Overview
This lecture focused on doxorubicin-induced cardiomyopathy, discussing its mechanisms, diagnosis, risk factors, current and emerging preventive strategies, and relevant research.
Doxorubicin and Its Use
- Doxorubicin is a chemotherapeutic agent derived from Streptomyces, used for many cancers including breast cancer.
- Its mechanism includes DNA damage via topoisomerase II inhibition and reactive oxygen species (ROS) formation.
- While effective, these actions also underlie its toxic effects, notably cardiomyopathy.
Risk Factors for Cardiotoxicity
- Risk increases with cumulative dose (>500 mg/m²) but may be lower.
- Other risk factors: female sex, age (>65 or <4 years), concurrent radiation, other drugs, and pre-existing heart disease.
- Genetic predisposition is suggested but no screening markers are validated yet.
Diagnosis of Doxorubicin-Induced Cardiomyopathy
- Diagnosed by >10% drop in ejection fraction to <53%, confirmed on repeat imaging within 2-3 weeks.
- 2D echocardiography is commonly used; modified Simpson’s method preferred.
- 3D echo and MUGA scans offer improved accuracy but have limitations.
- Advanced imaging methods (strain imaging, MRI) and biomarkers (troponin) are being investigated but lack clear guidelines.
Mechanisms of Cardiotoxicity
- Doxorubicin causes mitochondrial dysfunction, oxidative stress, iron accumulation, and impaired calcium handling.
- Binding to topoisomerase 2B leads to DNA damage and apoptosis.
- Cardiotoxicity is dose-dependent and generally irreversible.
Prevention and Therapeutic Approaches
- Standard heart failure therapies (beta-blockers, ACE inhibitors, ARBs) show some promise in prevention.
- Statins may prevent cardiotoxicity via anti-inflammatory effects (mainly preclinical data).
- Dexrazoxane chelates mitochondrial iron, reducing ROS, but is reserved for high-risk patients due to concerns about tumor response and myelosuppression.
Emerging Research: Podip2 and Onco-1
- Podip2 is a multifunctional protein involved in DNA repair and metabolism; its knockdown in cardiac cells protects against doxorubicin toxicity.
- Knockdown increases glycolysis in cardiac cells, reducing ROS formation, but enhances apoptosis in cancer cells.
- Onco-1, a drug activating mitochondrial proteins, mimics these effects and may offer dual benefit (cardiac protection, enhanced tumor cell death).
- Animal and cell studies show promise, but clinical validation is needed.
Clinical Considerations and Imaging
- Cardiotoxicity sometimes presents years after therapy, especially in childhood cancer survivors.
- Strain imaging may detect dysfunction earlier than ejection fraction.
- Echocardiography is recommended for baseline and follow-up assessments; local practice may favor echo over MUGA.
Key Terms & Definitions
- Doxorubicin — chemotherapy drug causing DNA damage and ROS, used to treat various cancers.
- Cardiomyopathy — disease of the heart muscle resulting in reduced cardiac function.
- Ejection Fraction — percentage of blood pumped out of the ventricles with each heartbeat.
- Reactive Oxygen Species (ROS) — harmful byproducts of cellular metabolism contributing to cell damage.
- Podip2 — protein involved in DNA repair and cellular metabolism; target for cardioprotection.
- Dexrazoxane — iron chelator used to prevent doxorubicin-induced cardiac injury.
- Strain Imaging — echocardiographic method to assess subtle changes in cardiac function.
Action Items / Next Steps
- Review assigned materials on current guidelines for cardiac monitoring in chemotherapy.
- Complete reading on emerging biomarkers and imaging technologies for early cardiotoxicity detection.
- Follow up on additional literature regarding Podip2 and Onco-1 for future seminar discussion.