Anthracyclines and the Heart: A Double-edged Sword With Therapeutic Hopes

Abstract

Background

Anthracyclines, notably doxorubicin, are potent cytotoxic agents that substantially improved outcomes across numerous malignancies. However, their use is restricted by their cardiotoxicity, a dose-dependent adverse effect that manifests acutely, during treatment, or years post-therapy. It encompasses a spectrum of phenotypes including asymptomatic ventricular dysfunction, heart failure, arrhythmias, and cardiomyopathy, contributing to considerable morbidity and mortality as cancer survival rates improve.

Objective

This narrative review summarises current insights into anthracycline-induced cardiotoxicity pathophysiology and evaluates pharmacologic strategies for its prevention and management.

Methods

A comprehensive literature search was conducted through August 2025, prioritizing randomised controlled trials, meta-analyses, observational studies, and guideline statements addressing pharmacologic interventions to mitigate anthracycline cardiotoxicity.

Results

Anthracycline cardiotoxicity arises from various mechanisms, including oxidative stress, mitochondrial dysfunction, topoisomerase IIβ–induced DNA damage, calcium dysregulation, and reticulum stress. Neurohormonal modulation with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers has shown modest preservation of left ventricular ejection fraction, especially when initiated early in high-risk patients; spironolactone appears more effective than eplerenone among mineralocorticoid receptor antagonists. Sacubitril/valsartan demonstrates promising superiority in preclinical and early clinical cohorts, though further randomised control trials are ongoing. Metabolic modulators such as metformin and sodium-glucose cotransporter 2 inhibitors exhibit cardio-protectivity via AMPK activation, attenuation of oxidative and inflammatory pathways, but evidence in non-diabetic cancer populations is limited. Statins have shown reduced left ventricular ejection fraction decline and lower cardiotoxicity rates in randomised studies, while dexrazoxane–through iron chelation and topoisomerase IIβ inhibition–remains the only approved agent for anthracycline-induced cardiotoxicity prevention, strongly supported by adult and paediatric data.

Conclusion

Several pharmacologic strategies offer potential benefit in limiting anthracycline-induced cardiotoxicity and preserving cardiac function. Tailored, risk-based approaches that incorporate cardioprotective therapies early in anthracycline treatment–guided by biomarkers and imaging–are most promising. Further large-scale randomised studies are required to establish optimal combinations and confirm long-term benefit.

1. Introduction

Anthracyclines such as doxorubicin (DOX) are widely used across multiple malignancies, including breast, lung, ovarian, and hematologic cancers, owing to their potent antineoplastic properties [1]. DOX exerts its anti-tumor activity through a combination of mechanisms, including inhibition of topoisomerase IIβ, intercalation into Deoxyribonucleic Acid (DNA), generation of reactive oxygen species (ROS), Mitochondrial dysfunction and destabilizer of myocardium metabolism, ultimately impairing DNA replication and inducing cell death [2–4].

Despite its clinical efficacy, long-term use of DOX is restricted by dose-dependent cardiotoxicity that may progress to anthracycline-induced cardiomyopathy (AIC). The incidence of AIC has been reported in up to 10 % of patients, even up to 10 years following the cessation of therapy [2]. The likelihood of developing AIC increases markedly with cumulative DOX doses above 400 mg/m², whereas the risk is minimal at doses below 250 mg/m² [1]. The clinical presentation of AIC varies and may include acute, chronic, and delayed cardiotoxicity. Acute toxicity, occurring within hours to weeks of anthracycline exposure, may manifest as QT wave prolongation or malignant arrhythmias. Interestingly, one case report in particular it presented as a microvascular angina in a medially free 23-year-old female patient with breast cancer treated with doxorubicin, triggered as cardiac syndrome X [5]. On the other hand, Chronic toxicity typically develops within the first year and often progresses to irreversible heart failure. Delayed cardiotoxicity can manifest several years after therapy and is characterized by late-onset cardiomyopathy and progressive systolic dysfunction [6]. Importantly, a recent paediatric cohort from Saudi Arabia reported a cardiomyopathy incidence of 7.3 %, majority are female children receiving anthracyclines, with thromboembolism and patent ductus arteriosus identified as potential risk factors, highlighting the relevance of regional data [7]. In addition, mean cumulative anthracycline dose correlated with chemotherapy induced cardiomyopathy was 209 mg/m², lower than reported in adult literature. These observations have led to increased efforts to identify effective strategies for mitigating AIC while preserving anticancer efficacy.

