which patients will develop
hypersensitivity to the stent we employ, it is prudent to adopt
a diet that generally possesses anti-allergic properties. This
approach helps minimize the likelihood of patients developing
ISR and ST due to allergic reactions [51,52]. Moreover, using
drugs to eliminate allergies, as experienced in the past, normally
carries side eects and will reduce patients' compliance to
adhere.
The gut microbiota is a complex community of microorganisms
that inhabit the gastrointestinal tract and play a crucial role
in regulating various physiological processes, including
metabolism, inammation, and immunity. Recent research
has revealed that the bacteria in atherosclerotic plaques share
DNA similarities with gut bacteria. One of the metabolites
produced by the gut microbiota, TMAO, is primarily derived
from dietary sources such as choline, betaine, and L-carnitine
found in an omnivorous diet. TMAO has been linked to the
development and progression of atherosclerosis due to its pro-
inammatory properties and inhibition of reverse cholesterol
transport. Additionally, elevated levels of plasma TMAO have
been associated with neoatherosclerosis, ruptured plaque,
and thrombosis, which may contribute to ISR and ST [53,54].
With a high intake of red meat, Omnivore's risk for developing
atherosclerosis is much higher compared to those who
consume PBDs [55]. Switching to a PBD may protect against
atherosclerosis by promoting endothelial protective mechanisms
and lowering TMAO, a pro-atherosclerotic metabolite.
Atherosclerosis patients often exhibit elevated production
of TMAO-producing microbiomes and reduced short-chain
fatty acid (SCFA)- producing species. SCFAs, a class of anti-
inammatory metabolites, are generated through a ber-rich
diet. By increasing the expression of anti-inammatory factors,
improving the integrity of the intestinal barrier, and inhibiting pro-
inammatory cytokines, SCFAs help to reduce inammation, a
key risk factor for coronary heart disease (CHD). An imbalance
between SCFAs and TMAOs can contribute to inammation and
exacerbate the risk of CHD.
Plant-based dieters have been shown to possess a microbiome
capable of producing a signicant amount of SCFAs, including
butyrate, and increased Acetyl-CoA and X4-aminobutyrate-
succinate pathways. Additionally, PBDs have been linked to
a lowered post-prandial glycemic response (PPGR), lowered
inammatory markers, improved cardio-metabolic health, low
T-cell repertoire diversity, and low IgE expression levels. These
benecial microbiome characteristics may help protect against
the development of CHD and other chronic inammatory
conditions like obesity, hypertension, hyperlipidemia, glucose
intolerance, insulin resistance, allergic reaction, and the
likelihood of ISR and ST.
Changes in gut microbiota have the potential to impact gut
permeability, which can lead to the translocation of bacterial
DNA, lipopolysaccharides (LPS), and proinammatory
cytokines into circulation. This phenomenon, known as leaky
gut syndrome, can result in the absorption of metabolites and
endotoxins into the bloodstream. Leaky gut syndrome has
been linked to the development of atherosclerosis and acute
coronary syndrome [56]. SCFAs can reduce gut permeability
by decreasing nuclear factor-kappa B (NF-kB) activation and
reducing proinammatory cytokines such as IL-1b, IL-6, IL-
8, and TNF-α [57]. Low consumption of plant-based foods
may lead to increased penetration of the intestinal barrier, as a
low-ber diet triggers a shift from ber-degrading to mucus-
degrading bacteria. This could promote a hyperactive immune
response, conceivably with the production of pro-inammatory
metabolites that fuel the disease process.
A healthy diet includes non-digestible carbohydrates, such as
resistant starch, soluble and insoluble dietary ber, and plant
wall polysaccharides and oligosaccharides, fermented by
benecial gut bacteria to produce butyrate and other SCFAs.
These SCFAs possess anti-inammatory properties and have
the ability to strengthen the intestinal barrier, thereby promoting
optimal gut health. Moreover, SCFAs can inhibit the formation
of foam cells by stimulating the expression of interleukin-10
(IL-10) and decreasing the production of pro-inammatory
cytokines by the endothelium. This contributes to the recovery
of endothelial damage post-coronary intervention and reduces
the occurrence of atherosclerosis, ISR, and ST.
