Cardioprotective effect of grape polyphenol extract against doxorubicin induced cardiotoxicity.

Doxorubicin is a chemotherapeutic agent known to cause cardiotoxicity that is thought to be associated with oxidative stress. The aim of the current study is to investigate the role of grape polyphenols' antioxidant property as cardioprotective against doxorubicin-induced cardiotoxicity. Adult Wistar rats weighing 200 ± 20 g were divided into 3 different groups: a doxorubicin group that received a single intraperitoneal administration of doxorubicin (8.0 mg/kg body weight), an experimental group that received doxorubicin and grape polyphenol concentrate (25 mg/kg) via intragastric route, and the third group was a negative control group that received water only. On day 8, blood samples and tissues were harvested for analyses. The results indicated that grape polyphenol concentrate was able to reduce the signs of cardiotoxicity of doxorubicin through the reduction of aspartate aminotransferase activation, increasing the plasma antioxidant levels and decreasing the level of free radicals. The results also showed that grape polyphenol concentrate was able to reverse doxorubicin-induced microscopic myocardial damage. The myocardial protective effect of grape polyphenol might likely be due to the increase in the level and activity of the antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. In conclusion, grape polyphenol concentrate displayed cardioprotective effect and was able to reverse doxorubicin-induced-cardiomyopathy in experimental rats.

Cardiovascular Toxicities of Immune Checkpoint Inhibitors: JACC Review Topic of the Week.

Immune checkpoint inhibitors (ICIs) have been an important therapeutic advance in the field of cancer medicine, resulting in a significant improvement in survival of patients with advanced malignancies. Recent reports provided greater insights into the incidence of cardiovascular adverse events (CVAEs) with ICI use. Myocarditis is the most common CVAE associated with ICI. Pericardial diseases, Takotsubo syndrome, arrhythmias, and vasculitis constitute other significant AEs. Physicians should be aware of these infrequent, but potentially fatal toxicities associated with ICIs as their therapeutic use becomes widespread with a myriad of approvals by the U.S. Food and Drug Administration. Management involves prompt administration of high-dose corticosteroids and discontinuation of ICIs in severe myocarditis. This review summarizes the most updated evidence on epidemiology, pathophysiological mechanisms, and management strategies of various CVAEs associated with ICIs. Highlights from recent guidelines published by National Comprehensive Cancer Network on ICI-related CV toxicities have also been incorporated.

Cancer therapy-induced cardiomyopathy: can human induced pluripotent stem cell modelling help prevent it?

Cardiotoxic effects from cancer therapy are a major cause of morbidity during cancer treatment. Unexpected toxicity can occur during treatment and/or after completion of therapy, into the time of cancer survivorship. While older drugs such as anthracyclines have well-known cardiotoxic effects, newer drugs such as tyrosine kinase inhibitors, proteasome inhibitors, and immunotherapies also can cause diverse cardiovascular and metabolic complications. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly being used as instruments for disease modelling, drug discovery, and mechanistic toxicity studies. Promising results with hiPSC-CM chemotherapy studies are raising hopes for improving cancer therapies through personalized medicine and safer drug development. Here, we review the cardiotoxicity profiles of common chemotherapeutic agents as well as efforts to model them in vitro using hiPSC-CMs.

Combination ART-Induced Oxidative/Nitrosative Stress, Neurogenic Inflammation and Cardiac Dysfunction in HIV-1 Transgenic (Tg) Rats: Protection by Mg.

