Journal Pre-proof

Non-Coding RNAs, Cancer Treatment and Cardiotoxicity: A Triad of

new hope

Rishabh Mittal , Sarath Krishnan M P , Rahul Saxena ,

Ananyan Sampath , Bela Goyal

PII: S2468-2942(23)00072-2
DOI: https://doi.org/10.1016/j.ctarc.2023.100750
Reference: CTARC 100750

To appear in: Cancer Treatment and Research Communications

Received date: 18 May 2023

Revised date: 13 June 2023
Accepted date: 25 July 2023

Please cite this article as: Rishabh Mittal , Sarath Krishnan M P , Rahul Saxena ,
Ananyan Sampath , Bela Goyal , Non-Coding RNAs, Cancer Treatment and Cardiotoxic-
ity: A Triad of new hope, Cancer Treatment and Research Communications (2023), doi:
https://doi.org/10.1016/j.ctarc.2023.100750

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Highlights
 CVD risk during cancer therapy depends on factors like disease severity, treatment course,
and complications.
 Cancer and CVD share common risk factors such as tobacco, alcohol, obesity, and diabetes.
 Anticancer drugs like doxorubicin can increase CVD risk due to their cardiotoxic effects.
 Cardiac tissue injury can result from hypoxia, ischemia, hypertrophy, and immune-mediated
fibrosis.
 miR-133 and miR-92a are key regulators of cardiac hypertrophy and angiogenesis,
respectively.
 Exosomes serve as potential diagnostic and therapeutic markers for CVDs and participate in
various cellular processes.

1
Title: Non-Coding RNAs, Cancer Treatment and Cardiotoxicity: A Triad of new hope

Authors: Rishabh Mittal1, Sarath Krishnan M P1, Rahul Saxena1, Ananyan Sampath1, Bela Goyal1*

Affiliation(s):
1* Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, Pin
code – 249203, India.

Email Addresses:

Name Email ID ORCID

Rishabh Mittal Drrish376@gmail.com 0000-0002-5723-6263

Sarath Krishnan M P sarathkrishnanmp@gmail.com 0000-0002-0140-6323

Rahul Saxena rahulsaxena.1701@gmail.com 0000-0002-9118-6036

Ananyan Sampath ananyansampath@gmail.com 0000-0001-6730-5886

Bela Goyal* bela.bchem@aiimsrishikesh.edu.in 0000-0001-8183-9956

*Corresponding Author: Dr. Bela Goyal, Associate Professor, Department of Biochemistry, All
India Institute of Medical Sciences, Rishikesh, Uttarakhand, India – 249203. Email:
bela.bchem@aiimsrishikesh.edu.in , ORCID: 0000-0001-8183-9956.

Running Title: Impact of non-coding RNAs on cardio-oncology

2
Abstract

The global health landscape has experienced a shift towards non-communicable diseases, with
cardiovascular diseases and cancer as leading causes of mortality. Although advancements in
healthcare have led to an increase in life expectancy, they have concurrently resulted in a greater
burden of chronic health conditions. Unintended consequences of anticancer therapies on various
tissues, particularly the cardiovascular system, contribute to elevated morbidity and mortality rates
that are not directly attributable to cancer. Consequently, the field of cardio-oncology has emerged to
address the prevalence of CVD in cancer survivors and the cardiovascular toxicity associated with
cancer therapies. Non-coding RNAs (ncRNAs) have been found to play a crucial role in early
diagnosis, prognosis, and therapeutics within the realm of cardio-oncology. This comprehensive
review evaluates the risk assessment of cancer survivors concerning the acquisition of adverse
cardiovascular consequences, investigates the association of ncRNAs with CVD in patients
undergoing cancer treatment, and delves into the role of ncRNAs in the diagnosis, treatment, and
prevention of CVD in patients with a history of anti-cancer therapy. A thorough understanding of the
pathogenesis of cancer therapy-related cardiovascular disease and the involvement of ncRNAs in
cardio-oncology will enable healthcare professionals to provide anticancer treatment with minimized
cardiovascular side effects, thereby improving patient outcomes. Ultimately, this comprehensive
analysis aims to provide valuable insights into the complex interplay between cancer and
cardiovascular diseases, facilitating the development of more effective diagnostic, therapeutic, and
preventive strategies in the burgeoning field of cardio-oncology.

3
Keywords: Cancer, Cardiovascular disease, Antineoplastic Agents, Cardiotoxicity, ncRNAs, Cardio-
oncology.

4
1. Introduction

The world has transitioned into the era of non-communicable diseases, wherein the most common and
dreadful causes of death arise due to non-communicable diseases. Most of these diseases affect people
of older ages and are generally due to a variety of causes, such as genetic causes, environmental and
lifestyle habits. These diseases have generally become more prevalent due to improvements in the
healthcare system, which have reduced mortality and morbidity due to infectious disease from
preventive strategies, management, and treatment to mitigation strategies, which have enabled
humankind to live longer lives, as compared to the earlier centuries. Cardiovascular (CV) diseases are
the leading cause of mortality worldwide.1,2 Cancer is also one of the major causes of death among
individuals, accounting for nearly one in every 6 deaths worldwide.3 Cancer is generally termed as a
disease of the older ages, where the risk of cancer acquisition increases dramatically as one grows
older, except for congenital or neonatal cancers.4 The availability of improved anticancer treatment
facilities through early detection and therapeutic advancements increases the survival rate of cancer
patients, similar to the trend of infectious diseases. The longevity of life comes with various chronic
health disease burdens and increased risk of non-cancer-related deaths.5 The benefits of anticancer
therapy carry untoward effects on various tissues; especially the cardiovascular system, as most
therapies focus on cell damage or destruction.

