Short-term doxorubicin cardiotoxic effects: involvement of cardiac Thyrotropin Releasing Hormone system.

Doxorubicin is an antineoplastic in the anthracycline class widely used for the treatment of several solid tumors and blood cancers. Cardiotoxicity is the major dose-limiting adverse effect of the drug. Chronic and accumulated doxorubicin administration cause myocyte damage and myocardial fibrosis. Doxorubicin-associated cardiotoxicity can be also observed after a short-course drug treatment even without clinical evidence of cardiac disease. Nevertheless, acute underlying mechanisms involved in the initiation of drug-induced cardiotoxicity remain poorly explored despite their similarities with pathophysiological conditions where cardiac TRH (cTRH) plays a central role. We showed that cTRH mediates myocardial injury induced by hypertension, and angiotensin II. Further, cTRH overexpression induces cardiac apoptosis, hypertrophy and fibrosis. AIM: To demonstrate that cTRH could mediate acute doxorubicin cardiotoxicity. MAIN METHOD: A single injection of doxorubicin (10 mg kg/day i.p.) was used to evaluate acute cardiac damage in a short-term experimental model of doxorubicin-induced cardiotoxicity. While inhibiting cTRH by small interfering RNA (siRNA), we evaluated the progression of cardiotoxicity. KEY FINDINGS: We found a doxorubicin-induced TRH overexpression in the LV, which was associated with apoptosis, hypertrophy and fibrosis. siRNA-mediated cTRH suppression prevented the doxorubicin-associated cardiac histological lesions. SIGNIFICANCES: doxorubicin requires an active cardiac TRH system to promote heart injury.

Trastuzumab emtansine (T-DM1)-associated cardiotoxicity: Pooled analysis in advanced HER2-positive breast cancer.

INTRODUCTION: T-DM1 has been approved for the treatment of HER2+ breast cancer. Cardiac dysfunction is a side effect of trastuzumab, a component of T-DM1. However, little is known about T-DM1-associated cardiotoxicity. METHODS: We have conducted a pooled analysis of T-DM1 trials in advanced HER2+ breast cancer cases to understand the incidence, clinical presentation as well as to establish possible risk factors for T-DM1-associated cardiotoxicity. The primary endpoint was the incidence of cardiac events (CEs). CEs were categorized as follows: (1) congestive heart failure (CHF) or grade 3/4 LVEF drop; (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Secondary endpoints included CE recovery rate and impact of CEs on treatment discontinuation. Logistic regression was used to assess possible risk factors for CEs. RESULTS: Individual patient-level data from 1961 patients exposed to T-DM1 in seven trials were pooled. Of these, 1544 received T-DM1 and 417 T-DM1 + pertuzumab. CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%. The total CE rate was 3.37% (95% confidence interval (CI), 2.6%-4.3%). Multivariate analysis showed patient's age ≥65 (OR 3.0; 95% CI, 1.77-5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29-5.32; P-value 0.008) as risk factors. CEs resolved in most (79%) patients after treatment discontinuation. CONCLUSION: The incidence of CEs in patients receiving T-DM1 was low. Older patients receiving T-DM1 should be carefully followed for cardiac safety during treatment.

Crataegus mexicana (Tejocote) Exposure Associated with Cardiotoxicity and a Falsely Elevated Digoxin Level.

INTRODUCTION: A species of hawthorn, Crataegus mexicana (tejocote), has been marketed as a weight-loss supplement that is readily available for purchase online. While several hawthorn species have shown clinical benefit in the treatment of heart failure owing to their positive inotropic effects, little is known about hawthorn, and tejocote in particular, when consumed in excess. We describe a case of tejocote exposure from a weight-loss supplement resulting in severe cardiotoxicity. CASE REPORT: A healthy 16-year-old girl presented to an emergency department after ingesting eight pieces of her mother's tejocote root weight-loss supplement. At arrival, she was drowsy, had active vomiting and diarrhea, and had a heart rate of 57 with normal respirations. Her initial blood chemistries were unremarkable, except for an elevated digoxin assay of 0.7 ng/mL (therapeutic range 0.5-2.0 ng/mL). All other drug screens were negative. She later developed severe bradycardia and multiple episodes of hypopnea that prompted a transfer to our institution, a tertiary pediatric hospital. Her ECG demonstrated a heart rate of 38 and Mobitz type 1 second-degree heart block. She was subsequently given two vials of Digoxin Immune Fab due to severe bradycardia in the setting of suspected digoxin-like cardiotoxicity after discussion with the regional poison control center. No clinical improvement was observed. Approximately 29 hours after ingestion, subsequent ECGs demonstrated a return to normal sinus rhythm, and her symptoms resolved. DISCUSSION: Tejocote root toxicity may cause dysrhythmias and respiratory depression. Similar to other species of hawthorn, tejocote root may cross-react with some commercial digoxin assays, resulting in a falsely elevated level.

Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children's Oncology Group.

