Cardiovascular Biomarkers in Cardio-Oncology: Antineoplastic Drug Cardiotoxicity and Beyond.

Serum biomarkers represent a reproducible, sensitive, minimally invasive and inexpensive method to explore possible adverse cardiovascular effects of antineoplastic treatments. They are useful tools in risk stratification, the early detection of cardiotoxicity and the follow-up and prognostic assessment of cancer patients. In this literature review, we aim at describing the current state of knowledge on the meaning and the usefulness of cardiovascular biomarkers in patients with cancer; analyzing the intricate relationship between cancer and cardiovascular disease (especially HF) and how this affects cardiovascular and tumor biomarkers; exploring the role of cardiovascular biomarkers in the risk stratification and in the identification of chemotherapy-induced cardiotoxicity; and providing a summary of the novel potential biomarkers in this clinical setting.

Gender Differences and Cardiometabolic Risk: The Importance of the Risk Factors.

Metabolic syndrome (Mets) is a clinical condition characterized by a cluster of major risk factors for cardiovascular disease (CVD) and type 2 diabetes: proatherogenic dyslipidemia, elevated blood pressure, dysglycemia, and abdominal obesity. Each risk factor has an independent effect, but, when aggregated, they become synergistic, doubling the risk of developing cardiovascular diseases and causing a 1.5-fold increase in all-cause mortality. We will highlight gender differences in the epidemiology, etiology, pathophysiology, and clinical expression of the aforementioned Mets components. Moreover, we will discuss gender differences in new biochemical markers of metabolic syndrome and cardiovascular risk.

Epicardial fat volume assessed with cardiac magnetic resonance imaging in patients with Takotsubo cardiomyopathy.

PURPOSE: The aims of our study were to investigate with cardiovascular magnetic resonance (CMR) the role of Epicardial Fat Volume (EFV) and distribution in patients with Takotsubo cardiomyopathy (TTC). Moreover, we explored EFV in patients with TTC and related this to comorbidities, cardiac biomarkers, and cardiac function. METHODS: This retrospective study performed CMR scans in 30 consecutive TTC patients and 20 healthy controls. The absolute amount of EFV was quantified in consecutive short-axis cine stacks through the modified Simpson's rule. In addition, the left atrio-ventricular groove (LV) and right ventricle (RV) Epicardial Fat Thickness (EFT) were measured as well. Besides epicardial fat, LV myocardial strain parameters and T2 mapping measurements were obtained. RESULTS: TTC patients and controls were of comparable age, sex, and body mass index. Compared to healthy controls, patients with TTC demonstrated a significantly increased EFV, epicardial fat mass, and EFV indexed for body 7surface area (p = 0.005; p = 0.003; p = 0.008; respectively). In a multiple regression model including age, sex, BMI, atrial fibrillation, and dyslipidemia, TTC remained an independent association with EFV (p = 0.008). Global T2 mapping and Global longitudinal strain in patients with TTC were correlated with EFV (r = 0.63, p = 0.001, and r = 0.44, p = 0.02, respectively). CONCLUSION: Patients with TTC have increased EFV compared to healthy controls, despite a similar body mass index. The amount of epicardial fat was associated with CMR markers of myocardial inflammation and subclinical contractile dysfunction.

Cardiovascular Risk Perception and Knowledge among Italian Women: Lessons from IGENDA Protocol.

A multicenter, cross-sectional observational study (Italian GENder Differences in Awareness of Cardiovascular risk, IGENDA study) was carried out to evaluate the perception and knowledge of cardiovascular risk among Italian women. An anonymous questionnaire was completed by 4454 women (44.3 ± 14.1 years). The 70% of respondents correctly identified cardiovascular disease (CVD) as the leading cause of death. More than half of respondents quoted cancer as the greatest current and future health problem of women of same age. Sixty percent of interviewed women considered CVD as an almost exclusively male condition. Although respondents showed a good knowledge of the major cardiovascular risk factors, the presence of cardiovascular risk factors was not associated with higher odds of identifying CVD as the biggest cause of death. Less than 10% of respondents perceived themselves as being at high CVD risk, and the increased CVD risk perception was associated with ageing, higher frequency of cardiovascular risk factors and disease, and a poorer self-rated health status. The findings of this study highlight the low perception of cardiovascular risk in Italian women and suggest an urgent need to enhance knowledge and perception of CVD risk in women as a real health problem and not just as a as a life-threatening threat.

Non-invasive coronary imaging in patients with COVID-19: A narrative review.