Chronic effects of a combination antiretroviral therapy (cART = tenofovir/emtricitatine + atazanavir/ritonavir) on systemic and cardiac oxidative stress/injury in HIV-1 transgenic (Tg) rats and protection by Mg-supplementation were assessed. cART (low doses) elicited no significant effects in normal rats, but induced time-dependent oxidative/nitrosative stresses: 2.64-fold increased plasma 8-isoprostane, 2.0-fold higher RBC oxidized glutathione (GSSG), 3.2-fold increased plasma 3-nitrotyrosine (NT), and 3-fold elevated basal neutrophil superoxide activity in Tg rats. Increased NT staining occurred within cART-treated HIV-Tg hearts, and significant decreases in cardiac systolic and diastolic contractile function occurred at 12 and 18 weeks. HIV-1 expression alone caused modest levels of oxidative stress and cardiac dysfunction. Significantly, cART caused up to 24% decreases in circulating Mg in HIV-1-Tg rats, associated with elevated renal NT staining, increased creatinine and urea levels, and elevated plasma substance P levels. Strikingly, Mg-supplementation (6-fold) suppressed all oxidative/nitrosative stress indices in the blood, heart and kidney and substantially attenuated contractile dysfunction (>75%) of cART-treated Tg rats. In conclusion, cART caused significant renal and cardiac oxidative/nitrosative stress/injury in Tg-rats, leading to renal Mg wasting and hypomagnesemia, triggering substance P-dependent neurogenic inflammation and cardiac dysfunction. These events were effectively attenuated by Mg-supplementation likely due to its substance P-suppressing and Mg's intrinsic anti-peroxidative/anti-calcium properties.

Doxorubicin-induced cardiotoxicity is suppressed by estrous-staged treatment and exogenous 17ß-estradiol in female tumor-bearing spontaneously hypertensive rats.

BACKGROUND: Doxorubicin (DOX), an anthracycline therapeutic, is widely used to treat a variety of cancer types and known to induce cardiomyopathy in a time and dose-dependent manner. Postmenopausal and hypertensive females are two high-risk groups for developing adverse effects following DOX treatment. This may suggest that endogenous reproductive hormones can in part suppress DOX-induced cardiotoxicity. Here, we investigated if the endogenous fluctuations in 17ß-estradiol (E2) and progesterone (P4) can in part suppress DOX-induced cardiomyopathy in SST-2 tumor-bearing spontaneously hypersensitive rats (SHRs) and evaluate if exogenous administration of E2 and P4 can suppress DOX-induced cardiotoxicity in tumor-bearing ovariectomized SHRs (ovaSHRs). METHODS: Vaginal cytology was performed on all animals to identify the stage of the estrous cycle. Estrous-staged SHRs received a single injection of saline, DOX, dexrazoxane (DRZ), or DOX combined with DRZ. OvaSHRs were implanted with time-releasing pellets that contained a carrier matrix (control), E2, P4, Tamoxifen (Tam), and combinations of E2 with P4 and Tam. Hormone pellet-implanted ovaSHRs received a single injection of saline or DOX. Cardiac troponin I (cTnI), E2, and P4 serum concentrations were measured before and after treatment in all animals. Cardiac damage and function were further assessed by echocardiography and histopathology. Weight, tumor size, and uterine width were measured for all animals. RESULTS: In SHRs, estrous-staged DOX treatment altered acute estrous cycling that ultimately resulted in prolonged diestrus. Twelve days after DOX administration, all SHRs had comparable endogenous circulating E2. Thirteen days after DOX treatment, SHRs treated during proestrus had decreased cardiac output and increased cTnI as compared to animals treated during estrus and diestrus. DOX-induced tumor reduction was not affected by estrous-staged treatments. In ovaSHRs, exogenous administration of E2 suppressed DOX-induced cardiotoxicity, while P4-implanted ovaSHRs were partly resistant. However, ovaSHRs treated with E2 and P4 did not have cardioprotection against DOX-induced damage. CONCLUSIONS: This study demonstrates that estrous-staged treatments can alter the extent of cardiac damage caused by DOX in female SHRs. The study also supports that exogenous E2 can suppress DOX-induced myocardial damage in ovaSHRs.

Development of In Vitro Drug-Induced Cardiotoxicity Assay by Using Three-Dimensional Cardiac Tissues Derived from Human Induced Pluripotent Stem Cells.

