Recomendaciones para el manejo de la cardiotoxicidad relacionada con el tratamiento del cáncer. Primera parte / Recommendations for the management of cardiotoxicity related to cancer treatment. Part one / Recomendações para a gestão de cardiotoxicidade relacionada com o tratamento do câncer. Primeira parte

Las nuevas terapias oncológicas han logrado aumentar la sobrevida del paciente con cáncer, observando, sin embargo, un incremento de la morbilidad y mortalidad vinculadas a sus efectos secundarios. El desarrollo de eventos cardiovasculares adversos impacta negativamente en el pronóstico durante el tratamiento del cáncer, pero también en los supervivientes al cáncer, donde las enfermedades cardiovasculares (ECV) y las segundas neoplasias son la principal causa de muerte1-5. La cardiotoxicidad inducida por el tratamiento del cáncer se define como el conjunto de ECV derivadas de los tratamientos oncológicos. Su manifestación es variada e incluye el desarrollo de disfunción ventricular, insuficiencia cardíaca (IC), isquemia miocárdica, hipertensión arterial y arritmias, entre otras. Puede ser consecuencia tanto del efecto directo del tratamiento sobre la estructura y función cardíacas, como del desarrollo acelerado de ECV6-9. Frecuentemente se utiliza el término cardiotoxicidad como sinónimo de disfunción ventricular por quimioterapia (DV-QT). Dado que la cardiotoxicidad abarca un espectro más amplio de afectación cardiovascular, creemos conveniente hablar de DV-QT para referirnos a la afectación de la función sistólica del ventrículo izquierdo. La DV-QT y el desarrollo de IC representan una de las complicaciones más temidas por su impacto pronóstico en la esfera cardiovascular y oncológica, dado que limitan el arsenal terapéutico para el tratamiento del cáncer5,10. Han sido creadas diversas sociedades de cardio-onco-hematología con el fin de generar recomendaciones de práctica clínica y formar profesionales capacitados para el manejo de las complicaciones cardiovasculares del tratamiento del cáncer11. La cardio-oncología es una disciplina en creciente y continuo desarrollo. Creemos que es fundamental realizar tareas de formación médica continua, así como también estimular el trabajo conjunto de diversas especialidades para brindar una mejor asistencia. Este texto es el resultado del trabajo de un equipo multidisciplinario que incluye cardiólogos, hematólogos y oncólogos, y pretende brindar información a los integrantes del equipo de salud involucrados en la asistencia de pacientes oncológicos. Debido a su extensión, hemos decidido fraccionar el contenido en tres partes para facilitar su publicación.

New oncological therapies have been successful in increasing cancer patient survival, but they have also led to an increase in morbidity and mortality linked to their side effects. During cancer treatment, the development of cardiovascular side effects has a negative impact in prognosis, but also in cancer survivors, in whom cardiovascular diseases and secondary malignancies are the main cause of death. Cancer related cardiotoxicity is defined as the development of cardiovascular diseases related to cancer treatment. Clinical presentation is broad involving ventricular dysfunction, heart failure, myocardial ischemia, arterial hypertension and arrhythmias among others. This may result from the direct cardiovascular effect of a cancer treatment or accelerated development of cardiovascular diseases. Frequently, in the literature cardiotoxicity and chemotherapy related ventricular dysfunction are used as synonyms. However, cardiotoxicity includes a broad spectrum of cardiovascular manifestations, thus in this text we refer to chemotherapy related ventricular dysfunction as the presence of left ventricular systolic impairment. Chemotherapy related ventricular dysfunction and heart failure are two of the most feared complications of cancer treatment due to its impact on cardiovascular and oncological prognosis, affecting treatment options. Numerous worldwide cardio-onco-hematology societies have emerged to generate clinical practice guidelines and improve the diagnosis and evaluation of cardiovascular cancer treatment side effects. Cardio-Oncology is a discipline in continuous growth and development. We strongly believe that continuum medical education and a multidisciplinary approach is necessary to provide a quality health care. This text is the result of a multidisciplinary work involving cardiologists, hematologists and oncologists. It is our goal to provide information to the health care team involved in the assistance of cancer patients. Due to its extension, it will be published in three parts.