SARS-CoV-2 infection, responsible for COVID-19 outbreak, can cause cardiac complications, worsening outcome and prognosis. In particular, it can exacerbate any underlying cardiovascular condition, leading to atherosclerosis and increased plaque vulnerability, which may cause acute coronary syndrome. We review current knowledge on the mechanisms by which SARS-CoV-2 can trigger endothelial/myocardial damage and cause plaque formation, instability and deterioration. The aim of this review is to evaluate current non-invasive diagnostic techniques for coronary arteries evaluation in COVID-19 patients, such as coronary CT angiography and atherosclerotic plaque imaging, and their clinical implications. We also discuss the role of artificial intelligence, deep learning and radiomics in the context of coronary imaging in COVID-19 patients.

Non-invasive estimation of stroke volume during exercise from oxygen in heart failure patients.

AIMS: In heart failure, oxygen uptake and cardiac output measurements at peak and during exercise are important in defining heart failure severity and prognosis. Several cardiopulmonary exercise test-derived parameters have been proposed to estimate stroke volume during exercise, including the oxygen pulse (oxygen uptake/heart rate). Data comparing measured stroke volume and the oxygen pulse or stroke volume estimates from the oxygen pulse at different stages of exercise in a sizeable population of healthy individuals and heart failure patients are lacking. METHODS: We analysed 1007 subjects, including 500 healthy and 507 heart failure patients, who underwent cardiopulmonary exercise testing with stroke volume determination by the inert gas rebreathing technique. Stroke volume measurements were made at rest, submaximal (∼50% of exercise) and peak exercise. At each stage of exercise, stroke volume estimates were obtained considering measured haemoglobin at rest, predicted exercise-induced haemoconcentration and peripheral oxygen extraction according to heart failure severity. RESULTS: A strong relationship between oxygen pulse and measured stroke volume was observed in healthy and heart failure subjects at submaximal (R2 = 0.6437 and R2 = 0.6723, respectively), and peak exercise (R2 = 0.6614 and R2 = 0.5662) but not at rest. In healthy and heart failure subjects, agreement between estimated and measured stroke volume was observed at submaximal (-3 ± 37 and -11 ± 72 ml, respectively) and peak exercise (1 ± 31 and 6 ± 29 ml, respectively) but not at rest. CONCLUSION: In heart failure patients, stroke volume estimation and oxygen pulse during exercise represent stroke volume, albeit with a relevant individual data dispersion so that both can be used for population studies but cannot be reliably applied to a single subject. Accordingly, whenever needed stroke volume must be measured directly.

Multimodality Imaging Diagnosis of Multiple Ventricular Thrombosis and Massive Stroke after Gemcitabine and Cisplatin Chemotherapy for Urothelial Cancer.

Cancer and chemotherapy are known to be risk factors for developing coagulative disorders, venous thrombosis, adverse cardiovascular events, and cardiotoxicity. Combined modality gemcitabine-cisplatin chemotherapy is often administered to treat a few solid tumors. We report the unusual case of a man suffering from urothelial cancer and admitted for chemotherapy, who developed an ischemic stroke after the last chemotherapeutical cycle. During his hospital stay, at echocardiographic examination, left ventricular transient hypokinesia and two intraventricular thrombi were detected, without evidence of acute coronary syndrome. Multimodality imaging approach (i.e., transthoracic echo, transoesophageal echo, computed tomography, and cardiac magnetic resonance imaging) played a pivotal role for a clear diagnosis and prompt decision-making. This is the first report of an intraventricular-related arterial thromboembolic event in a patient treated with the combination gemcitabine-cisplatin.

Women-specific predictors of cardiovascular disease risk - new paradigms.

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in women in spite of the overall reduction in age-adjusted CVD mortality in the past few years. Although traditional risk factors for CVD are predictors of increased risk in both men and women, risk factors that are unique to women and related to their reproductive history have recently been considered to be important. The development of CVD in women may correlate with specific events taking place throughout a woman's obstetric and gynaecological history. Gynaecological conditions such as polycystic ovary syndrome, premature ovarian failure, surgical and spontaneous menopause, and conditions related to pregnancy, i.e. gestational diabetes, preeclampsia, intrauterine growth restriction, miscarriages, and preterm birth, may affect the onset, clinical features, and prognosis of CVD later in women's lives. These pathological conditions that develop during the fertile period of life or peri-menopause have been suggested to be early markers of future CVD; their presence presents a unique opportunity for the early identification of women who may be at an increased risk of CVD. The assessment of CV risk in women should not just focus on conventional risk factors but also on different aspects of the gynaecological history to allow specific preventive and therapeutic strategies to be established. This paper reviews the various pathological conditions occurring in women during their fertile period of life and peri-menopause, which have been identified to potentially increase CVD risk.

From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview.