2. Mechanisms of anthracycline-induced cardiotoxicity

The pathogenesis of anthracycline cardiotoxicity is multifactorial and involves several interconnected mechanisms. One of the central contributors is oxidative stress. Doxorubicin undergoes redox cycling in the presence of iron, which leads to excessive formation of ROS–including superoxide anions, hydrogen peroxide, and hydroxyl radicals. The heart is especially vulnerable to oxidative damage due to its relatively low antioxidant capacity [8]. ROS promote lipid peroxidation, mitochondrial dysfunction, and DNA and protein damage, resulting in cardiomyocyte death and impaired contractile function. Another important oxidative stress damage published in Avagimyan paper in details of fundamental pathways of myocardium injuries due to AIC, is the role of Yes-associated protein (YAP) [4]. DOX is associated with reduction of the antioxidant (YAP) and ultimately leading to apoptosis, fibrosis and myocardial again. Mitochondrial injury also plays a major role in AIC. DOX preferentially accumulates in cardiomyocyte mitochondria through its interaction with cardiolipin, leading to disruption of respiratory chain complexes, formation of mitochondrial permeability transition pores, Adenosine triphosphate (ATP) depletion, and release of pro-apoptotic molecules such as cytochrome C [8]. These events activate intrinsic apoptotic pathways, including caspase-9 and caspase-3, and reduce the expression of pro-survival proteins such as GATA4 [9].

Another key mechanism involves topoisomerase IIβ (Top2β), an enzyme responsible for DNA repair and transcription regulation in cardiomyocytes. Doxorubicin stabilizes the Top2β–DNA cleavage complex, resulting in double-strand DNA breaks and transcriptional dysregulation, which further contribute to cardiotoxicity [10]. In addition, anthracyclines disrupt calcium homeostasis by downregulating SERCA2a (sarcoplasmic reticulum Ca²⁺ ATPase) and increasing sodium–calcium exchanger (NCX) activity, ultimately causing intracellular calcium overload and impaired myocardial relaxation [9]. Endoplasmic reticulum (ER) stress has also been implicated in AIC. Doxorubicin promotes the accumulation of misfolded proteins in the ER and activates the unfolded protein response (UPR). Sustained UPR activation leads to the induction of pro-apoptotic signalling pathways and further cardiomyocyte loss [11]. Lastly, DOX and Sirtuins (SIRT) system, are nicotinamide adenine dinucleotide dependent deacetylating enzymes that is essential in normal myocardial function. They participate gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and endothelial function. DOX disrupts the SIRT function by inhibiting SIRT3 (a mitochondrial sirtuin) and mitochondrial NAD + -dependent protein deacetylase. Anthracyclines inhibiting SIRT1 expression thus disrupting mitochondrial biogenesis and function. SIRT1 inhibition leads to NF-κB activation, thereby activating a series of genes that leads to further mitochondrial dysfunction [4]. Together, these mechanisms–oxidative injury, mitochondrial dysfunction, Top2β-mediated DNA damage, calcium dysregulation, ER stress, SIRT deficiency–act synergistically to promote cardiomyocyte death and adverse left ventricular remodelling.

2.1. Problem-oriented analysis of doxorubicin cardiotoxicity: translational gaps and emerging paradigms

2.1.1. Translational gaps between preclinical models and clinical CTRCD

Despite extensive mechanistic insights derived from experimental models, translation into consistent and durable clinical cardioprotection remains incomplete [12–14]. Preclinical studies have convincingly demonstrated that attenuation of oxidative stress, mitochondrial injury, apoptosis, and inflammatory signalling can substantially reduce doxorubicin-induced myocardial damage. However, many pharmacologic interventions that are effective in animal models have failed to demonstrate comparable benefit in randomized clinical trials.

Several translational gaps likely explain this discrepancy. First, most experimental models evaluate short-term myocardial injury, whereas clinical cardiotoxicity frequently evolves over years and manifests as progressive ventricular remodelling or late-onset heart failure. Second, animal studies typically involve young, metabolically healthy subjects, whereas real-world cancer populations are older and frequently burdened by hypertension, diabetes, obesity, and pre-existing cardiovascular disease factors that significantly modify myocardial susceptibility to anthracycline injury. Third, outcome measures differ substantially; preclinical studies rely on histopathology and molecular markers, whereas clinical trials primarily use left ventricular ejection fraction (LVEF), which is relatively insensitive to early myocardial dysfunction and fails to capture subclinical disease progression.

Collectively, these limitations underscore the need for improved translational alignment, incorporating cardiometabolic phenotyping, sensitive imaging markers such as global longitudinal strain, and longer-term follow-up to better reflect the natural history of cancer therapy–related cardiac dysfunction (CTRCD).

2.1.2. Doxorubicin cardiotoxicity as a cardiometabolic syndrome

Increasing evidence suggests that doxorubicin-induced cardiotoxicity should be conceptualized not solely as direct myocardial injury, but as a cardiometabolic syndrome [3,15,16] characterized by impaired myocardial energetics, insulin resistance, systemic inflammation, and endothelial dysfunction. Doxorubicin disrupts glucose and fatty acid utilization through mitochondrial injury and suppression of AMP-activated protein kinase (AMPK) signalling, leading to reduced metabolic flexibility and energetic inefficiency.

These metabolic disturbances are amplified in patients with obesity, diabetes, metabolic syndrome, or advanced age, who consistently demonstrate higher rates of CTRCD despite similar cumulative anthracycline exposure. Importantly, cardiometabolic risk factors appear to predict cardiotoxicity more strongly than traditional oncologic parameters alone, highlighting a shift from dosecentric to phenotype-centric risk assessment.

