Review

Overview of Oncology: Drug-Induced Cardiac Toxicity

Nilima Rajpal Kundnani 1,2 , Vincenzo Passini 3 , Iulia Stefania Carlogea 1 , Patrick Dumitrescu 3 , Vlad Meche 3 ,
Roxana Buzas 4,5, * and Daniel Marius Duda-Seiman 1,2

1 University Clinic of Internal Medicine and Ambulatory Care, Prevention and Cardiovascular Recovery,
Department VI—Cardiology, “Victor Babes” University of Medicine and Pharmacy, 3000041 Timisoara,
Romania; knilima@umft.ro (N.R.K.)
2 Research Centre of Timisoara Institute of Cardiovascular Diseases, “Victor Babes” University of Medicine and
Pharmacy, 3000041 Timisoara, Romania
3 Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 3000041 Timisoara, Romania
4 1st Medical Semiology, Internal Medicine, Department V, “Victor Babes” University of Medicine and
Pharmacy, 3000041 Timisoara, Romania
5 Center for Advanced Research in Cardiovascular Pathology and in Hemostaseology, “Victor Babes”
University of Medicine and Pharmacy, 3000041 Timisoara, Romania
* Correspondence: buzas.dana@umft.ro

Abstract: Cancer medications can cause cardiac issues, which are difficult to treat in
oncologic patients because of the risk of complications. In some cases, this may significantly
impact their well-being and treatment outcomes. Overall, these complications fall under the
term “drug induced cardiotoxicity”, mainly due to chemotherapy drugs being specifically
toxic to the heart, causing a decrease in the heart’s capacity to pump blood efficiently and
leading to a reduction in the left ventricular ejection fraction (LVEF), and subsequently
possibly leading to heart failure. Anthracyclines, alkylating agents, and targeted therapies
for cancer hold the potential of causing harmful effects on the heart. The incidence of heart-
related issues varies from patient to patient and depends on multiple factors, including the
type of medication, dosage, duration of the treatment, and pre-existing heart conditions.
The underlying mechanism leading to oncologic-drug-induced cardiovascular harmful
effects is quite complex. One particular group of drugs, called anthracyclines, have garnered
attention due to their impact on oxidative stress and their ability to cause direct harm to
Academic Editor: Jimmy T. Efird
heart muscle cells. Reactive oxygen species (ROS) cause harm by inducing damage and
Received: 6 February 2025 programmed cell death in heart cells. Conventional biomarkers alone can only indicate
Revised: 9 April 2025
some degree of damage that has already occurred and, therefore, early detection is key.
Accepted: 10 April 2025
Novel methods like genetic profiling are being developed to detect individuals at risk, prior
Published: 12 April 2025
to the onset of clinical symptoms. Key management strategies—including early detection,
Citation: Kundnani, N.R.; Passini, V.;
personalized medicine approaches, and the use of novel biomarkers—play a crucial role
Stefania Carlogea, I.; Dumitrescu, P.;
Meche, V.; Buzas, R.; Duda-Seiman, in mitigating cardiotoxicity and improving patient outcomes. Identification of generated
D.M. Overview of Oncology: genetic alterations and the association to an increased likelihood of cardiotoxicity will
Drug-Induced Cardiac Toxicity. allow treatment in a more personalized approach, aiming at decreasing rates of cardiac
Medicina 2025, 61, 709. https:// events while maintaining high oncological efficacy. Oncology drug-induced cardiotoxicity
doi.org/10.3390/medicina61040709
is managed through a combination of preventive strategies and therapeutic interventions
Copyright: © 2025 by the authors. from the union of cardiac and oncological knowledge.
Published by MDPI on behalf of the
Lithuanian University of Health Keywords: cardiotoxicity; chemotherapy; radiotherapy; anthracyclines; anti-HER2 receptor
Sciences. Licensee MDPI, Basel,
monoclonal antibody
Switzerland. This article is an open
access article distributed under the
terms and conditions of the Creative
Commons Attribution (CC BY) license
(https://creativecommons.org/
licenses/by/4.0/).

Medicina 2025, 61, 709 https://doi.org/10.3390/medicina61040709

Medicina 2025, 61, 709 2 of 21

1. Introduction
Importance of Recognizing Cardiotoxicity in Cancer Treatment
Taking into consideration the cardiotoxic effects of the drugs used in cancer treatment
marks the beginning of enhancing quality of life. Chemotherapies, radiotherapies, and
other anticancer modalities can cause significant cardiovascular complications. Treatment-
related cardiotoxicity is associated with a high morbidity and mortality burden observed in
cancer survivors [1,2]. Recent studies indicate a significant rise in cardiotoxic events among
cancer survivors, emphasizing the urgent need for improved cardiac monitoring.
The prevalence of cardiotoxicity varies depending on the type of cancer treatment
used. For instance, in patients treated with anthracyclines, cardiomyopathy is found
in approximately 1–26%, but this effect may be compounded by the concurrent use of
trastuzumab (a humanized anti-HER2 receptor monoclonal antibody) [2]. One recent study
indicated that as many as 25% of all cancer patients might be affected by some form of
cardiotoxicity, and survivors of pediatric cancers experienced a cardiac mortality risk that
is almost eight times larger compared to the general population [1,2]. This underscores the
evolution of cancer treatments and the importance of recognizing cardiotoxicity early in
the treatment continuum. A proper definition of chemotherapy-induced cardiotoxicity is
yet to be established [3].
To manage various cardio-toxic effects of the drugs, a multidisciplinary approach is
required between oncologists and cardiologists. The current guidelines suggest “dynamic
partnerships”, where both specialties are required to work closely together to monitor
patients at risk and provide preventive strategies [4]. Despite the recognition of this need,
many patients are not referred to cardiology services until after they develop symptoms
of cardiotoxicity. Studies have reported that only 15% of patients were referred to a
cardiologist before the administration of chemotherapy, revealing a serious, significant gap
in the standard of preventive practice [1,4]. With the availability of novel cancer therapies,
there arises a constant need for continuous monitoring of the patients in order to detect
possible adverse effects on the vital organs.

2. Background on Cancer Treatments: Evolution of Chemotherapy and

Targeted Therapies
Advancements in chemotherapy and targeted treatments have significantly trans-
formed the landscape of cancer treatment in the last five decades by converting aggressive
cancers from being rapidly fatal to being more effectively manageable by oncologists’ long-
term care strategies. The emergence of chemotherapy as a treatment option in the twentieth
century marked a revolutionary breakthrough in cancer therapy by employing cytotoxic
agents that target and eliminate both fast-growing normal cells and cancerous cells. The
approach often led to side-effects and proved ineffective in the long run, as the cancer cells
developed resistance to the treatments [5,6].
In the 1980s, there was a shift towards using a combination of chemotherapy treatments
for enhancing effectiveness to combat resistance in cancer therapy. The transition towards
targeted classes such as interferons and retinoids marked a significant advancement in
treatment strategies [7].
Since then, the field of oncology has seen great progress thanks to advancements in
biology and genetics, which allowed for the identification of specific genetic changes that
differentiate normal cells from cancerous ones, and the characterization of key molecular
alterations that trigger cancer growth. An example of this progress is the development of
imatinib in 2001 as targeted therapy for patients with chronic myeloid leukemia (CML),
marking a major breakthrough in targeted treatment by focusing on specific genetic muta-
tions instead of using harmful genotoxic substances to improve patient outcomes. These
Medicina 2025, 61, 709 3 of 21