The global health landscape has shifted towards the predominance of non-communicable diseases,
which now represent the most prevalent and alarming causes of mortality. These diseases
disproportionately affect people of old age and can be attributed to a range of factors, including
genetic predispositions, environmental influences, and lifestyle choices. The increased prevalence of
non-communicable diseases can be attributed to advancements in healthcare systems, which have
successfully reduced mortality and morbidity from infectious diseases through preventive measures,
effective management, and mitigation strategies. Consequently, human life expectancy has improved
significantly compared to previous centuries. Cardiovascular diseases (CVD) have emerged as the
leading cause of mortality worldwide. Moreover, cancer is also responsible for nearly one in every six
deaths globally. Generally considered a disease of older age, the risk of developing cancer increases
dramatically as individuals age, with the notable exception of congenital or neonatal cancers.

Improved anticancer treatment modalities, including early detection and therapeutic advancements,
have contributed to increased survival rates for cancer patients, mirroring the trend observed with
infectious diseases. However, increased life expectancy is accompanied by a greater burden of chronic
health conditions and an elevated risk of non-cancer-related deaths. Anticancer therapies, while
beneficial, can produce unintended consequences on various tissues, particularly the cardiovascular

5
system. This is due in part to the fact that many treatments target cell damage or destruction, which
can negatively impact healthy cells and tissues.

The very first description of an adverse cardiovascular event during the treatment of cancers was
made in 1968 with the treatment using anticancer drugs (anthracycline, causing dose-dependent CV
failure).6 Among cancer survivors, the risk of Cardiovascular disease (CVD) is 37 times higher than
that of normal people, as most modern cancer therapies such as Doxorubicin, and anthracyclines all
cause myocardial damage.1

These effects lead to left ventricular dysfunction, myocardial infarction, and heart failure which in the
long run increases the morbidity and mortality rate of individuals not attributed to cancer, but to its
treatment.7 Despite improvements in preventing cardiovascular diseases, the incidence of CV adverse
events are still on the rise.8 It is very important to understand the complete pathophysiology for the
early diagnosis and prevention of cardiovascular diseases attributed to cardiotoxic Oncotherapy. 9 The
new term cardio-oncology emerges as a connection between upcoming cardiovascular diseases in
cancer survivors or cancer therapy-related CV toxicity (CTR-CVT).10 As with modern technology and
advancement the rate of cancer survivors increases the role of side effects related to treatment also
gains importance. In today’s scenario, the main aim of healthcare professionals is to provide
anticancer treatment with minimal cardiovascular side effects. 11 Anthracycline-induced cardiotoxicity
involves various pathways, including genotoxic stress, mitochondrial dysfunction, and sarcomeric
disruption. Efforts to mitigate this toxicity have included the use of iron chelators such as
dexrazoxane and identifying biomarkers for early detection of cardiotoxicity.12 The interaction
between anthracyclines and the ErbB2 blockade remains an area of active research. Understanding the
underlying mechanisms of anthracycline-induced cardiotoxicity will enable oncologists to manage it
better.

Epigenetics bridges the gap between cancer and cardiovascular disease in the field of cardio-
oncology.13 Non-coding RNA emerges a significant role in early diagnosis, prognosis, and
therapeutics in cardio-oncology. The role of Non-coding RNA is seen in cardiac cell growth, cell
differentiation, cardiac function, metabolism, and cardiac rhythm. The absence of an open reading
frame in non-coding RNA is differentiating feature from coding RNA.14 Non-coding RNA (ncRNA)
transcripts are the untranslated region of transcripted genes. It forms the major portion of transcripted
genes as only 1% to 2% forms the protein. There are various types of noncoding(nc) RNA like long
ncRNAs (lnc RNA), PIWI-interacting RNAs, microRNAs (miRNAs), circular RNAs (circRNAs),
small nuclear (Sn RNA) nucleolar RNAs, and Y-RNAs. Among these major categories are miRNAs,
lnc RNA, circular RNAs (circRNAs), and Sn RNA.9,13 In cases of heart failure (HF) ncRNAs like

6
microRNA-433, microRNA-495, and, microRNA-22 play important roles as biomarkers.15,16,17 They
can also be used to predict the ejection fraction in cases of Heart Failure but due to an incomplete
understanding of their pathology they are not in clinical use.

