Cardiotoxicity: Symptoms, Types, Causes and Treatment

Cardiotoxicity is an increasingly recognized complication of many cancer therapies and other drugs, carrying significant potential for morbidity and mortality. As cancer survival rates improve, understanding and managing the risks of cardiotoxicity have become crucial for both clinicians and patients. This article explores the symptoms, types, causes, and treatments of cardiotoxicity, synthesizing the latest research to provide a comprehensive overview.

Symptoms of Cardiotoxicity

Cardiotoxicity can be insidious, sometimes presenting only subtle signs or remaining completely asymptomatic until significant heart damage has occurred. Recognizing the symptoms early is vital for prompt intervention and better outcomes. Symptoms may arise during, shortly after, or even years after the administration of cardiotoxic agents.

Symptom	Description	Severity Range	Source(s)
Chest Pain	Discomfort or pain in chest	Mild to Severe	1, 4
Palpitations	Abnormal heart sensations	Mild to Severe	1, 5
Dyspnea	Shortness of breath	Mild to Moderate	1, 5
Hypotension	Low blood pressure	Mild to Severe	1, 2
Arrhythmias	Irregular heart rhythms	Mild to Fatal	2, 3, 7
Heart Failure	Reduced heart pumping ability	Severe	5, 6, 9

Table 1: Key Symptoms

Recognizing Cardiotoxicity in Practice

Symptoms of cardiotoxicity vary widely depending on the agent, individual susceptibility, and pre-existing cardiac conditions.

• Chest Pain and Palpitations: These are among the most commonly reported early symptoms, especially in patients receiving 5-fluorouracil, capecitabine, and anthracyclines. In some studies, chest pain affected up to 19% of patients on 5-fluorouracil, while palpitations occurred in up to 23% 1.
• Dyspnea and Hypotension: Shortness of breath and low blood pressure are also reported, reflecting compromised cardiac output or arrhythmia 1, 5.
• Arrhythmias: Cardiotoxic agents can provoke both atrial and ventricular arrhythmias, presenting with symptoms such as palpitations, dizziness, or even sudden cardiac arrest 2, 3, 7.
• Heart Failure: The progression to heart failure is a severe outcome, often manifesting as exercise intolerance, fluid retention, and significant fatigue 5, 6.

Subclinical and Asymptomatic Manifestations

Not all cardiotoxicity is symptomatic. Patients may have:

• ECG Changes: Asymptomatic patients can show electrocardiographic abnormalities, including QT prolongation or ST-T changes 2, 4.
• Biomarker Elevations: Increased cardiac biomarkers like NT-proBNP or troponins may indicate silent cardiac injury 6.
• Imaging Findings: Echocardiography or cardiac MRI may reveal subclinical reductions in left ventricular ejection fraction (LVEF) 5, 17.

When to Seek Medical Attention

Patients undergoing potentially cardiotoxic therapy should report:

• New or worsening chest pain
• Unexplained palpitations
• Sudden shortness of breath
• Swelling in legs or abdomen
• Dizziness or fainting

Early recognition and intervention can dramatically improve outcomes and may prevent irreversible cardiac damage.

Types of Cardiotoxicity

Cardiotoxicity is not a single entity; it encompasses a diverse range of cardiac complications. Understanding the different types is essential for anticipating, diagnosing, and managing these adverse effects.

Type	Cardiac Effect	Common Agents	Source(s)
Arrhythmias	Irregular heart rhythms	Chemotherapy, TKIs	2, 7, 9
Cardiomyopathy	Heart muscle dysfunction	Anthracyclines, HER2	5, 8, 9
Heart Failure	Impaired ventricular function	Anthracyclines, HER2	5, 6, 9
Myocardial Ischemia	Reduced blood flow to heart	5-FU, Capecitabine	1, 9
Pericarditis	Inflammation of pericardium	Cyclophosphamide	2, 9, 12
Hypertension	Elevated blood pressure	TKIs, VEFG inhibitors	9

Table 2: Types of Cardiotoxicity

Arrhythmias

• Atrial Fibrillation: Increasingly common with newer cancer therapies, especially those provoking inflammation (e.g., immune checkpoint inhibitors) 7.
• Ventricular Arrhythmias: May be life-threatening and are sometimes seen with anthracyclines, antimicrotubule agents, and QT-prolonging drugs 2, 7.
• QT Prolongation: Notable with tyrosine kinase inhibitors (TKIs) and other targeted therapies, increasing the risk of torsades de pointes 7.

