Cardiotoxicity In Patients Research Articles

Early and late onset cardiotoxicity following anthracycline-based chemotherapy in breast cancer patients: Incidence and predictors

IntroductionCardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data on longitudinal studies about early and late onset cardiotoxicity in this group of patients is scarce. The objective of the present study was to assess predictors of early and late onset cardiotoxicity in patients with breast cancer treated with A. Methods100 consecutive patients receiving anthracycline-based chemotherapy (CHT) to treat breast cancer were included in this prospective study. All patients underwent evaluation at baseline, at the end of CHT, 3 months after the end of CHT and 1 and 4 years after the beginning of CHT. Clinical data, systolic and diastolic echo parameters and cardiac biomarkers including high sensitivity Troponin T (TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP) and Heart-type fatty acid binding protein (H-FABP) were assessed. ResultsMean doxorubicin dose was 243 mg/m2. Mean follow-up was 51.8 ± 8.2 months. At one-year incidence of anthracycline related-cardiotoxicity (AR-CT) was 4% and at the end of follow-up was 18% (15 patients asymptomatic left ventricular systolic dysfunction, 1 patients heart failure and 2 patients a sudden cardiac death). Forty-nine patients developed diastolic dysfunction (DD) during first year. In the univariate analysis DD during first year was the only parameter associated with AR-CT (Table 1). In the logistic regression model DD was independently related with the development of AR-CT, with an odds ratio value of 7.5 (95% CI 1.59–35.3). ConclusionsIncidence of late-onset cardiotoxicity is high but mostly subclinical. Diastolic dysfunction early after chemotherapy is a strong predictor of anthracycline cardiotoxicity.

Low incidence of cardiotoxicity in patients with non-Hodgkin lymphoma receiving EPOCH after prior anthracycline exposure.

To describe the incidence of cardiotoxicity in patients with anthracycline exposure who subsequently receive EPOCH for non-Hodgkin lymphoma (NHL). We conducted a retrospective cohort study of adults with anthracycline exposure who subsequently received EPOCH for NHL at Memorial Sloan Kettering Cancer Center. The primary outcome was cumulative incidence of arrhythmia, heart failure (HF), left ventricular (LV) dysfunction, or cardiac death. Among 140 patients, most had diffuse large B-cell lymphoma. Inclusive of EPOCH, median cumulative doxorubicin-equivalent dose was 364 mg/m2 ; exposure was 400 mg/m2 or higher in 41%. With median 36-month follow-up, 23 cardiac events were noted in 20 patients. Cumulative incidence of cardiac events at 60 months was 15% (95% confidence interval [CI]: 9%-21%). When limited to LV dysfunction/HF, cumulative incidence at 60 months was 7% (95% CI: 3%-13%), with most events occurring after the first year. Univariate analysis indicated only history of cardiac disease and dyslipidemia to be associated with cardiotoxicity; no other risk factors, including cumulative anthracycline dose, were identified. In this retrospective cohort, representing the largest experience in this setting with extended follow-up, cumulative incidence of cardiac events was low. Rates of LV dysfunction or HF were particularly low, suggesting infusional administration may mitigate risk despite prior exposure.

Prevalence of cancer therapy cardiotoxicity as assessed by imaging procedures: A scoping review.

Advances in treatment and optimization of chemotherapy protocols have greatly improved survival in cancer patients. Unfortunately, treatment can cause a reduction in left ventricular (LV) ejection fraction (EF) leading to cancer therapy-related cardiac dysfunction (CTRCD). We conducted a scoping review of published literature in order to identify and summarize the reported prevalence of cardiotoxicity evaluated by noninvasive imaging procedures in a wide-ranging of patients referred to cancer treatment as chemotherapy and/or radiation therapy. Different databases were checked (PubMed, Embase, and Web of Science) to identify studies published from January 2000 to June 2021. Articles were included if they reported data on LVEF evaluation in oncological patients treated with chemotherapeutic agents and/or radiotherapy, measured by echocardiography and/or nuclear or cardiac magnetic resonance imaging test, providing criteria of CTRCD evaluation such as the specific threshold for LVEF decrease. From 963 citations identified, 46 articles, comprising 6841 patients, met the criteria for the inclusion in the scoping review. The summary prevalence of CTRCD as assessed by imaging procedures in the studies reviewed was 17% (95% confidence interval, 14-20). The results of our scoping review endorse the recommendations regarding imaging modalities to ensure identification of cardiotoxicity in patients undergoing cancer therapies. However, to improve patient management, more homogeneous CTRCD evaluation studies are required, reporting a detailed clinical assessment of the patient before, during and after treatment.