modifications also notably reduced the levels of side effects while simultaneously improv-
ing the survival rates [5,6].
It is important to note that while these treatments have improved survival, they have
also introduced cardiotoxic risks. For example, immune checkpoint inhibitors have been
linked with immune-mediated myocarditis and other cardiac complications. A systematic
review and meta-analysis conducted by Nielson DL et al. highlighted the importance of early
detection of cardiovascular adverse effects of immune checkpoint inhibitors while stating that
in some cases, ceasing their use and initiating corticosteroids can prove beneficial [8].
Moreover, along with the development in cancer treatment through immunotherapy,
the usage of immune checkpoint blockers and monoclonal antibodies has recently been
on the rise as well. These treatments leverage the body’s natural defense mechanisms to
combat cancer efficiently by pinpointing and eliminating cancerous cells. Tailored therapies
have shown promising outcomes in terms of both survival rates, and in enhancing the
quality of life for individuals diagnosed a decade ago with breast cancer that tested positive
for human epidermal growth factor receptor 2 (HER2 positive) [9,10]. Although overall
survival rates have improved, these benefits are tempered by an increased incidence of
cardiac complications, making cardiac surveillance essential [11]. The extended life span
achieved with the help of modern oncology treatment drugs on hand helps deal with
cancers more efficiently, but on the other hand, it increases the burden of cardiovascular
pathologies, which are either due to the long-term usage of drugs or can be age-related [12].
They predispose patients to late-onset cardiovascular complications such as heart failure,
arrhythmias, and coronary artery disease. Hence, there exists an increasing clinical need
for cardio-oncology programs to address these risks proactively.
Worldwide medical research is being conducted to obtain a better understanding of
gene mapping technologies. Drug resistance remains a challenge despite advancements
in the field. Efforts are underway to explore alternative therapies, like chimeric antigen
receptor (CAR) T cell therapy, known for its efficacy in treating hematological cancers [13].

2.1. Patient Survival Rates and Quality of Life

Throughout the years, advancements in cancer treatment have increased the chances
of survival for cancer patients. However, the impact of these treatments on the quality of
life for patients is still uncertain. Due to advancements in cancer detection and therapies,
there is a probability of individuals surviving cancer [14]. For example, the overall five-year
survival rate for all types of cancers has increased from 50% in the mid-seventies to 67%.
Both negative impacts and receiving adequate support can affect a person’s quality of life,
not only during their journey as a cancer survivor but also throughout the entire spectrum
of cancer care [15,16].
Over the past few decades, cancer cures have enhanced the overall survival rate,
but their effects on the quality of life are complex. Cancer diagnosis, therapies, and
treatment have received increased attention over the years, providing patients with a
higher probability of surviving cancer [17].
Numerous individuals who have overcome cancer often mention experiencing symp-
toms that affect their well-being and various aspects of their lives. When examining fatigue
in cancer survivors according to four study outcomes, its occurrence was observed with
rates ranging from 50 to 90% in early stages, 25% in those in intermediate stages, and
between 40 and 50% for advanced cases. Fatigue is noted to persist during cancer therapy
and afterwards in about 30 to 40% of survivors [18]. Patients may also face challenges
such as pain issues, challenges with cognitive function post chemotherapy (referred to as
“chemo brain”), sexual difficulties, and disruptions in sleep patterns [18]. These symptoms
can significantly impact a person’s job performance and relationships.
Medicina 2025, 61, 709 4 of 21

The type of treatment given and the dosage can have an impact on the well-being of
individuals with cancer. For example, those undergoing chemotherapy often experience
more side effects and disruptions in their quality of life compared to those receiving
targeted therapies or immunotherapy [19]. Similarly, surgeries that aim to treat cancer can
sometimes lead to effects in terms of both function and physical appearance in the long
run, especially when they involve visible body parts or vital organs, like the breast, head,
or neck [19].
Survivorship care for cancer patients has developed as a part of cancer treatment
strategy with an emphasis on managing the long-term effects and ensuring a high quality
of life for survivors. This includes addressing well-being taking into consideration as well
as its mental and social aspects [20]. Programs promoting wellness through activities like
exercise programs and cognitive therapy along with medical services are shown to improve
aspects of the quality of life for cancer survivors [20].
The majority of cancer survivors claim improvements in the outlook of life, relation-
ships and personal development after cancer experience, which is called post-traumatic
growth [18]. This demonstrates the recovery ability of many cancer survivors and the
capability of achieving positive psychological changes regardless of unfavorable situations.

2.2. Definition of Cardiotoxicity: Variability in Definitions and Clinical Implications

Cardiotoxicity describes the side effects of cancer treatments on the heart and circula-
tory system. These effects range from unapparent changes in cardiac function to potentially
fatal heart failure. The primary objective clinical definition of cardiotoxicity uses changes
in the left ventricular ejection fraction (LVEF). There have been many proposed thresholds
defining cardiotoxicity using changes in LVEF [21].
The Cardiac Review and Evaluation Committee (CREC) defines cardiotoxicity as follows:
1. Concomitant signs or symptoms of congestive heart failure CHF characterized by a
reduction in LVEF of at least 5% to below 55%.
2. LVEF of at least 10% decrease to below 55% in the absence of clinical signs or symp-
toms [22].
Other definitions have been proposed, including the following:
• A drop of LVEF by a value of >10 percentage points to a value of <50%.
• >20 percentage points absolute decrease in LVEF.
• Any LVEF declines to <50%.
Cardiotoxicity onset can also occur at significantly different times.
Early onset: This may present acutely during treatment or within the first year after
treatment was discontinued (early based on blood count findings alone) [23].
Late onset: This occurs more than a year after treatment was completed (secondary to
bone marrow aplasia) [1]. The added variability in timing further complicates long-term
monitoring and follow-up strategies for cancer survivors.
While LVEF-based definitions are widely used, they have several limitations. Based on
the severity of the LVEF, different clinical signs and symptoms can develop leading to poor
QOL. For instance, reading of LVEF changes may not detect early, subclinical myocardial
dysfunction that later develops into symptomatic heart failure [22]. Loading conditions
can affect LVEF measurements and may not be representative of intrinsic myocardial
contractility. Without meeting the LVEF-based criteria for cardiotoxicity [21], some patients
may develop significant cardiovascular complications.
Because of these limitations, there has been a growing interest in other markers of
cardiac dysfunction including global longitudinal strain (GLS) and cardiac biomarkers like
troponin and natriuretic peptides.
Medicina 2025, 61, 709 5 of 21

2.3. Cardiotoxicity Mechanism and Types

2.3.1. Mechanisms of Cardiotoxicity
Cardiotoxicity due to oncologic drugs is diverse and often multifactorial.
Anthracyclines: For anthracyclines, one of the most well-studied classes of cardiotoxic
chemotherapeutics, several mechanisms have been identified: oxidative stress, mitochon-
drial dysfunction, DNA damage, calcium dysregulation, apoptosis induction, and disrup-
tion of normal cellular signaling pathways (Table 1).

Table 1. Main classes of chemotherapy medication and their proven mechanisms of cardiotoxicity.

