[Update cardio-oncology : Immune checkpoint inhibitor therapy]. / Update Kardioonkologie : Immuncheckpoint-Inhibitor-Therapie.

Cardiovascular diseases and cancer are the most common causes of death in Germany. Cancer treatment can lead to significant cardiovascular side effects and thus form a link between the two disease groups. The focus of cardio-oncology is on the best possible prevention, diagnostics and treatment of cardiovascular complications caused by cancer treatment. It is crucial for cardio-oncology to adapt to the continuous development of new forms of oncological treatment with previously unknown cardiovascular side effects. One such new form of treatment is immune checkpoint inhibitor (ICI) therapy, which is regarded as the most important oncological milestone of the last decade due to its excellent oncological efficacy; however, the growing use has revealed a high risk of diverse cardiovascular side effects with high morbidity and mortality, so that cardio-oncological care of affected patients is of particular importance. This review summarizes the current scientific and clinical state of the pathophysiology, incidence, diagnosis and treatment of cardiovascular side effects of ICI therapy.

Genome-wide analysis in PC6 electroacupuncture to ameliorate carfilzomib-induced cardiotoxicity in mice.

Carfilzomib (CFZ), a proteasome inhibitor commonly used in the treatment of multiple myeloma (MM), exhibits limited clinical application due to its cardiotoxicity. In our study, electroacupuncture (EA) at Neiguan acupoint (PC6) effectively reversed CFZ-induced reduction in ejection fraction (EF) and fractional shortening (FS), demonstrating great potential effect for heart protection. Through comparative analysis of the transcriptome profile from heart samples of mice treated with DMSO control, CFZ injection, and EA stimulation, we identified a total of 770 differentially expressed genes (DEGs) in CFZ (vs. Control) group and 329 DEGs in EA (vs. CFZ) group. Specifically, CFZ (vs. Control) group exhibited 65 up-regulated DEGs and 705 down-regulated DEGs, while EA (vs. CFZ) group displayed 251 up-regulated DEGs and 78 down-regulated DEGs. Metascape analysis revealed that among these treatment groups, there were 137 co-expressed DEGs remarkably enriched in skeletal system development, cellular response to growth factor stimulus, negative regulation of Wnt signaling pathway, and muscle contraction. The expression patterns of miR-8114, Myl4, Col1a1, Tmem163, Myl7, Sln, and Fxyd3, which belong to the top 30 DEGs, were verified by quantitative real-time PCR (RT-qPCR). In summary, this study firstly discloses novel insights into the regulatory mechanisms underlying PC6-based EA therapy against CFZ-induced cardiotoxicity, potentially serving as a theoretical foundation for further clinical applications.

Cardiotoxicity in breast cancer treatment: Causes and mitigation.

Survivorship issues and treatment related toxicities have considerably increased in breast cancer patients following improved therapeutic options. Cardiotoxicity has been a major treatment related side effects in these patients. Despite this being a well-known entity, the real magnitude of the problem remains an enigma. The amount of research in mitigation of cardiotoxicity or its management in breast cancer survivors is limited and there is an urgent need for finding solutions for the problem. In this article, we are reviewing the agents that cause cardiotoxicity and suggesting a proposal for follow up of breast cancer survivors in an attempt to reduce the magnitude of impact on their quality of life.

Equity in Cardio-Oncology Care and Research: A Scientific Statement From the American Heart Association.

Advances in cancer therapeutics have revolutionized survival outcomes in patients with cancer. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Recent studies have uncovered excess risks of these cardiotoxic events, especially in traditionally underrepresented populations. Despite advances in strategies to limit the risks of cardiovascular events among cancer survivors, relatively limited guidance is available to address the rapidly growing problem of disparate cardiotoxic risks among women and underrepresented patient populations. Previously decentralized and sporadic evaluations have led to a lack of consensus on the definitions, investigation, and potential optimal strategies to address disparate cardiotoxicity in contemporary cancer care (eg, with immunotherapy, biologic, or cytotoxic therapies) settings. This scientific statement aims to define the current state of evidence for disparate cardiotoxicity while proposing uniform and novel methodological approaches to inform the identification and mitigation of disparate cardio-oncology outcomes in future clinical trials, registries, and daily clinical care settings. We also propose an evidence-based integrated approach to identify and mitigate disparities in the routine clinical setting. This consensus scientific statement summarizes and clarifies available evidence while providing guidance on addressing inequities in the era of emerging anticancer therapies.

