Figure 1 - available via license: Creative Commons Attribution 3.0 Unported
Content may be subject to copyright.
Source publication
Cardiovascular complications are a leading cause of therapy-related morbidity and mortality in long-term survivors of childhood malignancy. In fact, childhood cancer survivors are at a 15-fold risk of developing CHF compared to age-matched controls. There is a strong dose-dependent association between anthracycline exposure and risk of CHF, and the...
Context in source publication
Context 1
... American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the diagnosis and management of CHF describe it as a progressive disorder (Figure 1) [12]. Left ventricular (LV) dysfunction begins with some injury to, or stress on, the myocardium (stage A) and may be progressive even in the absence of a new identifiable insult to the heart. ...
Similar publications
This study concerns the problem of late complications of antineo-plastic therapy. Reduced parameters of the cardiorespiratory system in childhood may have a tremendous impact on health. In order to assess the selected parameters, to evaluate physical endurance, and compare the results with those obtained for healthy children, a test was carried out...
Citations
... Because of the high risk of late-onset cardiotoxicity, international guidelines (including the International Late Effects of Childhood Cancer Guideline Harmonization Group Cardiomyopathy guideline) recommend life-long echocardiographic screening every three to five years in CCS treated with anthracyclines or radiotherapy involving the heart [15][16][17][18][19]. However, early detection of subclinical cardiac damage in children and adolescents is crucial to initiate treatment at an early stage, provide optimal circumstances for cardiac recovery and remodeling, and hopefully prevent progression of myocardial disease into clinical heart failure [10,20,21]. In 1992, the Cardiology Committee of the Children's Cancer Study Group formulated recommendations for cardiac monitoring of children duringcancer treatment with anthracyclines [22]. ...
Background
Cardiotoxicity is among the most important adverse effects of childhood cancer treatment. Anthracyclines, mitoxantrone and radiotherapy involving the heart are its main causes. Subclinical cardiac dysfunction may over time progress to clinical heart failure. The majority of previous studies have focused on late-onset cardiotoxicity. In this systematic review, we discuss the prevalence and risk factors for acute and early-onset cardiotoxicity in children and adolescents with cancer treated with anthracyclines, mitoxantrone or radiotherapy involving the heart.
Methods
A literature search was performed within PubMed and reference lists of relevant studies. Studies were eligible if they reported on cardiotoxicity measured by clinical, echocardiographic and biochemical parameters routinely used in clinical practice during or within one year after the start of cancer treatment in ≥ 25 children and adolescents with cancer. Information about study population, treatment, outcomes of diagnostic tests used for cardiotoxicity assessment and risk factors was extracted and risk of bias was assessed.
Results
Our PubMed search yielded 3649 unique publications, 44 of which fulfilled the inclusion criteria. One additional study was identified by scanning the reference lists of relevant studies. In these 45 studies, acute and early-onset cardiotoxicity was studied in 7797 children and adolescents. Definitions of acute and early-onset cardiotoxicity prove to be highly heterogeneous. Prevalence rates varied for different cardiotoxicity definitions: systolic dysfunction (0.0–56.4%), diastolic dysfunction (30.0–100%), combinations of echocardiography and/or clinical parameters (0.0–38.1%), clinical symptoms (0.0–25.5%) and biomarker levels (0.0–37.5%). Shortening fraction and ejection fraction significantly decreased during treatment. Cumulative anthracycline dose proves to be an important risk factor.
Conclusions
Various definitions have been used to describe acute and early-onset cardiotoxicity due to childhood cancer treatment, complicating the establishment of its exact prevalence. Our findings underscore the importance of uniform international guidelines for the monitoring of cardiac function during and shortly after childhood cancer treatment.