Cardiovascular Side Effects of Anthracyclines and HER2 Inhibitors among Patients with Breast Cancer: A Multidisciplinary Stepwise Approach for Prevention, Early Detection, and Treatment.

Cardiovascular (CV) diseases (CVD) are a major cause of long-term morbidity and mortality affecting life expectancy amongst cancer survivors. In recent years, because of the possibility of early diagnosis and the increased efficacy of neo-adjuvant and adjuvant systemic treatments (targeting specific molecular pathways), the high percentage of survival from breast cancer led CVD to become the first cause of death among survivors. Therefore, it is mandatory to adopt cardioprotective strategies to minimize CV side effects and CVD in general in breast cancer patients. Cancer therapeutics-related cardiac dysfunction (CTRCD) is a common group of side effects of chemotherapeutics widely employed in breast cancer (e.g., anthracycline and human epidermal growth factor receptor 2 inhibitors). The aim of the present manuscript is to propose a pragmatic multidisciplinary stepwise approach for prevention, early detection, and treatment of cardiotoxicity in patients with breast cancer.

Protective effects of protocatechuic acid against doxorubicin- and arsenic trioxide-induced toxicity in cardiomyocytes.

Some chemotherapeutic drugs are associated with an increased risk of cardiotoxicity in patients. Protocatechuic acid (PCA) is a phenolic acid with valuable cardiovascular, chemo-preventive, and anticancer activities. Recent studies have shown the cardioprotective effects of PCA in several pathological conditions. This investigation aimed to assess the possible protective effects of PCA on cardiomyocytes against toxicities caused by anti-neoplastic agents, doxorubicin (DOX), and arsenic trioxide (ATO). H9C2 cells were exposed to DOX (1 μM) or ATO (35 μM) after 24 h pretreatment with PCA (1-100 μM). MTT and lactate dehydrogenase (LDH) tests were used to define cell viability or cytotoxicity. Total oxidant and antioxidant capacities were evaluated by measuring hydroperoxides and ferric-reducing antioxidant power (FRAP) levels. Expression of the TLR4 gene was also quantitatively estimated by real-time polymerase chain reaction. PCA showed a proliferative effect on cardiomyocytes and significantly enhanced cell viability and reduced cytotoxicity of DOX and ATO during MTT and LDH assays. Pretreatment of cardiomyocytes with PCA significantly decreased hydroperoxide levels and elevated FRAP value. Moreover, PCA meaningfully decreased TLR4 expression in DOX-and ATO-treated cardiomyocytes. In conclusion, antioxidant and cytoprotective activities were found for PCA versus toxicities caused by DOX and ATO in cardiomyocytes. However, further in vivo investigations are recommended to assess its clinical value for the prevention and treatment of cardiotoxicity induced by chemotherapeutic agents.

The role of left ventricle global longitudinal srain in prediction of chemotherapy — induced cardiotoxicity in breast cancer patients treated by low and moderate cumulative doses of anthracyclines

Objective. To evaluate the alterations of Global longitudinsl strain (GLS) and it’s value for prediction of cardiotoxicity of low to moderate cumulative doses of anthracyclines. Methods. Forty-nine women 50 ± 10 years old with breast cancer, treated with anthracyclines (cumulative dose of 251 ± 60 mg/m2) were enrolled in the study. Echocardiography with GLS measurement was performed at baseline, at the end of anthracycline treatment, then every 3 months during 1 year. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) of at least 10 % to ≤ 53 %. Results. There was a significant increase in mean LVESV and LVEDV and decrease of GLS (р < 0,05) but not LVEF at 3 month post anthracycline treatment. Cardiotoxicity was detected in 8 patients (16 %) with moderate baseline risk. Absolute ≥ 4 % reduction of GLS during follow-up, GLS andpercent of it’s reduction from baseline to 3 month post-anthracycline were predictive of cardiotoxicity (AUC = 0,822 and 0,870, respectively). The reduction in GLS of >12,5 % from baseline at 3 month post anthracyclines was predictive of cardiotoxicity with sensitivity of 80 % and specificity of 95 %. Conclusions. GLS and its reduction from baseline has shown predictive value for development of cardiotoxicity in patients with moderate risk treated with low-to moderate cumulative doses of antracyclines. Additional echocardiography with GLS assessment at 3–6 month after completion of anthracycline treatment may be recommended irrespective of cardiotoxicity risk.