Foods high in ber, including barley, wheat bran, brown rice,
and other whole grains, legumes, fruits, and vegetables, as
well as prebiotics like fructo-oligosaccharides, are commonly
consumed by individuals following a PBD diet. Plant-based
foods also contain polyphenols such as lignans, isoavones,
anthocyanins, and avonols, as well as other phytochemicals
like carotenoids and phytosterols, which are metabolized into
bioactive compounds by benecial microbes, conferring health
Volume 9 | Issue 1 | 7
Cardio Open, 2024
benets and exhibiting anti-inammatory and antioxidant
activity. Phytochemicals have been shown to increase the
populations of benecial bacteria such as Lactobacillus and
, which are the primary species found in
probiotic supplements that are taken to improve gut health. In
addition, ber-rich plant foods like nuts (including walnuts,
almonds, and pistachios) have been found to have prebiotic
eects, leading to increases in butyrate-producing microbes and
other benecial microbes. Overall, the composition of the gut
microbiome is greatly inuenced by dietary ber, polyphenols,
and other phytochemicals and their metabolites, consumed in
greater quantities by those following PBDs [58]. Certainly, an
omnivorous diet that is low in ber, devoid of polyphenols and
phytochemicals, and decient in SCFAs while being high in
TMAO can contribute to the development of new atherosclerotic
plaques and increase the incidence of ISR and ST in patients
who have undergone coronary interventions. Thus, the gut and
the heart interaction is known as the gut-heart axis [59,60].
2.6. Caloric Restriction is an Essential Factor in Combating
In 2022, 43% of adults aged 18 years or older were considered
overweight, and 16% were diagnosed with obesity [61].
Overeating is a pervasive issue in contemporary society,
inuenced by various factors, including the availability of
copious amounts of food, stress, emotional eating, and social
tradition. While partaking in occasional feasts is an ingrained
aspect of human nature, persistent overeating can severely aect
an individual's health and society. Based on our analysis of
over 10,000 patients who have visited our cardiology clinic, we
have discovered that a signicant majority, or 90%, would be
classied as overweight using the BMI cuto point of 21 kg/
m2. This nding is not surprising, given the prevalence of CHD
among this group. Our clinic oers a lifestyle program to help
patients maintain their ideal weight by restricting their calorie
intake.
Caloric Restriction (CR), which involves reducing the intake of
calories without depriving essential nutrients, has consistently
demonstrated anti-aging eects across a broad range of
organisms. Furthermore, it has been shown to protect against
age-related diseases such as cardiovascular disease, diabetes,
hypertension, hypercholesterolemia, and cancer. CR achieves
this by reducing oxidative stress and inammation while
enhancing the production and activity of antioxidant and anti-
inammatory substances, thereby improving the body's overall
balance. Research has also shown that CR can improve overall
health and well-being, optimize energy metabolism, enhance
cellular protection, improve insulin sensitivity and glucose
regulation, induce functional changes in the neuroendocrine
systems, reduce oxidative damage and inammation, and even
shape the gut microbiota [62].
Implementing CR may improve cardiovascular health. By
promoting the activity of endothelial nitric oxide synthase
(eNOS) and sirtuin 1 (SIRT1), CR can enhance endothelial
function, leading to vasodilation, regulation of blood pressure,
and improved blood ow. Additionally, CR may also reduce the
development of atherosclerosis [63]. Eating an unhealthy diet
with calorie excess will certainly promote the development of
atherosclerosis, ISR, and ST [64]. CR protects DNA methylation,
histone modication, and non-coding RNA (nc-RNA), which
prevent VSMC proliferation, migration, and inammation,
which play an important role in developing atherosclerosis
and ISR [65,66]. Most individuals who follow PBDs generally
do not necessitate CR since these diets inherently promote a
sense of satiety. Additionally, the majority of items on PBD
menus are low in calories. In stark contrast, most omnivorous
individuals frequently experience feelings of hunger due to the
malfunctioning of their hormonal regulators, typically caused by
consuming unhealthy foods with minimal nutrients and empty
calories.
2.7. The Role of PBD as Mitochondrial Protectors
As we age, the powerhouses of our cells, called mitochondria,
undergo changes that lead to a decline in their function. This
decline is caused by the accumulation of oxidative damage and
mutations that induce ROS. As a result, the volume, integrity, and
functionality of mitochondrial DNA (mtDNA) decrease. In older
1
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adults, mitochondria are characterized by signicant increases in
ROS and decreased antioxidant defense, which lead to impaired
functions. These include decreased ATP production, lowered
oxidative capacity, and reduced oxidative phosphorylation.