An in vitro drug-induced cardiotoxicity assay is a critical step in drug discovery for clinical use. The use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is promising for this purpose. However, single hiPSC-CMs are limited in their ability to mimic native cardiac tissue structurally and functionally, and the generation of artificial cardiac tissue using hiPSC-CMs is an ongoing challenging. We therefore developed a new method of constructing three-dimensional (3D) artificial tissues in a short time by coating extracellular matrix (ECM) components on cell surfaces. We hypothesized that 3D cardiac tissues derived from hiPSC-CMs (3D-hiPSC-CT) could be used for an in vitro drug-induced cardiotoxicity assay. 3D-hiPSC-CT were generated by fibronectin and gelatin nanofilm coated single hiPSC-CMs. Histologically, 3D-hiPSC-CT exhibited a sarcomere structure in the myocytes and ECM proteins, such as fibronectin, collagen type I/III, and laminin. The administration of cytotoxic doxorubicin at 5.0 µM induced the release of lactate dehydrogenase, while that at 2.0 µM reduced the cell viability. E-4031, human ether-a-go-go related gene (hERG)-type potassium channel blocker, and isoproterenol induced significant changes both in the Ca transient parameters and contractile parameters in a dose-dependent manner. The 3D-hiPSC-CT exhibited doxorubicin-sensitive cytotoxicity and hERG channel blocker/isoproterenol-sensitive electrical activity in vitro, indicating its usefulness for drug-induced cardiotoxicity assays or drug screening systems for drug discovery.

Nonclinical and clinical pharmacology evidence for cardiovascular safety of saxagliptin.

BACKGROUND: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury. METHODS: In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). RESULTS: Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported. CONCLUSIONS: The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.

Cardiac voltage-gated ion channels in safety pharmacology: Review of the landscape leading to the CiPA initiative.

Voltage gated ion channels are central in defining the fundamental properties of the ventricular cardiac action potential (AP), and are also involved in the development of drug-induced arrhythmias. Many drugs can inhibit cardiac ion currents, including the Na+ current (INa), L-type Ca2+ current (Ica-L), and K+ currents (Ito, IK1, IKs, and IKr), and thereby affect AP properties in a manner that can trigger or sustain cardiac arrhythmias. Since publication of ICH E14 and S7B over a decade ago, there has been a focus on drug effects on QT prolongation clinically, and on the rapidly activating delayed rectifier current (IKr), nonclinically, for evaluation of proarrhythmic risk. This focus on QT interval prolongation and a single ionic current likely impacted negatively some drugs that lack proarrhythmic liability in humans. To rectify this issue, the Comprehensive in vitro proarrhythmia assay (CiPA) initiative has been proposed to integrate drug effects on multiple cardiac ionic currents with in silico modelling of human ventricular action potentials, and in vitro data obtained from human stem cell-derived ventricular cardiomyocytes to estimate proarrhythmic risk of new drugs with improved accuracy. In this review, we present the physiological functions and the molecular basis of major cardiac ion channels that contribute to the ventricle AP, and discuss the CiPA paradigm in drug development.

ß-Blocker and Calcium Channel Blocker Poisoning: High-Dose Insulin/Glucose Therapy.

Overdoses of ß-blockers and calcium channel blockers can produce significant morbidity and mortality, and conventional therapies often do not work as treatments for these poisonings. High-dose insulin/glucose therapy has been successful in reversing the cardiotoxic effects of these drugs in cases where the standard therapies have failed, and it appears to be relatively safe. Many successes have been well documented, but the clinical experience consists of case reports, the mechanisms of action are not completely understood, and guidelines for use of the therapy are empirically derived and not standardized. Regardless of these limitations, high-dose insulin/glucose therapy can be effective, it is often recommended by clinical toxicologists and poison control centers, and critical care nurses should be familiar with when and how the therapy is used.

Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment.