PURPOSE: Late cardiotoxicity after pediatric acute myeloid leukemia therapy causes substantial morbidity and mortality. The impact of early-onset cardiotoxicity on treatment outcomes is less well understood. Thus, we evaluated the risk factors for incident early cardiotoxicity and the impacts of cardiotoxicity on event-free survival (EFS) and overall survival (OS). METHODS: Cardiotoxicity was ascertained through adverse event monitoring over the course of follow-up among 1,022 pediatric patients with acute myeloid leukemia treated in the Children's Oncology Group trial AAML0531. It was defined as grade 2 or higher left ventricular systolic dysfunction on the basis of Common Terminology Criteria for Adverse Events (version 3) definitions. RESULTS: Approximately 12% of patients experienced cardiotoxicity over a 5-year follow-up, with more than 70% of incident events occurring during on-protocol therapy. Documented cardiotoxicity during on-protocol therapy was significantly associated with subsequent off-protocol toxicity. Overall, the incidence was higher among noninfants and black patients, and in the setting of a bloodstream infection. Both EFS (hazard ratio [HR], 1.6; 95% CI, 1.2 to 2.1; P = .004) and OS (HR, 1.6; 95% CI, 1.2 to 2.2, P = .005) were significantly worse in patients with documented cardiotoxicity. Impacts on EFS were equivalent whether the incident cardiotoxicity event occurred in the absence (HR, 1.6; 95% CI, 1.1 to 2.2; P = .017) or presence of infection (HR, 1.6; 95% CI, 1.0 to 2.7; P = .069) compared with patients without documented cardiotoxicity. However, the reduction in OS was more pronounced for cardiotoxicity not associated with infection (HR, 1.7; 95% CI, 1.2 to 2.5; P = .004) than for infection-associated cardiotoxicity (HR, 1.3; 95% CI, 0.7 to 2.4; P = .387). CONCLUSION: Early treatment-related cardiotoxicity may be associated with decreased EFS and OS. Cardioprotective strategies are urgently needed to improve relapse risk and both short- and long-term mortality outcomes.

Arterial Stiffness Use for Early Monitoring of Cardiovascular Adverse Events due to Anthracycline Chemotherapy in Breast Cancer Patients. A Pilot Study / Uso da Rigidez Arterial para Monitoramento Precoce de Eventos Adversos Cardiovasculares por Antracíclicos em Pacientes com Câncer de Mama. Um Estudo Piloto

Abstract Background: Chemotherapy with doxorubicin and cyclophosphamide, although efficient for treating breast cancer, is associated with cardiovascular complications. Recent studies seek to identify methods that can early detect cardiological and vascular changes as a strategy to decrease the incidence of cardiovascular comorbidities. Objective: To evaluate the role of arterial stiffness measurement in the monitoring of doxorubicin and cyclophosphamide-induced cardiotoxicity in breast cancer patients. Methods: Prospective longitudinal study in 24 breast cancer patients undergoing treatment with doxorubicin and cyclophosphamide. Patients underwent an indirect evaluation of arterial stiffness through non-invasive measurement of hemodynamic parameters such as pulse wave velocity with the Mobil-O-Graph® 24H PWA device at three different times of the chemotherapy treatment (pre-chemotherapy, after the first and the fourth cycle). The left ventricular ejection fraction was also evaluated by Doppler echocardiography (pre-chemotherapy and after the fourth chemotherapy cycle). Data were considered significant when p ≤ 0.05. Results: Patients had a mean age of 52.33 ± 8.85 years and body mass index of 31 ± 5.87 kg/m2. There was no significant difference between the hemodynamic parameters evaluated by the oscillometric method or in the left ventricular ejection fraction in the different evaluated periods. Conclusion: Evaluations of arterial stiffness by oscillometry and measurement of left ventricular ejection fraction by Doppler echocardiography showed equivalence in the values found, suggesting that the evaluation method of arterial stiffness studied could be used as a marker for cardiovascular adverse events associated with doxorrubicin-based chemotherapy drugs.

Resumo Fundamento: O tratamento quimioterápico com doxorrubicina e ciclofosfamida, apesar de eficiente no combate ao câncer de mama, está associado a complicações cardiovasculares. Trabalhos recentes identificam métodos que possam detectar alterações cardiológicas e vasculares precocemente, visando a uma estratégia para diminuição na incidência de comorbidades cardiovasculares. Objetivo: Avaliar o papel da medida da rigidez arterial no acompanhamento da ocorrência de eventos adversos cardiovasculares induzidos por doxorrubicina e ciclofosfamida em pacientes com câncer de mama. Métodos: Estudo longitudinal prospectivo realizado com 24 pacientes com câncer de mama em tratamento com doxorrubicina e ciclofosfamida. As pacientes foram submetidas à avaliação indireta da rigidez arterial, por mensuração não invasiva de parâmetros hemodinâmicos, como a velocidade de onda de pulso, pelo equipamento Mobil-O-Graph® 24H PWA em três diferentes momentos do tratamento quimioterápico (pré-quimioterapia, após o primeiro e após o quarto ciclos). Foi avaliada também a fração de ejeção do ventrículo esquerdo pelo ecoDopplercardiograma (pré-quimioterapia e após o quarto ciclo quimioterápico). Os valores de p ≤ 0,05 foram considerados significativos. Resultados: As pacientes apresentaram média de idade de 52,33 ± 8,85 anos e índice de massa corporal de 31 ± 5,87 kg/m2. Não houve diferença significativa entre os parâmetros hemodinâmicos avaliados pelo método oscilométrico ou na fração de ejeção do ventrículo esquerdo, nos diferentes períodos avaliados. Conclusão: As avaliações de rigidez arterial por oscilometria e medida da fração de ejeção do ventrículo esquerdo por ecoDopplercardiograma mostraram equivalência nos valores encontrados, sugerindo que o método de avaliação da rigidez arterial estudado possa ser utilizado como mais um marcador para eventos adversos cardiovasculares associados aos medicamentos quimioterápicos baseados em doxorrubicina.