O desenvolvimento de novas terapias oncológicas levou a um aumento na sobrevida dos pacientes, mas ao mesmo tempo traz consigo morbidades relacionadas aos tratamentos. O desenvolvimento de efeitos cardiovasculares adversos tem um impacto negativo no prognóstico dos pacientes em tratamento, bem como nos pacientes considerados curados, nos quais doença cardiovascular e malignidades secundárias são as principais causas de morte. Cardiotoxicidade relacionada ao câncer é definida como o desenvolvimento de doença cardiovascular secundária ao tratamento. A gama de apresentações clínicas é ampla, podendo se manifestar como disfunção ventricular, insuficiência cardíaca, isquemia miocárdica, hipertensão arterial, arritmias, entre outras. Isto pode ser resultante de desenvolvimento e progressão acelerados de doença cardiovascular ou por efeito direto das terapias. Frequentemente é dito na literatura que cardiotoxicidade e disfunção ventricular relacionada à quimioterapia são sinônimos. Entretanto, cardiotoxicidade engloba um amplo espectro de manifestações cardiovasculares. Neste texto, portanto, nos referimos à disfunção ventricular causada por quimioterápicos exclusivamente como a presença de disfunção sistólica ventricular esquerda. Disfunção ventricular relacionada à quimioterapia e insuficiência cardíaca são duas das mais temidas complicações do tratamento oncológico devido ao seu impacto no prognóstico cardiovascular e oncológico, podendo afetar ainda a escolha e manutenção das opções terapêuticas. Diversas sociedades cardio-onco-hematológicas surgiram ao redor do mundo com o objetivo de gerar diretriz clínicas práticas e melhorar o diagnóstico e tratamento das complicações cardiovasculares resultantes das terapias oncológicas. A cardio-oncologia é uma disciplina em contínuo crescimento e desenvolvimento. Nós acreditamos fortemente que educação médica continuada e uma abordagem multidisciplinar são necessárias para um cuidado médico de qualidade. Este texto é o resultado de um trabalho multidisciplinar envolvendo cardiologistas, hematologistas e oncologistas. Nosso objetivo é de oferecer informação à equipe de cuidados em saúde envolvido na assistência destes pacientes. Devido à sua extensão, este texto será publicado em três partes.

Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib.

The third-generation tyrosine kinase inhibitor (TKI) ponatinib has been associated with high rates of acute ischemic events. The pathophysiology responsible for these events is unknown. We hypothesized that ponatinib produces an endothelial angiopathy involving excessive endothelial-associated von Willebrand factor (VWF) and secondary platelet adhesion. In wild-type mice and ApoE-/- mice on a Western diet, ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Ibα was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice for 7 days, aortic molecular signal for endothelial-associated VWF and platelet adhesion were five- to sixfold higher in ponatinib vs sham therapy (P < .001), whereas dasatinib had no effect. In ApoE-/- mice, aortic VWF and platelet signals were two- to fourfold higher for ponatinib-treated compared with sham-treated mice (P < .05) and were significantly higher than in treated wild-type mice (P < .05). Platelet and VWF signals in ponatinib-treated mice were significantly reduced by N-acetylcysteine and completely eliminated by recombinant ADAMTS13. Ponatinib produced segmental left ventricular wall motion abnormalities in 33% of wild-type and 45% of ApoE-/- mice and corresponding patchy perfusion defects, yet coronary arteries were normal on angiography. Instead, a global microvascular angiopathy was detected by immunohistochemistry and by intravital microscopy observation of platelet aggregates and nets associated with endothelial cells and leukocytes. Our findings reveal a new form of vascular toxicity for the TKI ponatinib that involves VWF-mediated platelet adhesion and a secondary microvascular angiopathy that produces ischemic wall motion abnormalities. These processes can be mitigated by interventions known to reduce VWF multimer size.