... -Acute, occurs within 1 week of therapy in less than 1% of patients and manifests as arrhythmias, electrocardiogram (ECG) changes, transient depression of myocardial A long-term follow-up of 115 survivors showed that AC cardiomyopathy should be seen as a dynamic process, with a ventricular remodeling and a final shrinking myocardial cavity size for body surface area ("Grinch syndrome"). Chronic AC cardiomyopathy is of the most severe forms and causes HF, transplantation, and death in survivors of childhood cancer [25,26]. ...
Purpose of Review
Cardio-oncology is an increasingly important field of cardiology that focuses on the detection, monitoring, and treatment of cardiovascular disease (CVD) occurring during and after oncological treatments. The survival rate for childhood cancer patients has dramatically increased thanks to new treatment protocols and cardiovascular (CV) sequelae represent the third most frequent cause of mortality in surviving patients. This study aims to provide a complete and updated review of all the main aspects of cardio-oncology in childhood and to highlight the critical issues.
Recent Findings
The problem of CV complications in childhood cancer survivors raises the need to make an early diagnosis of cardiotoxicity by the new imaging and laboratory techniques in order to intervene promptly and to implement pharmacological strategies and lifestyle changes to reduce or even to prevent cardiac injury. Furthermore, a stratification of CV risk, also including new predisposing factors such as the presence of some genetic mutations, is of paramount importance before undertaking oncological treatments. Besides, a systematic and personalized planning of long-term follow-up is fundamental to ensure a transition from pediatric to adult hospital and to avoid missed or late diagnosis of cardiomyopathy.
Summary
We reviewed the main risk factors for cardiotoxicity in children, both traditional and emerging ones: the mechanisms of toxicity of both old and new antineoplastic therapies, the techniques for detecting cardiac damage, and the current evidence regarding pharmacological cardioprotection. At the end, we focused our attention on the existing guidelines and strategies about the long-term follow-up of childhood cancer survivors.
... Studies have demonstrated positive results in countering the cardiotoxic effects of chemotherapeutic agents, particularly anthracyclines, when patients are prescribed angiotensin-converting enzyme (ACE) inhibitors or beta-blockers [17,18]. Even in patients with chemotherapy-induced heart failure or hypertension, ACE inhibitors, beta-blockers, and statins have improved cardiac function and overall functional status of the patient [19]. ...
Cancer is the second most common cause of death in the United States and is a challenging disease to treat. The treatment options for various cancers include but are not limited to surgery, radiation, and chemotherapy. The mechanism behind chemotherapy is intended to promote cellular damage to cells that are proliferating uncontrollably. Unfortunately for the recipients, most chemotherapeutic agents cannot differentiate between malignant cells and healthy cells and tissues. Thus, chemotherapy-induced toxicities are often observed in once-healthy organs. These effects can be acute and self-limiting or chronic, appearing long after chemotherapy is completed. Cancer survivors can then present for non-cancer related surgeries later in life, due to this toxicity. Furthermore, the administration of chemotherapeutic agents can profoundly impact the anesthetic management of patients who are undergoing surgery. This review discusses how chemotherapy-induced organ toxicity can occur in multiple organ systems and what drugs should be avoided if prior toxicity exists in these organ systems.
... The most common fatal late complications in these survivors are secondary neoplasms and heart disease [3]. Epidemiological data has unequivocally linked doxorubicin (DOX), a chemotherapy agent used in over 50% of pediatric cancer cases [4], to acute and chronic cardiotoxicity [5][6][7]. While the drug has been in use since the 1970's, clinical and preclinical research has yet to produce an effective strategy to prevent chronic cardiotoxicity before or after exposure. ...
Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac disease is a common life-threatening outcome that is unequivocally linked to previous anthracycline exposure. The intricacies of how anthracyclines such as doxorubicin, damage the heart and initiate a disease process that progresses over multiple decades is not fully understood. One area left largely unstudied is the role of the cardiac fibroblast, a key cell type in cardiac maturation and injury response. In this study, we demonstrate the effect of doxorubicin on cardiac fibroblast function in the presence and absence of the critical DNA damage response protein p53. In wildtype cardiac fibroblasts, doxorubicin-induced damage correlated with decreased proliferation and migration, cell cycle arrest, and a dilated cardiomyopathy gene expression profile. Interestingly, these doxorubicin-induced changes were completely or partially restored in p53-/- cardiac fibroblasts. Moreover, in wildtype cardiac fibroblasts, doxorubicin produced DNA damage and mitochondrial dysfunction, both of which are well-characterized cell stress responses induced by cytotoxic chemotherapy and varied forms of heart injury. A 3-fold increase in p53 (p = 0.004) prevented the completion of mitophagy (p = 0.032) through sequestration of Parkin. Interactions between p53 and Parkin increased in doxorubicin-treated cardiac fibroblasts (p = 0.0003). Finally, Parkin was unable to localize to the mitochondria in wildtype cardiac fibroblasts, but mitochondrial localization was restored in p53-/- cardiac fibroblasts. These findings strongly suggest that cardiac fibroblasts are an important myocardial cell type that merits further study in the context of doxorubicin treatment. A more robust knowledge of the role cardiac fibroblasts play in the development of doxorubicin-induced cardiotoxicity will lead to novel clinical strategies that will improve the quality of life of cancer survivors.
... The most common fatal late complications in these survivors are secondary neoplasms and heart disease 3 . Epidemiological data has unequivocally linked doxorubicin (DOX), a chemotherapy agent used in over 50% of pediatric cancer cases 4 , to acute and chronic cardiotoxicity [5][6][7] . While the drug has been in use since the 1970's, clinical and preclinical research has yet to produce an effective strategy to prevent chronic cardiotoxicity before or after exposure. ...
Doxorubicin is a mainstay in pediatric chemotherapy treatment because of its efficacy treating leukemia and lymphoma. Unfortunately, every childhood cancer survivor will develop a chronic health problem, one of the most serious being cardiac disease. How doxorubicin damages the heart in such a way that disease progression occurs over multiple decades is still not understood.
The dose of doxorubicin selected does not cause apoptosis but does arrest cell cycle. It also decreases the cells ability to migrate. Gene profiling indicated a cardiac remodeling and inflammatory profile. Mitochondria increased ROS production and underwent membrane depolarization. Secondly, the Parkin:p53 interaction mechanism was investigated. Doxorubicin was found to increase p53 expression and it was shown to sequester Parkin. As a result, mitophagy in doxorubicin-treated cells was decreased. Lastly, cardiac fibroblasts were isolated from p53 null mice and treated with doxorubicin. The gene expression phenotype in these cells was attenuated and migration was restored. Proliferation was still decreased. Mitochondrial dysfunction was also partially attenuated. Without p53, Parkin could now localize to the mitochondria and mitophagy was restored.
Doxorubicin induces a deleterious phenotype in cardiac fibroblasts that may be due to the interaction between two stress responses caused by doxorubicin-induced DNA and mitochondrial damage. Cardiac fibroblasts are a viable target and further research needs to be done to elucidate other harmful mechanisms at play in the fibroblast. Knowledge about the importance of cardiac fibroblasts in the development of doxorubicin-induced cardiotoxicity and a pathological mechanism broadens our understanding and ability to develop protective therapies to improve the quality of life of cancer survivors.
... Because cardiac complications are frequently not detected until the manifestation of symptoms, these screening guidelines are designed to identify patients who are on the path to heart failure, before it becomes irreversible. While still being investigated, it is thought that DOX-induced congestive heart failure is refractory to standard pharmacological treatment used for heart failure caused by other etiologies (11). Another aspect of patient care is education and the importance of long-term follow up must be impressed upon all cancer survivors. ...