The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the identification of predictive genomics biomarkers of functional relevance for drug-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The hiPSC-CMs were incubated with 156 nM doxorubicin, which is a well-characterized cardiotoxicant, for 2 or 6 days followed by washout of the test compound and further incubation in compound-free culture medium until day 14 after the onset of exposure. An xCELLigence Real-Time Cell Analyser was used to monitor doxorubicin-induced cytotoxicity while also monitoring functional alterations of cardiomyocytes by counting of the beating frequency of cardiomyocytes. Unlike single exposure, repeated doxorubicin exposure resulted in long-term arrhythmic beating in hiPSC-CMs accompanied by significant cytotoxicity. Global gene expression changes were studied using microarrays and bioinformatics tools. Analysis of the transcriptomic data revealed early expression signatures of genes involved in formation of sarcomeric structures, regulation of ion homeostasis and induction of apoptosis. Eighty-four significantly deregulated genes related to cardiac functions, stress and apoptosis were validated using real-time PCR. The expression of the 84 genes was further studied by real-time PCR in hiPSC-CMs incubated with daunorubicin and mitoxantrone, further anthracycline family members that are also known to induce cardiotoxicity. A panel of 35 genes was deregulated by all three anthracycline family members and can therefore be expected to predict the cardiotoxicity of compounds acting by similar mechanisms as doxorubicin, daunorubicin or mitoxantrone. The identified gene panel can be applied in the safety assessment of novel drug candidates as well as available therapeutics to identify compounds that may cause cardiotoxicity.

Bridging Functional and Structural Cardiotoxicity Assays Using Human Embryonic Stem Cell-Derived Cardiomyocytes for a More Comprehensive Risk Assessment.

More relevant and reliable preclinical cardiotoxicity tests are required to improve drug safety and reduce the cost of drug development. Current in vitro testing strategies predominantly take the form of functional assays to predict the potential for drug-induced ECG abnormalities in vivo. Cardiotoxicity can also be structural in nature, so a full and efficient assessment of cardiac liabilities for new chemical entities should account for both these phenomena. As well as providing a more appropriate nonclinical model for in vitro cardiotoxicity testing, human stem cell-derived cardiomyocytes offer an integrated system to study drug impact on cardiomyocyte structure as well as function. Employing human embryonic stem cell-derived cardiacmyocytes (hESC-CMs) on 3 assay platforms with complementary insights into cardiac biology (multielectrode array assay, electrophysiology; impedance assay, cell movement/beating; and high content analysis assay, subcellular structure) we profiled a panel of 13 drugs with well characterized cardiac liabilities (Amiodarone, Aspirin, Astemizole, Axitinib, AZT, Bepridil, Doxorubicin, E-4031, Mexiletine, Rosiglitazone, Sunitinib, Sibutramine, and Verapamil). Our data show good correlations with previous studies and reported clinical observations. Using multiparameter phenotypic profiling techniques we demonstrate the dynamic relationship that exists between functional and structural toxicity, and the benefits of this more holistic approach to risk assessment. We conclude by showing for the first time how the advent of transparent MEA plate technology enables functional and structural cardiotoxic responses to be recorded from the same cell population. This approach more directly links changes in morphology of the hESC-CMs with recorded electrophysiology signatures, offering even greater insight into the wide range of potential drug impacts on cardiac physiology, with a throughput that is more amenable to early drug discovery.

Dietary phytoestrogens present in soy dramatically increase cardiotoxicity in male mice receiving a chemotherapeutic tyrosine kinase inhibitor.

Use of soy supplements to inhibit cancer cell growth is increasing among patients due to the perception that phytoestrogens in soy inhibit carcinogenesis via induction of apoptosis. Genistein, the most prevalent phytoestrogen in soy, is a potent endocrine disruptor and tyrosine kinase inhibitor (TKI) that causes apoptosis in many cells types. Chemotherapeutic TKIs limit cancer cell growth via the same mechanisms. However, TKIs such as Sunitinib cause cardiotoxicity in a significant number of patients. Molecular interactions between Sunitinib and dietary TKIs like genistein have not been examined in cardiomyocytes. Significant lethality occurred in mice treated with Sunitinib and fed a phytoestrogen-supplemented diet. Isolated cardiomyocytes co-treated with genistein and Sunitinib exhibited additive inhibition of signaling molecules important for normal cardiac function and increased apoptosis compared with Sunitinib alone. Thus, dietary soy supplementation should be avoided during administration of Sunitinib due to exacerbated cardiotoxicity, despite evidence for positive effects in cancer.

Administration of chromium(III) and manganese(II) as a potential protective approach against daunorubicin-induced cardiotoxicity: in vitro and in vivo experimental evidence.

