5.4 Cardiotoxicity

Cardiotoxicity is a serious concern in medical treatments, affecting the heart and cardiovascular system. Various agents can cause harm, from therapeutic drugs to environmental toxins. Understanding the mechanisms and risk factors is crucial for preventing and managing these effects.

Cardiotoxic agents work through direct or indirect means, often involving multiple pathways. Key mechanisms include oxidative stress, mitochondrial dysfunction, ion channel disruption, and altered signaling. Recognizing these processes helps in developing targeted prevention and treatment strategies.

Mechanisms of cardiotoxicity

• Cardiotoxicity refers to the harmful effects of various agents on the heart and cardiovascular system
• Understanding the underlying mechanisms is crucial for predicting, preventing, and managing cardiotoxic effects
• Mechanisms can be broadly categorized as direct or indirect, and often involve multiple pathways and cellular processes

Direct vs indirect toxicity

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• Direct cardiotoxicity occurs when an agent directly damages cardiomyocytes or other cardiac structures (anthracyclines)
• Indirect cardiotoxicity arises from systemic effects that secondarily impact the heart (cytokine release, hypertension)
• Some agents may exhibit both direct and indirect cardiotoxic effects (cocaine)
• Distinguishing between direct and indirect mechanisms informs targeted prevention and treatment strategies

Oxidative stress in cardiomyocytes

• Oxidative stress results from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses
• Cardiomyocytes are particularly susceptible to oxidative damage due to high mitochondrial density and energy demands
• ROS can damage cellular macromolecules (lipids, proteins, DNA), leading to cell death and dysfunction
• Antioxidant therapies (dexrazoxane) aim to mitigate oxidative stress-induced cardiotoxicity

Mitochondrial dysfunction

• Mitochondria play a critical role in energy production, calcium homeostasis, and cell death signaling in cardiomyocytes
• Cardiotoxic agents can impair mitochondrial function through various mechanisms:
  • Inhibition of electron transport chain complexes (doxorubicin)
  • Increased mitochondrial permeability and cytochrome c release (sunitinib)
  • Disruption of mitochondrial biogenesis and dynamics (statins)
• Mitochondrial dysfunction leads to energy depletion, oxidative stress, and apoptosis, contributing to cardiac injury

Ion channel disruption

• Ion channels regulate the flow of ions (sodium, potassium, calcium) across cardiomyocyte membranes, essential for proper cardiac electrical activity and contractility
• Cardiotoxic agents can disrupt ion channel function through direct binding, altered expression, or modulation of regulatory proteins
• Examples include:
  • QT prolongation and Torsades de Pointes arrhythmia (antipsychotics, antihistamines)
  • Calcium channel blockade and reduced contractility (verapamil)
  • Sodium channel inhibition and conduction abnormalities (tricyclic antidepressants)
• Ion channel disruption can lead to arrhythmias, conduction disorders, and impaired cardiac function

Altered cardiac signaling pathways

• Cardiotoxic agents can interfere with various signaling pathways that regulate cardiomyocyte growth, survival, and function
• Examples include:
  • Inhibition of tyrosine kinase receptors and downstream signaling (trastuzumab, sunitinib)
  • Modulation of adrenergic and muscarinic receptors (beta-blockers, organophosphates)
  • Disruption of nitric oxide signaling and endothelial function (cocaine, radiation)
• Altered signaling can lead to maladaptive cardiac remodeling, hypertrophy, fibrosis, and impaired contractility

Types of cardiotoxic agents

• Cardiotoxicity can be caused by a wide range of agents, including therapeutic drugs, environmental toxins, and recreational substances
• Understanding the specific agents associated with cardiotoxicity is essential for risk assessment, monitoring, and management
• Cardiotoxic agents can be classified based on their mechanism of action, clinical indications, or chemical structure