The expression of miRNA-206 and let-7a, both of which are associated with preventing tumors, was
observed to be higher, while the expression of the oncomiR miR-21, linked to cancer growth, was
lower in cancerous tissue. Additionally, lower levels of ERα and HIF-1 mRNA, associated with tumor
growth and angiogenesis, as well as lower levels of Ki67 expression, which is associated with lower
survival rates in breast cancer patients, were also noted. Although the role of c-miRNAs in breast
cancer patients triggered by regular exercise remains unclear, the modulation of a broad range of
miRNAs, including miR-1, -206, -21, -378, -133a, -133b, and -486, occurs in skeletal muscle tissue
and the bloodstream after various exercise-based interventions. Among these, miR-133a is notably
lower in breast cancer cell lines and human breast cancer tissue, indicating its potential as a systemic
factor that downregulates tumor progression and may be transported from skeletal muscle to cancer
cells via the bloodstream following exercise. It is noteworthy that several miRNAs possess inhibitory
or decelerating properties against cancer development, metastasis, and progression. 18,19 In this study,
we explore the risk assessment of cancer survivors with respect to acquiring an adverse cardiovascular
consequence.

1.1 Objectives

(i) To understand the association of non-coding RNAs in cardiovascular disease in patients

undergoing/ past history of cancer treatment.
(ii) To understand the role of non-coding RNAs in the diagnosis, treatment, and prevention of
cardiovascular diseases in patients with a previous history of anti-cancer therapy.

1.2 Materials and Methods

1.2.1 Inclusion criteria

All peer-reviewed studies regardless of language (as long as an English translation is available) or
study design were included from January 1st, 2000 to 1st April 2023.

1.2.2 Search strategy

PubMed, Scopus, Embase, and Web of Science databases were used apart from other sources of
updates from Up To Date and were screened by 4 independent reviewers and pooled into categories as

7
designated in the discussion. No specific search terms or Boolean operations were used. Studies from
references of selected studies were further screened for selection.
1.2.3 Study selection
The studies were then screened for appropriateness by an expert reviewer based on the abstracts and
tables before narrative synthesis, and tabulation of results.

2. Discussion

2.1 Cancer Therapy and Cardiovascular Risk

The risk associated with cancer therapy is not the same throughout the course it changes as the course
of treatment changes. Cardiovascular risk follows a paradigm with cancer therapy, low risk, and high
risk follows the path later on during the therapy. The risk varies with various factors like severity of
the disease, course of treatment, any complication, and whether primary prevention was given or not,
all these parameters define the CVD risk and survival rate. 11 The patient should be assessed properly
for all the risk factors and probable causes of cardiovascular risk under the following headings
(Figure 1).20

a. History
b. Clinical Examination
c. Diagnostic tools

8
 Figure 1 Cardiovascular risk assessment in cancer patient.

The treating oncologist must look for any long-term complications in cancer patients. The complete
history and physical examination along with the combination of diagnostic tools form the basis of a
complete risk evaluation for cancer-related cardiovascular events.21 Even after the proper precautions
cardiac complications can occur. It is very important to understand the proper pathogenesis of the
disease. With the help of clinical assessment and diagnostic tools, early detection should be made.
Currently, available diagnostic tools lack the sensitivity needed for early detection. ncRNAs as
diagnostic biomarkers have shown promising results in numerous animal studies. In the future, these
ncRNAs in combination with current diagnostic and treatment modalities can guide us toward better
patient care.

Anthracyclines are a class of chemotherapy drugs that are commonly used to treat various cancers.
However, their use is limited due to their potential to cause cardiotoxicity, which is damage to the
heart muscle. The mechanism behind anthracycline-induced cardiotoxicity involves several pathways,
mostly these pathways disrupt the sarcomere structure and impair relaxation, and systolic dysfunction
of the heart. This causes the oxidation of cellular components, and mitochondrial dysfunction which
leads to degradation of sarcomere.

Anthracyclines induce p21 and phosphorylate p53 and histones in cardiomyocytes. In recent animal
studies resistance in cardiac myocytes was observed towards the doxorubicin toxicity after ablation of

9
p21 or knockout of p53.22 The role of p53 in oxidative stress and apoptosis of cardiomyocytes was
also observed in the p53 -/- mice.23

Anthracyclines cause dysfunction of cardiac contractility by inducing oxidative stress through

mitochondrial and nuclear DNA damage. Furthermore, it also disrupts the sarcomere structural
filaments by activating the ubiquitin-proteasome system.24,25 The role of regulators of transcription for
instance cardiac ankyrin repeat protein (CARP) and GATA4 was also seen.26,27

Iron chelator dexrazoxane emerges as a cardioprotector in cancer-related cardiotoxicity but it causes

hindrance in the anticancer activity of anthracycline activity so not widely used by treating
oncologists.12 The degree of cardiotoxicity throughout exposure to anthracycline includes cellular
activation of drug efflux mechanisms.28 Additionally, efforts to identify biomarkers for anthracycline
cardiotoxicity have been ongoing for some time. Some promising candidate biomarkers have been
identified, such as cardiac troponins, natriuretic peptides, and galectin-3.29 However, these have
failed to meet the stringent criteria necessary for routine clinical use, and much work remains to be
done in this area.

