Abstract
Chemotherapy-induced cardiotoxicity represents a
major complication in the care of cancer patients, presenting as systolic
ventricular dysfunction, arrhythmias and myocardial ischemia. While modern
chemotherapy regimens have improved survival rates, cardiovascular adverse
effects may compromise prognosis and quality of life. Definitions of
cardiotoxicity vary but often rely on a ≥10% reduction in left ventricular
ejection fraction (LVEF) or a drop below 53%. Classically, cardiotoxicity is
categorized as acute (within 14 days of treatment), subacute (during treatment)
and late (after one year), with late toxicity being the most prevalent and
often irreversible. Key agents include anthracyclines, with a cumulative risk
of cardiac dysfunction ranging from 5% to 25% depending on the total dose;
anti-HER2 antibodies, which are generally reversible; fluoropyrimidines, linked
to coronary vasospasm; taxanes, which induce arrhythmias; and tyrosine kinase
inhibitors, with a broad spectrum of ventricular damage and hypertension. The
pathophysiology involves free radical generation, myocardial DNA damage,
mitochondrial dysfunction and blockade of the neuregulin/HER signaling pathway.
Early detection relies on high-sensitivity biomarkers and echocardiography with
longitudinal strain, essential to prevent irreversible progression. Guidelines
recommend baseline cardiovascular evaluation, periodic monitoring and
prophylactic use of beta-blockers and ACE inhibitors in cases of subclinical
decline. Management includes discontinuation or modification of treatment,
cardioprotective drugs and cautious reintroduction, balancing risks and
benefits. In conclusion, integrated collaboration between oncologists and
cardiologists is vital to optimize antineoplastic therapy, minimize cardiovascular
morbidity and ensure better long-term outcomes, making early monitoring a
fundamental pillar in modern cancer care.
Keywords: Cardiotoxicity; Chemotherapy; Left ventricular
ejection fraction; Anthracyclines; Cardio-Oncology
Introduction
Recent advances in oncology, particularly the development of
highly effective chemotherapeutic agents, have significantly increased cancer
patient survival. However, there has been a growing incidence of cardiovascular
complications during and after treatment, representing a new clinical and
scientific challenge: chemotherapy-induced cardiotoxicity. This condition is
characterized by changes in cardiac structure and function resulting from the
direct or indirect effects of chemotherapeutic agents, potentially manifesting
as systolic ventricular dysfunction, myocardial ischemia, arrhythmias,
pericarditis, myocarditis and hypertension. Although anthracyclines remain a
cornerstone in the treatment of several tumours, their mechanism of free
radical generation and interference with topoisomerase II-β results in
mitochondrial damage and cellular apoptosis, with a cumulative risk of
dysfunction exceeding 20% at doses above 400 mg/m².
Beyond cardiac effects, chemotherapeutic agents can also
disrupt hormonal balance by altering the function of glands such as the
thyroid, adrenal glands and gonadal axis, justifying a multidisciplinary
approach involving both cardiology and endocrinology in oncologic practice. In
comparison, targeted therapies such as trastuzumab present functional
cardiotoxicity through inhibition of the neuregulin/HER2 pathway, though
reversible in most cases with appropriate cardiovascular measures.
Fluoropyrimidines are notably associated with coronary vasospasm and acute
ischemia, while taxanes and tyrosine kinase inhibitors broaden the range of
adverse manifestations. Consequently, early detection of subclinical changes
using biomarkers and advanced imaging techniques becomes imperative for
preserving cardiac function.
Objectives
This study aims to characterize the definitions,
classifications and mechanisms of chemotherapy-induced cardiotoxicity; identify
risk factors associated with cardiac dysfunction in cancer patients; and assess
strategies for early detection, prevention and management of this adverse
event.
Materials and Methods
A narrative review of the scientific literature was
conducted from January to March 2025 using the PubMed, SciELO, Google Scholar
and ScienceDirect databases. Keywords included “cardiotoxicity,”
“chemotherapy,” “left ventricular ejection fraction,” “cardiac biomarkers,” and
“cancer treatment.” Articles published in the last ten years with proven
clinical relevance were included, while case reports and non-peer-reviewed
publications were excluded.