Anthracyclines

• Anthracyclines (doxorubicin, daunorubicin) are chemotherapeutic agents used to treat various cancers (leukemia, lymphoma, breast cancer)
• Cardiotoxicity is a dose-dependent and cumulative adverse effect, often manifesting as cardiomyopathy and heart failure
• Mechanisms include oxidative stress, mitochondrial dysfunction, and topoisomerase II inhibition
• Risk factors include high cumulative dose, age extremes, and pre-existing heart disease

Tyrosine kinase inhibitors

• Tyrosine kinase inhibitors (TKIs) (imatinib, sunitinib) are targeted anticancer agents that inhibit specific kinase signaling pathways
• Cardiotoxicity can manifest as hypertension, left ventricular dysfunction, and heart failure
• Mechanisms involve disruption of cardiac signaling, mitochondrial dysfunction, and endothelial dysfunction
• Risk factors include pre-existing hypertension, coronary artery disease, and concomitant cardiotoxic therapies

Monoclonal antibodies

• Monoclonal antibodies (trastuzumab, bevacizumab) are targeted therapies used in cancer and autoimmune diseases
• Cardiotoxicity can present as left ventricular dysfunction, heart failure, and arrhythmias
• Mechanisms include inhibition of cardiac signaling pathways (HER2, VEGF) and immune-mediated inflammation
• Risk factors include prior anthracycline exposure, older age, and pre-existing cardiac conditions

Antipsychotics

• Antipsychotics (haloperidol, clozapine) are used to treat schizophrenia, bipolar disorder, and other psychiatric conditions
• Cardiotoxicity can manifest as QT prolongation, Torsades de Pointes arrhythmia, and sudden cardiac death
• Mechanisms involve ion channel disruption (potassium, sodium) and altered autonomic regulation
• Risk factors include high doses, concomitant QT-prolonging drugs, and electrolyte imbalances

Cocaine and amphetamines

• Cocaine and amphetamines are illicit stimulant drugs with significant cardiovascular toxicity
• Cardiotoxic effects include hypertension, arrhythmias, myocardial infarction, and cardiomyopathy
• Mechanisms involve increased sympathetic activity, coronary vasoconstriction, and direct myocardial toxicity
• Risk factors include high doses, chronic use, and pre-existing cardiovascular disease

Clinical manifestations

• Cardiotoxicity can present with a wide range of clinical manifestations, depending on the agent, dose, and individual susceptibility
• Recognizing the signs and symptoms of cardiotoxicity is crucial for early detection, intervention, and management
• Clinical manifestations can be acute or chronic and may involve various cardiac structures and functions

Acute vs chronic cardiotoxicity

• Acute cardiotoxicity occurs within hours to days of exposure and may present as arrhythmias, myocardial infarction, or sudden cardiac death (cocaine, antipsychotics)
• Chronic cardiotoxicity develops over weeks to years and often manifests as cardiomyopathy, heart failure, or valvular disease (anthracyclines, tyrosine kinase inhibitors)
• Some agents may cause both acute and chronic cardiotoxicity (radiation, alcohol)
• Distinguishing between acute and chronic manifestations guides monitoring, treatment, and long-term follow-up strategies

Arrhythmias

• Cardiotoxic agents can cause a variety of arrhythmias, including:
  • Tachyarrhythmias: sinus tachycardia, atrial fibrillation, ventricular tachycardia (amphetamines, alcohol)
  • Bradyarrhythmias: sinus bradycardia, atrioventricular block (beta-blockers, digoxin)
  • QT prolongation and Torsades de Pointes (antipsychotics, antihistamines)
• Arrhythmias may be asymptomatic or present with palpitations, syncope, or cardiac arrest
• Diagnosis involves electrocardiogram (ECG), ambulatory monitoring, and electrophysiological studies

Myocardial infarction

• Myocardial infarction (MI) can result from coronary artery spasm, thrombosis, or direct myocardial injury
• Cardiotoxic agents associated with MI include cocaine, amphetamines, and certain chemotherapeutic agents (5-fluorouracil, capecitabine)
• Clinical presentation includes chest pain, dyspnea, and ECG changes (ST-segment elevation or depression)
• Diagnosis involves cardiac biomarkers (troponins), ECG, and coronary angiography