Class of Chemotherapy
Mechanism of Cardiotoxicity
Medication
Anthracyclines cause cardiotoxicity primarily via
Anthracyclines oxidative stress, mitochondrial dysfunction, and
DNA damage.
TKIs disrupt normal cellular signaling and can impair
Tyrosine Kinase Inhibitors
mitochondrial function, leading to
(TKIs)
cardiomyocyte apoptosis.
Recent findings have revealed that immune checkpoint
Immune Checkpoint inhibitors not only enhance anti-tumor immunity but also
Inhibitors may induce myocarditis, arrhythmias, and other
immune-related cardiac events.
Anti-Angiogenic Drugs Inducing microvascular rarefaction, reducing myocardial
(anti-VEGF) capillary density, and impairing cardiac perfusion.
Anti-Angiogenic Drugs
Safer than anti-VEGF.
(anti-PIGF)

• Oxidative Stress: Cardiac myocytes are similarly damaged by oxidative damage from
the generation of reactive oxygen species and free radicals by anthracyclines [24].
• Mitochondrial Dysfunction: These drugs could influence their mitochondrial function
and, thus, energy production in the cardiomyocytes [24].
• DNA Damage: Anthracyclines may intercalate into DNA synthesis, causing breaks
and inhibition of DNA repair mechanisms [24].
Additionally, genome editing, which enables precise and highly reproducible genome
manipulation, has enabled the study of disease genetics and pathogenesis, and the devel-
opment of targeted human therapeutics.
• Calcium Dysregulation: Chemotherapy with anthracyclines can affect calcium home-
ostasis, causing cardiac contractility [24].
• Apoptosis Induction: Programmed cell death can be triggered in cardiomyocytes by
anthracyclines [24].
Other drugs have different molecular mechanisms of cardiotoxicity, as follows:
• Tyrosine kinase inhibitors: tyrosine kinase inhibitors can disrupt important normal
cellular signaling pathways needed for cardiac function [25]. Imatinib, for example,
inhibits the BCR-ABL tyrosine kinase and other kinases, including c-Abl, which
play crucial roles in cardiac function. Inhibition of c-Abl can disrupt mitochondrial
integrity and function, leading to cardiomyocyte apoptosis and subsequent cardiac
dysfunction [26].
Additionally, imatinib has been shown to induce endoplasmic reticulum (ER) stress
and inflammation in cardiomyocytes, further contributing to its cardiotoxic effects [27].
Medicina 2025, 61, 709 6 of 21

Moreover, imatinib can interfere with autophagic processes by accumulating in lyso-

somes and blocking the fusion of autophagosomes and lysosomes, resulting in impaired
cellular homeostasis and cardiotoxicity [28].
• Immune checkpoint inhibitors: Another notable class of antitumoral drugs, immune
checkpoint inhibitors (ICIs), specifically inhibitors of anticytotoxic T-lymphocyte asso-
ciated antigen 4 and anti-PD/PD-L1 (anti-programmed death receptor and receptor
ligand-1), are the mainstay of treatment for many malignancies. The mechanism of
immune-related adverse events is mainly related to the aberrant activity of autoreactive
T cells, which leads to autoimmune inflammatory reactions affecting both on-target
and off-target organs [29]. Immune-related adverse events have variable presenta-
tions, ranging from asymptomatic laboratory findings to fulminant life-threatening
diseases. There are specific guidelines for treating these immune-related adverse
events, depending on the severity of toxicity (graded from 1 to 4) [30].
These ICIs refer to specialized monoclonal antibodies that have the ability to boost
the body’s immune response against cancer by interfering with immune system regulators
known as down-regulators. These down-regulators include PD-1 and CTLA-4, as well as their
associated ligand, PD-L1. By blocking these immune checkpoints, ICIs effectively unleash the
activity of effector T-cells, thus facilitating a more robust anti-tumor response. When T-cells are
activated, the CTLA-4 activation occurs. Activated T-cells and a specific subgroup of CD25+
CD4+ T-cells known as T-regulatory (T-reg) cells both exhibit the presence of CTLA-4. Being a
member of the immunoglobulin supergene family, CTLA-4 shares about 30% similarity with
CD28. The affinity and avidity of its binding to CD80/86 are significantly greater than that
of CD28. The binding of CTLA-4 to CD80/86 leads to the suppression of T-cell-mediated
immune responses. This occurs through the reduction in IL-2 and IL-2 receptor expression,
ultimately resulting in a decrease in overall immune activity. Additionally, CTLA-4 can also
influence immunity through its impact on T-reg cells [31].
There are distinct differences between the regulation of T cells through the PD-1-
PD-L1 axis and that of CTLA-4. PD-1, a component of the immunoglobulin superfamily,
becomes activated in peripheral T cells and B cells upon stimulation. Its primary role is to
maintain peripheral tolerance. PD-1 engages with two ligands, namely PD-L1 and PD-L2,
within the peripheral tissues. PD-L1 can be found in B cells, macrophages, T cells, and
dendritic cells when they are in a resting state. The expression of PD-L2 is uncommon in
quiescent immune cells; however, pro-inflammatory cytokines can stimulate its synthesis.
The activation of both PD-1 and CTLA-4 pathways ultimately impacts the Akt signaling
pathway, however, the specific pathways and outcomes of antibody inhibition vary. Akt,
also known as protein kinase B (PKB), plays a pivotal role in regulating important cellular
functions, including metabolism, programmed cell death (apoptosis), and cell proliferation.
The CD28 binding in T cells induces the activation of phosphatidylinositol 3-kinase (PI3K),
which then associates with Akt, leading to its phosphorylation. While PD-1 signaling
directly counteracts PI3K, CTLA-4 exerts its effects through the activation of PP2A, a
phosphatase. Overall, these findings serve to emphasize the distinctions in the effects of
anti-PD-1/PD-L1 and anti-CTLA-4 antibodies on T cells in relation to their activation stage,
downstream pathways engaged, and site of action.
Currently, the FDA has granted approval to numerous ICIs for the management
of diverse forms of cancer. These include ipilimumab (anti-CTLA-4), nivolumab, pem-
brolizumab, and cemiplimab (anti-PD-1), as well as avelumab, atezolizumab, and durval-
umab (anti-PD-L1). With the ability to hinder the interactions between PD-L1 and PD-L2,
anti-PD-1 agents hold promise. However, it has been noted that specific anti-PD-1 and
anti-PD-L1 agents exhibit variations in terms of autoimmune toxicity. Numerous studies
Medicina 2025, 61, 709 7 of 21

have unequivocally shown that the efficacy of a PD-1 blockade and a PD-L1 blockade in
diminishing tumor growth is essentially identical.
The most alarming side effect of ICIs is the occurrence of myocarditis [8]. Vascular
dysfunction, hypertension, and thromboembolism can also occur.
• Anti-angiogenic drugs: another class of anti-tumoral drugs, called anti-angiogenic drugs,
particularly those targeting the vascular endothelial growth factor (VEGF) pathway, have
been instrumental in cancer therapy but are associated with cardiotoxic effects through
various mechanisms. Inhibition of VEGF signaling can lead to hypertension, as VEGF
plays a crucial role in maintaining endothelial function and nitric oxide production; its
inhibition results in vasoconstriction and elevated blood pressure [32].
Additionally, VEGF inhibitors can cause left ventricular dysfunction and heart failure
by inducing microvascular rarefaction, reducing myocardial capillary density, and impair-
ing cardiac perfusion. Furthermore, these agents may promote thromboembolic events due
to endothelial dysfunction and a pro-coagulant state [33].
In contrast, drugs from the same class targeting the placental growth factor (PlGF)
pathway may exhibit a different cardiotoxicity profile. PlGF is involved in pathological
angiogenesis, and its inhibition has been explored as a therapeutic strategy with potentially
fewer cardiovascular side effects. Studies suggest that anti-PlGF therapies might avoid
some of the hypertension and thrombotic complications associated with VEGF inhibition,
as PlGF is less involved in maintaining normal vascular homeostasis. However, compre-
hensive clinical data are limited, and further research is necessary to fully elucidate the
cardiovascular safety profile of anti-PlGF therapies [34].