This framework provides mechanistic context for the heterogeneous efficacy observed with metabolic modulators. Agents such as metformin and sodium–glucose cotransporter 2 inhibitors (SGLT2i) may exert cardioprotective effects not merely through antioxidant pathways, but by restoring myocardial metabolic homeostasis, improving mitochondrial efficiency, and suppressing inflammatory signalling. Conversely, their limited benefit in metabolically healthy, non-diabetic cohorts reinforces the need for risk-stratified cardioprotection, rather than universal prophylaxis.

2.1.3. Mechanistic pathway–target mismatch in current cardioprotective strategies

Most established cardioprotective therapies target downstream neurohormonal activation rather than upstream anthracycline-specific mechanisms [10,17,18]. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and mineralocorticoid receptor antagonists primarily attenuate adverse remodelling once myocardial injury has occurred, which may explain their modest and variable efficacy when used prophylactically.

In contrast, dexrazoxane remains uniquely effective because it directly targets anthracycline-specific injury pathways, including iron-mediated reactive oxygen species generation and topoisomerase IIβ –induced DNA damage. This mechanistic alignment likely accounts for its consistent benefit across adult and pediatric populations.

Sacubitril/valsartan represents an intermediate strategy, addressing both neurohormonal activation and myocardial stress signalling. While early clinical data are promising, robust randomized trials are required to define its role in primary prevention. Overall, these observations suggest that cardioprotective efficacy is maximized when therapeutic targets align closely with dominant injury pathways.

2.1.4. Re-examining SGLT2 inhibitors beyond glycemic control

SGLT2 inhibitors have emerged as promising agents in CTRCD prevention, with effects that appear disproportionate to glucose lowering alone [19–21]. Experimental data suggest that these agents improve myocardial energetics, stabilize calcium handling, suppress inflammasome activation, and reduce oxidative and inflammatory stress.

Preliminary clinical studies indicate potential benefit even in non-diabetic populations, raising the possibility that SGLT2 inhibitors may represent disease-modifying therapies rather than adjunctive metabolic agents. However, current trials remain underpowered and heterogeneous, precluding definitive conclusions. Larger, phenotype-enriched randomized studies are required to determine whether SGLT2 inhibitors should be selectively deployed in high-risk cardiometabolic phenotypes or more broadly as primary prevention strategies.

2.1.5. Implications for future trial design and clinical practice

The heterogeneity of doxorubicin-induced cardiotoxicity necessitates a shift away from one-size-fits-all prevention strategies. Future trials should prioritize: Cardiometabolic risk stratification Mechanism-matched pharmacologic interventions, Composite endpoints incorporating imaging, biomarkers, and clinical outcomes Long-term follow-up extending beyond chemotherapy completion. Such approach may reconcile conflicting trial results and enable precision cardio-oncology strategies that balance cardiovascular protection with oncologic efficacy.

3. Risk stratification and monitoring in anthracycline-induced cardiotoxicity

Effective prevention of anthracycline-induced cardiotoxicity requires early identification of patients at highest risk and longitudinal surveillance to detect subclinical myocardial injury. Contemporary cardio-oncology practice increasingly emphasizes risk-adapted strategies, integrating baseline clinical characteristics with serial biomarker and imaging assessment [22–24] before, during, and after chemotherapy exposure.

3.1. Baseline risk stratification prior to anthracycline therapy

Multiple clinical and treatment-related factors have been consistently associated with an increased risk of cancer therapy–related cardiac dysfunction (CTRCD). Among these, cumulative anthracycline dose remains the most robust predictor, with a marked rise in cardiotoxicity observed at doxorubicin- equivalent doses exceeding 250–300 mg/m². However, dose alone does not fully account for interindividual susceptibility.

Patient-related risk factors include advanced age, female sex, pre-existing cardiovascular disease, hypertension, diabetes mellitus, obesity, and chronic kidney disease. Prior or concurrent exposure to thoracic radiotherapy, particularly involving the left chest or mediastinum, synergistically increases the risk of myocardial injury and accelerates adverse remodeling. Pediatric cancer survivors represent a uniquely vulnerable population, as early myocardial injury may remain clinically silent for decades before manifesting as overt cardiomyopathy.

These observations support a shift from dose-centric assessment toward multidimensional baseline risk stratification, allowing clinicians to identify patients who may benefit from intensified monitoring or early cardioprotective therapy.

3.2. Role of cardiac biomarkers in early detection and surveillance

Cardiac biomarkers provide a sensitive and reproducible means of detecting subclinical myocardial injury before irreversible dysfunction occurs. Cardiac troponins, particularly when measured serially during anthracycline therapy, are strong predictors of subsequent left ventricular dysfunction. Early troponin elevation reflects acute cardiomyocyte injury and has been shown to identify patients who derive the greatest benefit from early initiation of cardioprotective therapy. N-terminal pro–B-type natriuretic peptide (NTproBNP) serves as a complementary marker of myocardial wall stress and ventricular remodelling. While less specific than troponin for direct injury, persistently elevated or rising NT-proBNP levels during chemotherapy are associated with increased risk of future heart failure and adverse outcomes.

Incorporating baseline and serial biomarker measurements enables dynamic risk reassessment throughout treatment, facilitating timely intervention before overt systolic dysfunction develops.