Cardiomyopathy and heart failure

• Cardiomyopathy refers to structural and functional abnormalities of the myocardium, leading to impaired cardiac function
• Cardiotoxic agents can cause dilated, hypertrophic, or restrictive cardiomyopathy (anthracyclines, alcohol, cobalt)
• Heart failure presents with dyspnea, fatigue, edema, and reduced ejection fraction
• Diagnosis involves echocardiography, cardiac biomarkers (BNP, NT-proBNP), and functional assessment (NYHA class)

Valvular heart disease

• Valvular heart disease involves structural and functional abnormalities of cardiac valves, leading to regurgitation or stenosis
• Cardiotoxic agents associated with valvular disease include:
  • Serotonergic drugs (fenfluramine, pergolide): valvular regurgitation
  • Bisphosphonates: calcific aortic stenosis
  • Radiation therapy: valvular fibrosis and stenosis
• Clinical presentation includes murmurs, dyspnea, and signs of heart failure
• Diagnosis involves echocardiography and cardiac catheterization

Risk factors for cardiotoxicity

• Identifying risk factors for cardiotoxicity is essential for patient selection, monitoring, and preventive strategies
• Risk factors can be related to the agent, patient characteristics, or concomitant therapies
• Assessing and modifying risk factors can help minimize the incidence and severity of cardiotoxicity

Cumulative dose and duration of exposure

• Many cardiotoxic agents exhibit dose-dependent toxicity, with higher cumulative doses increasing the risk of cardiotoxicity (anthracyclines, tyrosine kinase inhibitors)
• Prolonged duration of exposure, even at lower doses, can also contribute to cardiotoxicity (alcohol, cocaine)
• Dose reduction, alternative scheduling, or early discontinuation may be considered in high-risk patients
• Therapeutic drug monitoring can help optimize dosing and minimize toxicity for certain agents (digoxin, lithium)

Age and pre-existing heart disease

• Older age is a significant risk factor for cardiotoxicity due to age-related changes in cardiac structure and function, comorbidities, and polypharmacy
• Children and adolescents may also be more susceptible to certain cardiotoxic agents (anthracyclines) due to developing cardiovascular system
• Pre-existing heart disease (coronary artery disease, heart failure, valvular disease) increases the risk of cardiotoxicity
• Careful assessment of baseline cardiac function and comorbidities is essential before initiating potentially cardiotoxic therapies

Genetic susceptibility

• Genetic factors can influence individual susceptibility to cardiotoxicity
• Examples include:
  • Polymorphisms in drug-metabolizing enzymes (CYP450) affecting pharmacokinetics and toxicity
  • Variants in genes involved in cardiac signaling, ion channels, and mitochondrial function
  • Familial predisposition to cardiomyopathies and arrhythmias
• Pharmacogenomic testing may help identify high-risk individuals and guide personalized therapy
• Genetic counseling may be considered for patients with a family history of cardiotoxicity or inherited cardiac conditions

Concomitant cardiotoxic therapies

• Concomitant use of multiple cardiotoxic agents can potentiate the risk of cardiotoxicity
• Examples include:
  • Combination chemotherapy regimens (anthracyclines + trastuzumab)
  • Concurrent use of QT-prolonging drugs (antipsychotics + antibiotics)
  • Polypharmacy in elderly patients with multiple comorbidities
• Careful review of medication regimens and potential drug interactions is essential to minimize additive or synergistic toxicity
• Alternative non-cardiotoxic therapies or dose adjustments may be considered when feasible

Monitoring and diagnosis

• Regular monitoring and early diagnosis of cardiotoxicity are crucial for timely intervention and prevention of irreversible cardiac damage
• Monitoring strategies should be tailored to the specific agent, patient risk factors, and expected toxicity profile
• A multimodal approach combining clinical assessment, imaging, and biomarkers is often necessary for comprehensive evaluation