Daunorubicin (DNR) is a widely used antitumor drug, but its application is limited because of its cardiotoxic side effects. The present study was designed to investigate the interaction between DNR and cardiac myosin (CM) in the presence of chromium(III) (Cr(3+)) and manganese(II) (Mn(2+)) using fluorescence spectrometry under simulative physiological conditions with the aim of exploring the influence of metal ion on DNR-CM complex and finding out an aggressive approach to abrogate of DNR-induced cardiotoxicity. In detail, the quenching and binding constant of ternary system, including metal ion, DNR, and CM, were measured and compared with the DNR-CM. The data from in vitro experiments indicate that the presence of Cr(3+) or Mn(2+) distinctly decreased the binding force between DNR and CM, and alleviated the cardiac toxicity caused by DNR. In addition, the variations in mice body weight and myocardial enzyme level were examined by in vivo experiments. Animals receiving Cr(3+) or Mn(2+) supplementation of DNR showed preservation of the normal pattern of the heart, especially 2.0 mg Cr(3+)/kg body wt or 50.0 mg Mn(2+)/kg body wt exhibited an obviously protective effect accompanied with body weight raise when compared with the mice treated with DNR alone, decreased the ratio of heart to body weight (BW) and the ratio of left ventricular mass to BW to the normal levels, and inhibited the leak of myocardial enzyme caused by DNR. As a result, this study suggests that pretreatment of lower dose of Cr(3+) (2 mg/kg wt) and moderate dose of Mn(2+) (50 mg/kg wt) might be useful and play an important role in ameliorating the cardiotoxicity of DNR treatment in cancer patients.

Drug attrition during pre-clinical and clinical development: understanding and managing drug-induced cardiotoxicity.

Cardiovascular toxicity remains a major cause of concern during preclinical and clinical development as well as contributing to post-approval withdrawal of medicines. This issue is particularly relevant for anticancer drugs where, the significant improvement in the life expectancies of patients has dramatically extended the use and duration of drug therapies. Nevertheless, cardiotoxicity is also observed with other classes of drugs, including antibiotics, antidepressants, and antipsychotics. This article summarizes the clinical manifestations of drug-induced cardiotoxicity by various cancer chemotherapies and novel drugs for the treatment of other diseases. Furthermore, it presents on overview of biomarker and imaging techniques for the detection of drug-induced cardiotoxicity. Guidelines for the management of patients exposed to drugs with cardiotoxic potential are presented as well as a checklist for collecting information when a safety signal is observed in clinical trials to more effectively assess the risk of cardiotoxicity and manage patient safety.

Cancer genetics and the cardiotoxicity of the therapeutics.

Cancer genomics has focused on the discovery of mutations and chromosomal structural rearrangements that either increase susceptibility to cancer or support the cancer phenotype. Protein kinases are the most frequently mutated genes in the cancer genome, making them attractive therapeutic targets for drug design. However, the use of some of the kinase inhibitors (KIs) has been associated with toxicities to the heart and vasculature, including acute coronary syndromes and heart failure. Herein we discuss the genetic basis of cancer, focusing on mutations in the kinase genome (kinome) that lead to tumorigenesis. This will allow an understanding of the real and potential power of modern cancer therapeutics. The underlying mechanisms that drive the cardiotoxicity of the KIs are also examined. The preclinical models for predicting cardiotoxicity, including induced pluripotent stem cells and zebrafish, are reviewed, with the hope of eventually being able to identify problematic agents before their use in patients. Finally, the use of biomarkers in the clinic is discussed, and newer strategies (i.e., metabolomics and enhanced imaging strategies) that may allow earlier and more accurate detection of cardiotoxicity are reviewed.

Cardioprotective effect of grape-seed proanthocyanidins on doxorubicin-induced cardiac toxicity in rats.