3.3. Advanced cardiac imaging and the central role of global longitudinal strain

Echocardiographic assessment remains the cornerstone of cardiac monitoring in anthracycline-treated patients. However, reliance on left ventricular ejection fraction alone is insufficient, as LVEF decline represents a late manifestation of myocardial injury.

Global longitudinal strain (GLS) has emerged as a sensitive and reproducible imaging marker capable of detecting early myocardial dysfunction before changes in LVEF occur. A relative reduction in GLS of >10–15 % from baseline has been consistently associated with future development of CTRCD and is now incorporated into contemporary cardiooncology recommendations. Baseline GLS assessment establishes an individualized reference point, while serial measurements during therapy allow early identification of subclinical injury. Importantly, GLS-guided strategies have demonstrated improved preservation of ventricular function when cardioprotective therapy is initiated at the time of strain deterioration rather than waiting for LVEF decline.

Cardiac magnetic resonance imaging may provide additional value in selected cases, particularly for tissue characterization, fibrosis assessment, and clarification of equivocal echocardiographic findings.

3.4. Longitudinal monitoring: before, during, and after therapy

Optimal surveillance extends beyond chemotherapy completion. Anthracycline-induced cardiotoxicity may evolve months to years after exposure, particularly in high-risk patients.

Before therapy: Comprehensive cardiovascular assessment including clinical risk factors, baseline echocardiography with GLS, and cardiac biomarkers.

During therapy: Periodic biomarker measurement and interval imaging in high-risk individuals or those receiving high cumulative doses.

After therapy: Continued surveillance to detect late-onset cardiomyopathy, especially in pediatric survivors and patients with prior abnormalities.

This longitudinal approach enables early detection, risk reclassification, and timely escalation of cardioprotective strategies.

3.5. Toward a precision-based cardio-oncology framework

Integrating clinical risk factors with biomarkers and imaging surveillance allows clinicians to move beyond uniform monitoring protocols toward precision cardio-oncology. High-risk patients may benefit from intensified surveillance and early initiation of cardioprotective therapies, while low-risk individuals may safely undergo less intensive monitoring. Such risk-adapted strategies optimize resource utilization, minimize treatment interruptions, and may ultimately improve long-term cardiovascular outcomes without compromising oncologic efficacy.

4. Pharmacologic prevention and treatment strategies

4.1. Neurohormonal blockade (ACEi/ARB/ARNI/-blockers/MRAs)

Neurohormonal modulation remains the most extensively examined cardioprotective strategy in anthracycline-treated patients. Data from multiple randomized and observational studies support the use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), although trial results have been variable. In the Cardinale et al. trial (n = 114), patients with early biomarker evidence of cardiac injury were randomized to receive enalapril or standard care one month after completing anthracycline-based chemotherapy [25]. The study included patients with leukaemia, lymphoma, myeloma and Ewing sarcoma. However, most of the sampled patients have advance or primary resistant breast cancer and non-Hodgkin lymphoma. Chemotherapy type was not restricted to anthracycline only, as it included patients who received other types of therapy, some never received any anthracycline. Fifty-six patients received Enalapril with a starting dose of 2.5 mg once daily, increased to reach 20 mg and was started 1 month after the last cycle of chemotherapy and continued for one year. In both arms of the population, most patients did not have risk factors such as, diabetes, hypertension, and dyslipidaemia. Majority of patients did receive a previous anthracycline therapy course before enrolment, and cumulative dose of anthracycline reached in the study was around 330mg/m2, some of the sample did have radiation therapy in addition to anthracycline. At 12-month follow-up, left ventricle ejection fraction (LVEF) was preserved in the enalapril group (−1.5 % vs. −9.6 % in controls; p < 0.001), no cases of heart failure were observed, and no cardiovascular mortality. In comparison, the control group reported (24 %) of heart failure incidences, (17 %) of arrhythmias requiring treatment, and two cardiac deaths reported. Similarly, in the SAFE-HEART trial (n = 174), prophylactic ramipril initiated 1 week prior to chemotherapy reduced LVEF decline (−3.0 % vs. −4.4 % with placebo) and preserved global longitudinal strain over 24 months [26]. However, the PRADA trial by Gulati et al. in 2016 which employed a 2 × 2 factorial design of candesartan and metoprolol in early-stage breast cancer, included patients with risk profiles such as active smokers and hypertensive at baseline. The study included 130 females with early-stage breast cancer and no significant other co-morbidities, of which 32 patients received only candesartan with a mean dose of 23 mg once daily started prior to initiation of chemotherapy. Patients received Epirubicin with concomitant therapy Taxanes (78 %), and Trastuzumab (21.9 %). Cardiac dysfunction measured by cardiac magnetic resonance showed reduction of LVEF was modest in the candesartan group compared to placebo group. A follow up of this trial was done in 2021 with Heck et al. This extended follow-up showed no effect on the primary end point of overall decline in LVEF compared to control, as in it did not persist on the long-term. However, the secondary end point of end-diastolic volume measured by Global longitudinal strain (GLS), was attenuated by candesartan in preserving cardiac decline, attritable to long term cardiac remodelling effect [27,28]. The study did report that one participant did develop both atrial fibrillation with heart failure in the intervention group with candesartan. The aforementioned trials might have resulted in heterogenicity of outcomes because Cardinale et al. trial initiated enalapril after completing anthracycline-based chemotherapy and included in their studied population patients who never received anthracycline, also it included a large number of patients with non-Hodgkin lymphoma. Whereas PRADA trial-initiated candesartan earlier before chemotherapy initiation and studied population with only early breast cancer. In addition, both trials end points included the effect of anthracycline on cardiotoxicity however, Cardinale et al. paper focused on hard clinical outcomes such as heart failure and cardiovascular morality. On the other hand, the PRADA trial relied on surrogate endpoints of (LVEF, GLS) using cardiac magnetic resonance and echocardiographs imaging. These findings suggest that ACEi/ARB benefits may depend on baseline risk profiles, timing of therapy and type of cancer treated.