Significance: Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. Critical Issues: CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Future Directions: Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system.

Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective.

Antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity (CTX). Biochemical studies have identified multiple mechanisms of CTX. Chemoterapeutic agents can alter redox homeostasis by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species RNS. Cellular sources of ROS/RNS are cardiomyocytes, endothelial cells, stromal and inflammatory cells in the heart. Mitochondria, peroxisomes and other subcellular components are central hubs that control redox homeostasis. Mitochondria are central targets for antineoplastic drug-induced CTX. Understanding the mechanisms of CTX is fundamental for effective cardioprotection, without compromising the efficacy of anticancer treatments. Type 1 CTX is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents. Type 2 CTX, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs. Although oxidative/nitrosative reactions play a central role in CTX caused by different antineoplastic drugs, additional mechanisms involving directly and indirectly cardiomyocytes and inflammatory cells play a role in cardiovascular toxicities. Identification of cardiologic risk factors and an integrated approach using molecular, imaging, and clinical data may allow the selection of patients at risk of developing chemotherapy-related CTX. Although the last decade has witnessed intense research related to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental and clinical studies are urgently needed to balance safety and efficacy of novel cancer therapies.

Gender differences in the development of cardiac complications: a multicentre study in a large cohort of thalassaemia major patients to optimize the timing of cardiac follow-up.

We assessed whether male gender was associated with a higher risk of cardiac iron accumulation and fibrosis, heart dysfunction and complications in a large, multicentre cohort of thalassaemia major (TM) patients, in order to optimize the timing in cardiac follow-up. We considered 1711 TM patients (899 females, 31·09 ± 9·08 years), enrolled in the Myocardial Iron Overload in Thalassaemia Network. Clinical/instrumental data are recorded from birth to the first Cardiovascular Magnetic Resonance Imaging scan. Although having a similar risk of accumulating iron, males showed a significantly higher risk of developing cardiac dysfunction, heart failure, arrhythmias and cardiac complications overall, when compared to females (P < 0·0001). Up to 20-30 years of follow-up, the Kaplan-Meier curves for the outcomes for which the male sex was a significant prognosticator almost overlapped, whereas they clearly diverged after this period. In patients with follow-up longer than 20 years, males exhibited a significantly higher risk of ventricular dysfunction, heart failure, arrhythmias, and cardiac complications. Female patients may have an intrinsically better tolerance for iron toxicity. International guidelines suggest annual cardiac evaluation for thalassaemia patients. It is possible that female patients can be evaluated at longer intervals, thus reducing health costs.

Effects of a mini-trampoline rebounding exercise program on functional parameters, body composition and quality of life in overweight women.

BACKGROUND: Mini-trampoline rebounding exercise (MRE) is becoming a very popular form of fitness training. Despite awareness of this activity worldwide, a limited number of studies have systematically investigated the health effects correlated with MRE training. The aim of our study was to evaluate manifold health outcomes after 12 weeks of an MRE program in a group of overweight Italian women. METHODS: Eighteen overweight women (age 38.05±10.5 years, BMI: 27.6±2.1 kg/m2) were enrolled in this study. Functional profile, strength, body composition, quality of life and pain intensity were assessed at baseline and after 12 weeks of MRE. RESULTS: Significant improvements were observed in the measurements of anthropometric profile and body composition (circumferences, fat mass, lean and muscular mass). Both a significant decrease in systolic and diastolic blood pressure values (from 128/80.5 to 123/71 mmHg, P<0.05) and an improvement in lipid and glucose profiles were observed. At maximal exercise testing, an increase in work capacity (from 104 to 123 watts, P=0.003) and VO2max (from 15.4 to 16.9 mL/kg/min, P=0.04) was found. SF-36 showed positive changes in four of the eight items as well as in the Mental Component Summary. With regard to the Brief Pain Inventory-SF, a decrease in both pain severity and the pain interference score was detected. CONCLUSIONS: MRE appears feasible to ensure positive effects on overall health and can be proposed to populations that could greatly benefit from training programs, such as overweight women.

Modelling Chemotherapy-induced Cardiotoxicity by Human Pluripotent Stem Cells.

Novel antineoplastic therapies have greatly improved cancer survival; nevertheless they are bringing in new forms of cardiomyopathy, that can often limit proper cancer treatments. Novel cardioprotective therapies are therefore needed, for improving clinical outcomes in cancer patients. In order to test novel therapeutic strategies, there is an increasing need for appropriate experimental models of chemotherapy-induced cardiomyopathy. Induced pluripotent stem (iPS) cell- and human embryonic stem cell (hESC )-derived cardiomyocytes may be used as alternative in vitro models for studying mechanisms that underly chemotherapy-induced cardiomyopathy. In this review we discuss the use of iPS- and hESC-derived cardiomyocytes for evaluating additional pharmacological targets and for predicting chemotherapy-induced cardiotoxicity.