Natural history of myocardial deformation in children, adolescents, and young adults exposed to anthracyclines: Systematic review and meta-analysis.

OBJECTIVE: Anthracyclines are widely used to treat solid and hematologic malignancies, but are known to cause cardiotoxicity. As more childhood cancer survivors reach adulthood due to improvements in oncologic treatments, they become susceptible to late and progressive anthracycline-induced cardiotoxicity. Nonetheless, diagnostic criteria for early detection of cardiac dysfunction are not well defined in children, adolescent, and young adults (CAYA, ages 1-40 years). We present a natural history of the changes in myocardial deformation in CAYA patients after anthracycline therapy. METHODS: We performed a literature review search between 2001 and 2016 using PubMed with the following search terms: strain (or deformation), torsion (or twist), children (or adolescent or young adult), cardiotoxicity (or dysfunction), and anthracyclines (or doxorubicin). A total of 23 articles were reviewed. Fourteen articles were incorporated in the meta-analysis. RESULTS: Strain abnormalities are observed at both short-term and long-term follow-up. Global longitudinal strain (GLS) abnormalities are common during or early after chemotherapy, whereas changes in global circumferential strain (GCS) are more significant and consistent on long-term follow-up. Although global radial strain and torsional parameters are also often abnormal late after chemotherapy, there are few studies evaluating these parameters. CONCLUSION: There are significant abnormalities in GLS and GCS following anthracycline therapy acutely and late after treatment. The prognostic value of these strain abnormalities warrants further investigation.

Usefulness of Integrating Heart Failure Risk Factors Into Impairment of Global Longitudinal Strain to Predict Anthracycline-Related Cardiac Dysfunction.

The prediction of cancer therapeutics-related cardiac dysfunction (CTRCD) is an essential aspect of care for individuals who receive potentially cardiotoxic oncologic treatments. Certain clinical risk factors have been described for incident CTRCD, and measurement of left ventricular (LV) longitudinal strain by speckle tracking 2-dimensional echocardiography (2DE) is the best-validated myocardial mechanical imaging assessment to detect subtle changes in LV function during cancer treatment. However, the direct integration of clinical and imaging risk factors to predict CTRCD has not yet been extensively examined. This was a retrospective study of 183 women with breast cancer aged 50.9 ± 10.8 years who received treatment with anthracyclines (doxorubicin dose of 422 ± 69 mg/m2, with 41.2% of subjects also receiving trastuzumab) and underwent 2DE at clinically determined intervals. CTRCD was diagnosed when LV ejection fraction dropped ≥10% to a subnormal (<53%) value by 2DE. Left ventricular global longitudinal strain (LV-GLS) was assessed offline. The risk prediction tool based only on clinical factors previously described by Ezaz et al was applied to our cohort and accurately stratified these subjects into low-, intermediate-, and high-risk groups, with incident CTRCD in 7.4%, 26.9%, and 54.6%, respectively (chi-square = 20.7, p <0.0001). We developed novel multivariate models to predict CTRCD using (1) demographic variables only (c = 0.8674), (2) echocardiographic (peak LV-GLS) variables only (c = 0.8440), or (3) a combination of demographic and echocardiographic variables, with the combined model exhibiting superior receiver-operating characteristics (c = 0.9629). In conclusion, estimation of CTRCD risk should integrate all available data, including both clinical variables and an imaging assessment.

Case report and review of the literature: the utilisation of a ventricular assist device as bridge to recovery for anthracycline-induced ventricular dysfunction.