β-Blockers have also been evaluated. In the OVERCOME trial, combined enalapril and carvedilol therapy initiated 24 h prior to anthracycline administration prevented LVEF decline at 6 months (61.5 % vs. 56.0 % with placebo; p = 0.01) and significantly reduced heart failure-related treatment interruptions [29]. The study included 90 patients with only haematological malignancy, of which 45 received both Enalapril and Carvedilol and compared to placebo. Maximum dose, at the end of the 6 months of Enalapril was 10.9 mg twice daily and 33.4 mg once daily for carvedilol. The two groups were balanced in respect to baseline patient risk factors, except the prevalence of smokers were three times more in the intervention group. In addition, prior anthracycline treatment course was present in almost (40 %) of both groups. Interestingly, more patients in the placebo group prematurely ended the study (22 %) due to death, clinical or imaging-based heart failure. It was difficult to assess the clinical benefits, as more patients in the placebo group had a higher rate of dropouts. However, this publication supported the findings of the previously discussed Cardinale et al. trial [25]. Both literatures had enrolled patients who did receive a previous anthracycline therapy course, similar cumulative dose of anthracycline given, and partially same intervention with Enalapril. However, it was difficult to elucidate the beneficial outcomes of the treatment came upon as a result of Enalapril versus Carvedilol, as it lacked the comparison of these two medications individually compared to placebo. More recent data from the SAFE trial, one of the largest published literatures on this topic, showed that bisoprolol (initiated 1 week before chemotherapy) had greater protective effects than ramipril in reducing both LVEF (−1.4 % vs. −4.4 %) and Global longitudinal strain (GLS) decline (−1.5 % vs. −6.0 %) over 24 months [26]. The median age was 48 years, and most patients were early-stage breast cancer with balanced patient risk profiles heterogeneity across all four groups. The primary end point focused on surrogate pf cardiac toxicity with changes in (LVEF, GLS) using imaging rather than clinical outcomes such as heart failure and cardiovascular morality. Importantly, follow up to 24 months showed that the benefits were maintained. However, the study showed more significant results in the bisoprolol arm compared to the ramipril arm. A meta-analysis including 17 randomized studies including 1291 patients demonstrated that β-blockers were associated with a significantly smaller decline in LVEF (mean difference 3.44 %, p = 0.001) and a lower risk of symptomatic heart failure (RR 0.29, 95 % CI 0.10–0.85), particularly when treatment exceeded 6 months [11]. The presented evidence from the SAFE, OVERCOME trial, and the aforementioned meta-analysis can suggest that β-blockers could have a more significant and consistent cardioprotective role in from anthracycline based chemotherapy in comparison to ACE/ARB.

Sacubitril/valsartan, an angiotensin Receptor Neprilysin Inhibitor (ARNI) has shown promising results in both preclinical and clinical settings. In rodent anthracycline models, sacubitril/valsartan improved LVEF and reduced oxidative and ER stress more effectively than valsartan alone [30]. Clinically, case series and observational studies have reported significant improvements in cardiac function. In the Martin-García et al. cohort (n = 67 cancer patients, ~70 % anthracycline-treated), switching to sacubitril/valsartan from ACEi/ARB resulted in LVEF improvement from 32–35 % to 41–45 % over 6–12 months and substantial reductions in N-terminal pro b-type natriuretic peptide (NT-proBNP) [31]. The sampled population were majority females, almost (90 %) had at least one cardiovascular risk factors with a median age of 63 years, treated for breast cancer and lymphoma. This study highlighted the significant positive impact of reverse remodelling (ARNI) have both clinically with improvement in exercise tolerance and biochemically with an excellent safety profile regardless of the achieved dose of the (ARNI). However, the study lacks any evidence of heart failure hospitalization and cardiovascular mortality benefits. More importantly most of the population were already on β-Blockers and MRAs which adds confabulation to the outcomes of the study. These findings were replicated in smaller single-center series, including a Saudi cohort, suggesting ARNI may offer superior reverse remodelling and improvement in LVEF compared with conventional neurohormonal blockade [32]. Similar to Martin-García et al. cohort, it lacks any remarks of heart failure hospitalization and cardiovascular mortality benefits. In addition, it was deficient in describing patients risk profiles.