Trastuzumab is a humanized monoclonal antibody that targets ErbB2, which slows the progression of
aggressive breast cancers.30 However, studies reveal that using trastuzumab alone or in combination
with anthracyclines increases the occurrence of heart failure. ErbB signaling is crucial in the heart,
and stimulation of ErbB2 and ErbB4 receptors with neuregulin-1 activates cell growth and survival
effects. The deletion of ErbB2 in the adult heart resulted in dilated cardiomyopathy, with increased
mortality and susceptibility to anthracyclines. Studies examining the effects of anti-ErbB2 on
anthracycline-induced cardiotoxicity suggest that ErbB2 blockade enhances anthracycline-induced
cardiac dysfunction, but the exact mechanism behind this interaction is still under investigation. Table
1 summarizes the cardiotoxic effects of various known anticancer drugs, their epidemiology, and
postulated pathophysiology.

Table 1 Cardiotoxic effects of various Chemotherapeutic Agents.

Chemotherapeuti Cardiovascular Pathophysiolog

Epidemiology Management
c Agents Consequences y
Prevalenc Reactive
Congestive Heart DOXO e of oxygen species Iron-chelating
Failure (CHF), dose: DOXO- (ROS) driven drug:
Anthracyclines Left Ventricular (mg/m2 induced dysfunction of dexrazoxane12
and anthracycline Dysfunction ) heart mitochondria, Beta- Blockers
analogs. (LVD), acute failure in iron-catalyzed
myocarditis, patients formation of RAAS inhibitors
arrhythmia without free radicals, Alpha-adrenergic
risk lipid

10
 factor31,32 peroxidation, antagonists
and cardiolipin
300 sequestration. Ischemic
<2% Preconditioning
Alteration of
structural PPAR-alpha
400 integrity in activators,
3-5% mitochondria,
RAAS inhibitors
topoisomerase and alpha-
550 7-26%
2(Top2 induced blockers SGLT2
DNA double- selective
strand breaks inhibitors,
(DSBs)
break.33,34 Phosphodiesteras
e-5 inhibitor
700 18-48%
Metabolic agents
Growth factors

Incidence of 1-4% Increased

of heart failure in Nuclear factor
cases of 2-5% kappa-beta Beta-blockers
cardiotoxicity activation,
patients, mostly overexpression, RAAS inhibitors
Arrhythmias, and production
alteration of Combination of
Trastuzumab angioedema, of
cardiomyocyte both RAASi and
CHF, LVD proinflammator
function.35 Beta-blockers
Myocardial toxicity y cytokines.
worsened by Inhibition of Statins
anthracyclines, neuregulin
reaching 28%. growth factors.

Coronary artery Aspirin

vasoconstriction
mediated by Beta-blockers
Capecitabine, 5-
Ischemia, protein-C
fluorouracil, 1-19% cardiotoxic Calcium Channel
pericarditis, CHF,
cytarabine events.36 Myocardial Blockers
cardiogenic shock
(antimetabolites) necrosis and Nitrates
coronary artery
thrombosis Hydralazine

Ventricular Hypersensitivity
tachycardia, sinus reaction with
bradycardia, histamine
Paclitaxel, vinca atrioventricular release.
5-20% cardiotoxic
alkaloids (Spindle block, Conduction
events
blockers) hypotension, system
Congestive Heart disturbances.
Failure,
ischemia37 Increases
reactive oxygen

11
 species by
mitochondria.
The collapse
and opening of
the
mitochondrial
membrane and
the release of
Cytochrome C
lead to
apoptosis.

Oxidative stress
and direct
endothelial
Neurohumoral 7-32% of patients damage, Taurine, NADPH
Cyclophosphamid exudative
activation, mitral experience adverse Oxidase
e edema, and
regurgitation CV events.38 inhibitors
increased stasis.
Increased
platelet activity.

Arrhythmias,
CHF, Less than 1% of the
Imatinib angioedema, patients develop Unknown Growth Factors
Ventricular heart failure.39
Dysfunction

Hypertension, CHF in 5% of
arrhythmias, patients, and More
Thrombotic
thromboembolic than 20% of patients
Ponatinib microangiopath Growth Factors
disease, experienced adverse
y
Myocardial cardiovascular
Infarction events.40
Hypertension,
thromboembolis 2-4% will develop Endothelial
Bevacizumab m, Gastro- congestive heart Damage, Cell Uncertain
Intestinal tract failure.41 survival block
bleeding.