Vagus nerve stimulation exerts cardioprotection against doxorubicin-induced cardiotoxicity through inhibition of programmed cell death pathways.

The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3 mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1 mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5 mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR.

Breast milk mesenchymal stem cells abate cisplatin-induced cardiotoxicity in adult male albino rats via modulating the AMPK pathway.

Myocardial injury influenced by cisplatin (Cis) is a compelling reason to hunt out a treatment modality to overcome such a threat in cisplatin-treated patients. Breast Milk mesenchymal stem cells (Br-MSCs) are a non-invasive, highly reproducible source of stem cells. Herein, we investigate Br-MSCs' role in cardiotoxicity induced by cisplatin. Rats were divided into; control, Cis-treated (received 12 mg/kg single intraperitoneal injection), BrMSCs-treated (received single intraperitoneal injection of 0.5 ml sterilized phosphate-buffered saline containing 2 × 107 cells of Br-MSCs); metformin-treated (received 250 mg/kg/day orally) and BrMSCs + metformin + Cis treated groups. At the experiment end, serum creatine kinase (CK-MB) and cardiac troponin T (cTnT) activates were estimated, cardiac malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) levels were measured, cardiac expression of Bax and Bcl-2 and AMP-activated protein kinase (AMPK), as well as heart histopathology, were evaluated. Study results showed that Cis explored acute cardiotoxicity evidenced by deteriorated cardiac indices, induction of oxidative stress, and inflammation with myocardium histological alterations. Treatment with Br-MSCs restored heart function and structure deteriorated by Cis injection. The antioxidant/anti-inflammatory/anti-apoptotic results of Br-MSCs were supported by AMPK activation denoting their protective role against cisplatin-induced cardiac injury. These results were superior when metformin was added to the treatment protocol.

Intravenously transplanted mesenchymal stromal cells: a new endocrine reservoir for cardioprotection.

BACKGROUND: Intravenous administration of mesenchymal stromal cells (MSCs) has an acknowledged competence of cardiac repair, despite a lack of systematic description of the underlying biological mechanisms. The lung, but not the heart, is the main trapped site for intravenously transplanted MSCs, which leaves a spatial gap between intravenously transplanted MSCs and the injured myocardium. How lung-trapped MSCs after intravenous transplantation rejuvenate the injured myocardium remains unknown. METHODS: MSCs were isolated from human placenta tissue, and DF-MSCs or Gluc-MSCs were generated by transduced with firefly luciferase (Fluc)/enhanced green fluorescence protein (eGFP) or Gaussia luciferase (Gluc) lactadherin fusion protein. The therapeutic efficiency of intravenously transplanted MSCs was investigated in a murine model of doxorubicin (Dox)-induced cardiotoxicity. Trans-organ communication from the lung to the heart with the delivery of blood was investigated by testing the release of MSC-derived extracellular vesicles (MSC-EVs), and the potential miRNA inner MSC-EVs were screened out and verified. The potential therapeutic miRNA inner MSC-EVs were then upregulated or downregulated to assess the further therapeutic efficiency RESULTS: Dox-induced cardiotoxicity, characterized by cardiac atrophy, left ventricular dysfunction, and injured myocardium, was alleviated by consecutive doses of MSCs. These cardioprotective effects might be attributed to suppressing GRP78 triggering endoplasmic reticulum (ER) stress-induced apoptosis in cardiomyocytes. Our results confirmed that miR-181a-5p from MSCs-derived EVs (MSC-EVs) inhibited GRP78. Intravenous DF-MSCs were trapped in lung vasculature, secreted a certain number of EVs into serum, which could be confirmed by the detection of eGFP+ EVs. GLuc activity was increased in serum EVs from mice administrated with GLuc-MSCs. MiR-181a-5p, inhibiting GRP78 with high efficacy, was highly expressed in serum EVs and myocardium after injecting consecutive doses of MSCs into mice treated with Dox. Finally, upregulation or downregulation of miR-181a-5p levels in MSC-EVs enhanced or weakened therapeutic effects on Dox-induced cardiotoxicity through modulating ER stress-induced apoptosis. CONCLUSIONS: This study identifies intravenously transplanted MSCs, as an endocrine reservoir, to secrete cardioprotective EVs into blood continuously and gradually to confer the trans-organ communication that relieves Dox-induced cardiotoxicity.