Ventricular assist devices are used in children with heart failure as a bridge to myocardial recovery or cardiac transplantation. Anthracyclines cause cardiac toxicity and may result in acute or long-term cardiac failure. We describe the use of a ventricular assist device as a bridge to recovery in a child with severe acute anthracycline-induced cardiomyopathy, and we review the associated literature. A 6-year-old girl was treated for acute myeloblastic leukaemia with daunorubicin and mitoxantrone. After 2 weeks her final dose of chemotherapy, her Left Ventricular Ejection Fraction decreased to 21%. Despite initiation of medical therapy, she had continued deterioration of left ventricular function and developed evidence of poor end-organ perfusion. She was not a candidate for cardiac transplantation, as the post-transplant immune suppression therapy would put her at risk for recurrence of her malignancy. We placed her on a short-term ventricular assist device as a bridge to ultimately placing her on a long-term ventricular assist device versus continuing medical therapy. Her left ventricular ejection fraction improved to 55% 24 days after ventricular assist device insertion. She was separated from the ventricular assist device 26 days after its insertion. She was discharged home 29 days later and is now 28 months after ventricular assist device implantation with stable ventricular function, as documented by a left ventricular ejection fraction of 55%, and normal end organ function. This case is one of the only reports known describing successful use of a short-term ventricular assist device as a bridge to recovery in a child with severe acute anthracycline-induced cardiotoxicity.

Heterozygous caveolin-3 mice show increased susceptibility to palmitate-induced insulin resistance.

Insulin resistance and diabetes are comorbidities of obesity and affect one in 10 adults in the United States. Despite the high prevalence, the mechanisms of cardiac insulin resistance in obesity are still unclear. We test the hypothesis that the insulin receptor localizes to caveolae and is regulated through binding to caveolin-3 (CAV3). We further test whether haploinsufficiency forCAV3 increases the susceptibility to high-fat-induced insulin resistance. We used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of theIR We show that haploinsufficiency forCAV3 increases susceptibility to palmitate-induced global insulin resistance and causes cardiomyopathy. On the basis of fluorescence energy transfer (FRET) experiments, we show thatCAV3 andIRdirectly interact in cardiomyocytes. Palmitate impairs insulin signaling by a decrease in insulin-stimulated phosphorylation of Akt that corresponds to an 87% decrease in insulin-stimulated glucose uptake inHL-1 cardiomyocytes. Despite loss of Akt phosphorylation and lower glucose uptake, palmitate increased insulin-independent serine phosphorylation ofIRS-1 by 35%. In addition, we found lipid induced downregulation ofCD36, the fatty acid transporter associated with caveolae. This may explain the problem the diabetic heart is facing with the simultaneous impairment of glucose uptake and lipid transport. Thus, these findings suggest that loss ofCAV3 interferes with downstream insulin signaling and lipid uptake, implicatingCAV3 as a regulator of theIRand regulator of lipid uptake in the heart.

Predictors of incipient dysfunction of all cardiac chambers after treatment of metastatic renal cell carcinoma by tyrosine kinase inhibitors.

PURPOSE: We aimed to explore the hypothesis that early subclinical cardiac chamber dysfunction secondary to tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma could be signaled by abnormal cardiac mechanics demonstrated by velocity vector imaging. METHODS: Echocardiographic images were acquired from the apical views in 23 metastatic renal cell carcinoma patients. All patients had baseline and at least a 3-month follow-up echocardiogram after receiving TKI therapy. Subendocardial borders of all the cardiac chambers were traced to obtain volumetric and deformation indices. RESULTS: Mean age was 67 ± 9 years with 92% men. The right ventricle peak systolic global longitudinal strain (GLɛ) and strain rate were significantly lower after TKIs (-23.49 ± 5.1 versus -19.81 ± 5.5, p = 0.002 and -1.52 ± 0.52 versus -1.24 ± 0.35 p = 0.02, respectively). LV GLɛ was not statistically different. Volumetric and deformation indices showed a minimal decrease of the right atrium reservoir and conduit functions, and no significant changes of left atrial function. CONCLUSIONS: The right heart exhibited greater strain changes than the left heart after TKI treatment. The implications of these findings and their potential significance warrant further work.

Temporal Trends of Cardiac Chambers Function with Trastuzumab in Human Epidermal Growth Factor Receptor II-Positive Breast Cancer Patients.