Uncertain
COX-2–specific Thromboembolis Endothelial
prevalence, but the Uncertain
inhibitors m Damage
risk is present.42

2.2 Cardiotoxicity and Role of ncRNAs in the Pathogenesis of CVD

12
Internal and external factors play a major role in the pathogenesis of cancer. The role of internal
factors like immune imbalance, and mutations, is very limited nearly 10% of the major accountability
of cancer through external factors like tobacco, alcohol, reduce physical activity, and environmental
changes. Alcohol and tobacco dysregulate various miRNAs and sncRNAs which trigger the change in
the epigenetic profile of the person.14 Risk factors like obesity, diabetes, tobacco, and alcohol which
increase the risk of cancer in an individual can also increase the risk of CVD diseases. The risk of
CVDs gets enhanced after the administration of anticancerous drugs.43 Doxorubicin is one of the
major anticancer drugs which we are currently using in the treatment of various cancers. But the
beneficial effect of DOXO also comes with its side effects. The major side effect of heart failure (HF),
cardiomyopathy, and arrhythmia from using DOXO as an anticancer drug is its toxicity to cardiac
cells.44 The role of anthracyclin toxicity specially Doxorubicin (DOXO) is extensively studied and
significantly associated with cardiovascular toxicity.

Various mechanisms involved in the pathogenesis include biological processes like hypoxia/ischemia,
apoptosis, autophagy, angiogenesis, reperfusion injury, and fibrosis of cardiomyocytes. Various
mechanisms have been proposed, that lead to DOXO toxicity-induced apoptosis or necrosis of
cardiomyocytes.45 Antracylin antibiotics reference DOXO and its dose equivalence Daunorubicin,
Idarubicin, Mitoxantrone, and Epirubicin tend to increase the oxidative stress in the body which
damages the DNA and causes lipid peroxidation which further leads to alteration of autophagy and
apoptosis of cardiomyocytes.46 Autophagy regulates the apoptosis of cardiomyocytes, autophagy is
essential for the cardiomyocytes to maintain their homeostasis.47 Alteration in the autophagy of
cardiomyocytes is a debatable topic for many years. It is still controversial whether there is
upregulation or downregulation of autophagy that occurs in DOXO toxicity. In recent studies, it was
shown that the DOXO downregulates autophagy by acting through The Akt/mTOR pathway.48 Apart
from increasing the Reactive oxygen species (ROS) anticancer agents distress the electrophysiological
activity of cardiac tissues by inhibiting ion channels which leads to heart failure.49 The major
mechanism of cardiac tissue injury through hypoxia and ischemia. Excessive hypertrophy without
proper vascularization creates a hypoxic condition. miR-133 is one of the prominent regulators of
cardiac hypertrophy, its reduce amount is significantly associated with myocardial infarction.
Angiogenesis is also one of the major factors which prevent cardiomyocyte death and also helps in
recovery after Myocardial infarction (MI). It was demonstrated that by regulating the expression of
miR-92a we can enhance or reduce the amount of angiogenesis. The overexpression of miR-
92a inhibited angiogenesis while under expression, enhances the angiogenesis. The immune system
acts as double edge sword on the cardiovascular system (CVS). It is necessary for cardiac remodeling
however it can also damage the surrounding normal tissue through fibrosis. Many ncRNAs are present
in our CVS which fine-tune this regulation and thus prevent us from excessive fibrosis.50

13
The clinical utility of ncRNAs has been widely studied for its potential diagnostic, therapeutic, and
preventive application as summarized in Figure 2.

The extracellular vesicles (EVs) having diameters of 40 to 160 nm are called exosomes. The
composition of exosomes is specific to their site of origin as it is based on surface and cytosolic
protein and other genetic and non-genetic material by identifying the exosome of it we can identify
their site of origin. Exosomes are secreted into various body fluids like cerebrospinal fluid (CSF),
bile, blood, semen, urine, and sputum in nearly all the cells. So exosomes serve as a potential
diagnostic and therapeutic marker for CVDs. Exosomes act as intercellular messengers between two
cells or tissues situated at various distances. Exosomes play a role in various processes like apoptosis,
inflammation, angiogenesis, also in cell signaling, cell communication through RNA(coding and
noncoding), and miRNA transport.51 Valadi et al. were the first to identify the presence of miRNA,
small nuclear RNAs (snRNAs), piwi-interacting RNA (piRNA), and noncoding RNA in exosomes.
Cardiomyocytes maintain their homeostasis through the release of exosomes which increases in the
case of hypoxia. Researchers across the globe are trying to explore exosomal ncRNAs in oncology as
well as various cardiac disorders for their potential clinical utility.

Figure 2 Clinical Role of ncRNA’s in cardio-oncology.