Cardio-Oncology Care Delivered in the Non-academic Environment.

OPINION STATEMENT: It is a fact that the field of Cardio-Oncology is growing rapidly throughout the USA and abroad. Cancer and heart disease continue to be the leading causes of death in the USA, and oncologic therapies are evolving to the point that cancer survivors are increasing yearly, some living long enough to develop cardiovascular disease, and others living with sequelae from their cancer therapy. The financial burdens to the healthcare system continue to present barriers for the delivery of healthcare, especially for patients with heart disease and cancer as chronic diseases. Collaboration between cardiologists and oncologists is paramount to ensure timely cancer care while minimizing cardiotoxicity. The field of Cardio-Oncology is the perfect model for the current management of these patients, positioned to break down silos, avoid delays in cancer care, and treating potential short- and long-term sequela of cancer therapy in a cost-efficient manner. While cardio-oncology programs initially sprang from the academic and defined cancer centers, it is rapidly growing in the nonacademic settings. This paper explores reasons that occurred and explores some of the unique aspects to cancer care and cardio-oncology delivery in the nonacademic setting. The ultimate goal is to achieve the best cancer care with the least degree of disruption to therapy that also minimizes cardiotoxicity, lowering costs, and improving outcomes for patients.

Efficacy of lipid emulsion therapy in treating cardiotoxicity from diphenhydramine ingestion: a review and analysis of case reports.

INTRODUCTION: Lipid emulsion therapy (LET) has been most thoroughly studied to reverse local anesthetic systemic toxicity (LAST). Case reports suggest that LET can successfully rescue cardiovascular collapse from bupropion, amitriptyline, and propranolol. The efficacy of LET against refractory hypotension and dysrhythmias from diphenhydramine, a commonly ingested lipophilic cardiotoxic agent, is less well described. OBJECTIVE: Summarize the evidence that LET rescues cardiac ion channel blockade (QRS, QTc widening) or hypotension attributable to diphenhydramine overdose. METHODS: We searched MEDLINE, EMBASE, and Google Scholar for English-language full-length case reports of diphenhydramine (DPH) intoxication in patients 17 years of age or older. We extracted data with a PRISMA-compliant protocol, dividing the case reports into two groups, one that received LET and one that did not. We performed a pooled analysis to compare the change in mean arterial pressure (MAP), QRS duration, and QTc duration between the two groups. RESULTS: We identified 23 reports (25 patients). Lipid emulsion therapy (LET) was used in 6 cases because the patient suffered from hypotension refractory to traditional resuscitation. Those who received LET and those who did not were comparable in age, gender, amount ingested, and frequency of seizures. The mean arterial pressure (MAP) decreased by 4.5 ± 11.5 mm Hg in those who did not receive LET compared to an increase in MAP 37 ± 17.5 mm Hg in those who did receive LET. The QRS narrowed by 29 ± 33.9 ms (no LET group) vs 68 ± 49.5 ms (LET group) and QTc by 168.5 ± 126.75 ms (no LET group) vs 134 ± 88 ms (LET group). All values are expressed as median ± interquartile range. One out of the 6 patients who received LET died after withdrawal of care. In the group that did not receive LET 4 out of 19 died and 3 had no outcome reported. DISCUSSION: LET may improve MAP in patients with hypotension refractory to vasopressors due to diphenhydramine toxicity. We found no significant effect of LET on QRS or QTc duration. These results are limited by a small sample size, reporting bias of case reports, incomplete data, and heterogeneity. CONCLUSION: An analysis of pooled case reports suggests that LET may rescue hypotension when other methods have failed in patients with hypotension attributable to diphenhydramine overdose.