Mineralocorticoid receptor antagonists (MRAs) also target neurohormonal signalling. In the Akpek et al. trial (n = 83), prophylactic spironolactone (25 mg daily, initiated 1 week prior to doxorubicin and stopped three weeks after finishing chemotherapy course) preserved LVEF (67 %→66 % vs. 67 %→54 % in placebo; p < 0.001) and attenuated troponin rise [33]. Conversely, the ELEVATE trial (n = 69) found no significant benefit with eplerenone when initiated within one-week pre chemotherapy (LVEF decline: −3.5 % vs. −2.0 %, NS) [34]. These two studies were similar in patients risk profiles, timing of MRA initiation, sample size, and type of cancer. Although follow up time varied as in Akpek et al. trial was 2 years with spironolactone and ELEVATE trial with eplerenone was 6 months. Nonetheless, it supports the meta-analyses finding that MRAs confer an average 3–4% LVEF preservation compared with control, with spironolactone showing stronger effects than eplerenone [35] (see Tables 1–3).

Table 1.

Summary of Pharmacologic Agents in the literature reviewed for Anthracycline-induced cardiotoxicity prevention.

Medication/Class	Proposed Mechanism	Key Evidence	Strength of Evidence	Key limitation/Gaps
ACE inhibitors/ARBs	Reduce neurohormonal activation, preserve LVEF	Cardinale 2004, SAFE-HEART, PRADA – modest preservation of LVEF	Moderate	Heterogenous study population in the literature and questionable effectiveness on extended follow-up.
Beta-blockers	Reduce oxidative stress, sympathetic blockade, preserve LVEF	OVERCOME, SAFE trial – reduced LVEF decline, HF prevention	Moderate to strong	Meta-analysis showed variable effectiveness of different types of Beta-blockers on AIC [9]
ARNI (Sacubitril/ Valsartan)	Neprilysin inhibition + ARB: reduces oxidative stress, ER stress, improves remodelling	Preclinical strong; observational clinical cohorts show benefit	Emerging	Randomised control trials are ongoing
MRAs (Spironolactone, Eplerenone)	Aldosterone antagonism: reduces remodelling and fibrosis	Akpek 2015 (spironolactone positive), ELEVATE (eplerenone neutral)	Moderate (spironolactone stronger)	Need more RCT to show effectiveness on AIC
Metformin	AMPK activation, mitochondrial protection, reduce ROS	Mixed RCTs; observational benefit in diabetics	Low–moderate	Inconsistent RCT results
SGLT2 inhibitors	Reduce oxidative stress, inflammation, stabilize Ca handling	EMPA-COG (reduced CTRCD, preserved GLS), observational HF benefit	Emerging	Lack of RCT data in non-diabetics
Statins	Antioxidant, anti-inflammatory, endothelial protection	STOP-CA (↓LVEF decline), meta-analyses confirm benefit	Strong (several RCTs, meta-analyses)	Not applicable
Dexrazoxane	Iron chelation + Topoisomerase IIβ inhibition	Cochrane review, meta-analysis, FDA/EMA approved	Very strong (robust RCTs, guidelines)	Not applicable

Abbreviations: ACE: Angiotensin converting enzyme; ARB: Angiotensin receptor blocker; ARNI: angiotensin Receptor Neprilysin Inhibitor; AMPK: adenosine 5′-monophosphate-activated protein kinase; CTRCD: Cancer therapy-related cardiac dysfunction; EMA: European medicines agency; FDA: Food drug administration; GLS: Global longitudinal strain; HF: Heart failure; LVEF: Left ventricular ejection fraction; MRA: Mineralocorticoid receptor antagonist; ROS: Reactive Oxygen Species; RCT: Randomized controlled trial; SGLT: Sodium-glucose transport protein.

Table 2.

Indications of Anthracycline neoplastic use.

Common/standard clinical Indications of Anthracycline use as Antineoplastic (Regulatory approval may vary by region)
Acute lymphocytic leukaemia Acute myelogenous leukaemia Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Bladder cancer (rapidly recurrent, metastatic transitional cell bladder cancer) Breast cancer Ovarian cancer Osteogenic sarcoma Ewing sarcoma Soft tissue sarcoma Thyroid cancer Wilm’s tumor	Advanced endometrial carcinoma Metastatic hepatocellular cancer Multiple myeloma Advanced renal cell carcinoma (with sarcomatoid features) Thymomas and thymic malignancies Uterine sarcoma Waldenstrom macroglobulinemia

Indications of Anthracycline Use as Antineoplastic.

Abbreviations: FDA: Food Drug Administration.

Table 3.

Mechanisms of Anthracycline-Induced Cardiotoxicity and consequences.