BACKGROUND: Trastuzumab has substantially improved overall survival and reduced the risk of disease recurrence in patients with human epidermal growth factor receptor type II (HER-II)-positive breast cancer. However, this benefit may be at the increased risk of cardiotoxicity. We aimed to explore the early subclinical left and right ventricular as well as atrial dysfunction, in trastuzumab-treated patients with HER-II-positive breast cancer, using velocity vector imaging. METHODS: Echocardiography images were acquired in 50 patients with HER-II-positive breast cancer undergoing trastuzumab therapy. All patients had baseline and 3-6 months and 12-15 months of follow-up echocardiograms after initiation of trastuzumab therapy. Subendocardial borders of all the cardiac chambers were traced from the apical views to obtain volumetric and deformation indices. RESULTS: Mean age was 60 ± 13 years. Left ventricular (LV) ejection fraction as well as conventional indices of right ventricular (RV) function did not change with trastuzumab. The RV peak systolic global longitudinal strain (GLε) significantly decreased (-24.53 ± 6.03 vs. -21.28 ± 5.11 vs. -21.84 ± 5.15, baseline vs. first and second follow-ups, P = 0.01). LV peak systolic GLε was reduced by 1.19 at early follow-up (P < 0.05). Left atrial reservoir and booster pump functions as well as right atrial reservoir function were reduced through follow-up as well. CONCLUSIONS: The RV exhibited greater change in strain after trastuzumab treatment when compared to the LV. Atria function was reduced by trastuzumab as well. The repercussion of these findings and their potential implication will warrant further study.

Downregulation of stanniocalcin 1 is responsible for sorafenib-induced cardiotoxicity.

Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish and human cardiomyocytes. Fluorescent cardiac imaging using pigmentless zebrafish with green fluorescent protein hearts revealed that the ventricular dimensions of the longitudinal axis with sorafenib were significantly shorter than those of the control group. Transcriptome analysis of their hearts revealed that stanniocalcin 1 (stc1) was downregulated by sorafenib. stc1 knockdown in zebrafish revealed that reduction of stc1 decreased the longitudinal dimensions of zebrafish ventricles, similar to that which occurs during sorafenib treatment. STC1 downregulation and cytotoxicity were also seen in human cardiomyocytes exposed to sorafenib. To clarify the molecular function of stc1 in sorafenib-induced cardiotoxicity, we focused on oxidative stress in cardiomyocytes treated with sorafenib. Reactive oxygen species (ROS) production significantly increased in both species of human cardiomyocytes and zebrafish exposed to sorafenib and STC1 knockdown compared with the controls. Finally, we found that forced expression of stc1 normalized impairment, decreasing the longitudinal dimensions in zebrafish treated with sorafenib. Our study demonstrated that STC1 plays a protective role against ventricular dysfunction and ROS overproduction, which are induced by sorafenib treatment. We discovered for the first time that STC1 downregulation is responsible for sorafenib-induced cardiotoxicity through activated ROS generation.

Cardiotoxicity following cyclophosphamidetherapy: a case report.

INTRODUCTION: Cardiac toxicity is one of the life-threatening complications of cancer therapy. Systemic anticancer treatments may exert their own toxic effects or can aggravate adverse effects of other drugs. We report a case of cyclophosphamide-induced cardiotoxicity in a patient with normal cardiac functions before chemotherapy. CASE PRESENTATION: A 66-year-old Caucasian woman with a mediastinal mass diagnosed with Burkitt lymphoma underwent chemotherapy with rituximab-hyperfractionated-cyclophosphamide-vincristine-doxorubicin-dexamethasone. On the seventh day of chemotherapy, she developed dyspnea. An electrocardiogram demonstrated low voltage in the limb and precordial leads. It also showed diffusely increased myocardial echogenicity, mild pericardial and pleural effusion, generally impaired biventricular systolic functions with a left ventricular ejection fraction of 31%, and right ventricular mid-apical akinesia, even though she had normal biventricular functions before chemotherapy. Cyclophosphamide-induced cardiotoxicity was suspected and she was given treatment for congestive heart failure. Her dyspnea decreased and she was discharged on the tenth day with a left ventricular ejection fraction of 37% and normal right ventricular function. After 1 month, echocardiography showed normal biventricular functions with a left ventricular ejection fraction of 60%. CONCLUSIONS: Drug-induced cardiotoxicity, therefore, should be taken into consideration when using cyclophosphamide therapy, especially when anthracyclines are co-administered. Close communication between hematologists and cardiologists is required.

Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice.

Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken beta-actin promoter. Mice were backcrossed in the C57Bl/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25- to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.

Doxorubicin and trastuzumab regimen induces biventricular failure in mice.

BACKGROUND: An increased risk for cardiac dysfunction is reported when the anti-epidermal growth factor receptor type 2 (ErbB2) antibody trastuzumab (Trz) is combined with doxorubicin (Dox) as adjuvant chemotherapy for patients with ErbB2-positive breast cancer. The aim of this study was to develop and characterize a novel mouse model of cardiotoxicity that recapitulates the clinical therapeutic protocols of consecutive cycles of Dox followed by Trz therapy. METHODS: Chronic cardiotoxicity was induced in mice by administering six intraperitoneal injections of Dox weekly over a 2-week period (n = 38; cumulative dose, 24 mg/kg), Trz alone (n = 15; cumulative dose, 10 mg/kg), Trz administered 1 week after Dox treatment (n = 35), or an equivalent volume of saline (n = 24). RESULTS: Echocardiography and pressure-volume analysis indicated that Dox administration was responsible for both left ventricular (LV) and right ventricular (RV) systolic dysfunction and dilatation, further exacerbated by subsequent Trz treatment. Trz alone induced a short down-regulation of LV ErbB2/4 expression associated with reversible LV dysfunction but did not affect receptor expression and RV performance. Dox and Trz in combination decreased the ratio of LV weight to tibia length as well as LV and RV wall thickness compared with Dox treatment. Plasma cardiac troponin I levels and myocardial oxidative stress were higher in mice treated with Dox and Trz than in those treated with Dox alone, while a similar increase of interstitial collagen I deposition was observed in both groups. Trz alone did not affect LV and RV remodeling. CONCLUSIONS: These findings suggest that a combined Dox and Trz regimen provokes a detrimental synergistic global cardiac injury extending to both the LV and RV chambers.

Assessment of early-onset chronic progressive anthracycline cardiotoxicity in children: different response patterns of right and left ventricles.

We aimed to assess early-onset chronic progressive cardiotoxicity in the left and right ventricles with increasing cumulative anthracycline doses. We evaluated 72 patients within the first year after doxorubicin and/or daunorubicin treatment (median 1.3 months; range 0.3-11.5) and 31 healthy controls. Pretreatment and posttreatment QT interval analyzes were performed in 27 newly diagnosed patients. The echocardiographic data of all examinations of 72 patients were classified into three groups according to instant cumulative anthracycline doses: treatment group (TG)-I (≤120 mg/m(2); n = 26), TG-II (120-240 mg/m(2); n = 39), and TG-III (≥240 mg/m(2); n = 40). Diastolic and systolic parameters were analyzed by conventional echocardiography and tissue Doppler imaging (TDI) and compared with those of healthy controls. The mean age for patients and controls was 8.2 ± 4.5 and 9.6 ± 4.2 years, respectively (p > 0.05). QTc dispersion significantly increased after anthracycline treatment (p = 0.02). TDI showed decreased E' velocity (p < 0.001) and E'/A' ratio (p < 0.001) at lateral tricuspid annulus segment in TG-I, and these findings continued in TG-II and -III. In addition, S' velocity decreased in TG-I, -II, and -III at lateral mitral annulus (10.5 ± 2.6 cm/s, p < 0.05; 9.9 ± 2.2 cm/s, p < 0.001; and 10.1 ± 2.3 cm/s, p < 0.01, respectively). However, decrease in left-ventricular ejection fraction was statistically significant in TG-II and -III (p < 0.001). Although myocardial performance index was significantly increased in all treatment groups in both segments, it was primarily due to significant increases in isovolumic relaxation time at the lateral tricuspid annulus and isovolumic contraction time at the lateral mitral annulus. Abnormalities in diastolic function in right ventricle and systolic function in the left ventricle were observed even with a cumulative anthracycline dose <120 mg/m(2) by TDI. In addition, anthracycline treatment led to an increase in QTc dispersion.