Discussion
The reviewed studies first highlight the heterogeneity in
definitions of chemotherapy-induced cardiotoxicity, which hampers comparison
between studies and standardization of clinical protocols. Spinelli, et al.1
classify toxicity into three severity grades based on changes in LVEF, while
Medeiros and Wiehe adopt a ≥10% reduction in LVEF to a final value below 53% as
a diagnostic threshold, emphasizing the predictive role of longitudinal strain
detected by speckle-tracking echocardiography. This discrepancy underscores the
need for international consensus to standardize criteria and enable robust
meta-analyses. Regarding pathophysiological mechanisms, Pinto, et al.2 describe
how anthracyclines induce mitochondrial damage and apoptosis via reactive
oxygen species and inhibition of topoisomerase II-β in cardiomyocytes. In
contrast, trastuzumab blocks the neuregulin/HER2 survival pathway and typically
leads to reversible ventricular dysfunction if cardioprotective measures are
promptly applied3. The distinction between type I (irreversible) and type II
(generally reversible) toxicity is crucial for therapeutic decision-making,
such as cautious reintroduction of trastuzumab after LVEF recovery.
Fluoropyrimidines exhibit a unique profile, with coronary
vasospasm and acute ischemia incidence ranging from 1% to 18% depending on
regimen and combination with other cytotoxic agents2. This phenomenon results
from endothelial damage and activation of prothrombotic pathways, requiring
continuous ECG monitoring and immediate drug withdrawal at the first ischemic
sign. Taxanes and tyrosine kinase inhibitors exhibit more diverse toxicities,
including arrhythmias and systemic hypertension, significantly increasing the
risk of severe adverse events, particularly in patients with prior
cardiovascular risk factors such as coronary disease or thoracic radiotherapy3.
Another relevant point is the early detection of subclinical
cardiotoxicity. Boas, et al. report that elevations in high-sensitivity
troponin and 10-15% reductions in global longitudinal strain precede LVEF
decline, creating a therapeutic window for introducing β-blockers and ACE
inhibitors before symptomatic impairment occurs4. This finding supports the
routine inclusion of combined biomarker and imaging protocols, especially in
high-risk patients. Pharmacological prophylaxis has also gained momentum. Spinelli,
et al. and Medeiros and Wiehe report that prior use of β-blockers and
aldosterone antagonists reduces the incidence of ventricular dysfunction1,3,
while Pinto, et al. describe LVEF improvements of up to 10% when these drugs
are introduced at the first sign of subclinical decline2. These findings
support guidelines recommending cardioprotective therapy initiation in patients
showing elevated troponin or reduced strain in the absence of clinical
symptoms.
The implementation of integrated Cardio-Oncology units, as
described by Boas, et al.4, has demonstrated a positive impact on
cardiovascular outcomes without compromising cancer control. In these
multidisciplinary teams, oncologists, cardiologists, nurses and imaging
specialists collaborate to adjust dosages, modify regimens and optimize
interventions, resulting in fewer heart failure admissions and maintenance of
effective anticancer therapy5-9. However, important gaps remain, such as the
lack of randomized prospective trials comparing different surveillance and
cardioprotective strategies, as well as studies exploring new biomarkers and
noninvasive imaging techniques10,11. There is also a lack of data in specific
populations, including the elderly, pediatric patients and individuals with
pre-existing cardiovascular disease. Overall, the current body of evidence
highlights three key pillars for mitigating chemotherapy-induced
cardiotoxicity: (1) standardization of diagnostic criteria; (2) early
surveillance using biomarkers and advanced imaging; and (3) pharmacological
prophylaxis and multidisciplinary management in Cardio-Oncology units. The
integration of these elements may significantly improve event-free survival and
quality of life in patients undergoing chemotherapy12,13. Although the
literature mainly focuses on cardiac dysfunction, there is growing evidence
that chemotherapy also affects the endocrine axis, with reports of
hypogonadism, subclinical hypothyroidism and alterations in the hypothalamic-pituitary
axis. These effects, although less documented, may negatively impact
metabolism, mood and quality of life, warranting periodic hormonal evaluations
in integrated surveillance protocols14,15.
Conclusion
Chemotherapy-associated cardiotoxicity has emerged as a
central challenge at the intersection of oncology and cardiology, requiring a
careful balance between antitumor efficacy and cardiac function preservation.
The variability in diagnostic criteria highlights the need for unified
standards to support clinical decision-making and comparative research.
Moreover, further studies are needed to investigate the hormonal impacts of
chemotherapy in greater depth, advocating for multidisciplinary care protocols
that also involve endocrinologists. Finally, the consolidation of
Cardio-Oncology units with multidisciplinary collaboration is essential for
optimizing cardiovascular outcomes without compromising anticancer
effectiveness.
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