Cardiotoxicity of Antineoplastic Therapies and Applications of Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

The therapeutic landscape for the treatment of cancer has evolved significantly in recent decades, aided by the development of effective oncology drugs. However, many cancer drugs are often poorly tolerated by the body and in particular the cardiovascular system, causing adverse and sometimes fatal side effects that negate the chemotherapeutic benefits. The prevalence and severity of chemotherapy-induced cardiotoxicity warrants a deeper investigation of the mechanisms and implicating factors in this phenomenon, and a consolidation of scientific efforts to develop mitigating strategies. Aiding these efforts is the emergence of induced pluripotent stem cells (iPSCs) in recent years, which has allowed for the generation of iPSC-derived cardiomyocytes (iPSC-CMs): a human-based, patient-derived, and genetically variable platform that can be applied to the study of chemotherapy-induced cardiotoxicity and beyond. After surveying chemotherapy-induced cardiotoxicity and the associated chemotherapeutic agents, we discuss the use of iPSC-CMs in cardiotoxicity modeling, drug screening, and other potential applications. Improvements to the iPSC-CM platform, such as the development of more adult-like cardiomyocytes and ongoing advances in biotechnology, will only enhance the utility of iPSC-CMs in both basic science and clinical applications.

An Emergent Form of Cardiotoxicity: Acute Myocarditis Induced by Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system, aiming at enhancing antitumor immunity. ICIs have shown great promise in the treatment of several advanced malignancies. However, therapy with these immunomodulatory antibodies may lead to a wide spectrum of immune-related adverse events in any organ and any tissue. Cardiologic immune-related events include pericarditis, pericardial effusion, various types of arrhythmias including the occurrence of complete atrioventricular block, myocardial infarction, heart failure, and myocarditis. Although relatively rare, myocarditis is associated with a very high reported mortality in comparison to other adverse events. Myocarditis often presents significant diagnostic complexity and may be under-recognized. When confronted with an unexpected change in the clinical picture, the physician must differentiate between immune-related adverse events, cancer worsening, or other causes unrelated to the cancer or its therapy. However, this is not always easy. Therefore, with the increasing use of checkpoint inhibitors in cancer, all providers who care for patients with cancer should be made aware of this rare, but potentially fatal, cardiologic immune-related adverse event, and able to recognize when prompt consultation with a cardiologist specialist is indicated. In this review, we evaluate currently available scientific evidence and discuss clinical manifestations and new potential approaches to the diagnosis and therapy of acute myocarditis induced by ICIs. Temporary or permanent discontinuation of the ICIs and high-dose steroids have been administered to treat myocarditis, but symptoms may worsen in some patients despite therapy.

Recognition, Prevention, and Management of Arrhythmias and Autonomic Disorders in Cardio-Oncology: A Scientific Statement From the American Heart Association.

With the advent of novel cancer therapeutics and improved screening, more patients are surviving a cancer diagnosis or living longer with advanced disease. Many of these treatments have associated cardiovascular toxicities that can manifest in both an acute and a delayed fashion. Arrhythmias are an increasingly identified complication with unique management challenges in the cancer population. The purpose of this scientific statement is to summarize the current state of knowledge regarding arrhythmia identification and treatment in patients with cancer. Atrial tachyarrhythmias, particularly atrial fibrillation, are most common, but ventricular arrhythmias, including those related to treatment-induced QT prolongation, and bradyarrhythmias can also occur. Despite increased recognition, dedicated prospective studies evaluating true incidence are lacking. Moreover, few studies have addressed appropriate prevention and treatment strategies. As such, this scientific statement serves to mobilize the cardio-oncology, electrophysiology, and oncology communities to develop clinical and scientific collaborations that will improve the care of patients with cancer who have arrhythmias.