Doxorubicin‐induced cardiotoxicity in childhood cancer survivors is a growing problem. The population of patients at risk for cardiovascular disease is steadily increasing, as five‐year survival rates for all types of childhood cancers continue to improve. Doxorubicin affects the developing heart differently from the adult heart and in a subset of exposed patients, childhood exposure leads to late, irreversible cardiomyopathy. Notably, the prevalence of late‐onset toxicity is increasing in parallel with improved survival. By the year 2020, it is estimated that there will be 500,000 childhood cancer survivors and over 50,000 of them will suffer from doxorubicin‐induced cardiotoxicity.
The majority of the research to‐date, concentrated on childhood cancer survivors, has focused mostly on clinical outcomes through well‐designed epidemiological and retrospective cohort studies. Preclinical studies have elucidated many of the cellular mechanisms that elicit acute toxicity in cardiomyocytes. However, more research is needed in the areas of early‐ and late‐onset cardiotoxicity and more importantly improving the scientific understanding of how other cells present in the cardiac milieu are impacted by doxorubicin exposure.
The overall goal of this review is to succinctly summarize the major clinical and preclinical studies focused on doxorubicin‐induced cardiotoxicity. As the prevalence of patients affected by doxorubicin exposure continues to increase, it is imperative that the major gaps in existing research are identified and subsequently utilized to develop appropriate research priorities for the coming years. Well‐designed preclinical research models will enhance our understanding of the pathophysiology of doxorubicin‐induced cardiotoxicity and directly lead to better diagnosis, treatment, and prevention. © 2019 American Physiological Society. Compr Physiol 9:905‐931, 2019.
... Successful prevention of cardiotoxicity in childhood cancer patients requires a multifactorial approach (Figure 3). 64 Primary prevention strategies include the evolution of oncology treatment protocols to reduce the exposure to anthracyclines, radiation, and other agents known to be cardiotoxic, as well as development of effective cardioprotective strategies. Secondary prevention strategies are directed towards survivors who have already been exposed to cardiotoxic agents but in whom clinical changes and symptoms have not yet occurred. ...
... Overview of cancer-related cardiomyopathy prevention strategies. From Armenian et al.64 ...
With five-year survival of children with cancer exceeding 80% in developed countries, premature cardiovascular disease is now a major cause of early morbidity and mortality. In addition to the acute and chronic cardiotoxic effects of anthracyclines, related chemotherapeutics, and radiation, a growing number of new molecular targeted agents may also have detrimental effects on the cardiovascular system. Survivors of childhood cancer also may have earlier development of conventional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes, which further increase their risk of serious cardiovascular disease. This review will examine the epidemiology of acute and chronic cardiotoxicity relevant to pediatric cancer patients, including genetic risk factors. We will also provide an overview of current screening recommendations, including the evidence regarding both imaging (e.g., echocardiography and magnetic resonance imaging) and blood-based biomarkers. Various primary and secondary prevention strategies will also be discussed, primarily in relation to anthracycline-related cardiomyopathy. Finally, we review the available evidence related to the management of systolic and diastolic dysfunction in pediatric cancer patients and childhood cancer survivors.
... As discussed previously, important risk factors for anthracycline-related CHF include anthracycline dose, chest radia on, presence of conven onal cardiovascular risk factors, and, in some studies, age at ini al cancer diagnosis and sex. 45 Given the high incidence of and poor outcomes a er anthracycline-related CHF, anthracycline-exposed survivors may benefi t from customized and validated risk predic on models. Leveraging the resources off ered by the Childhood Cancer Survivor Study (CCSS) cohort, the inves gators created a clinically useful model that incorporated demographic and cancer treatment informa on available at the end of therapy to predict subsequent CHF risk with reasonable discrimina on among 5-year survivors and then validated the resul ng risk scores in two external cohorts. ...
Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are among the most potent chemotherapeutic agents and have truly revolutionized the management of childhood cancer. They form the backbone of chemotherapy regimens used to treat childhood acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin lymphoma, Ewing sarcoma, osteosarcoma, and neuroblastoma. More than 50% of children with cancer are treated with anthracyclines. The clinical utility of anthracyclines is compromised by dose-dependent cardiotoxicity, manifesting initially as asymptomatic cardiac dysfunction and evolving irreversibly to congestive heart failure. Childhood cancer survivors are at a five- to 15-fold increased risk for congestive heart failure compared with the general population. Once diagnosed with congestive heart failure, the 5-year survival rate is less than 50%. Prediction models have been developed for childhood cancer survivors (i.e., after exposure to anthracyclines) to identify those at increased risk for cardiotoxicity. Studies are currently under way to test risk-reducing strategies. There remains a critical need to identify patients with childhood cancer at diagnosis (i.e., prior to anthracycline exposure) such that noncardiotoxic therapies can be contemplated.
... Studies on pediatric ALL survivors have reported a high prevalence of the typical components of the metabolic syndrome (MetS) such as obesity (7), hypertension (8), glucose tolerance (9) or dyslipidemia (10), and clustering of the 3 surrogates of MetS was also described (11). While chemo-and radiotherapy have often been associated with the development of these disorders in childhood cancer survivors (12)(13)(14)(15), the precise etiology and the mechanisms of these late complications are not fully understood. ...
Survivors of acute lymphoblastic leukemia (ALL), the most common cancer in children, are at increased risk of developing late cardiometabolic conditions. However, the mechanisms are not fully understood. The study aimed to characterize plasma lipid profile, Apolipoprotein (Apo) distribution and lipoprotein composition of 80 childhood ALL survivors compared to 22 healthy controls. Our results show that, despite their young age, 50% of the ALL survivors displayed dyslipidemia, characterized by increased plasma TG and LDL-cholesterol, as well as decreased HDL-cholesterol. ALL survivors exhibited lower plasma Apo A-I and higher Apo B-100 and C-II levels, along with elevated Apo C-II/C-III and B-100/A-I ratios. VLDL fractions of dyslipidemic ALL survivors contained more TG, free cholesterol and phospholipid moieties, but less protein. Differences in Apo content were found between ALL and controls for all lipoprotein fractions except HDL3. Especially, HDL2 showed reduced Apo A-I and raised Apo A-II, leading to a depressed Apo A-I/A-II ratio. Analysis of VLDL-Apo Cs disclosed a trend for higher Apo C-III1 content in dyslipidemic ALL survivors. In conclusion, this thorough investigation demonstrates a high prevalence of dyslipidemia in ALL survivors while highlighting significant abnormalities in their plasma lipid profile and lipoprotein composition. Special attention must, therefore, be paid to these subjects given the atherosclerotic potency of lipid and lipoprotein disorders.
... In contrast, ACEI therapy has appeared to be only marginally effective in anthracycline-induced CM. A retrospective review of doxorubicin-exposed survivors of childhood cancer with HF revealed that treatment with enalapril was associated with only transient improvement in LV dimension, afterload, and systolic function (Armenian et al., 2012). ...
The renin-angiotensin system (RAS) is one of important systems among homeostatic mechanisms that controls the function of cardiovascular, renal and adrenal systems. As RAS has a very complex nature, it has been also found as related to the control of cell migration and apoptosis. Angiotensin-converting enzyme inhibitors (ACEI) are drugs most commonly used in the modulation of RAS activity. ACEI have been extensively described as effective in the treatment of hypertension among adults, but also as drugs delaying progression in diabetic nephropathy and reducing mortality in left ventricular dysfunction and congestive heart failure. What is less obvious, ACEI are also widely used in pediatric nephrology and cardiology. Moreover, there are more and more reports showing evidence that ACEI can be beneficial in the treatment of many other diseases and the pleiotropic activity of ACEI is mainly based on their antioxidant properties. In this paper we focus on the less obvious possibilities of the clinical use of ACEI in neurological or oncological patients, discuss the role of ACE gene polymorphism and show the perspectives of potentially new applications of ACEI in contemporary pharmacotherapy.