Cardiomyopathy and Heart Failure

• Dilated Cardiomyopathy: Most frequently associated with cumulative anthracycline exposure, such as doxorubicin and daunorubicin, but also seen with trastuzumab 5, 8, 15.
• Congestive Heart Failure: Can occur acutely or years after therapy, with symptoms of fluid overload and reduced exercise tolerance 5, 6, 17.

Myocardial Ischemia and Infarction

• Vasospastic Angina and Infarction: Particularly linked to 5-fluorouracil and capecitabine, which can induce coronary artery spasm 1, 4, 9.
• Cardiogenic Shock and Cardiac Arrest: Rare but severe, reported with high-dose infusion protocols 1, 4.

Pericarditis

• Inflammatory Pericardial Disease: Certain agents, such as cyclophosphamide and radiation therapy, can cause pericarditis, sometimes leading to constrictive disease 2, 9, 12.

Hypertension

• Treatment-Induced Hypertension: Especially notable with VEGF inhibitors and some TKIs, contributing to overall cardiac risk 9.

Causes of Cardiotoxicity

The causes of cardiotoxicity are multifactorial, involving a complex interplay between drug mechanisms, patient factors, and treatment regimens. Understanding these causes helps in risk stratification and prevention.

Cause	Mechanism/Pathway	Risk Factors	Source(s)
Chemotherapeutic Agents	Direct myocardial injury	Dose, schedule, age	2, 3, 8
Targeted Therapies	HER2 inhibition, TKIs	Prior anthracyclines	5, 9, 17
Radiation Therapy	Fibrosis, vascular lesions	Mediastinal exposure	9, 12
Metabolic Stress	Oxidative damage, ROS	Iron overload, stress	8, 12, 13
Patient Factors	Pre-existing heart disease	Age, sex, comorbidity	1, 2, 3
Administration Factors	Dose, infusion rate, combo	Concomitant agents	1, 2, 3

Table 3: Causes of Cardiotoxicity

Chemotherapy-Induced Cardiotoxicity

• Anthracyclines (e.g., Doxorubicin):

  • Mechanism: DNA intercalation, inhibition of topoisomerase II, mitochondrial dysfunction, and generation of reactive oxygen species (ROS) 8, 10, 12, 13, 15.
  • Cumulative, dose-dependent risk—greater total exposure equals higher risk 2, 3, 15.
  • Doxorubicinol, a metabolite, may be particularly toxic to cardiac tissue 10.
  • Ferroptosis and impaired mitochondrial biogenesis are emerging as key mechanisms 11, 13.

• Antimetabolites (5-FU, Capecitabine):

  • Mechanism: Coronary vasospasm, direct endothelial injury, and potential for acute ischemic events 1, 4.
  • Risk increased with continuous infusion, prior cardiac disease, and combination with cisplatin 1.

• Targeted Therapies (e.g., Trastuzumab, TKIs):

  • Mechanism: Inhibition of HER2/ErbB2, leading to compromised myocardial survival pathways 5, 17.
  • Non-dose-dependent, often reversible upon discontinuation 5.
  • Risk is potentiated when combined with anthracyclines 5, 17.

Radiation-Induced Cardiotoxicity

• Mechanisms:
  • Fibrosis of myocardium, pericardium, and coronary vessels
  • Valvular disease and conduction system injury 9, 12.

Metabolic, Genetic, and Other Factors

• Oxidative Stress and Iron Overload: Contribute to mitochondrial injury and apoptosis 8, 12, 13.
• Genetic Predisposition: Individual susceptibility plays a role, but is not yet fully understood 13.
• Patient-Specific Factors: Older age, female gender, pre-existing cardiovascular disease, electrolyte imbalances, and concurrent use of other cardiotoxic agents increase risk 1, 2, 3.

Administration-Related Risks

• Dose and Infusion Rate: Higher total doses and rapid infusions raise risk 1, 2, 3.
• Concurrent Therapies: Combination regimens (e.g., anthracyclines with trastuzumab or cisplatin) dramatically raise cardiotoxicity risk 1, 5, 17.