Additionally, with aging, mitochondrial biogenesis will decline
due to inhibition of mitophagy and alterations in mitochondrial
dynamics (ssion and fusion). Mitophagy, an autophagy
process that eliminates defective mitochondria, also deteriorates
with aging. An excessive generation of ROS characterizes
acute and chronic inammatory diseases, which can cause
damage to mtDNA, mitochondrial proteins, and lipids. This
negatively aects normal mitochondrial function and dynamics.
Inammation is generated by various mitochondrial products
called damage-associated molecular patterns (DAMPs) and is
released into the cytosol or extracellular environment. Protective
measures are in place to prevent mitochondria from triggering
harmful inammatory responses, such as disposing of damaged
mitochondria through mitophagy. However, if these mechanisms
are overwhelmed or not functioning correctly, inammatory
reactions instigated by mitochondria can become problematic,
contribute to developing disorders, and impede healing [67].
Atherosclerosis arises due to the malfunction of endothelial
cells and the accumulation of lipids. Mitochondrial malfunction
can have deleterious eects on various cells in the arterial wall,
such as endothelial cells, smooth muscle cells, macrophages,
monocytes, and lymphocytes. This can result in increased levels
of ROS, chronic inammation, oxidative stress, and intracellular
lipid deposition. Also, mitochondrial dysfunction is crucial
in chronic inammatory diseases, including hypertension,
obesity, hyperlipidemia, insulin resistance, and atherosclerosis.
Mitochondria are essential for cellular metabolism, energy
production, and cell survival. When these mechanisms
are impaired, it can lead to cellular dysfunction, excessive
ROS production, cellular damage, and the initiation of the
inammatory response. Mitochondria have been implicated in
the pathogenesis of cardiovascular diseases [68].
Normal mitochondrial functioning is vital for cell survival, and
it is determined by the equilibrium between mitophagy (the
autophagic degradation of mitochondria) and mitochondria
biogenesis (fusion and ssion). Mitophagy is crucial
in eliminating damaged mitochondria, preventing their
accumulation and associated cell malfunction and subsequent
apoptosis. Mitophagy acts as a barrier against ROS accumulation
in damaged mitochondria. Inadequate mitophagy has been linked
to the development of atherosclerosis, which contributes to
progressive cell death, cell stress, and ROS accumulation. This
results in the formation of a necrotic core and the destabilization
of the atherosclerosis plaque. The mitochondrial dysfunction
resulting in increased ROS generation causes damage to
mtDNA, which is more susceptible to mutagenesis than
nuclear DNA due to dierences in DNA packaging and repair
mechanisms. The accumulation of specic mtDNA mutations
further contributes to mitochondrial dysfunction and the
progression of atherosclerotic lesions and is involved in plaque
destabilization processes. Mutations in mtDNA can decrease the
synthesis of respiratory complexes and weaken mitochondrial
respiration in VSMC and macrophages. ROS plays a crucial
role in damaging mtDNA, decreasing the amount of coding
mtDNA, impairing mitochondrial protein synthesis, altering
mitochondrial membrane potential, and decreasing total ATP
production in smooth muscle and endothelial cells, all of which
are important factors in the development of atherosclerosis.
Mitochondrial genome changes, such as an increase in mtDNA
copy number, mtDNA methylation, and the appearance of
mutations (insertions, deletions, and insertions), are associated
with the development of atherosclerosis. Damaged mtDNA was
detected before the appearance of other atherosclerotic signs,
suggesting that mtDNA damage may be the primary event
that induces excessive ROS generation, violates mitochondrial
membrane potential, and causes mitochondrial dysfunction,
followed by the release of cytochrome C and the activation
of apoptotic pathways. Furthermore, damaged mtDNA can be
recognized by the body as an endogenous DAMP, which triggers
the inammatory response [69].
Vascular endothelial cells play a crucial role in regulating
apoptosis and NO production. They are also important in
modulating cell signaling and the cellular response to stress,
which this type of cell is particularly sensitive to. In addition
to their barrier function, endothelial cells are involved in
regulating vascular tone, the transport of blood plasma
molecules, hemostasis, inammation, and lipid metabolism. A
healthy endothelial barrier prevents the inltration of circulating
cells, such as monocytes/macrophages, into the vascular
wall. Endothelial dysfunction is one of the earliest signs of
mitochondrial disorder [70].