Salidroside improves doxorubicin-induced cardiac dysfunction by suppression of excessive oxidative stress and cardiomyocyte apoptosis.

Doxorubicin (DOX) is a potent available antitumor drug; however, its clinical use is limited by the cardiotoxicity. Salidroside (SLD), with strong antioxidative and cytoprotective actions, is of particular interest in the development of antioxidative therapies for oxidative injury in cardiac diseases. Now, the protection and underlying mechanisms of SLD against DOX-induced cardiotoxicity are still unknown. In the present study, we revealed both antioxidative mechanism and Bcl2-dependent survival signaling involved in SLD's protection. We observed that DOX exposure induced mortality elevation, body weight loss, and cardiac dysfunction in mice, increased lactate dehydrogenase leakage and cardiomyocyte apoptosis, but decreased cell viability and size in cardiac tissues and cultured H9c2 cells, respectively, which were effectively antagonized by SLD supplement. We further observed that SLD significantly reduced the intercellular oxidative stress level, partly by inhibiting NOX1 expression and augmenting the expression and activities of the endogenous antioxidative enzymes, catalase, and manganese superoxide dismutase. In addition, SLD treatment upregulated the antiapoptotic Bcl2 and downregulated the proapoptotic Bax and inhibited a downstream pathway of Bcl2/Bax and caspase-3 activity. Our results indicated that SLD effectively protected the cardiomyocytes against DOX-induced cardiotoxicity by suppressing the excessive oxidative stress and activating a Bcl2-mediated survival signaling pathway.

Cardiac expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice.

Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates. Insulin-stimulated glucose uptake in heart was not altered, but basal myocardial glucose metabolism was increased by more than two-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall up-regulation of cardiac metabolism in these mice. The effects of doxorubicin (DOX) treatment on cardiac function and structure were examined using M-mode echocardiography. DOX treatment caused a significant reduction in ventricular fractional shortening and resulted in more than 50% death in WT mice. In contrast, MHC-D2 mice showed increased survival rate after DOX treatment, and this was associated with a six-fold increase in myocardial glucose metabolism and improved cardiac function. Myocardial activity and expression of AMPK, GLUT1, and Akt were also elevated in MHC-D2 and WT mice following DOX treatment. Thus, our findings indicate an important role of thyroid hormone in cardiac metabolism and further suggest a protective role of glucose utilization in DOX-mediated cardiac dysfunction.

[Monitoring of cardiac damage in cancer patients treated with cardiotoxic drugs]. / Monitoraggio del danno cardiaco nel paziente oncologico in trattamento con farmaci cardiotossici.

In recent years, thanks to advances in early diagnosis and especially to substantial improvements in therapy, there has been a significant increase in the survival of cancer patients. Almost all cancers can be cured today, and survival of patients over 5-10 years is a tangible goal in many types of cancer. Cardiovascular complications are a growing problem in clinical practice that may frustrate modern oncological outcome of therapy. For this reason, a careful evaluation of the patient risk profile through a close collaboration among physicians and careful monitoring of patients are necessary for a successful treatment. Among the most common and dangerous complications of many drugs used in cancer chemotherapy, there is the development of myocardial damage and heart failure. The present review focuses on the type of cancer drugs that may induce cardiac dysfunction and provides the clinical cardiologist monitoring schemes applicable in daily clinical practice aimed at early detection of cardiac damage.