2.3.2. Types of Cardiotoxicity

Cardiotoxicity is a monumental problem in the treatment of cancer because many
cancer drugs can have adverse effects on the heart. Cardiotoxicity can vary considerably de-
pending on the type of drug and the patient factors involved as well as on the mechanisms,
timing, and types of disease [35] (Table 2).

Table 2. Summary of Oncology Drug-Induced Cardiotoxicity Types.

Type of Common Oncology Drugs Potential Long-Term

Description
Cardiotoxicity Involved Effects
Left Ventricular Anthracyclines (e.g.,
Progressive decline in heart’s Chronic heart failure,
Dysfunction and doxorubicin), Anti-HER2
ability to pump blood effectively. reduced ejection fraction.
Heart Failure agents (trastuzumab).
Tyrosine kinase inhibitors Increased risk of sudden
Irregular heartbeats, which may
Arrhythmias (TKIs), Immune checkpoint cardiac events, atrial
be benign or life-threatening.
inhibitors. fibrillation.
Reduced blood flow to the heart Coronary artery disease,
Myocardial Fluoropyrimidines (e.g.,
muscle, leading to chest pain and increased risk of heart
Ischemia 5-FU), VEGF inhibitors.
infarction. attacks.
Elevated blood pressure due to VEGF inhibitors, certain Increased risk of stroke and
Hypertension
vascular dysfunction. TKIs. heart failure.
Formation of blood clots that can Pulmonary embolism,
VEGF inhibitors,
Thromboembolism lead to deep vein thrombosis or increased cardiovascular
Immunotherapy agents.
pulmonary embolism. mortality.
Inflammation or fluid Radiation therapy, certain Pericardial effusion,
Pericardial Disease
accumulation around the heart. targeted therapies. chronic pericarditis.
Medicina 2025, 61, 709 8 of 21

• Left Ventricular Dysfunction and Heart Failure: This is the most prevalent and known
manifestation, shared with anthracyclines (and some targeted therapies) [24,25].
• Arrhythmias: General chemotherapeutics can affect the complex rhythms, from benign
to life-threatening [25].
• Myocardial Ischemia: For example, fluoropyrimidines can induce coronary vasospasm,
resulting in ischemia [25].
• Hypertension: VEGF inhibitors have specifically been shown to exacerbate (or in some
cases, cause) hypertension [25].
• Thromboembolism: Some chemotherapies are associated with an increased risk of
thromboembolic events [25].
Pericardial Disease: Pericarditis or pericardial effusion [25] also from certain drugs.

2.4. Acute vs. Chronic Cardiotoxicity

The timing of cardiotoxicity onset is an important consideration in cancer treatment.

2.4.1. Acute Cardiotoxicity

Acute cardiotoxicity occurs during or shortly after treatment (within 2 weeks) [24].
It usually manifests as transient arrhythmias, pericarditis, or acute left ventricular
dysfunction [24]. Most are usually reversible and not dose dependent [24]. It is also notable
that anthracyclines can be seen with immediate effects like arrhythmias or myocarditis [36].

2.4.2. Chronic Cardiotoxicity

Chronic cardiotoxicity may be further divided into early onset (<1 year) and late onset
(>1 year after treatment). The most common form is early onset chronic cardiotoxicity,
typically dilated cardiomyopathy [24]. Late-onset can occur years or even decades after
the treatment is complete [24]. The irreversible complications often concur with a poorer
prognosis [24], especially for anthracyclines [24], where the effect is dose-dependent.
Recent findings are challenging traditional classification of the acute, early on chronic,
and late on chronic cardiotoxicity. According to these researchers, anthracycline-induced
cardiotoxicity may now be viewed as a continuum from subclinical myocardial cell injury
to asymptomatic left ventricular dysfunction to symptomatic heart failure if unidentified
untreated [24].

2.5. Immediate Effects Versus Long-Term Consequences

Cardiotoxicity induced by oncology drugs is complex and polyphasic, combining
immediate effects and long-term consequences.

2.6. Cardiotoxicity Pathways

Oncology drugs can cause cardiotoxicity through various mechanisms:
• Oxidative Stress: Reactive oxygen species (ROS) produced by many chemotherapeutic
agents (e.g., anthracyclines) have been shown to damage cellular components (pro-
teins, lipids, DNA). Cardiomyocyte death can result from this oxidative stress and a
malfunctioning mitochondrial system [24].
• Mitochondrial Dysfunction: Anthracyclines are used as drugs that directly impair
mitochondrial function to reduce energy production in cardiomyocytes closing cellular
dysfunction or death [24].
• DNA Damage: Anthracyclines are drugs which intercalate with DNA and create
breaks in the DNA, disturbing DNA repair mechanisms. Apoptosis or senescence of
cardiac cells [27].
Medicina 2025, 61, 709 9 of 21

• Calcium Homeostasis Disruption: Chemotherapeutics can alter calcium handling in

cardiomyocytes, thus reducing contractility and potentially causing arrhythmias [22].
• Vascular Toxicity: Consequently, certain targeted therapies such as VEGF inhibitors
may lead to endothelial dysfunction and indeed hypertension, in turn affecting cardiac
function [37].
• Immune-Mediated Damage: Immune mediated myocarditis downstream of immune
checkpoint inhibitors may result in severe cardiac complications [37].
All of these will be elaborated in their own specific paragraph.

2.6.1. Short-Term vs. Long-Term Consequences

The cardiotoxic effects of oncology drugs can be categorized into immediate effects
and long-term consequences.

2.6.2. Short Term Effects

1. Acute Arrhythmias: Some drugs, such as anthracyclines, can provoke immediate
rhythm disturbances, from benign to lethal [22].
2. Acute Left Ventricular Dysfunction: The activity can occur shortly after or during
treatment, and tends to reverse when the drug is discontinued [24].
3. Myocarditis: Acute myocarditis has been particularly associated with immune check-
point inhibitors and appears as early as weeks after treatment initiation [37].
4. Acute Hypertension: Hypertension related to VEGF inhibitors can occur rapidly and
may need to be managed immediately [37].

2.6.3. Long-Term Consequences

Chronic Cardiomyopathy: Left ventricular function can progress to heart failure, many
years after the end of treatment in the setting of progressive degeneration (anthracyclines
or some targeted therapies) [22,24].
Accelerated Coronary Artery Disease: In some cases, the therapies may in fact acceler-
ate atherosclerosis and increase the long-term risk for coronary events [22].
Valvular Heart Disease: Radiation therapy in combination with chemotherapy tend to
cause progressive valvular dysfunction over time [22].
Subclinical Cardiac Dysfunction: Long-term survivors may have subclinical cardiac
abnormalities leading to future cardiovascular events and with or without overt clinical
symptoms [24].
Secondary Cardiovascular Risk Factors: Long-term cardiovascular risk to Cancer
survivors may be further increased by metabolic abnormalities (e.g., hypertension, dyslipi-
demia) [19].