Mitochondrial dysfunction was observed in VSMC isolated
from human atherosclerotic plaques. These cells exhibited
the presence of mtDNA mutations, reduced mitochondrial
mass, and defects in ATP synthase. Impaired mitochondrial
dynamics in SMC from atherosclerotic plaques can contribute
to their proliferation. The morphology of the mitochondria is
determined by fusion and ssion processes, which also control
the eectiveness of ATP synthesis, oxygen consumption, and
the potential of the mitochondrial membrane. These processes
are regulated by mitochondria-associated small GTPases,
including the mitochondrial fusion protein mitofusin 2 (Mfn2),
which reduces proliferation and promotes apoptosis of SMCs.
Mitochondrial malfunctioning could potentially exacerbate the
activation of Poly (ADP-ribose) polymerase-1 (PARP-1), a
critical component in the pathogenesis of atherosclerosis.
Mitochondrial oxidative stress associated with atherosclerosis
contributes to inammation activation through the NF-kB-
mediated pathway in macrophages. This process is characterized
by a system of pro-inammatory cytokines, adhesion molecules,
and growth factors that, in turn, can trigger inammatory
signaling [71].
Chronic metabolic-inammatory conditions can impact
mitochondrial functionality and energy production capacity.
Addressing these conditions, including obesity, hypertension,
glucose intolerance, hyperlipidemia, and atherosclerosis, can
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aid in mitochondrial regeneration. The relationship between
mitochondria and metabolic-inammatory disorders is reciprocal
in that both conditions can exacerbate one another. Metabolic-
inammatory disorders can lead to mitochondrial dysfunction,
and conversely, mitochondrial dysfunction can contribute to the
development of these disorders, as illustrated in Fig. 5. Thus,
the term secondary mitochondrial dysfunction is used since,
typically, it is acquired during a person's lifetime and is often
associated with chronic diseases and age-related changes.
Mechanisms of Mitochondrial Dysfunction Induce Atherosclerosis, ISR, and ST
Promoting healthy mitochondrial function can be achieved
through various lifestyle adjustments, including following a
balanced diet, engaging in regular physical activity, and taking
supplements containing vitamins (such as vitamin C, E, and
biotin), minerals (zinc), or nutraceuticals (ubiquinone or CoQ10,
NMN-precursor of NAD+, Quercetin, Astaxanthin, Resveratrol)
[72]. The concept of Mitochondrial nutrients has gained
momentum in recent years and refers to the essential nutrients
necessary to maintain optimal mitochondrial function. Recent
investigations have demonstrated that a Mediterranean diet,
characterized by the consumption of plant-derived compounds
such as vegetables, fruits, and nuts, which are rich in polyphenols
(isoavones, phytoestrogens) and other phytochemicals
(phytosterols, carotenoids, luteolin, organosulfur, terpenes,
saponins) as well as polyunsaturated fatty acids from axseeds
and sunower seeds and can enhance mitochondrial function
[73]. Polyphenols have been demonstrated to hinder the
activity of PARP-1, a crucial component in the pathogenesis of
atherosclerosis [74].
Enhancing mitochondrial function can potentially expedite the
healing process after coronary interventions, such as ballooning
and stent implantation. As illustrated in Fig. 5, this could
substantially decrease the incidence of new atherosclerosis, ISR,
and ST.