Potential of primary drug prevention of cardiotoxicity in the context of anticancer therapy

Aim. To search early signs of cardiotoxicity in patients receiving anticancer therapy and evaluate the effectiveness of cardioprotection with an angiotensin-converting enzyme inhibitor, beta-blocker and myocardial cytoprotector.Material and methods. The study included 98 patients with high and very high risk of cardiotoxicity according to the Mayo Clinic scale (USA). Cancer patients with hypertension were offered cardioprotective treatment with a fixed-dose combination of perindopril and bisoprolol, and patients with very high risk and concomitant coronary artery disease additionally trimetazidine.The patients were divided into 2 following groups: the experimental group (n=50), where patients were prescribed cardioprotective therapy, and the control group (n=48), which consisted of patients who refused or had contraindications to cardioprotection. All patients underwent an examination, including the collection of complaints and anamnesis, physical examination, electrocardiography and echocardiography with an assessment of left ventricular (LV) global longitudinal strain before chemotherapy and 1, 3, 6, 9 and 12 months after initiation of anticancer therapy.Results. In patients of the control group, by the end of the follow-up, the left atrial volume index and LV end-diastolic volume index significantly increased. In the main group, these indicators did not change significantly. In the control group, by the final visit, the LV ejection fraction significantly decreased in comparison with the initial value and the value in the first group. After 6, 9 and 12 months, there was a significant decrease in the LV global longitudinal strain in the control group, while in the main group this indicator remained within the normal range. The mortality rate in the control group was significantly higher (15% vs 2% in the experimental group). In the experimental group, cardiotoxic complications occurred in 28%, while in the control group — in 78% of patients.Conclusion. The study demonstrated the significant importance of cardiac monitoring and primary drug prevention of cardiotoxicity of anticancer therapy. A sig nificant deterioration in LV systolic function was shown in patients with a high and very high risk of cardiotoxicity who did not receive cardioprotective therapy, while its high efficiency was demonstrated in patients of the experimental group.

Retracted: Grading Evaluation of Cardiotoxicity in Patients with Breast Cancer Treated with Adjuvant Paclitaxel Anthracycline/Cyclophosphamide Chemotherapy: A Meta-Analysis.

[This retracts the article DOI: 10.1155/2022/7963146.].

Retracted: The Value of Left Atrial Volume Changes in Predicting Cardiotoxicity in Patients Undergoing Anthracycline Chemotherapy.

[This retracts the article DOI: 10.1155/2022/2590847.].

Cardiotoxicity during and after oncological treatment − role of cardio-magnetic resonance

The purpose of this review article is to inform practicing cardiologists about the manifestations of cardiotoxicity in patients on or after antitumor therapy and about the potential of cardiac magnetic resonance imaging (CMR) in the diagnosis and follow-up of these patients. The definitions and classification of cardiotoxicity associated with antitumor treatment, the mechanisms of cardiac and vascular damage of some of the important groups of antitumor drugs, and the potential CMR findings are reviewed. The main clinical situations related to manifestations of cardiotoxicity in which CMR has or is expected to have a leading role are outlined.