2.7. Reversible vs. Irreversible Cardiotoxicity

Historically, cardiotoxicity has often been categorized into two main types:
1. Type I (Irreversible): This type had typically been linked with anthracyclines, and was
thought to have caused permanent cardiac damage. Traditionally, cardiac dysfunction
previously believed to be basically irreversible and having a poor prognosis [38].
2. Type II (Reversible): This type was often linked to targeted therapies such as
trastuzumab (anti-HER2 receptor monoclonal antibody) and was often reversible
with discontinuation of the drug with recovery of cardiac function to normal [38].

2.8. Recovery in Anthracycline Induced Cardiotoxicity

Unlike earlier beliefs, anthracycline-induced cardiotoxicity is not always irreversible. The
potential for recovery appears to be closely tied to early detection and prompt intervention:
Medicina 2025, 61, 709 10 of 21

1. Time-Dependent Recovery: An inverse relationship between the time of heart failure

therapy initiation versus improvement of left ventricular ejection fraction (LVEF) was
seen in a study of 201 patients with anthracycline-induced cardiotoxicity. Recovery
of the LVEF at 2 months following completion of chemotherapy was 64%, while for
those beyond 6 months, recovery was significantly reduced [24,38,39].
2. Early Intervention: There have been promising results (close monitoring of LVEF post-
chemotherapy combined with early treatment with ACE inhibitors and beta-blockers)
in LVEF after chemotherapy. When treated early, 82% of patients with cardiotoxicity
achieve normalization of cardiac function in large study (n = 2625). However, only
11% of these patients regained their baseline LVEF [24,38,39], but it is likely that some
degree of permanent damage remains.

2.9. Long Term Consequences of Permanent Damage

Despite the potential for recovery, some degree of permanent cardiac damage may
persist, as follows:
1. Subclinical Damage: Despite normalization of LVEF, subclinical cardiac abnormalities
may persist and continue to be at risk of future cardiovascular events [38].
2. Late-Onset Cardiotoxicity: This could mean patients may develop cardiac dysfunction
years or decades even after treatment completion, that initial damage can progress
overtime [24,38,39].

2.10. Other Oncology Drugs: Reversibility

The concept of reversibility extends beyond anthracyclines:
1. Tyrosine Kinase Inhibitors: This drug related cardiotoxicity may be partially reversible
with drug discontinuation or dose reduction [23].
2. Proteasome Inhibitors: The cardiotoxicity of carfilzomib appears to be largely re-
versible with treatment cessation [23].

2.11. Implications for Management

Understanding the potential for reversibility has important implications for pa-
tient management:
1. Early Detection: Monitoring of the heart at regular intervals either during or following
cancer treatment identifies changes before they become symptomatic heart failure [24,38,39].
2. Prompt Intervention: Because of this, the early initiation of cardioprotective therapies,
e.g., ACE inhibitors or beta blockers, reduces mortality and improves the likelihood
of cardiac function recovery [24,38,39].
3. Long-Term Follow-Up: Due to the possibility of late onset cardiotoxicity, cancer
survivors require long term cardiac surveillance [24,38,39].

2.12. Molecular Mechanisms

The cardiotoxicity of oncology drugs is an enormously complex process with oxidative
stress, inflammation, and cytokine involvement having been shown to be important in
inducing cardiac dysfunction. Awareness of these processes is critical to devising strategies
to avert and control cardiac problems in cancer patients [40].
Cardiotoxicity is a diverse and often drug specific phenomenon with known molecular
mechanisms. For anthracyclines, one of the most well-studied cardiotoxic agents, several
key mechanisms have been identified, as follows:
1. Topoisomerase 2β (Top2β) inhibition: Anthracyclines in cardiomyocytes bind to
Top2β and produce DNA double strand breaks, mitochondrial dysfunction, and cell
death [23,24].
Medicina 2025, 61, 709 11 of 21

2. Mitochondrial dysfunction: anthracyclines induce an effect on mitochondrial function

which disrupts energy production and increases oxidative stress [23,24].
3. Calcium dysregulation: Oncology drugs may interfere with calcium homeostasis, with
deleterious effects on cardiac contractility or through provoking arrhythmias [24].
4. DNA damage: The apoptosis or senescence of cardiomyocytes can be direct or indirect
due to DNA damage [23].

2.13. Role of Oxidative Stress and Inflammation

Oxidative stress plays a central role in the cardiotoxicity of many oncology drugs,
particularly anthracyclines:
1. ROS generation: Anthracyclines can redox the cycle, and hence generate ROS that
damaged cellular components [23,24].
2. Antioxidant depletion: Depletions of cellular antioxidant defenses by cancer treat-
ments can exacerbate oxidative damage [22,23].
3. Lipid peroxidation: Damage of cellular membranes, including those of mitochon-
dria [24], can be caused by ROS induced lipid peroxidation.
4. Iron-mediated damage: One group of drugs does not tolerate being around iron, as
anthracyclines can bind to iron and generate highly reactive hydroxyl radicals in the
presence of oxygen [24].

2.14. Inflammation and Cytokine Involvement in Cardiac Dysfunction

Inflammation and cytokine signaling contribute significantly to cardiac dysfunction in
cancer therapy:
1. Pro-inflammatory cytokine release: Pro-inflammatory cytokines such as TNF-α, IL-1β,
and IL-6 can be released by cancer treatments directly impairing cardiac function [22,23].
2. NF-κB activation: Oncology drugs that activate NF-κB signaling induce inflammation,
and may cause cardiac remodeling [23].
3. Immune cell infiltration: Myocarditis was recently reported as a consequence of
some immune checkpoint therapy, including immune cell infiltration into the heart
(myocardium) [22].
4. Vascular inflammation: VEGF inhibitors, for example, cause endothelial dysfunction
and vascular inflammation (indirectly affecting cardiac function) [22,23].
5. Cytokine-induced contractile dysfunction: Direct cardiomyocyte contractility can
be directly impaired by pro-inflammatory cytokines through various mechanisms,
including alterations in calcium handling [22].
6. Fibrosis promotion: Both chronic inflammation and some cytokines promote cardiac
fibrosis with long-term cardiac dysfunction [22,23].
The interplay between these mechanisms produces a rich landscape of cardiotoxicity.
Inflammation is capable of causing severe oxidative stress, aggravating the situation. After
cessation of the cancer therapy, this vicious cycle can result in progressive cardiac damage.
Understanding these molecular mechanisms has important implications for preven-
tion and treatment strategies. This has included failed attempts aimed at cardiovascular
protection with antioxidants or anti-inflammatory agents. Top2β’s role as a causative agent
in anthracycline-induced cardiotoxicity has led to the development of Top2α selective
drugs with retained anticancer activity, but reduced cardiac side effects [41].