Evaluation of left atrial appendage function and thrombi in patients with atrial fibrillation: from transthoracic to real time 3D transesophageal echocardiography.

The detection of embolic sources in patients with atrial fibrillation (AF) is important to guide anticoagulant therapy. Two-dimensional transesophageal echocardiography (TEE) is the gold standard to study left atrial appendage (LAA) anatomy and morphology, despite some false-positive diagnosis. We hypothesized that real time 3D TEE (RT3DTEE) is superior to 2DTEE in detecting and/or excluding LAA thrombi. We studied 93 patients with non-valvular AF (60 males, age = 67.1 ± 14.2 years) referred for electric cardioversion with transthoracic, 2DTEE and RT3DTEE. Before cardioversion, TTE allowed a confident measurement of emptying velocity of LAA (LAAeV) only in 59/93 patients (63%). On the contrary a good quality TEE LAAeV was obtained in all patients with 49/93 (53%) dysfunctional LAA (LAAeV < 40 cm/s). A subgroup of 5 patients (7.2% of the 69 effective cardioversion) presented a persistent dysfunction after cardioversion (with LAAeV values of <40 cm/s on the TEE post-CV). TEE allowed to observe a bilobed shape in 45 patients (48.4%) and three lobes in 22 patients (23.7%). In addition, besides to several additional findings, 2DTEE managed to detect thrombi with certainty in 8/93 patients (8.6%). In other 5 cases with diagnostic doubts for thrombi with 2DTEE (5/93 patients: 5.4%), the addition of the RT3DTEE mode allowed to discriminate with certainty the presence of just pectinate muscles in 4 patients RT3DTEE in patients with AF at risk of embolism is feasible, accurate and showed an additional diagnostic capability in the differential diagnosis of selected cases with suspected LAA thrombi.

Timing of the negative effects of trastuzumab on cardiac mechanics after anthracycline chemotherapy.

Trastuzumab (TZB) has been shown to be extremely effective in breast cancer patients over-expressing HER-2, but careful cardiac monitoring is required when TZB is administered with anthracyclines, since the combination can increase its toxicity. Myocardial deformation indexes associated with speckle tracking echocardiography (STE) have proven to be very sensitive in identifying early myocardial dysfunction. An observational, prospective study was designed to assess TZB-induced cardiac damage using STE in patients with HER-2 positive breast cancer who had been sequentially treated with TZB following epirubicin (EPI). Conventional echocardiographic parameters and STE deformation indexes (longitudinal, radial, and circumferential strain/strain rate and apical rotation) were analyzed at baseline, after each EPI treatment, and 1 week after every other dose of TZB administration until 1 year follow up, in order to focus on the timing and extent of myocardial impairment. In the forty-five enrolled patients, a reduction in subendocardial function after EPI treatment was observed by a significant impairment of the global longitudinal strain/strain rate (GLS/SR), while a significant increase in the activity of the subepicardial fibers was highlighted by an increase in apical rotation. After the second TZB dose, a sudden reduction of the apical rotation was seen, together with circumferential and radial strain/SR. Most importantly, the extent to which the apical rotation increased and decreased was found to strictly correlate with the GLS reduction at follow up. We found that after EPI therapy, subendocardial function was impaired, even while a compensatory increase in apical rotation occurred. Following TZB treatment, we observed impairment in apical rotation, which seems to be the first sign of global LV dysfunction predicting GLS reduction found at the end of treatment.

Pathophysiology of cardiotoxicity induced by nonanthracycline chemotherapy.

The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes). Here, we review the incidence, clinical impact, and potential mechanisms of CTX associated with nonanthracycline chemotherapy used for cancer patients. The published data support a marked increase in CTX risk, particularly with certain drugs such as 5-fluorouracil and cisplatin. Each anticancer regimen is associated with distinct modes of heart damage, both symptomatic and asymptomatic. However, the underlying mechanisms of CTX have been established only in a few cases, and only few nonanthracycline chemotherapeutics (mitoxantrone, mitomycin, ifosfamide) act through a recognizable mechanism and show a predictable dose dependence. Lastly, nonanthracycline chemotherapy can induce both chronic lesions, such as systolic dysfunction, and acute lesions, such as the ischemia that occurs within hours or days after treatment. An increased understanding of the incidence, mechanisms, and potential therapeutic targets of CTX induced by various nonanthracycline chemotherapeutic agents is clearly required.