14
2.3 Cardiovascular Diseases and Diagnostic Biomarkers

Cancer therapy drugs not only target the cancer cells but also the surrounding tissue and lie their
harmful effect on other body tissue also. The major victim of these toxic effects is cardiac cells called
cardiomyocytes. Acute coronary syndrome (ACS) is the major problem that cardiologists come across
in oncology patients.52 Conventially markers like troponin and creatinine kinase(CK-MB) are done
routinely to diagnose acute myocardial infarction (AMI) along with ECG and clinical findings. The
first 3 hours are very crucial in case of myocardial infarction (MI), the serum troponin levels reach
their peak level in 12-48 hours and CK-MB in 6-12 hours. The major issue with these conventional
biomarkers is their low sensitivity and specificity, they also tend to increase in other muscle injuries
and renal dysfunction.53 So along with these routine markers, there is a need for other biomarkers
which aid in early detection, reduce the time of diagnosis, and help in initiating prompt prevention
therapy. Many Non-coding RNAs are very stable they can survive in the bloodstream for a prolonged
period and could serve as a diagnostic tool for cardiotoxicity in major human cancers. 54 ncRNAs
emerging as promising biomarkers for the detection of CVDs, due to their better stability and
detectable nature in various fluids like blood, cerebrospinal fluid (CSF), Saliva, and other body fluids.
Many ncRNAs have better predictive value for diagnosing cardiotoxicity which standalone or in
combination with cardiac troponins can make a significant difference in early detection of it. In recent
studies, it was observed that mi-R1 better predicts cardiotoxicity as compared with cardiac troponin I
(cTnI).55 Recently many exosomal miRNAs were found whose concentration increases within 4 hours
of initiation of chest pain.56 Exosomal upregulation of hsa-miRNA-133a and hsa-miRNA-1 was seen
in the serum of acute coronary syndrome(ACS) patients. miRNA-208a member of the miR‐ 208
family regulates cardiac contractility and conduction, its presence was detected in patients with MI
which is absent in healthy individuals.57 The plasma levels of miRNA-208a and miRNA-208b doesn’t
get affected by stroke, muscle, or renal injury, unlike the cardiac troponins which show an increase in
concentration.58 It was also observed in animal studies, on the administration of DOXO in rats there is
a rise in miR-208 levels which persists throughout the 24 hours however the concentration of cardiac
troponin T (cTnT) in plasma only increases for a transient period.59 Likewise, miRNA-133a miRNA-
208b, miRNA-1, and miRNA-499 were found to be significantly associated with MI patients within
12 hours of symptoms. The presence of miRNA-499–5p and miRNA-208b increases the chances of
mortality in an individual, and miRNA-208b overexpression increases the chances of ventricular
hypertrophy and atrial fibrillation (AF). The low levels of Many non-coding RNAs like let-7c, miR-
145, and miR-155 were observed to be associated with the risk of Cardiovascular system(CAD).60
Concentration of miRNA‐ 499 was found to be significantly high in the case of acute myocardial
infarction (AMI) and its higher sensitivity proves it worth for potential biomarker for myocardial
infarction.61 Diagnosis and prognosis of heart failure miRNA-495, miRNA-22, and miRNA-43 can
represent important biomarkers. miRNAs can serve as a reliable diagnostic biomarker along with

15
routine tests for early diagnosis of CVDs.56 Shortly the use of these ncRNAs in combination with
other biomarkers can pave the way for early detection and prevention of cancer-related cardio-toxicity
and can help us improve the diagnostic and treatment modality further. Some of the miRNAs
associated with diagnosis of cardiotoxicity related to anticancer drugs is summarised in Table-2.

Table 2 Dysregulated ncRNAs related to Cardiac Toxicity associated with cancer therapy in
oncology patients.

Cardiac Toxicity
S.No. ncRNA Expression Cancer type Associated with cancer Reference
therapy
Chronic myeloid
1 miR-320a Downregulated Chronic heart failure 14
leukemia

miR-92b-
2 Upregulated Melanoma Dilated Cardiomyopathy 62
5p
Acute leukemia,
miR- Malignant lymphoma,
3 1/miR- Downregulated or Multiple Long QT syndrome 63
133a
myeloma

Breast cancer,
Contractility/
4 miR-208a Upregulated Leukaemia, and 64
Myocardial infarction
Lymphomas

miR- Hematological Dilated Cardiomyopathy

5 Upregulated 65
208b malignancies / Myocardial infarction

6 miR-21 Upregulated Prostate cancer Myocardial infarction 66

Triple-negative breast
7 let-7f Upregulated Myocardial infarction 67
cancer

Hematological
8 miR-155 Upregulated Dilated Cardiomyopathy 68
malignancy
9 miR-22 Downregulated Renal cell carcinoma Hypertrophy 69

Myocardial infarction
10 miR-433 Upregulated Renal cell carcinoma 70
/fibrosis

2.4 Non-coding RNA as a Treatment Modality

With the advancement of the field of RNA, medicine ncRNAs can be used as a targeted therapy in
various cancers which will reduce our dependency on chemotherapy and thus prevents various
cardiovascular disease. The pavement for ncRNAs-based therapies was already being laid by Levin et