780 POTENTIAL RELATIONSHIP BETWEEN MITOCHONDRIAL FERRITIN EXPRESSION AND CARDIOTOXICITY IN PATIENTS UNDERGOING ANTHRACYLINE CHEMOTHERAPY

Abstract Background Anthracyclines effectiveness is burdened by numerous side effects, among which cardiotoxicity (CTX) is the one carrying the highest impact on survival. Prevention of CTX is known to be far more effective than its treatment. Nonetheless, present patients stratification does not predict different post-treatment outcomes. The inter-individual variability in the response to treatment likely resides at the molecular level. In this context, mitochondrial ferritin (FtMt) has been studied in preclinical models of doxorubicin-induced cardiotoxicity. Both in cell lines and animal models, overexpression of this protein has been found to be protective against the cytotoxic oxidative damage deriving from anthracycline use. Aim of the study The primary aim of the study was to evaluate – for the first time in humans and in mouse myocardial cells lines – the expression of FtMt and its relationship with the potential development of cardiotoxicity in patients undergoing chemotherapy with anthracyclines. Methods Twenty-nine patients referred to our Oncology Outpatient Clinic to start treatment with anthracyclines – for either lymphoma or breast cancer – were enrolled before treatment initiation. All patients were above 18 years of age and free from any cardiovascular pathology at baseline. Troponin T (TnT), Brain Natriuretic Peptide (NT-proBNP), FtMt and creatinine were evaluated at baseline, before any chemotherapy cycle, at the end of the protocol, at 6 and 12 months from the first cycle. TnT and NT-proBNP were quantified through ECLIA and the expression of FtMt through qRT-PCR performed on peripheral white blood cells. Left ventricular function was evaluated through standard echocardiography at baseline, at the end of chemotherapy, at 6 and 12 months. Furthermore, variations in FtMt expression in response to doxorubicin treatment were studied on mouse primary cardiomyocytes. Results Direct evaluation of FtMt expression in mouse myocardial cells showed higher levels of FtMt in cardiomyocytes exposed to doxorubicin (p=0.0239). In the clinical model FtMt expression was found to be decreased after treatment initiation, with a trend that in the descriptive analysis appeared to be opposite to the one registered for TnT. For any unit of FtMt at baseline, single TnT values after treatment and at one year were found to be decreased of 1,89 ng/L and of 1,57 ng/L, respectively. TnT was the only cardiac parameter showing significant variation following anthracycline administration, with an average increase of 10 ng/L (p<0,0001) and 15,8 ng/L (p=0,0071) in breast cancer and lymphoma patients respectively and remained elevated at follow-up only in the lymphoma group with a difference of 11,35ng/L at 1 year (p=0,0017). No occurrence of CTX – defined according to international guidelines - was found in the population under study. Conclusions Our results confirm that exposure to anthracyclines influences FtMt expression. The study performed on mouse primary cardiomyocytes demonstrate for the first time the ability of cardiac myocytes to increase FtMt expression in response to doxorubicin. In the clinical model any additional unit of FtMt at baseline was associated with a reduction in TnT values at the end of the treatment and at 1 year, potentially indicating a protective role of this protein in this context. The lack of frank cardiotoxicity in this group impeded the evaluation of the prognostic meaning of this event. In the future drugs able to upregulate the expression of this protein should be investigated as potential strategy to prevent anthracycline-induced cardiotoxicity.