Atherosclerosis, ISR, and ST Utilizing PBD
Aging is a progressive deterioration of biological functions that
results in cellular malfunction and can lead to diseases such
as hypertension, CHD, and stroke. Numerous physiological
changes occur as time passes, including genomic instability,
epigenetic irregularities, loss of proteostasis, altered
intercellular communication, abnormal nutrient absorption,
altered mitochondrial function, depletion of stem cells, cellular
senescence, and shortened telomeres. Telomeres are the protective
caps at the ends of chromosomes, consisting of non-coding DNA
sequences that prevent chromosomal breaks and clustering. With
each cell division, telomeres become shorter, resulting in faster
15
Figure 5. Bidirectional: metabolic- chronic inflammatory diseases cause mitochondrial
dysfunction and vice-versa. Mechanisms of mitochondrial dysfunction induce
atherosclerosis, ISR, and ST
Promoting healthy mitochondrial function can be achieved through various lifestyle adjustments,
including following a balanced diet, engaging in regular physical activity, and taking supplements
containing vitamins (such as vitamin C, E, and biotin), minerals (zinc), or nutraceuticals (ubiquinone or
CoQ10, NMN-precursor of NAD+, Quercetin, Astaxanthin, Resveratrol) [72]. The concept of
Mitochondrial nutrients has gained momentum in recent years and refers to the essential nutrients
necessary to maintain optimal mitochondrial function. Recent investigations have demonstrated that a
Mediterranean diet, characterized by the consumption of plant-derived compounds such as vegetables,
fruits, and nuts, which are rich in polyphenols (isoflavones, phytoestrogens) and other phytochemicals
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aging. Telomerase, a ribonucleoprotein enzyme, can synthesize
telomeric repeats at the ends of chromosomes, slowing down
the shortening of telomeres. By increasing telomerase enzyme
activity, the rate of telomere shortening (TeS) can be slowed
[75].
Various external factors, including lifestyle, nutrition, genetics,
and heredity, can inuence aging. Research on twin subjects
has revealed that only 20-30% of an individual's lifespan is
determined by genetic factors, while a signicant portion
depends on behavior and environmental factors. Some age-
related diseases, such as hypertension, obesity, hyperlipidemia,
insulin resistance, and atherosclerosis, are associated with
increased inammation, oxidative stress, decreased telomerase
activity, and TeS. Certain lifestyle habits, such as leading a
sedentary lifestyle, smoking, experiencing emotional stress,
being exposed to pollution, and engaging in unhealthy eating
behaviors, can signicantly increase oxidative stress and TeS,
accelerating the aging and disease process [76].
Several longitudinal studies have demonstrated that TeS is
strongly associated with mortality and age-related diseases such
as acute myocardial infarction (AMI), atherosclerosis, stroke,
hypertension, and type 2 diabetes mellitus. In one population-
based study, individuals with the longest telomeres had the
lowest risk of dying during a 10-year follow-up period. In
another study, participants with TeS had the lowest survival
rates. Large-scale studies have also found that subjects with
the shortest telomeres had a 17-66% increase in mortality risk
compared to those with the longest telomeres. Thus, TeS are
associated with early death, most likely due to cardiovascular
risk factors, including obesity, CHD, AMI, hyperlipidemia,
hypertension, and diabetes mellitus. Consequently, individuals
with the longest telomeres had the lowest risk of developing
CHD, AMI, stroke, and vascular death [77].
Oxidative stress and persistent inammation have the potential
to lead to TeS, dysregulation of genes associated with telomeres,
and a decrease in telomerase activity. The relationship between
inammation and TeS is reciprocal. Inammatory stimuli can
accelerate telomere attrition and result in telomere dysfunction
and shortening. Conversely, TeS can contribute to low-grade
inammation [78].
Eating edible plants can be advantageous because they are
abundant in compounds with antioxidant and anti-inammatory
properties. These compounds can counteract the negative impact
of oxidative stress and persistent inammation, contributing
to the TeS. According to observational studies, consuming
polyphenol/ phytochemicals-rich diets, such as vegetables,
fruits, nuts, seeds, and their derivatives, can prevent TeS. This,
in turn, can result in improved overall health and longevity. [79].
Elizabeth Blackburn, a Nobel laureate, discovered that adopting
a vegan diet can activate over 500 genes within a three-month
period. This diet has the ability to activate genes that help prevent
diseases and deactivate genes that cause chronic inammatory
diseases. There are various methods for strengthening telomeres,
such as regular exercise, avoiding smoking, and consuming a
diet rich in plant-based foods that protect telomeres. Dean Ornish
and Elizabeth Blackburn conducted a study demonstrating
how a vegan diet can increase telomerase activity, the enzyme
responsible for maintaining the length of telomeres. The ability
to lengthen telomeres is critical for longevity. Although we
cannot reverse our chronological age, we can reverse our
biological age, which can help us reverse chronic illnesses in
our patients. Furthermore, reducing our patients' biological age
by one or two decades will automatically decrease their risk of
developing atherosclerosis, ISR, and ST [80].
Figure 6 demonstrates the advantages of a healthy lifestyle,
specically adopting a well-balanced diet, in preventing TeS. By
doing so, the aging process is slowed down or halted, thereby
inhibiting the progression of atherosclerosis. Moreover, this
approach can prevent the onset of ISR and the incidence of ST.