2.15. Risk Factors for Cardiotoxicity

In general, patient-specific and drug-specific risk factors for cardiotoxicity can be
grouped. This is important for knowing which patients are at high risk and how to monitor
them and prevent problems.
Medicina 2025, 61, 709 12 of 21

2.15.1. Patient-Specific Factors

Cardiotoxicity is a major risk factor for age. Patients with cancer are most susceptible
to the cardiotoxic effects of cancer therapies, and these patients tend to be older. In
a study of 5445 patients receiving anthracyclines, the age > 65 years was shown to be
independently associated with cardiotoxicity [24]. Cardiotoxicity is much more likely if
you already have pre-existing cardiovascular conditions. These patients are at high risk
of developing ischemic heart disease and infarction, specifically those with hypertension,
coronary artery disease, or preexisting left ventricular dysfunction. A meta-analysis of
6647 patients showed that patients with pre-existent cardiovascular disease were 2.4 times
more at risk of cardiotoxicity [23].
Individual susceptibility to cardiotoxicity is highly determined by genetic predis-
positions. Various genetic polymorphisms that might enhance the risk of anthracycline
cardiotoxicity have been characterized. For instance, increased risk [22] has been found
to be associated with variants in the NADPH oxidase and doxorubicin efflux transporter
genes. Specific single nucleotide polymorphisms (SNPs) in the CELF4 gene were implicated
in a 2977 patient study as a predictor of anthracycline-induced cardiotoxicity [22].
Other patient-specific factors include female sex, obesity, and previous or concurrent
radiation therapy to the chest. A review of 18 studies of 49,017 patients found a 1.5 fold
increased risk of cardiotoxicity with the female sex [39]. Radiation-induced cardiovascular
disease is an increasing concern in long-term survivors of breast cancer, lymphoma, and
other malignancies who received chest-directed radiation [42]. The fibrosis caused by
radiation therapy holds the potential to cause coronary artery disease, valvular disease,
cardiomyopathies, arrhythmias as well as pericardial diseases, but rarely, these can be
related to radiation therapy as the root cause [43].

2.15.2. Drug-Specific Factors

Cardiotoxic risk is, in large part, a function of drugs. Cardiotoxicity associated with
anthracyclines is the highest risk. The incidence of clinical heart failure for cumulative
anthracycline dose varied from 5% to 48% in a large meta-analysis [44].
Anthracyclines are dose-limiting. With higher cumulative doses, cardiotoxicity risk
is greatly increased. In accrual to doxorubicin, if cumulative doses above 400 mg/m2 are
exceeded, the risk increases from 3 to 5% to 18 to 48% [45]. Based upon this dose dependence,
recommended maximum cumulative doses of anthracyclines have been established.
Cardiotoxicity risk is also influenced by treatment duration and schedule. The longer
you are exposed to cardiotoxic agents, the more likely your heart is to be damaged. Further-
more, the speed of administration of the drug can play a role in risk. For instance, slower
rates of infusion of anthracyclines decrease the risk of cardiotoxicity when compared to
bolus administration [21].
The risk of cardiotoxicity is greatly increased by combination therapies. For example,
anthracyclines in combination with trastuzumab (anti-HER2 receptor monoclonal antibody)
have shown higher rates of cardiac dysfunction than the agent alone. Anthracyclines with
trastuzumab were associated with 27% increased risk of cardiac events compared with
anthracyclines alone and 3–7% increased risk with trastuzumab alone.
The time when drugs are given in relation to other therapies can also affect risk. For
instance, the co-administration of anthracyclines and radiation therapy to the chest has
been found to be more hazardous to the heart than sequentially.
Medicina 2025, 61, 709 13 of 21

2.16. Clinical Manifestations

Symptoms and Diagnosis
Oncology drugs can cause cardiotoxicity, which can present as asymptomatic car-
diac dysfunction or even severe, life-threatening cardiotoxicity. Cardiotoxicity manifests
clinically with a variety of manifestations, some of which affect any component of the
cardiovascular system.
Common symptoms of cardiotoxicity include the following:
1. Arrhythmias: Cardiac rhythm disturbances can be benign or potentially even fa-
tal. They may include atrial fibrillation, ventricular tachycardia, and QT interval
prolongation [23]. There may be palpitations, dizziness, or syncope.
2. Heart Failure: This is one of the most serious manifestations of cardiotoxicity. Exer-
tional dyspnea, fatigue, peripheral edema, and reduced exercise tolerance [24] are
symptoms of the disease. In severe cases patients may go as far as to develop acute
pulmonary edema or cardiogenic shock.
3. Decreased Cardiac Function: This can be the first sign of cardiotoxicity, with an
asymptomatic descent in left ventricular ejection fraction (LVEF). Left untreated, this
can progress to symptomatic heart failure [22].
4. Myocardial Ischemia: Coronary vasospasm can occur, causing chest pain with chronic
coronary syndrome or acute coronary syndrome in some oncology drugs, particularly
fluoropyrimidines [23].
5. Hypertension: It is known that certain targeted therapies, notably vascular endothelial
growth factor (VEGF) inhibitors, have caused or exacerbated hypertension [21].
6. Thromboembolism: Thromboembolic events such as deep vein thrombosis or pul-
monary embolism [23] are increased by some chemotherapies.
Diagnosis of cardiotoxicity relies on a combination of clinical assessment, imaging
studies, and biomarker analysis such as the following:
1. Echocardiography: the cornerstone of cardiac assessment of cancer patients. It enables
the measurement of the LVEF, the most common parameter used to characterize
cardiotoxicity. Cardiotoxicity is diagnosed when a LVEF (typically defined as <50%
absolute decrease, usually >10 percentage points) is observed to decrease from >50%
to <50% [22]. In particular, more advanced echocardiographic techniques such as
global longitudinal strain (GLS) may detect subclinical cardiac dysfunction prior to a
drop in LVEF [24].
2. Biomarkers: Troponins (troponin I and T) are highly sensitive, specific markers of
myocardial injury. When episodes of elevated troponin were associated with an
increased risk of subsequent cardiac dysfunction, such episodes had been reported
during cancer therapy [46]. Both cardiac stress markers (BNP and NT-pro BNP) have
also been shown to have utility in predicting and diagnosing cardiotoxicity [24].
3. Other Imaging Modalities: Cardiac MRI is useful for the detailed assessment of
cardiac structure and function, and particularly to assess for myocarditis, a potential
complication of immune checkpoint inhibitors [21]. Advanced techniques such as
cardiac MRI have emerged as valuable in detecting subclinical cardiotoxicity while
emerging biomarkers like specific microRNAs are under investigation for earlier
detection. Cardiac function may also be assessed, and early cardiotoxicity is recorded
with use of nuclear imaging techniques [47].
4. Electrocardiogram (ECG): This is not specific to cardiotoxicity but can reveal arrhyth-
mias and conduction abnormalities that may be due to cardiac injury.
Medicina 2025, 61, 709 14 of 21

5. Endomyocardial Biopsy: It is rarely used, although it can offer definitive proof of

cardiotoxicity treatment, particularly where the diagnosis cannot be otherwise deter-
mined [21].
The clinical manifestations and diagnosis of cardiotoxicity are often variable and
potentially have a late onset. Cardiotoxicity can develop while some patients are treated,
and others are asymptomatic even years after therapy is complete. This underscores the
need for long-term cardiac surveillance in cancer survivors [22].
The important point is that cardiotoxicity needs to be detected early in order to have a
chance of stopping progression towards irreversible cardiac damage. An optimal balance
between the early diagnosis and monitoring of cardiotoxicity in cancer patients is optimally
identified by the use of a multimodal approach that includes regular clinical assessment,
imaging studies, and biomarker analysis [24,46].

2.17. Long-Term Consequences

Certain oncology drugs, unfortunately, can be cardiotoxic with significant long-term
consequences for cancer survivors, subsequently having to transition to a risk of cardiovas-
cular disease well into the post-treatment phase.