Enfermedad cardíaca inducida por radiación: Implicaciones prácticas en su prevención, diagnóstico y tratamiento / Radiation-Induced Heart Disease: Practical Implications for Its Prevention, Diagnosis, and Treatment

Resumen La radioterapia representa una herramienta terapéutica de gran utilidad en el tratamiento de varios tipos de cáncer. Cuando se emplea a lesiones en tórax existe el riesgo de aplicar determinada radiación en el corazón y consecuentemente presentar complicaciones cardíacas. Los efectos adversos se pueden observar en los distintos componentes del corazón y las manifestaciones pueden apreciarse principalmente a largo plazo. Mediante una evaluación integral del riesgo cardiovascular, la identificación de las terapias concomitantes con potencial cardiotóxico, la aplicación de técnicas de radioterapia con función protectora del corazón y el control con estudios cardiológicos se intenta optimizar el desenlace oncológico y cardiovascular de los pacientes. En aquellos pacientes que se presenten con complicaciones cardíacas, existen varias opciones terapéuticas tanto quirúrgicas como percutáneas, que implican un desafío dado la complejidad de los casos. Finalmente, existen distintas consideraciones de manejo para los pacientes con dispositivos electrónicos cardíacos implantables. Estrategia de búsqueda: Se realizó una búsqueda en Pubmed de artículos bajo el criterio de radioterapia y corazón, con un intervalo de tiempo de los últimos 5 años hasta agosto 2020, escritos en inglés. Además, se buscaron referencias cruzadas y se incluyeron documentos de consenso de parte de sociedades de cardiología internacionales.

Abstract Radiation-Induced Heart Disease: Practical Implications for Its Prevention, Diagnosis, and Treatment The radiotherapy represents a very useful therapeutic tool for the treatment of different types of cancer. When it is used to treat thoracic lesions there is a risk of appliying a determined radiation dose to the heart and consequently develop cardiac complications. The adverse effects can be seen in distinct heart components and the manifestations can be appreciated mainly in the long term. Through an integral evaluation of the cardiovascular risk, the identification of concomitant therapies with cardiotoxic potential, the application of heart sparing radiotherapy techniques and the control with cardiac tests, it is intended to optimize the oncologic and cardiovascular outcomes of the patients. In those patients who present with cardiac complications, there are several therapeutic options ranging from chirurgic to percutaneous, which are challenging given the complexity of the cases. Finally, there are different considerations in regard to the management of patients with electronically implantable cardiaca devices. Search strategy: A search was carried out in Pubmed for articles under the criteria of radiotherapy and heart, with a time interval of the last 5 years until August 2020, written in English. In addition, cross-references were searched and consensus documents from international cardiology societies were included.

What the Cardiologist Needs to Know About Cancer Immunotherapies and Complications.

OPINION STATEMENT: Immunotherapies have transformed the current landscape for cancer treatment and demonstrated unparalleled improvements in survival rates. Now, a third of cancer patients are eligible for treatment with the most widely used class of immunotherapy, immune checkpoint inhibitors (ICIs). As more patients are treated with these novel agents, it is critical for both oncologists and subspecialists to establish a better understanding of the adverse events which can occur. The incidence of myocarditis associated with ICI therapy has been reported to be between 0.27 and 1.14%, 5 times that of myocarditis from other cancer therapies, and, of those patients, 20-50% develop a fulminant form. However, because of unclear risk factors, a broad clinical spectrum, and lack of specific noninvasive studies for diagnosis, the care of patients with ICI-associated cardiotoxicity can be challenging. Here, we have provided a brief overview of the current immunotherapy agents with a focus on the emerging evidence regarding diagnosis and management of cardiac adverse events.

Saved by the pump: Two successful resuscitations utilising emergency department-initiated extracorporeal cardiopulmonary resuscitation in South Africa.