Treatment of Cardiotoxicity

Treating cardiotoxicity involves a multi-pronged approach, including prevention, monitoring, acute management, and long-term follow-up. The strategies vary depending on the type and severity of cardiac involvement.

Approach	Intervention	Indication/Target	Source(s)
Prevention	Risk stratification, monitoring	All patients	2, 3, 16
Pharmacologic	Dexrazoxane, beta-blockers, ACEi, statins	Anthracycline/HER2 therapy	14, 15, 16, 18
Acute Management	Discontinue/adjust agent	Symptomatic toxicity	4, 5, 2
Heart Failure	ACEi, beta-blockers, diuretics	Symptomatic HF	5, 17, 18
Arrhythmias	Antiarrhythmics, monitoring	Documented arrhythmia	2, 7, 9
Long-term Care	Surveillance, rehab	Survivors	16, 17

Table 4: Treatment Strategies

Prevention and Monitoring

• Baseline Assessment: All patients scheduled for potentially cardiotoxic therapy should undergo cardiac risk assessment, including history, physical exam, ECG, and echocardiography 2, 16, 17.
• Ongoing Surveillance: Regular monitoring with echocardiography, cardiac biomarkers (troponin, NT-proBNP), and ECG is recommended, especially for high-risk regimens 5, 6, 17.
• Patient Education: Patients should be informed about the signs and symptoms of cardiotoxicity and encouraged to report them promptly 4.

Pharmacologic Protection

• Dexrazoxane: FDA-approved for anthracycline-induced cardiotoxicity; chelates iron and reduces free radical formation 14, 15, 18.
• Beta-blockers and ACE Inhibitors: May reduce the risk of heart failure and left ventricular dysfunction; evidence is strongest for patients receiving anthracyclines or HER2-targeted therapies 14, 16, 18.
• Statins and Angiotensin Antagonists: Emerging evidence suggests potential benefit in reducing cardiotoxicity 14.

Acute Management

• Discontinuation or Dose Adjustment: Immediate cessation or modification of the causative agent often leads to symptom resolution, especially in cases of 5-FU or trastuzumab-induced toxicity 4, 5.
• Symptomatic Therapy: Standard management of heart failure (diuretics, ACEi, beta-blockers) or arrhythmias as per clinical guidelines 5, 17, 18.

Long-term Follow-up and Cardio-Oncology

• Cardio-Oncology Collaboration: Multidisciplinary care between oncologists and cardiologists is critical for optimizing cancer treatment while minimizing cardiac risk 9, 17.
• Survivorship Care: Long-term cardiac monitoring, rehabilitation, and lifestyle modification are important for cancer survivors exposed to cardiotoxic agents 16, 17.

Future Directions

• Novel Agents: Research is ongoing into new cardioprotective strategies, including mitochondrial biogenesis enhancers and targeted therapies for specific molecular pathways 13, 15, 16.
• Personalized Medicine: Improved risk prediction and tailored interventions based on genetic and biomarker data are on the horizon 17.

Conclusion

Cardiotoxicity is a multifaceted and evolving challenge in modern medicine, particularly as cancer survival improves and the spectrum of therapies broadens. Early recognition, prevention, and coordinated care are key to minimizing its impact.

Key Takeaways:

• Cardiotoxicity can present with symptoms ranging from mild chest pain to life-threatening heart failure and arrhythmias 1, 2, 5.
• It encompasses a variety of cardiac complications, including arrhythmias, cardiomyopathy, ischemia, and pericarditis 2, 5, 7.
• Causes are multifactorial, involving drug mechanisms, patient factors, and treatment regimens, with anthracyclines, HER2-targeted agents, and radiation being major culprits 8, 9, 12.
• Treatment focuses on prevention, risk assessment, early detection, symptomatic management, and long-term follow-up, with dexrazoxane and neurohormonal antagonists showing benefit in select populations 14, 15, 16, 18.
• Emerging strategies, including cardio-oncology services and novel cardioprotective agents, hold promise for better outcomes in the future 9, 13, 17.

By staying vigilant and fostering collaboration between specialties, we can reduce the burden of cardiotoxicity and help patients thrive during and after cancer therapy.