2.17.1. Impact on Survivors’ Quality of Life

Long term challenges for survivors of cancer with cardiotoxicity are common and
often impact daily life. In a cross-sectional case–control study involving 42 breast cancer
survivors, those who had experienced cardiotoxicity during treatment had significantly
lower left ventricular ejection fraction, global longitudinal strain, and peak oxygen con-
sumption compared with those with and without cardiotoxicity and healthy controls [48].
The cardiotoxicity group had a mean peak oxygen consumption that was 15% lower vs. the
non-cardiotoxicity group and 25% lower vs. healthy controls [48]. Reduction in survivors’
ability to perform daily activities and exercise and increase in a decreased quality of life is
a result of this reduction in cardiopulmonary function.
Cardiotoxicity has long-term lasting effects that persist for years after completion of
treatment. This evidence was taken from the aforementioned study, the median time of
therapy was approximately 7 years, indicating the cardiopulmonary impairments observed
are not transient, but rather can be long lasting [48]. This prolonged impact on physical
function may contribute to increased fatigue, reduced exercise capacity, and work and
social activities limitations, all of which negatively affect a survivor’s overall quality of life.

2.17.2. Increased Risk of Cardiovascular Diseases Post-Treatment

Cancer survivors who have experienced cardiotoxicity as a complication of cancer
treatment are at an increased risk of developing cardiovascular diseases in the years after
said cancer treatment. Cellular and interstitial changes occur in the heart, caused by car-
diotoxic agents such as anthracyclines [44]. These changes fall under chronic cardiotoxicity,
which appears years after the end of treatment [44].
Whether the risk of late-onset cardiotoxicity is high is of particular concern. Acute
cardiotoxicity, though often transitory and generally dose-independent, is contrasted by
chronic cardiotoxicity, which can result in severe cardiomyopathy and even death [44].
Ventricular systolic or diastolic dysfunction is the most characteristic manifestation of
chronic cardiotoxicity that can evolve to heart failure [44].
However, there were no differences in cardiovascular outcomes after six years, al-
though those treated with potentially cardiotoxic therapies had a significantly higher risk of
cardiovascular events compared to the general population. Even years after ceasing cancer
Medicina 2025, 61, 709 15 of 21

treatment, this increased risk persisted, proving the need for long term cardiovascular
monitoring in cancer survivors [22].
This increased cardiovascular risk has complex underlying mechanisms. For instance,
anthracyclines have been shown to induce cardiomyocyte death cell non-specifically by means
of apoptosis, autophagy, necrosis, necroptosis, and ferroptosis [22]. Thus, this progressive
loss of cardiomyocytes combines with the heart’s low regenerative capacity, and can result in
ventricular remodeling and increased propensity to cardiovascular diseases [44].

2.18. Management Strategies

Oncology drug-induced cardiotoxicity is a major problem in cancer treatment, there-
fore, a complete management strategy for preventing and treating cardiotoxicity is needed.
Cardiotoxicity management involves a multimodal approach, which involves the principles
of cardio-oncology into cancer care.
Recent advances in cardio-oncology emphasize structured exercise programs and
nutraceutical interventions as additional strategies to mitigate cardiotoxicity. Moreover,
multidisciplinary care models—where oncologists, cardiologists, and rehabilitation special-
ists coordinate treatment—have shown promising results [49].
For symptomatic patients, standard heart failure treatments (ACE inhibitors, beta-
blockers) are used, often in combination with the temporary or permanent discontinuation
of the offending agent.

2.18.1. Preventive Measures

The use of cardioprotective agents is one of the key preventive strategies. The most
tested cardioprotective agent is dexrazoxane in the setting of anthracycline-related car-
diotoxicity. It also works as a free radical chelator, limiting the formation of free radicals
that damage cardiac tissue. In patients with metastatic breast cancer who are expected
to have further anthracycline treatment, dexrazoxane is recommended by the American
Society of Clinical Oncology for those with cumulative doxorubicin dose greater than
300 mg/m2 [45]. Nevertheless, its use is constrained by apprehensions about its potential
interference with antitumor efficacy, although these fears have been receded recently [38].
Early detection of cardiotoxicity depends on monitoring protocols in at risk patients.
These protocols typically include the following:
1. Echocardiography and biomarker assessment (troponin, BNP) [45] baseline cardiac
evaluation before starting potentially cardiotoxic therapy.
2. Left ventricular ejection fraction (LVEF) should be regularly monitored during treat-
ment [50] with the dose depending on the specific drug and patient risks.
3. Subclinical cardiac dysfunction that can be detected before a decline in LVEF [50] and
use of more delicate imaging approaches, such as quantitative global longitudinal
strain (GLS) echocardiography.
4. Some forms of cardiotoxicity may not manifest for up to 15 years after completion of
treatment [45] (Table 3).

Table 3. Preventive Strategies and Treatment Approaches for Cardiotoxicity.

Strategy Description Application

Cardiovascular screening before Identifying high-risk patients based on
Baseline Risk Assessment
initiating cancer therapy. comorbidities, prior cardiac history.
Routine imaging and biomarker Echocardiography (LVEF, GLS), troponin
Regular Cardiac Monitoring
assessment. levels, BNP/NT-proBNP.
Medicina 2025, 61, 709 16 of 21

Table 3. Cont.

Strategy Description Application

Use of ACE inhibitors, beta-blockers, Preventing or mitigating drug-induced
Cardioprotective Medications
and dexrazoxane. cardiotoxicity.
Adjusting dosage, infusion rates, or Reducing peak plasma concentrations of
Modified Drug Administration
drug combinations. cardiotoxic drugs.
Exercise and Lifestyle Structured exercise programs and Improving cardiac resilience and
Interventions dietary interventions. mitigating treatment effects.
Early Intervention and Initiating heart failure treatments at Improving recovery rates and reducing
Treatment the first sign of dysfunction. progression to irreversible damage.
Multidisciplinary Close coordination between Optimizing both cancer therapy and
Cardio-Oncology Collaboration oncologists and cardiologists. cardiac protection.

2.18.2. Treatment Approaches: Management of Symptomatic Patients

Management of symptomatic patients with cardiotoxicity often follows standard heart
failure treatment guidelines, with some modifications:
1. For patients with reduced LVEF, the first line of treatment is with ACE inhibitors or
angiotensin receptor blockers, and some evidence suggests that the drugs may also
have a preventive benefit if used early in cancer treatment [38].
2. The antioxidant properties of beta-blockers, particularly carvedilol, have been shown
to be useful both as a preventative as well as a treatment for chemotherapy-induced
cardiotoxicity [38].
3. Referrals to cardiology services are made for patients with severe heart failure where
temporary or permanent discontinuation of cardiotoxic agents may be necessary in
collaboration with an oncology and cardiology team [50].

2.18.3. Integration of Cardio-Oncology Principles in Cancer Care

Participation in cardio-oncology is essential for the effective management of cardiotox-
icity within cancer care. This includes the following:
1. The importance of early screening for cardiovascular risk factors before initiating can-
cer therapy, taking into account cardiac risk factors, including potential cardiotoxicity
of planned therapies [45].
2. Minimizing cardiovascular risk in cancer treatment regimes without compromising
the oncological efficacy. This may use less cardiotoxic alternatives or modified dosing
schedules [50].
3. Cardio-protective strategies, including exercise programs and control of cardiotoxicity
risk factors [38].
4. The use of cardioprotective strategies, including ACE inhibitors, beta-blockers, and
exercise programs.
5. Facilitation of communication between oncologists and cardiologists in the creation
of multidisciplinary cardio oncology teams to coordinate care for a patient during the
cancer treatment journey [45].
6. Survivorship care plans that include long-term cardiovascular monitoring and man-
agement strategies for cancer survivors [50], allows survivors to receive the right
cancer treatment especially, long-term cardiovascular monitoring and management
strategies. Long-term follow-up and survivorship care plans for cancer survivors at
high risk of late-onset cardiotoxicity require the constant monitoring of patients.
Medicina 2025, 61, 709 17 of 21

2.19. Future Directions

Cardio-oncology is an extremely new field of study that is progressing rapidly, and
there is ongoing study to fill the significant gaps in our knowledge of oncology drug
induced cardiotoxicity. Ongoing research is exploring the mechanisms, genetic risk factors,
and novel therapies to better predict and prevent cardiotoxicity. The integration of artificial
intelligence and machine learning for risk prediction is a promising avenue that could refine
early detection and personalized treatment strategies. Additionally, regenerative medicine
approaches—such as stem cell therapies—are being investigated to repair long-term cardiac
damage. Further studies on adjunct therapies, including advanced nutraceuticals and
exercise interventions, are also warranted.