Although our current capabilities do not permit altering our
patients' genetics through the manipulation of mitochondria
and telomeres, there is potential for modifying epigenetic
markers to activate healthy genes and deactivate unhealthy
ones. Epigenetics can inuence the body's interpretation of
specic DNA sequences. As research progresses, the possibility
of manipulating mitochondria and telomeres and even altering
genes may become a reality.
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3. Conclusions
The signicance of the relationship between nutrition and health
should be acknowledged. Research has demonstrated that an
unhealthy diet can result in a heightened risk of developing
metabolic chronic inammatory diseases, such as hypertension,
hyperlipidemia, obesity, insulin resistance, and atherosclerosis.
To promote optimal health and prevent these conditions, it is
essential to adopt a healthy lifestyle that includes balanced-
proper nutrition, regular exercise, abstinence from harmful
substances (such as smoking, alcohol, and unhealthy foods),
stress management, adequate sleep, and social support.
Managing atherosclerosis and preventing ISR and ST solely by
concentrating on the local coronary vessel is no longer justiable
in modern medical practice. Trials from Courage (2007) to
Ischemia (2019) have demonstrated that optimal medical
therapies are as eective as performing coronary intervention in
stable coronary disease patients with chronic coronary syndrome
18
Figure 6. Mechanism of how preventing telomeres shortening will prevent
new atherosclerosis, ISR, and ST
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[81-83]. Thus, the prerequisites for conducting coronary
interventions have become progressively more stringent [84].
Providing optimal medical treatment (OMT) prior to performing
an intervention in stable patients is a reasonable choice. Given that
most interventional cardiologists have traditionally concentrated
on the local concerns of their patients rather than addressing
the metabolic-chronic inammation issues. The ACC/AHA
guidelines recommend that patients with coronary artery disease
should primarily consume PBDs (COR 1 and LOE B-R), but it is
essential to note that the majority of patients who have received
coronary interventions have not adhered to this recommendation.
Furthermore, many interventional cardiologists do not follow
this nutrient recommendation themselves. Although medication
is crucial for addressing systemic issues, neglecting a patient's
dietary habits may not be considered ethical or noble.
Unhealthy diets signicantly contribute to the development of
atherosclerosis and the processes of ISR and ST.
Last year, Rathod et al. from St. Bartholomew's Hospital,
London, presented the NITRATE-OCT ndings, an ISR study
at TCT 2023, demonstrating that those who consumed a daily
serving of beet juice experienced signicantly less late lumen
loss compared to those who received a nitrate-depleted placebo.
Additionally, there was a trend towards fewer major adverse
cardiovascular events at two years. After six months, the median
stent late lumen loss in the nitrate-depleted beet juice group
was 0.244 mm, while it was 0.117 mm in the natural beet juice
group (P = .0165). Similarly, the mean segment late lumen loss
favored the natural beet juice group (0.269 vs. 0.050 mm; P
= .0011). Over the 24-month follow-up period, there were 18
major adverse cardiovascular events in the control group and 9
in the group randomized to dietary nitrate (P = .0718). Although
no in-stent thromboses were observed in either group, death,
myocardial infarction, and target-vessel revascularization were
all numerically lower in the group receiving dietary nitrate.
The results of the study have not yet been disclosed in a nal
report. However, these ndings are of great signicance, as
they indicate that a daily serving of beet juice may signicantly
decrease the likelihood of experiencing ISR. Compared to
a limited serving of beet juice, the whole food form of PBD
contains more antioxidants, anti-inammatory compounds, and
other benecial components, providing even greater protection
against ISR.
Elucidating the pathways by which benecial nutrients exert a
substantial impact on the progression of coronary artery disease
and its role in mitigating the occurrence of ISR and ST is
paramount. Acquiring this knowledge will facilitate larger-scale
studies and encourage the adoption of healthy lifestyle choices
within the interventional cardiac community.
Author Contributions: Conceptualization, D.M.; Writing-
original draft, D.M.; Writing-review and editing, D.M., A.M.H.,
I.N.E.L., M.K.S., and H.U. All authors have read and agreed to
the published version of the manuscript.
Funding: This research received no external funding.
Data Availability Statement: Data sharing is not applicable to
this article.
The author declares no conict of interest.
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