383 TAKOTSUBO SYNDROME AFTER CAR-T CELL INFUSION

Abstract Introduction The mechanisms of cardiotoxicity during CAR-T cell therapy remain unclear to this day. We present the case of a 63-year-old woman with diffuse large B-cell lymphoma, who underwent CAR-T cell therapy. Five days after the infusion, she developed takotsubo cardiomyopathy. This is one of the rare cases of CAR-T cell-induced takotsubo cardiomyopathy. Case Description a 63-year-old woman with a diffuse large B-cell lymphoma and without significant cardiovascular history was treated with CAR-T cell therapy. The patient had arterial hypertension, dyslipidemia and history of CAD in the family. Prior to CAR-T cell therapy, she underwent baseline cardiac evaluation with an echocardiogram which showed a normal biventricular function. Within 24 hours of the infusion of CAR-T cells, she developed grade I cytokine release syndrome (CRS) with high-grade fever and sinus tachycardia. On day four, she developed grade three immune effector cell associated neurological syndrome which was treated with tocilizumab and dexamethasone. On day five laboratory testing showed a disproportionate elevation of BNP compared to hs-TnI. An ECG reported diffuse new-onset T wave inversion in all the precordial leads and a prolonged QT interval, and an echocardiogram showed severely reduced left ventricular ejection fraction (EF = 30%) with evidence of apical ballooning and right ventricular systolic dysfunction. Coronary angiography showed significant stenosis of the middle segment of the circumflex artery, which poorly could explain the clinical presentation of the patient. Ventriculography was also performed, which confirmed the ultrasound findings. During the next 48 hours, ECG and left ventricular function improved along with a gradual reduction of BNP and hs-TnI. We concluded that takotsubo syndrome was the most likely diagnosis. The InterTAK score was 89, which corresponded to a probability of takotsubo of 99.4%. The patient's therapy was then optimized with an increase in the dosage of angiotensin receptor antagonists and beta blockers. One month after CAR-T cell infusion, echocardiography showed complete recovery of biventricular function and ECG completely normalized, together with the values of BNP and TnI-hs. Medical treatment was left unmodified. Conclusions the pathophysiology of left ventricular systolic dysfunction during CAR-T cell therapy is unclear, but the main hypotheses are IL-6 mediated myocardial depression during CRS, stress-induced or takotsubo cardiomyopathy, and direct toxicity from CAR-T cells. From the currently available data from retrospective studies, cardiovascular events strongly overlap with CRS and, particularly, with high-grade CRS. Therefore, there is a strong rationale for early treatment with tocilizumab as it has been postulated from retrospective data a lower risk of cardiovascular events with earlier administration of tocilizumab during CRS. Surveillance for cardiotoxicity in patients receiving CAR-T cell therapy is mandatory for prompt recognition and treatment of cardiovascular complications. Our understanding of CAR-T cell-induced cardiomyopathy is still limited, and data regarding predictive factors for persistent cardiac dysfunction are lacking. It is important to differentiate cardiovascular events related to CAR-T cell therapy from epiphenomenon of CRS and capillary leak, to allow for a broader assessment of cardiac events among future CAR T-cell trials.

Possibilities of a new method for evaluating myocardial work in patients with breast cancer after anthracycline chemotherapy

Objective: to study the possibility of a new echocardiographic technology for assessing the effectiveness of myocardial work in detecting cardiotoxicity in patients with breast cancer, depending on the level of blood pressure during anthracycline chemotherapy.Material and methods: 30 women with triple-negative breast cancer were enrolled, 13 of them (43.3%) had arterial hypertension (AH). All patients underwent standard transthoracic echocardiography with assessment of left ventricular systolic function. The STE method was used to estimate the LV global longitudinal strain (GLS) in a two-dimensional mode. The efficiency of myocardial work was also evaluated.Results. After chemotherapy in patients with breast cancer the LVEF remained within normal values. After chemotherapy in breast cancer patients revealed a statistically significant decrease in GLS and myocardial work parameters. Also it has been shown that myocardial work parameters seem to better reflect the LV mechanical dysfunction compared to the GLS, especially in patients with breast cancer and high blood pressure.Conclusion. The first results of the study showed that in breast cancer patients who had high blood pressure at the time of the study, myocardial work parameters better reflect of the LV mechanical dysfunction than the GLS parameter. A new method for evaluating the effectiveness of myocardial work requires further research and study in cancer patients undergoing chemotherapy and radiation therapy.

Association of Neurohormonal Antagonists on Incident Cardiotoxicity in Patients With Breast Cancer