Mechanism	Description	Key Consequence
Reactive Oxygen Species Generation	Anthracyclines (e.g., doxorubicin) undergo redox cycling with NADPH and form semiquinone radicals. In the presence of iron, these radicals generate ROS (superoxide, hydrogen peroxide).	Oxidative stress → lipid peroxidation → mitochondrial and sarcolemmal membrane damage
Iron–Anthracycline Complex Formation	Anthracyclines chelate iron, forming anthracycline–iron complexes that catalyze further ROS production via Fenton reaction.	Oxidative stress → lipid peroxidation → mitochondrial and sarcolemmal membrane damage
Topoisomerase IIβ Inhibition	Doxorubicin binds to DNA-topoisomerase IIβ complexes in cardiomyocytes, causing double-strand DNA breaks and transcriptional dysregulation.	DNA damage → mitochondrial dysfunction → impaired cardiomyocyte survival
Mitochondrial Dysfunction	Anthracyclines accumulate in mitochondria due to affinity for cardiolipin, disrupting the electron transport chain and decreasing ATP production.	Energy depletion → contractile dysfunction and apoptosis
Inflammation and Fibrosis	Oxidative injury triggers pro-inflammatory and pro-fibrotic cytokines (e.g., TNF-α, TGF-β). Combined effects of oxidative stress, DNA damage, and mitochondrial dysfunction activate caspases.	Myocardial remodelling → chronic cardiomyopathy; Progressive loss of cardiomyocytes → decreased (LVEF)
Apoptosis and Necrosis	ROS intracellular signals promote mitochondrial outer membrane permeabilization and the release of cytochrome c.	Activate intrinsic apoptotic cascade → caspase-9 and caspase-3 → programmed cell death

Abbreviations: ATP: Adenosine triphosphate; DNA: Deoxyribonucleic Acid; LVEF: Left ventricular ejection fraction; NADPH: Nicotinamide Adenine Dinucleotide Phosphate; ROS: Reactive Oxygen Species; TNF-α: Tumor necrosis factor alpha; TGF-β: Tissue growth factor beta.

4.2. Metabolic modulators (metformin and sodium-glucose cotransporter 2 inhibitors (SGLT-2))

Metformin is thought to confer cardioprotection through activation of adenosine 5′-monophosphate-activated protein kinase (AMPK), reduction of oxidative stress, and preservation of mitochondrial biogenesis [9]. In murine models, metformin restored (AMPK) signalling and reduced myocardial ROS generation, leading to improved survival. Observational data from a large diabetic cohort (n = 561) receiving anthracyclines demonstrated that continued metformin use was associated with a lower incidence of new-onset heart failure at 1 year (3.8 % vs. 10.8 %; OR = 0.35; p < 0.01) and higher overall survival [36]. However, randomized trials in non-diabetic patients have been inconsistent. In an open-label RCT of non-diabetic breast cancer patients (n = 70), prophylactic metformin begun 1 week before anthracycline therapy preserved LVEF (65.9 % vs. 62.2 %; p = 0.04) and reduced non-cardiac toxicities [37]. Conversely, another double-blind trial found no difference in LVEF or troponin levels, though mitochondrial respiration was maintained [38]. Collectively, these data suggest metformin may be cardioprotective in diabetic or metabolically vulnerable patients, but evidence for primary prevention in non-diabetic patients remains limited.

SGLT2 inhibitors have demonstrated pleiotropic cardioprotective effects in experimental anthracycline cardiotoxicity through reduction of oxidative stress, suppression of NF-κB and NLRP3 inflammasome signalling, and stabilization of Ca²⁺ handling. In the EMPA-COG study (n = 86 high-risk breast cancer patients), prophylactic empagliflozin (10 mg daily, initiated 7 days prior to doxorubicin) significantly reduced cancer therapy-related cardiac dysfunction at 6 months (RR 0.18; p=0.01), preserved GLS, and blunted NT-proBNP rise [39]. Observational cohorts in diabetic patients have reported similar results: in the Fath et al. cohort (n = 288), SGLT2i use was associated with lower rates of heart failure hospitalization (HR 0.44; p = 0.03) and arrhythmias [40]. These data are encouraging, although large placebo-controlled RCTs in non-diabetic cancer patients are still needed before routine prophylactic use can be recommended.

4.3. Antioxidant and iron-chelating agents (statins and dexrazoxane)

Beyond lipid-lowering, statins exert antioxidant and anti-inflammatory effects that may mitigate anthracycline cardiotoxicity. The STOP-CA trial (multicenter, double-blind RCT; n = 300) demonstrated that atorvastatin 40 mg daily reduced the incidence of LVEF decline ≥10 % to <55 % compared with placebo in lymphoma patients receiving anthracyclines (9.5 % vs. 22 %; p < 0.01) [41]. The protective effect was maintained across predefined subgroups, including baseline cardiovascular risk status. Smaller trials in breast cancer patients have shown similar trends. For example, Alemany et al. (n = 110) found that statin therapy resulted in a significantly smaller mean LVEF decline at 6 months (−3.6 % vs. −7.0 %; p = 0.03) [42]. A recent meta-analysis of six RCTs confirmed a lower risk of cardiotoxicity with statin use (OR 0.41; 95 % CI 0.27–0.63) [43]. Although guidelines have not yet endorsed universal prophylaxis, statin use appears reasonable in high-risk patients or those with concomitant dyslipidemia.