Extracorporeal life support is the utilisation of advanced techniques to sustain circulatory and/or ventilatory functions in critically ill patients when standard therapies fail. It is well established in developed countries. There is increasing literature supporting its application in refractory cardiac arrest with a potential reversible cause, a procedure also known as extracorporeal cardiopulmonary resuscitation (eCPR). Two cases where eCPR was successfully utilised in a busy (>30 000 visits per year) private South African emergency department are described here, the first such cases to be reported on the African continent. The first patient had a life-threatening cardiac arrhythmia due to toxin ingestion, and the second a refractory ventricular fibrillation due to acute myocardial infarction. In both these cases the cardiac arrest was witnessed, occurred in the emergency department, and failed to respond to standard advanced resuscitative measures. Both the patients were discharged neurologically intact. Although it is effective, the benefit of this advanced method of resuscitation in a low- to middle-income country is debated.

PD-1/PDL-1 Inhibitors and Cardiotoxicity; Molecular, Etiological and Management Outlines.

Background: The US Food and Drug Administration (FDA) has approved several immunotherapeutic drugs for cancer since 2010, and many more are still being evaluated in other clinical studies. These inhibitors significantly increase response rates and result in the treatment of patients with advanced cancer. However, cancer immunotherapy leads to essential cardiac toxicity properties that have become distinct from other cancer patients' care and are mostly related to their etiology. Aim of review: As potential implications, the occurrence of cardiovascular adverse events is particularly challenging and needs a comprehensive understanding of overall cancer-related etiology, clinical outcomes with different variable severity, and management. Key scientific concepts of review: In terms of improving the overall survival of patients with cancer, clinicians should be careful in selecting either programmed cell death-1 (PD-1) or its programmed cell death ligand (PDL-1) inhibitors by evaluating their risk and clinical benefit for early intervention and decrease the level of morbidity and mortality of their patients. This review focuses on the effectiveness of PD-1/PL-1 antibodies and associated cardiotoxicity adverse events, including etiological mechanisms, diagnosis, and treatment.

Incidence and Management of Carfilzomib-induced Cardiovascular Toxicity; A Systematic Review and Meta-analysis.

BACKGROUND: The ASPIRE and ENDEAVOUR trials have shown cardiovascular adverse effects in patients treated with carfilzomib-based regimens. Therefore, we conducted this meta- analysis of published clinical trials to identify the cumulative incidence and risk of cardiovascular adverse effects due to carfilzomib. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed, and we identified 45 prospective trials of carfilzomib with data on 5583 patients. Among all patients being treated with carfilzomib (N=5,583), 8.9% sustained all grade cardiotoxicity, while 4.4% sustained high-grade cardiotoxicity. All-grade hypertension was present in 13.2%, while the incidence of high-grade hypertension was 5.3%. RESULTS: The observed incidences of all-grade heart failure, edema, and ischemia were 5.1%, 20.7%, and 4.6%, respectively. Likewise, for high-grade heart failure and edema observed incidence was 3.2%, and 2.7%, respectively. There was no difference in the event rate of all and highgrade cardiotoxicity between newly diagnosed multiple myeloma and relapsed/refractory (p-value 0.42 and 0.86, respectively). Likewise, we did not observe any difference in the event rate of all and high-grade cardiotoxicity when carfilzomib was used as a single agent versus when used in combination therapy with other agents (p-value 0.43 and 0.73, respectively). CONCLUSION: Carfilzomib is associated with a significant risk of cardiovascular toxicity and hypertension. With the increasing utilization of carfilzomib, it is critical for primary care physicians, oncologists and cardiologists to be aware of the risk of cardiotoxicity associated with the use of carfilzomib to recognize and treat baseline cardiovascular risk factors in such patients.

Cardioprotective effects of exercise training on doxorubicin-induced cardiomyopathy: a systematic review with meta-analysis of preclinical studies.