16
al 2019; by treating hereditary transthyretin amyloidosis with siRNAs based drug patisiran. 54 Several
ncRNAs have been discovered so far which can be regulating cardiomyocyte (CM) proliferation.
These ncRNA can play a significant role in cardiomyocyte (CM) regulation and aid in cardiac
regeneration post-MI. Many ncRNAs like members of miR family miR-290, miR-302/367,miR-19a,
miR-199a and miR-590, miR-19b, and various lncRNAs like ECRAR stimulate the cardiomyocyte
proliferation likewise lncRNAs like CAREL, and CRRL can repress the (CM) proliferation. 71 Various
new modalities are emerging nowadays which reduce the toxic effect of DOXO. The Non-coding
RNAs based therapy in which circular RNA (circRNA) shows promising results as targeted therapy in
patients with heart failure. Breast cancer type 1 susceptibility protein (Brca1) regulates the circRNA
insulin receptor (Circ-INSR) a type of ncRNA that is responsible for the regulation of apoptosis in
cardiomyocytes. The Circ-INSR gets downregulated by the action of DOXO which leads to the death
of the cardiomyocyte. Following Circ-INSR are found to have a beneficial role in preventing DOXO
centered Cardiotoxicity Circ-ATP1A1 (hsa_circ_0013692 and mmu_circ_0010303), and Circ-GAB1
(hsa_circ_0125422 and mmu_circ_0015017). Administration of these Circ-INSR helps in reducing
the oxidative stress produced by DOXO thus protecting cardiac function.72

In studies involving animal models, the use of exosome microRNA as a therapeutic agent in cardiac
injury patients produced favorable results. For instance, a research conducted by Park et al. in 2018
utilized a mouse model to simulate ischemia/reperfusion (IR) injury. The study demonstrated that
microRNA-26a exerted a positive effect by downregulating the expression of glycogen synthase
kinase 3 beta (GSK3β).73 Another study that employed a murine model investigated the therapeutic
role of exosomes containing microRNA-146a in acute myocardial injury. The results indicated a
beneficial effect.74 Furthermore, an additional research using a murine model showed that microRNA-
146a contributed to the reduction of cell apoptosis and the regulation of autophagy pathways.75

Mesenchymal stem cell-derived (MSCs) exosome microRNA therapy acts through miRNA and
prevents cardiac remodeling and apoptosis of cardiomyocytes, inhibits autophagy, reduces endothelial
dysfunction, promotes angiogenesis, prevents remodeling of cardiac tissue, and reduces fibrosis of the
myocardium, thus helping in the repair and prevention of cardiac ischemic injury.76 These exosomal
microRNAs prevent the translation of mRNA of the target cell by degrading its mRNA through
downregulation. Following MSCs exosome microRNAs have been identified which have a significant
role in treating the cardiac ischemic injury. miR-126, miR-21, miR-221, miR-210, and miR-222
increase the formation of new blood vessels and enhances the expression of vascular endothelial
growth factor, while miR-760-3p decreases myocardial fibrosis. miR-125b, miR-146a, miR-125a-5p,
and miR-24 reduce apoptosis of cardiomyocytes and inhibit their autophagy75, and miR-182 through
macrophage polarization helps in halting the progression of Reperfusion Injury.51,77

17
Recently circular RNAs are in the limelight for controlling gene expression by degrading certain
mRNAs through the sponge effect. Many studies have reported the role of circular RNA in the
regulation of the cardiovascular system. They act on their target miRNA by downregulating them
which decreases their expression. Many Circular RNAs have shown their role in preventing
myocardial infarction, reperfusion injury, and heart failure and regulating autophagy and apoptosis of
cardiomyocytes. CircSry prevents hypoxic injury by downregulating miR-138, likewise, circNcx1 and
circTtc3 prevent myocardial infarction by regulating gene expression. A freshly narrated circular
RNA Heart-related circRNA (HRCR) downregulates the activity of miRNA whose overexpression is
responsible for cardiac hypertrophy. Likewise, miR-133a also downregulates various factors which
regulate cardiac hypertrophy.78 Cardiac microRNA-132-3p (miR-132) was reported to participate in
signaling pathways and be responsible for the regulation of cardiomyocyte stress, apoptosis, and
autophagy. Recently CDR132L (antisense oligonucleotide inhibitor) underwent phase 1 human trials
to inhibit the expression of miR-132 and shows promising results in preventing and reverting cardiac
remodeling and can be used as a targeted therapy for heart failure in the upcoming future.79 In the
future combined effect of these ncRNAs shows great targeted therapeutic potential through various
pathological mechanisms.

2.5 Non-coding RNAs as Preventive Measures

The role of physical exercise in cardio-oncology by altering the epigenetics of a person is very
evident. A sedentary lifestyle is strongly associated with the risk of cancer and CVDs. Several studies
have recognized the beneficial potential of exercise, and even World Health Organization (WHO)
applauds the small dose of exercise in improving cardiovascular health.14,80 Various beneficial effects
of physical exercise have been seen that protect the CVS through the ncRNAs. The rising shreds of
evidence show the influence of physical exercise-driven epigenetic changes like DNA methylation
and histone modification, which alters the regulation of ncRNAs and influences the cardiac cells. 19
Exercise induces the growth of cardiomyocytes by modulating the expression of several miRNAs. 81
Furthermore, exercise can induce epigenetic changes in the germ cells, leading to intergenerational
inheritance.82 These altered ncRNAs reduce the chances of cancer and cancer therapy-related
cardiotoxicity. Following miRNAs, miR-27, miR-21, miR-144, exosomal miR-342-5p, and miR208
show their protective role in preventing cardiac disease by strengthening vascular and cellular growth.
Even though the complete potential of physical exercise preventing cancer therapy-related
cardiotoxicity is still under study but carries great potential.14

3. Conclusion

18
Cardiovascular disease (CVD) risk is not constant during cancer therapy and may increase as the
therapy progresses. The risk of CVDs depends on several factors, including the severity of the
disease, course of treatment, and presence of complications. Cancer patients should undergo a proper
evaluation to assess the probable causes of cardiovascular risk, including history, clinical
examination, and diagnostic tools. Despite precautions, cardiac complications may still occur,
emphasizing the need to understand the pathogenesis of the disease.