Dexrazoxane is the only pharmacologic agent currently approved specifically for the prevention of anthracycline-induced cardiotoxicity. It acts by chelating intracellular iron and inhibiting topoisomerase IIβ, thereby preventing the formation of ROS and DNA strand breaks [44]. In the Cochrane review of randomized controlled trials (n = 1379), dexrazoxane reduced the risk of clinical heart failure by 68 % (RR 0.32; 95 % CI 0.20–0.50) without compromising oncologic efficacy [45]. A more recent meta-analysis (n = 2177) reported an 81 % relative risk reduction in clinically overt heart failure (RR 0.19) and a 64 % reduction in composite cardiac events (RR 0.36) [46]. Paediatric data are similarly robust; in the Children’s Oncology Group HEART study (median follow-up >15 years), dexrazoxane recipients had significantly higher LVEF and lower rates of major cardiovascular events compared with controls (5.6 % vs. 17.6 %; p = 0.02) [47]. Current ESC cardio-oncology guidelines therefore recommend considering dexrazoxane in patients receiving cumulative anthracycline doses >250–300 mg/m² or those with pre-existing cardiovascular risk factors [48].

5. Conclusion

Anthracycline-induced cardiotoxicity represents a complex, multifactorial disease process that extends beyond direct myocardial injury. While preclinical models have elucidated numerous molecular pathways–including oxidative stress, mitochondrial dysfunction, topoisomerase IIβ–mediated DNA damage, calcium dysregulation, and endoplasmic reticulum stress–translation of these findings into consistent clinical cardioprotection has been limited. This discrepancy reflects fundamental differences between experimental models and real-world cancer populations, particularly with respect to aging, cardiometabolic comorbidities, and long-term disease evolution.

Increasing evidence supports reframing doxorubicin-related cardiotoxicity as a cardiometabolic syndrome, in which systemic metabolic dysfunction, impaired myocardial energetics, and inflammatory signalling amplify vulnerability to anthracycline injury. This paradigm provides mechanistic context for the heterogeneous efficacy observed across cardioprotective trials and explains why metabolic modulators such as SGLT2 inhibitors and metformin may offer selective benefit in high-risk phenotypes rather than universal protection.

Current cardioprotective strategies largely target downstream neurohormonal consequences of injury and therefore demonstrate modest preventive efficacy. In contrast, dexrazoxane remains uniquely effective due to its direct alignment with anthracycline-specific mechanisms. Emerging therapies such as sacubitril/valsartan and SGLT2 inhibitors may bridge upstream and downstream pathways, but robust randomized data are still required.

Future progress in cardio-oncology will depend on precision-based prevention strategies, integrating cardiometabolic risk profiling, mechanism-matched pharmacologic interventions, and sensitive longitudinal endpoints beyond left ventricular ejection fraction alone. Such an approach may ultimately resolve conflicting trial data and enable durable cardiovascular protection without compromising oncologic efficacy.

In this context, systematic risk stratification and longitudinal monitoring using biomarkers and advanced imaging are central to enabling precision-based cardioprotection in anthracycline-treated patients.

5.1. Limitations

Although the current evidence base for cardioprotective strategies in anthracycline-treated patients has expanded considerably, several important limitations should be acknowledged. Most of the available randomized trials are relatively small, include heterogeneous patient populations, and are limited by short follow-up durations, which restrict the ability to assess long-term clinical outcomes such as heart failure hospitalization and cardiovascular mortality. Moreover, definitions of cardiac dysfunction and biomarker thresholds vary across studies, limiting direct comparability. Few trials directly compare different pharmacologic agents or combination strategies, and the majority focus on early-stage breast cancer or hematologic malignancies, with limited representation of other tumor types. The generalizability of existing data to patients with significant pre-existing cardiac comorbidities also remains uncertain. Additionally, as this is a narrative review, the selection and synthesis of evidence were not performed using a formal systematic review methodology. Therefore, publication bias or selective reporting may influence the conclusions drawn. Nevertheless, an effort was made to review the most recent and high-quality clinical data available and to provide a balanced interpretation of the current literature.

Abbreviation list

AIC

Anthracycline-induced cardiomyopathy

ATP

Adenosine triphosphate

ACEi

Angiotensin-converting enzyme inhibitors

ARBs

Angiotensin receptor blockers

ARNI

Angiotensin Receptor Neprilysin Inhibitor

AMPK

Adenosine 5′-monophosphate-activated protein kinase

CTRCD

Cancer therapy–related cardiac dysfunction

DOX

Doxorubicin

DNA

Deoxyribonucleic Acid

ER

Endoplasmic reticulum

EMA

European medicines agency

FDA

Food and drug administration

GLS

Global longitudinal strain

LVEF

Left ventricular ejection fraction

MRAs

Mineralocorticoid receptor antagonists

NT-proBNP

N-terminal pro b-type natriuretic peptide

ROS

Reactive oxygen species

SERCA2a

sarcoplasmic reticulum Ca²⁺ ATPase

NCX

Sodium–calcium exchanger

SGLT-2

Sodium-glucose cotransporter 2 inhibitors

Top2β

Topoisomerase IIβ

UPR

Unfolded protein response

YAP

Yes-associated protein