Doxorubicin (DOX)-induced cardiotoxicity in chemotherapy is a major treatment drawback. Clinical trials on the cardioprotective effects of exercise in cancer patients have not yet been published. Thus, we conducted a systematic review and meta-analysis of preclinical studies for to assess the efficacy of exercise training on DOX-induced cardiomyopathy. We included studies with animal models of DOX-induced cardiomyopathy and exercise training from PubMed, Web of Sciences and Scopus databases. The outcome was the mean difference (MD) in fractional shortening (FS, %) assessed by echocardiography between sedentary and trained DOX-treated animals. Trained DOX-treated animals improved 7.40% (95% CI 5.75-9.05, p < 0.001) in FS vs. sedentary animals. Subgroup analyses revealed a superior effect of exercise training execution prior to DOX exposure (MD = 8.20, 95% CI 6.27-10.13, p = 0.010). The assessment of cardiac function up to 10 days after DOX exposure and completion of exercise protocol was also associated with superior effect size in FS (MD = 7.89, 95% CI 6.11-9.67, p = 0.020) vs. an echocardiography after over 4 weeks. Modality and duration of exercise, gender and cumulative DOX dose did were not individually associated with changes on FS. Exercise training is a cardioprotective approach in rodent models of DOX-induced cardiomyopathy. Exercise prior to DOX exposure exerts greater effect sizes on FS preservation.

Extract from Arrabidaea chica (Fridericia chica) leaves show preventive action for the mitigation of doxorubicin-induced cardiotoxicity / [Extrato das folhas de Arrabidaea chica (Fridericia chica) mostrou potencial ação no combate à cardiotoxicidade induzida pela doxorrubicina]

A doxorrubicina (dox) é um medicamento antineoplásico que induz cardiotoxicidade por estresse oxidativo. Os flavonoides são antioxidantes extraídos de plantas como Camellia sinensis e Arrabidaea chica (Fridericia chica). Esta pesquisa objetivou avaliar efeitos protetores do extrato de A. chica (AC), comparado ao de C. sinensis (CS), frente ao estresse oxidativo induzido pela dox, no coração. Cardiomiócitos e células neoplásicas MDA-MB 231 foram incubados com AC e CS. Depois, adicionou-se dox e avaliaram-se taxas de viabilidade e morte celular. A citometria de fluxo para o ensaio de iodeto de propídeo (IP) em cardiomiócitos mostrou as seguintes taxas de morte celular: controle 53%; dox 78% (maior que controle, P=0,015); AC_12,5µg/mL + dox 65% (menor que dox, P=0,031); AC_25µg/mL + dox 62% (menor que dox, P=0,028); AC_50µg/mL + dox 63% (menor que dox, P=0,030); CS_12,5µg/mL + dox 71% (menor que dox, P=0,040); CS_25µg/ml + dox 69% (menor que dox, P=0,037); CS_50µg/mL + dox 74% (menor que dox, P=0,044). Resultados das células MDA-MB 231 mostraram que nenhum extrato interferiu na atividade antitumoral da dox. Os dados de IP foram corroborados pelos de MTT. Este estudo reporta promissora utilização de A. chica na prevenção da cardiotoxicidade induzida pela dox.(AU)

Telomerase therapy attenuates cardiotoxic effects of doxorubicin.

Doxorubicin is one of the most potent chemotherapeutic agents. However, its clinical use is restricted due to the severe risk of cardiotoxicity, partially attributed to elevated production of reactive oxygen species (ROS). Telomerase canonically maintains telomeres during cell division but is silenced in adult hearts. In non-dividing cells such as cardiomyocytes, telomerase confers pro-survival traits, likely owing to the detoxification of ROS. Therefore, we hypothesized that pharmacological overexpression of telomerase may be used as a therapeutic strategy for the prevention of doxorubicin-induced cardiotoxicity. We used adeno-associated virus (AAV)-mediated gene therapy for long-term expression of telomerase in in vitro and in vivo models of doxorubicin-induced cardiotoxicity. Overexpression of telomerase protected the heart from doxorubicin-mediated apoptosis and rescued cardiac function, which was accompanied by preserved cardiomyocyte size. At the mechanistic level, we observed altered mitochondrial morphology and dynamics in response to telomerase expression. Complementary in vitro experiments confirmed the anti-apoptotic effects of telomerase overexpression in human induced pluripotent stem cell-derived cardiomyocytes after doxorubicin treatment. Strikingly, elevated levels of telomerase translocated to the mitochondria upon doxorubicin treatment, which helped to maintain mitochondrial function. Thus, telomerase gene therapy could be a novel preventive strategy for cardiotoxicity by chemotherapy agents such as the anthracyclines.