Various internal and external factors play a significant role in the pathogenesis of cancer, including
mutations and immune imbalances. Risk factors such as tobacco, alcohol, obesity, and diabetes that
increase the risk of cancer also increase the risk of CVD. The administration of anticancerous drugs
such as doxorubicin can also enhance the risk of CVDs, leading to heart failure, cardiomyopathy, and
arrhythmia. The toxicity of doxorubicin to cardiac cells is the primary cause of its cardiotoxicity.
Various mechanisms that lead to doxorubicin-induced apoptosis or necrosis of cardiomyocytes have
been proposed, including oxidative stress, lipid peroxidation, and alteration of autophagy. Alteration
in the autophagy of cardiomyocytes is still a controversial topic, and its role in doxorubicin toxicity
needs further study.

Cardiac tissue injury can also occur due to hypoxia and ischemia, excessive hypertrophy without
proper vascularization, and immune system-mediated fibrosis. The regulation of cardiac hypertrophy
and angiogenesis is critical to prevent cardiac tissue injury. miR-133 and miR-92a are among the
prominent regulators of cardiac hypertrophy and angiogenesis, respectively. The immune system
plays a double-edged sword on the cardiovascular system, necessary for cardiac remodeling but
damaging the surrounding normal tissue through fibrosis. Many non-coding RNAs fine-tune this
regulation and prevent excessive fibrosis.

Exosomes, which are extracellular vesicles, serve as a potential diagnostic and therapeutic marker for
CVDs, as they carry genetic and non-genetic material specific to their site of origin. Exosomes act as
intercellular messengers between two cells or tissues, playing a role in various processes, including
apoptosis, inflammation, angiogenesis, and cell signaling. They contain RNA, including miRNA and
small nuclear RNAs, that can be used as biomarkers for CVDs.

4. Future perspectives

Cancer and cardiac complications form the major disease burden worldwide as far as mortality is
concerned. Managing Cancers with an attitude to indifferent attitude to Cardiotoxicity may disturb the
risk-benefit ratio. Understanding the molecular mechanisms behind the cardiotoxicity induced by
anticancer may widen the scope of benefits to patients by using molecular mechanism-based adjunct
therapies or substituting with drugs that target ncRNAs involved in the pathogenesis.

19
ncRNAs are emerging as key players in regulating pathogenic processes and also have the potential to
help in patient care as diagnostic markers or as potential therapeutic targets cardio-oncology is
relatively a new field that has now started gathering considerable attention. However, the scientific
data is still in its novice stage. Next-generation sequencing is being widely utilized to identify
ncRNAs involved in pathogenesis and as biomarkers in a multitude of disorders in different
populations. Further studies utilizing Next generation sequencing(NGS) in the field of cardio-
oncology can help in unraveling molecular mechanisms. Moreover translating molecular
underpinning into the clinics with the help of clinical trials is a need of the hour in the field of cardio-
oncology.

5. Limitations

The field of cardio-oncology faces multiple challenges due to limitations in the availability and
quality of studies, as well as heterogeneity in patient populations and treatment regimens. There is a
lack of standardization in diagnosis and management, limited long-term follow-up data, and potential
for publication bias. Determining causality is difficult, and there is limited understanding of
underlying mechanisms. Additionally, there is a lack of consensus on optimal screening strategies and
limited data on the impact of cardio-oncology interventions on patient outcomes. Observational
studies face potential confounding factors, and there is limited data on the effects of newer cancer
therapies on cardiovascular health. Extrapolating results from animal studies to humans is also
challenging. There is limited data on the effectiveness of preventive measures, and the long-term
effects of cardiotoxicity are not fully understood. Additionally, there is limited data on the impact of
cardio-oncology care on healthcare costs, and on the effectiveness of multidisciplinary care models.
Studies funded by industry face potential bias. Lastly, there is limited data on the impact of cardio-
oncology interventions on patient quality of life and cancer treatment outcomes.

6. Conflict of interest statement

The authors have no conflict of interest.

20
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Credit author statement

1. Rishabh Mittal
2. Sarath Krishnan M P
3. Rahul Saxena
4. Ananyan Sampath
5. Bela Goyal*

Authors Number 1 2 3 4 5

Data curation □ □ □ □

Formal analysis □ □ □

Funding acquisition

Investigation □ □ □ □ □

Project administration □

Resources □

Software □ □ □ □

29
 Supervision

Validation □ □

Roles/Writing – original draft □ □ □

Writing – review & editing □ □ □

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.

☐ The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:

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