Cardiovascular disease is the leading cause of mortality among breast cancer survivors. Anthracyclines and trastuzumab have been associated with an increased risk of cardiotoxicity, requiring close follow-up for signs of clinical heart failure or asymptomatic left ventricular systolic dysfunction. Whether neurohormonal antagonism with angiotensin-converting enzyme inhibitor (ACE-I), angiotensin receptor blockers (ARBs), or β-blockers can prevent the development of chemotherapy-induced cardiomyopathy in this population remains unknown. We studied 459 women who were diagnosed with breast cancer at our medical center from January 2014 to December 2021 and evaluated baseline characteristics, oncologic treatment, and outcomes. The primary end point was the development of cardiotoxicity, defined as symptomatic decline in ejection fraction of ≥5% below 55% or an asymptomatic decline of ≥10% after treatment with chemotherapy. Patients who were exposed to neurohormonal antagonists were more likely to have hypertension, hyperlipidemia, and diabetes. There was an increased risk of cardiotoxicity noted for patients who were older (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.01 to 1.1), smokers within the past 10years (HR 2.54, 95% CI 1.41 to 4.6), or who received a combination of both trastuzumab and anthracycline therapy (HR 2.52, 95% CI 1.01 to 6.3). Over a median follow-up of 12months, there were no significant protective benefits noted for patients who were taking ACE-I/ARBs (HR 0.49, 95% CI 0.17 to 1.4), β-blockers (HR 0.50, 95% CI 0.16 to 1.6), or both (HR 1.30, 95% CI 0.44 to 3.9). In conclusion, previous use of ACE-I/ARBs and β-blockers, separately or in combination, was not associated with a reduction in the development of cardiotoxicity in patients receiving anthracycline or trastuzumab therapies. Older age, smoking, and combination chemotherapy were found to be associated with an increased risk.

Preventing cardiotoxicity in patients with breast cancer and lymphoma: protocol for a multicentre randomised controlled trial (PROACT)

IntroductionAnthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can...

Global longitudinal strain: an early marker for cardiotoxicity in patients treated for breast cancer.

Patients treated with anthracyclines and trastuzumab are at increased risk of developing heart failure. Early diagnosis and treatment may prevent irreversible left ventricular (LV) dysfunction. This study investigates whether subclinical deterioration of global longitudinal strain (GLS) is amore reliable early predictor for LV dysfunction than three-dimensional (3D) LV ejection fraction (LVEF). Adult patients receiving anthracyclines and trastuzumab for breast cancer who had serial echocardiographic follow-up were included in this retrospective study. The primary endpoint was the necessity to temporarily pause chemo- or immunotherapy due to declining LVEF (decline in 3D LVEF of > 10percentage points to < 53%). Linear mixed-effects models were used to assess the longitudinal evolution of 3D LVEF and GLS over time. Fifty-one women were included, mean age 54 (50.5-57.6) years, with atotal of 216 follow-up echocardiograms (mean follow-up 1.1 ± 0.45years). GLS and 3D LVEF were significantly correlated (Spearman's rho: -0.36, p < 0.001). Adecrease in GLS significantly predicted alower LVEF on the subsequent echocardiogram [ß -0.6, 95% confidence interval (CI) (-1.0 to -0.2), p < 0.006]. Conversely, prior LVEF did not significantly predict GLS on the subsequent echocardiogram [ß -0.04, 95% CI -0.1 to -0.01, p = 0.12]. Nine patients reached the primary endpoint. On average, patients who reached the primary endpoint had arelative decrease of 15% GLS at day 205 and an absolute 10% decrease of LVEF to LVEF < 53% at day 235. GLS is able to identify subclinical LV dysfunction earlier than 3D LVEF measurement in women undergoing treatment for breast cancer with anthracyclines followed by trastuzumab.

Trastuzumab-induced cardiotoxicity in patients with HER-2 positive breast cancer

Introdução: Trastuzumabe é um anticorpo monoclonal humanizado precursor de inibidores HER-2 positivos. A cardiotoxicidade é uma das reações adversas mais importantes do ponto de vista clínico, associada ao uso de trastuzumabe. Estudos mostram que 12,6% dos pacientes tratados com o inibidor de HER-2 apresentaram cardiotoxicidade. Objetivo: Identificar a presença de cardiotoxicidade induzida por trastuzumabe em pacientes com câncer de mama HER-2 positivo. Método: O estudo foi transversal e retrospectivo, realizado em um hospital filantrópico oncológico da cidade de Salvador, Bahia, Brasil. Os dados foram coletados por meio de prontuários eletrônicos. Foram incluídos no estudo pacientes com diagnóstico de câncer de mama HER-2 positivo, do sexo feminino, maiores de 18 anos, que utilizaram trastuzumabe no período de setembro a dezembro de 2020. As variáveis analisadas foram: idade, comorbidade, combinação de quimioterapia (monoterapia, associada) e tipo de terapia (adjuvante, neoadjuvante). Resultados: 159 pacientes foram incluídas no estudo. 10 (6%) deles apresentaram cardiotoxicidade durante o tratamento, a maioria com idade entre 40-59 anos (70%). Quanto às comorbidades, 6 (60%) pacientes eram hipertensos. 7 dos pacientes (70%) estavam em monoterapia com trastuzumabe. Todos os pacientes usaram trastuzumabe como tratamento adjuvante. Conclusão: No presente estudo, foi possível identificar a presença de cardiotoxicidade em pacientes que utilizaram trastuzumabe. Assim, é fundamental uma atenção especial ao monitoramento da função cardíaca, bem como ao acompanhamento clínico desses pacientes para identificar, precocemente, os sinais e sintomas apresentados e, assim, prevenir possíveis danos. Em pesquisas futuras, novos parâmetros de monitoramento devem ser estudados para identificar precocemente a cardiotoxicidade induzida pelo trastuzumabe.