CONTEXT: Doxorubicin (Dox) is an anthracycline antibiotic used as anticancer agent. However, its use is limited due to its cardiotoxicity which is mainly attributed to accumulation of reactive oxygen species. OBJECTIVE: This study was conducted to assess whether the antioxidant, proanthocyanidins (Pro) can ameliorate Dox-induced cardiotoxicity in rats. MATERIALS AND METHODS: Male Sprague-Dawely rats were divided into four groups. Group I was control. Group II received Pro (70 mg/kg, orally) once daily for 10 days. Group III received doxorubicin 15 mg/kg i.p. as a single dose on the 7th day and Group IV animals were treated with Pro once daily for 10 days and Dox on the 7th day. The parameters of study were serum biomarkers, cardiac tissue antioxidant status, ECG, and effect on aconitine-induced cardiotoxicity. RESULTS: Cardiac toxicity of doxorubicin was manifested as a significant increase in heart rate, elevation of the ST segment, prolongation of the QT interval and an increase in T wave amplitude. In addition, Dox enhanced aconitine-induced cardiotoxicity by a significant decrease in the aconitine dose producing ventricular tachycardia (VT). Administration of Pro significantly suppressed Dox-induced ECG changes and normalized the aconitine dose producing VT. The toxicity of Dox was also confirmed biochemically by significant elevation of serum CK-MB and LDH activities as well as myocardial MDA and GSH contents and decrease in serum catalase and myocardial SOD activities. Administration of Pro significantly suppressed these biochemical changes. DISCUSSION AND CONCLUSION: These results suggest that proanthocyanidins might be a potential cardioprotective agent against Dox-induced cardiotoxicity due to its antioxidant properties.

Effect of long-term music therapy intervention on autonomic function in anthracycline-treated breast cancer patients.

Anthracyclines are potent antineoplastic agents associated with cardiotoxicity, which may lead to congestive heart failure, causing impairment of autonomic cardiovascular function as assessed by heart rate variability (HRV). This decreases survival rates. This study aimed to determine whether music therapy intervention improves autonomic function in anthracycline-treated breast cancer patients, and if so, whether such improvements persist after cessation of the intervention. Participants were 12 women with breast cancer who had undergone mastectomy or breast-conserving treatment and adjuvant chemotherapy; they attended 8 weekly music therapy sessions, each lasting 2 hours. Electrocardiogram traces (5 minutes) for HRV analysis were recorded 4 times: prior to the first music session, T1; after the fourth music session, T2; after the eighth music session, T3; and 4 weeks after the completion of music therapy, T4. HRV parameters were subjected to a nonparametric Friedman test on the differences between T1 and T2, T3, and T4. The standard deviation of normal intervals and the total power of HRV parameters, related to global autonomic function, were significantly higher at T3 than at T1. The root-mean-square differences of successive normal R-R intervals and high-frequency (HF) HRV parameters, related to parasympathetic activity, were significantly increased, but no change was seen in the LF/HF ratio of HRV parameters (which is related to sympathetic activity) during the music therapy. Global autonomic function and parasympathetic activity had not changed significantly at T4 relative to T1. The authors provide preliminary evidence of the benefits of music therapy for anthracycline-treated breast cancer survivors.

Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes.

Targeted therapeutics, particularly those that inhibit the activity of protein kinases that are mutated and/or overexpressed in cancer, have revolutionized the treatment of some cancers and improved survival rates in many others. Although these agents dominate drug development in cancer, significant toxicities, including cardiotoxicity, have emerged. In this Review, we examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of small molecule kinase inhibitors. We also discuss how well the various preclinical safety models and strategies might predict clinical cardiotoxicity. It is hoped that a thorough understanding of the mechanisms underlying cardiotoxicity will lead to the development of safe, effective drugs and consequently, fewer costly surprises as agents progress through clinical trials.

Predicting and preventing cardiotoxicity in the era of breast cancer targeted therapies. Novel molecular tools for clinical issues.

Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists.

Preclinical evaluation of potential nilotinib cardiotoxicity.

In vitro, concentrations ≥ 10 µM of nilotinib were needed to induce markers of cytotoxicity, apoptosis, and endoplasmic reticulum stress in both neonatal rat ventricular myocytes, a putative target tissue, and non-target heart fibroblasts, indicating a lack of cardiomyocyte-specific nilotinib toxicity in vitro. In rats, oral nilotinib treatment at 80 mg/kg for 4 weeks induced increased heart weight; however, this was not associated with relevant histopathological changes or effects on heart function. Thus, nilotinib at and above clinically relevant concentrations (4.27 µM) did not induce overt cardiovascular pathologies or heart failure in vitro or in vivo under study conditions.