Cardio-Oncology: Managing Heart Failure in Survivors of Cancer

Introduction: The Growing Intersection of Oncology and Cardiology

Advances in cancer therapy have dramatically improved survival rates, creating a burgeoning population of cancer survivors. However, this success has unmasked a critical challenge: the long-term cardiovascular toxicity of oncological treatments. Heart failure (HF) secondary to cancer therapy, termed cancer therapy-related cardiac dysfunction (CTRCD), has emerged as a leading cause of morbidity and mortality among survivors. This review explores the pathophysiological mechanisms, risk stratification strategies, and evolving management paradigms for HF in cancer survivors, emphasizing the importance of interdisciplinary collaboration in cardio-oncology.

Epidemiology: The Burden of Heart Failure in Cancer Survivors

The incidence of HF in cancer survivors varies widely based on treatment type, cumulative dose, and pre-existing cardiovascular risk factors. Anthracyclines, cornerstone agents in hematological and solid tumor therapies, confer a 5-10% risk of HF at standard doses, escalating to 48% at cumulative doses exceeding 550 mg/m². HER2-targeted therapies like trastuzumab are associated with a 10-15% risk of asymptomatic left ventricular dysfunction, while radiation therapy to the chest increases HF risk by 2.5-fold over 20 years. With over 20 million cancer survivors globally, CTRCD represents a public health crisis demanding proactive detection and mitigation.

Pathophysiological Mechanisms of Cancer Therapy-Induced Heart Failure

Chemotherapy-Induced Cardiotoxicity

Anthracyclines (e.g., doxorubicin) cause irreversible myocardial injury through free radical generation, mitochondrial dysfunction, and topoisomerase IIβ inhibition, leading to cardiomyocyte apoptosis. Taxanes exacerbate this toxicity by altering anthracycline pharmacokinetics. Alkylating agents like cyclophosphamide induce endothelial damage and capillary leak syndrome, precipitating acute HF.

Targeted Therapies and Immune Checkpoint Inhibitors

HER2 inhibitors (e.g., trastuzumab) disrupt ErbB2 signaling, which is critical for cardiomyocyte survival, causing reversible ventricular dysfunction. Tyrosine kinase inhibitors (e.g., sunitinib) impair angiogenesis via VEGF inhibition, promoting hypertension and microvascular ischemia. Immune checkpoint inhibitors (e.g., pembrolizumab) trigger myocarditis in 1-2% of patients, often presenting as fulminant HF due to T-cell-mediated myocardial inflammation.

Radiation-Induced Heart Disease (RIHD)

Chest radiation causes endothelial damage, fibrosis, and accelerated atherosclerosis. Late effects include constrictive pericarditis, valvular stenosis, and coronary artery disease, culminating in HF with preserved ejection fraction (HFpEF). Modern techniques like proton beam therapy aim to reduce cardiac exposure, but legacy effects persist in survivors treated before the 2000s.

Risk Stratification: Identifying Vulnerable Patients

Pre-treatment cardiovascular risk assessment is paramount. The EACVI/HFA Cardio-Oncology Toxicity Score integrates variables like age (>65 years), hypertension, prior HF, and cumulative anthracycline dose to stratify risk. Biomarkers such as troponin and BNP/NT-proBNP predict subclinical injury: a rise in troponin post-chemotherapy correlates with a 60% risk of LVEF decline. Advanced imaging techniques, including global longitudinal strain (GLS) on echocardiography, detect early systolic dysfunction before LVEF reduction. Cardiac MRI, with late gadolinium enhancement, identifies fibrosis in RIHD. Genetic predisposition (e.g., RARG variants) may explain interindividual susceptibility to anthracycline toxicity.

Surveillance Protocols: Early Detection of Cardiac Dysfunction

Serial monitoring is recommended for high-risk patients. The ESC Guidelines advocate baseline echocardiography with LVEF and GLS measurement, repeated every 3 months during anthracycline therapy and every 6 months for HER2-targeted agents. For radiation survivors, lifelong echocardiograms every 5-10 years are advised. Biomarker-guided strategies, such as the ICOS-ONE Trial protocol, use troponin elevations to trigger ACE inhibitor initiation, reducing HF incidence by 50%. Wearable devices enabling remote heart rate variability monitoring represent a frontier in real-time surveillance.

Management Strategies: From Prevention to Advanced Therapies

Primary Prevention

Dexrazoxane, an iron chelator, reduces anthracycline cardiotoxicity by 80% in breast cancer patients without compromising oncological efficacy. Liposomal doxorubicin formulations minimize myocardial exposure. Statins and beta-blockers (e.g., carvedilol) attenuate oxidative stress and apoptosis in preclinical models, though clinical data remain mixed.

Treatment of Established HF

For asymptomatic LVEF decline, ACE inhibitors/ARBs and beta-blockers (e.g., bisoprolol) are first-line. The PRADA Trial demonstrated that candesartan prevents trastuzumab-induced LVEF decline. In symptomatic HF, guideline-directed medical therapy (GDMT) with ARNI (sacubitril/valsartan) and SGLT2 inhibitors (dapagliflozin) is recommended. For refractory cases, mechanical circulatory support or transplantation may be considered, though comorbidities often limit eligibility.

Radiation-Specific Interventions

RIHD management focuses on comorbidity control: aggressive lipid-lowering, anti-inflammatory agents (e.g., colchicine), and pericardiectomy for constrictive physiology. Coronary revascularization is complicated by mediastinal fibrosis, favoring CABG over PCI.

Emerging Therapies and Research Frontiers

Mitochondrial-targeted antioxidants (e.g., elamipretide) and senolytics (e.g., dasatinib/quercetin) show promise in reversing chemotherapy-induced mitochondrial damage. CAR T-cell therapy is being explored for immune checkpoint inhibitor myocarditis. Gene therapy to upregulate SERCA2a may enhance contractility in anthracycline cardiomyopathy. AI-driven predictive models integrating multi-omics data (e.g., proteomics, epigenetics) aim to personalize risk prediction.

The Role of Multidisciplinary Cardio-Oncology Teams

Dedicated cardio-oncology clinics improve outcomes by harmonizing cancer treatment and cardiovascular protection. Key strategies include:

• Pre-treatment optimization: Managing hypertension, diabetes, and obesity.

• Real-time communication: Oncologists and cardiologists co-manage dose modifications (e.g., trastuzumab pause for LVEF <45%).

• Survivorship programs: Long-term follow-up addressing HF, arrhythmias, and psychosocial distress.

Conclusion: Toward a Heart-Healthy Future for Cancer Survivors

Heart failure in cancer survivors is a preventable and treatable complication, not an inevitable trade-off for oncological efficacy. Advances in risk prediction, biomarker surveillance, and targeted therapies are reshaping cardio-oncology. However, disparities in access to specialized care persist, underscoring the need for global advocacy and education. As precision medicine evolves, the goal is clear: to ensure that cancer survival is not overshadowed by cardiovascular morbidity, enabling patients to live longer, fuller lives.

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