Electrocardiogram (ECG) changes

• ECG is a simple and widely available tool for detecting cardiotoxicity-related abnormalities
• Key ECG changes to monitor include:
  • QT prolongation: indicator of delayed repolarization and risk of Torsades de Pointes (antipsychotics, antihistamines)
  • ST-segment changes: suggestive of myocardial ischemia or infarction (5-fluorouracil, capecitabine)
  • Arrhythmias: atrial fibrillation, ventricular tachycardia, bradyarrhythmias (amphetamines, beta-blockers)
• Serial ECG monitoring, especially during initiation or dose escalation of cardiotoxic agents, can help detect early changes
• ECG findings should be interpreted in the context of clinical presentation and other diagnostic modalities

Cardiac biomarkers (troponins, BNP)

• Cardiac biomarkers are sensitive indicators of myocardial injury and dysfunction
• Troponins (troponin I, troponin T) are specific markers of cardiomyocyte damage and are elevated in acute cardiotoxicity (anthracyclines, cocaine)
• Brain natriuretic peptide (BNP) and its precursor (NT-proBNP) are markers of ventricular stretch and are elevated in heart failure and cardiomyopathy
• Serial monitoring of biomarkers can help detect subclinical cardiotoxicity and guide therapy
• Interpretation of biomarker levels should consider assay-specific cut-offs, patient factors, and clinical context

Echocardiography and cardiac imaging

• Imaging modalities provide valuable information on cardiac structure and function
• Echocardiography is the first-line imaging tool for assessing cardiotoxicity
  • Evaluates left ventricular ejection fraction (LVEF), a key indicator of systolic function
  • Detects regional wall motion abnormalities, diastolic dysfunction, and valvular lesions
  • Serial monitoring of LVEF can guide dose modification or discontinuation of cardiotoxic agents
• Other imaging modalities (cardiac MRI, nuclear imaging) offer additional insights into myocardial tissue characterization, perfusion, and metabolism

Endomyocardial biopsy

• Endomyocardial biopsy involves sampling of myocardial tissue for histopathological and molecular analysis
• Indications for biopsy in cardiotoxicity evaluation include:
  • Unexplained cardiomyopathy or heart failure unresponsive to conventional therapy
  • Suspected infiltrative or inflammatory myocardial diseases (amyloidosis, sarcoidosis)
  • Research settings to study mechanisms of cardiotoxicity and develop biomarkers
• Biopsy findings (myocyte damage, fibrosis, inflammation) can guide diagnosis and targeted therapy
• Risks of biopsy (bleeding, perforation) should be weighed against potential benefits, and the procedure should be performed by experienced operators

Prevention and management strategies

• Preventing and mitigating cardiotoxicity is a key goal in the use of potentially cardiotoxic agents
• Prevention strategies aim to minimize the risk of cardiotoxicity while optimizing the therapeutic benefits
• Management approaches focus on early detection, prompt intervention, and long-term surveillance to improve cardiovascular outcomes

Dose modification and alternative therapies

• Dose reduction or modification of the cardiotoxic agent may be necessary to balance efficacy and toxicity
• Examples include:
  • Dexrazoxane administration before anthracycline therapy to reduce oxidative stress and cardiomyocyte damage
  • Liposomal formulations of anthracyclines to alter pharmacokinetics and reduce cardiac exposure
  • Intermittent dosing schedules or lower cumulative doses of tyrosine kinase inhibitors
• Alternative non-cardiotoxic therapies should be considered when available and appropriate for the underlying condition
• Multidisciplinary discussion involving oncologists, cardiologists, and other specialists is essential for optimizing treatment plans

Cardioprotective agents (dexrazoxane, beta-blockers)

• Cardioprotective agents can be used prophylactically or concurrently with cardiotoxic therapies to mitigate toxicity
• Dexrazoxane is an iron chelator that reduces anthracycline-induced oxidative stress and topoisomerase II inhibition
• Beta-blockers (carvedilol, metoprolol) have been shown to attenuate left ventricular dysfunction and heart failure in patients receiving anthracyclines or trastuzumab
• ACE inhibitors and ARBs may also have cardioprotective effects through reduction of afterload and neurohormonal