Abstract 12041: Tyrosine Kinase Inhibitors Leads to Sodium Channel Dysfunction in the Heart

Tyrosine Kinase Inhibitors (TKIs) are used by tens of thousands of patients and are efficacious for treating renal cell carcinoma . However, TKIs have been reported to have numerous off-target effects, including arrhythmias and heart failure. Many patients who receive TKIs are over 60 years of age and have existing cardiac diseases, thus increasing their risk of cardiotoxicity. However, the exact mechanism to how these TKIs cause cardiotoxicity remains unclear. Our research goal is to understand how TKIs lead to cardiotoxicity by learning what proteins are being targeted and what are potential upstream regulators so we can introduce possible treatments that can combat these effects. Recent literature has stated that the TKI Sorafenib led to increased reactive oxygen species (ROS) production and Calcium (Ca 2+ )/Calmodulin dependent kinase II (CaMKII) activity in rat ventricular cardiomyocytes. ROS can activate CaMKII, and increased CaMKII activity can lead to hyperphosphorylation of the voltage-gated sodium channel, leading to pathophysiological enhancement of late sodium current (I Na,L ). Increased activity of CaMKII and I Na,L can be seen in arrhythmias and heart failure. We hypothesize that TKIs lead to an increase enhancement of I Na,L due to an increase in ROS production and increased CaMKII activity. To test this hypothesis, we treated H9c2 myoblasts with Pazopanib (n=3) or DMSO (n=3) and wild-type mice with Pazopanib (n=5) or DMSO (n=5). After treatment, we assessed cytosolic and mitochondrial ROS production in vitro and functional affects, CaMKII activity, and I Na,L current in vivo . Results showed that Pazopanib led to a significant increase in ROS production in H9c2 cells and more arrhythmogenic events in WT mice. While CaMKII activity or I Na,L expression was not significantly changed between the two groups, with electrophysiology studies Pazopanib did lead to alterations in amplitude, peak current, ultra-slow inactivation, and recovery. In conclusion, Pazopanib leads to cardiovascular dysfunction and this could be due to an increase in ROS production and altered sodium channels. Our study indicates a potential mechanism as to how TKI treatment leads to cardiotoxicity in patients.

Abstract 13198: Cardiac TRPC6 N338S is a Gain-of-Function Mutation Associated With Doxorubicin-Induced Cardiomyopathy