Cardiovascular imaging in the diagnosis and monitoring of cardiotoxicity: role of echocardiography.

The evaluation by cardiovascular imaging of chemotherapy patients became a central topic in the last several years. The use of drugs for the treatment of cancers increased, and new molecules and protocols were developed to improve outcomes in these patients. Although, these novel approaches also produced a progressive increase in side effects, particularly myocardial dysfunction. Imaging of the heart was highly accurate in the early diagnosis of cancer therapeutics related-cardiac dysfunction. Echocardiography is the first-line method to assess ventricular function alterations, and it is required to satisfy the need for an early, easy and accurate diagnosis to stratify the risk of heart failure and manage treatments. A careful monitoring of cardiac function during the course of therapy should prevent the onset of severe heart impairment. This review provides an overview of the most important findings of the role of echocardiography in the management of chemotherapy-treated patients to create a clear and complete description of the efficacy of conventional measurements, the importance of comprehensive heart evaluations, the additional role of new echocardiographic techniques, the utility of integrated studies using other imaging tools and the positions of the most important international societies on this topic.

Role of biomarkers in monitoring antiblastic cardiotoxicity.

Early detection of anticancer drug-induced cardiotoxicity (CTX) has been evaluated by most international scientific cardiology and oncology societies. High expectations have been placed on the use of specific biomarkers. In recent years, conventional biomarkers and molecules of more recent interest have been tested and compared in the context of anticancer drug-related CTX. Encouraging results were obtained from studies on molecules of myocardial damage, such as troponin and markers of myocardial wall stress, including circulating natriuretic peptides, as well as from the assessment of the products of inflammation or circulating levels of free radicals. However, clear guidelines on their sensitivity, specificity, and accuracy are not yet available, and many challenges, such as the optimal time of assessing, optimal schedule for evaluation, optimal cut-off point for positivity with the highest level of specificity, and optimal comparability of different assays for the measurements, remain unresolved. Given the importance of having a reliable and accurate tool for monitoring anticancer drug-induced CTX, this review will focus on the available data on the most effective and widely used biomarkers and the studies that are currently underway that aim to identify the effectiveness of new approaches in this therapeutic setting.

Cardiovascular imaging in the diagnosis and monitoring of cardiotoxicity: cardiovascular magnetic resonance and nuclear cardiology.

Chemotherapy-induced cardiotoxicity (CTX) is a determining factor for the quality of life and mortality of patients administered potentially cardiotoxic drugs and in long-term cancer survivors. Therefore, prevention and early detection of CTX are highly desirable, as is the exploration of alternative therapeutic strategies and/or the proposal of potentially cardioprotective treatments. In recent years, cardiovascular imaging has acquired a pivotal role in this setting. Although echocardiography remains the diagnostic method most used to monitor cancer patients, the need for more reliable, reproducible and accurate detection of early chemotherapy-induced CTX has encouraged the introduction of second-line advanced imaging modalities, such as cardiac magnetic resonance (CMR) and nuclear techniques, into the clinical setting. This review of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology aims to afford an overview of the most important findings from the literature about the role of CMR and nuclear techniques in the management of chemotherapy-treated patients, describe conventional and new parameters for detecting CTX from both diagnostic and prognostic perspectives and provide integrated insight into the role of CMR and nuclear techniques compared with other imaging tools and versus the positions of the most important international societies.

Preventing antiblastic drug-related cardiomyopathy: old and new therapeutic strategies.

Because of the recent advances in chemotherapeutic protocols, cancer survival has improved significantly, although cardiovascular disease has become a major cause of morbidity and mortality among cancer survivors: in addition to the well-known cardiotoxicity (CTX) from anthracyclines, biologic drugs that target molecules that are active in cancer biology also interfere with cardiovascular homeostasis.Pharmacological and non-pharmacological strategies to protect the cardiovascular structure and function are the best approaches to reducing the prevalence of cardiomyopathy linked to anticancer drugs. Extensive efforts have been devoted to identifying and testing strategies to achieve this end, but little consensus has been reached on a common and shared operability.Timing, dose and mode of chemotherapy administration play a crucial role in the development of acute or late myocardial dysfunction. Primary prevention initiatives cover a wide area that ranges from conventional heart failure drugs, such as ß-blockers and renin-angiotensin-aldosterone system antagonists to nutritional supplementation and physical training. Additional studies on the pathophysiology and cellular mechanisms of anticancer-drug-related CTX will enable the introduction of novel therapies.We present various typologies of prevention strategies, describing the approaches that have already been used and those that could be effective on the basis of a better understanding of pharmacokinetic and pharmacodynamic CTX mechanisms.