2.19.1. Gaps in Understanding Mechanisms and Risk Factors

For many of these oncology drugs, those important gaps in our understanding of the
precise mechanisms of cardiotoxicity remain despite significant advances. For example,
the activity of topoisomerase 2β (Top2β) in anthracycline induced cardiotoxicity is well
documented, but not the mechanisms of cardiotoxicity of newer targeted therapies [23].
Much research is currently devoted to the identification of genetic and molecular
biomarkers that are useful for predicting individual susceptibility to cardiotoxicity. Al-
though several genetic polymorphisms for increased risk of anthracycline induced car-
diotoxicity have been identified [22], the clinical utility of these polymorphisms has yet to
be established. Future research should be directed at ensuring that high risk patients are
identified more accurately through the construction of complete predictive risk models
based on genetic, molecular and clinical risk factors [51].

2.19.2. Importance of Personalized Medicine in Oncology

Personalized medicine appears to be coming of age in cardio-oncology. Flipping
this around, cancer treatments could be tailored to factors that influence both efficacy
and cardiotoxicity in each individual patient: genetic profile, preexisting cardiovascular
risk factors, and tumor biology, reducing cardiotoxicity plus maximizing efficacy [23]. To
develop personalized risk assessment and treatment strategies, this approach needs to
integrate multi-omics data (genomics, proteomics, metabolomics) into clinical information.
The development of precision cardio-oncology approaches may involve the following:
1. Testing of patients at higher risk for cardiotoxicity, using pharmacogenomic testing.
2. Individual risk-based monitoring protocols.
3. Targeted cardioprotective agents use, such as dexrazoxane, and personalized cardio-
protective strategies.
4. Balanced oncological efficacy and cardiovascular risk for individualized cancer treat-
ment regimens.

2.19.3. Innovative Therapies

The key research involves inventing new drugs with reduced cardiotoxic profiles.
A highly promising strategy is to design anthracycline analogs selective for Top2α (the
sole target in cancer cells) and inducing the minimum level of Top2β (the promoter of
cardiotoxicity) [23]. Targeted approaches of this nature, however, could maintain anti-tumor
efficacy while minimizing cardiac side effects.

2.19.4. Development of New Drugs with Reduced Cardiotoxic Profiles

The development of another innovative direction has been the exploration of drug
delivery systems based on nanotechnology. We have identified anthracycline liposomal
formulations as a promising example of delivery vector modulations that can preserve
Medicina 2025, 61, 709 18 of 21

anti-tumor efficacy but reduce cardiotoxicity [2]. Future research into nanoparticle-based
delivery systems may enhance targeting of anticancer drug delivery, minimizing cardiac
tissue exposure to toxic agents [52].

2.19.5. Exploration of Adjunct Therapies to Mitigate Cardiac Risks

Active research also examines adjunct therapies that will help reduce cardiac risks.
These include the following:
1. Cardioprotective agents: Researchers are also studying other potential cardioprotec-
tive agents, such as antioxidants, iron chelators and modulators of cellular signaling
pathways that have been implicated as sources of toxicity [53].
2. Exercise interventions: Evidence is emerging for cardio protection associated with
structured exercise programs during cancer treatment. More research is needed to
find out how to best optimize exercise and who is best likely to benefit [23].
3. Nutraceuticals and dietary interventions: Other studies have attempted to minimize
the cardiotoxicity potential of nutraceuticals (such as coenzyme Q10 and L-carnitine).
Although preliminary results are promising, larger clinical trials are required to
establish efficacy and safety [54].
4. Cell-based therapies: Cardiac tissue damaged by cancer treatments is being inves-
tigated to repair and regenerate through stem cell therapies and exosome-based
approaches [55].

3. Discussion
Analyzing the above-mentioned clinical studies, it can be stated that cardiotoxicity
rates vary greatly across different agents. Nearly 25% of all cancer patients may experience
some form of cardiotoxicity, and the risk of cardiac mortality for pediatric cancer survivors
is eightfold greater than in the general population. The need for cardiovascular monitoring
both during and after cancer treatment is underscored.
The management of cardiotoxicity is dependent on the close collaboration of on-
cologists and cardiologists, and patients are frequently not referred to cardiology until
symptoms have arisen. The reason that only 15% were referred prior to chemotherapy
suggests a considerable decrease in preventive care. Cancer therapies have, however,
progressed: survival rates have improved-up from 50% in the 1970s to 67% in recent years,
but these treatments come at a price-all, leading to long-term quality of life issues, such as
fatigue, pain, and cognitive problems.
Interestingly, early detection and intervention for anthracycline-induced cardiotox-
icity is not always irreversible, and cardiac function can be recovered. Timely treatment
improves heart function in many suspected patients. But factors such as age, pre-existing
cardiovascular conditions, and genetic grounds also play a role in who may or may not
be susceptible to cardiotoxicity. To protect patients’ cardiovascular health from cancer
treatment, studies stress the need for ongoing research into these risks and into developing
effective preventative strategies and point towards a new science, “cardio-oncology”, where
the central role is represented by personalized medicine studies.

4. Conclusions
The cardiac toxicity of oncology drugs is a significant issue in the management of
cancer. In addition, the economic burden of cardiotoxicity and the importance of patient
education and shared decision-making should not be overlooked. Potential solutions could
be the integration of cardio-oncology practices, in which oncologists and cardiologists
collaborate to assess heart related risks prior to and during cancer treatment. This joint
work may also result in the creation of new guidelines factoring cardiovascular health into
Medicina 2025, 61, 709 19 of 21

cancer treatment decisions. The novel biomarkers might enable the identification of cardiac
injury upon presentation, allowing for timely intervention. Understanding and using
cardioprotective agents is essential in order to reduce the risk of cardiac injury without
diminishing the efficacy of oncologic therapies. Stem cell therapies can be beneficial in
safeguarding patients from long-term side effects of chemotherapy.
Therefore, it can be concluded that the treatment of oncology patients necessitates a
holistic view of the risks inherent to cancer management, where the key to success will be
the fusion of cardiology and oncology specialties.

Author Contributions: Conceptualization: N.R.K. and V.P., collecting data and resources: V.P. and
V.M., literature analysis and concluding: V.M. and R.B., writing—original draft: N.R.K. and V.P.,
reviewing and editing: D.M.D.-S., I.S.C. and P.D., project administration: N.R.K. and D.M.D.-S. All
authors have read and agreed to the published version of the manuscript.

Funding: We would like to acknowledge “Victor Babes” University Of Medicine And Pharmacy
Timisoara, Romania for their support in covering the publication costs for this review article.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Conflicts of Interest: The authors declare no conflicts of interest.

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