Introduction: Doxorubicin (DOX) is widely used for chemotherapy, but cardiotoxicity and cardiomyopathy are major adverse effects. The canonical transient receptor potential 6 gene ( TRPC6) is a putative risk gene for cardiomyopathy. Recently, a TRPC6 N338S mutation was found in a patient with DOX-induced heart failure. However, the TRPC6 N338S mutant has not been characterized, and how it affects cardiac function is unknown. Hypothesis: We hypothesized that TRPC6 N338S is a gain-of-function mutation producing intracellular Ca 2+ overload in cardiomyocytes. Methods: Using patch clamp recording, molecular biological and molecular docking analyses, we assessed the function of TRPC6 N338S heterologously expressed in HL-1 cardiac cells. Results: TRPC6 N338S significantly increased the current densities of TRPC6 (defined as 1 μM BI-749327 sensitive components, a highly selective TRPC6 inhibitor) in HL-1 cells at baseline and after exposure to 50 μM 1-oleoyl 2-acetyl-sn-glycerol (OAG, an activator of TRPC6), compared to cells expressing TRPC6 WT. Moreover, a 24-h pretreatment with 0.5 μM DOX further potentiated the OAG effects on TRPC6 WT currents with a significantly greater response in the N338S currents. Ca 2+ imaging also showed enhanced intracellular Ca 2+ levels in cells expressing the N338S mutant with OAG and DOX treatment. Biological studies found that the cytoplasmic and surface expression of TRPC6 WT and N338S mutant were identical in HL-1 cells, but those of TRPC6 N338S were markedly upregulated after treatment with 0.5 μM DOX, compared to TRPC6 WT. Molecular docking and dynamics simulation analysis unraveled that OAG binds to a pocket constituted by the pore-helix, S5 and S6 domains of TRPC6 through polar interactions. OAG binds to the same site in TRPC6 N338S with shortened interfacial distances due to additional polar and hydrogen bonding between OAG and the N338S mutant. Conclusions: TRPC6 N338S mutation strengthens the interaction with OAG, stabilizes the OAG-TRPC6 N338S complex, and enhances the OAG effects. Treatment with DOX significantly increases the expression and function of TRPC6 N338S in HL-1 cells. Hence, the TRPC6 N338S is a gain-of-function mutation and may contribute to cardiotoxicity in patients with anthracycline treatment.

Cardiotoxicity in Patients with Ductal Carcinoma In Situ (DCIS) in the Contemporary Radiotherapy Era

<h3>Purpose/Objective(s)</h3> Risk of radiation induced cardiotoxicity with modern radiotherapy (RT) for patients with DCIS is unclear. Many studies have observed a higher risk of cardiac toxicity for women treated with left vs right breast RT. However, most analyses were conducted in an older era and included patients with invasive disease, who also have risk of cardiac toxicity from anthracycline, taxane, and/or Herceptin-based systemic therapy and have more limited long-term follow up due to risk of death due to breast cancer. In this study, we evaluated the impact of modern RT on cardiac events in patients with DCIS. Our hypothesis is that toxicity rates will not differ significantly between left and right DCIS patients treated with modern breast RT. <h3>Materials/Methods</h3> We identified patients with DCIS who were treated with breast conserving surgery and RT at our institution between 2006-2017. Patients with bilateral breast RT or prior thoracic RT were excluded. Patients were treated using CT simulation and modern RT techniques including 3D-CRT, brachytherapy, and IMRT. Prone and deep inspiration breath hold (DIBH) delivery were utilized. Patients received either whole breast or partial breast RT. We recorded 5 cardiac event classes: ischemic, valvular, arrhythmia, cardiomyopathy, and pericardial events. Incidence of cardiac events were compared for right vs left DCIS, and stratified by age and risk factors such as previous cardiac disease, BMI, tobacco use, hyperlipidemia, hypertension, and diabetes. Comparisons were done using Fisher's exact test. <h3>Results</h3> 546 patients (262 left and 284 right) met the inclusion criteria for our study. Mean age at diagnosis was 57.8 years and mean follow up was 105 months. Cardiac events occurred at median of 52 months, mean of 59 months, and range of 7-147 months after RT. There was no significant difference in incidence of overall cardiac events among patients with left vs. right DCIS (p>0.05). There was also no significant difference among left vs. right DCIS patients for any event class, including ischemic, valvular, arrhythmia, cardiomyopathy, and pericardial events (p>0.05). Similarly, we did not observe a significant difference in rate of cardiac events for patients with left vs. right DCIS when patients were divided into two groups based on year of RT delivery and when stratified by risk factors for any cardiac outcome. <h3>Conclusion</h3> Incidence of cardiac events after adjuvant breast RT did not differ significantly between left and right DCIS patients, including overall risk as well as risk of each cardiac event class (ischemic, valvular, arrhythmia, cardiomyopathy, and pericardial). This suggests that modern radiotherapy techniques such as partial breast RT or whole breast RT using 3D-CRT, prone, or DIBH techniques, with CT simulation based planning and strict cardiac dose-volume constraints are effective in limiting cardiac events for left breast RT. Further studies and continued follow-up are necessary to confirm these observations.