Arterial Stiffness Use for Early Monitoring of Cardiovascular Adverse Events due to Anthracycline Chemotherapy in Breast Cancer Patients. A Pilot Study.

BACKGROUND: Chemotherapy with doxorubicin and cyclophosphamide, although efficient for treating breast cancer, is associated with cardiovascular complications. Recent studies seek to identify methods that can early detect cardiological and vascular changes as a strategy to decrease the incidence of cardiovascular comorbidities. OBJECTIVE: To evaluate the role of arterial stiffness measurement in the monitoring of doxorubicin and cyclophosphamide-induced cardiotoxicity in breast cancer patients. METHODS: Prospective longitudinal study in 24 breast cancer patients undergoing treatment with doxorubicin and cyclophosphamide. Patients underwent an indirect evaluation of arterial stiffness through non-invasive measurement of hemodynamic parameters such as pulse wave velocity with the Mobil-O-Graph® 24H PWA device at three different times of the chemotherapy treatment (pre-chemotherapy, after the first and the fourth cycle). The left ventricular ejection fraction was also evaluated by Doppler echocardiography (pre-chemotherapy and after the fourth chemotherapy cycle). Data were considered significant when p ≤ 0.05. RESULTS: Patients had a mean age of 52.33 ± 8.85 years and body mass index of 31 ± 5.87 kg/m2. There was no significant difference between the hemodynamic parameters evaluated by the oscillometric method or in the left ventricular ejection fraction in the different evaluated periods. CONCLUSION: Evaluations of arterial stiffness by oscillometry and measurement of left ventricular ejection fraction by Doppler echocardiography showed equivalence in the values found, suggesting that the evaluation method of arterial stiffness studied could be used as a marker for cardiovascular adverse events associated with doxorrubicin-based chemotherapy drugs.

Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients.

Cardiotoxicity is associated with the chronic use of doxorubicin leading to cardiomyopathy and heart failure. Identification of cardiotoxicity-specific miRNA biomarkers could provide clinicians with a valuable prognostic tool. The aim of the study was to evaluate circulating levels of miRNAs in breast cancer patients receiving doxorubicin treatment and to correlate with cardiac function. This is an ancillary study from "Carvedilol Effect on Chemotherapy-induced Cardiotoxicity" (CECCY trial), which included 56 female patients (49.9±3.3 years of age) from the placebo arm. Enrolled patients were treated with doxorubicin followed by taxanes. cTnI, LVEF, and miRNAs were measured periodically. Circulating levels of miR-1, -133b, -146a, and -423-5p increased during the treatment whereas miR-208a and -208b were undetectable. cTnI increased from 6.6±0.3 to 46.7±5.5 pg/mL (p<0.001), while overall LVEF tended to decrease from 65.3±0.5 to 63.8±0.9 (p=0.053) over 12 months. Ten patients (17.9%) developed cardiotoxicity showing a decrease in LVEF from 67.2±1.0 to 58.8±2.7 (p=0.005). miR-1 was associated with changes in LVEF (r=-0.531, p<0.001). In a ROC curve analysis miR-1 showed an AUC greater than cTnI to discriminate between patients who did and did not develop cardiotoxicity (AUC = 0.851 and 0.544, p= 0.0016). Our data suggest that circulating miR-1 might be a potential new biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients.

Cardiac Sympathetic Hyperactivity after Chemotherapy: Early Sign of Cardiotoxicity? / Hiperatividade Simpática Cardíaca Após Quimioterapia: Sinal Precoce de Cardiotoxicidade?

Background:Chemotherapy with anthracyclines and trastuzumab can cause cardiotoxicity. Alteration of cardiac adrenergic function assessed by metaiodobenzylguanidine labeled with iodine-123 (123I-mIBG) seems to precede the drop in left ventricular ejection fraction.Objective:To evaluate and to compare the presence of cardiovascular abnormalities among patients with breast cancer undergoing chemotherapy with anthracyclines and trastuzumab, and only with anthracycline.Methods:Patients with breast cancer were analyzed clinical, laboratory, electrocardiographic and echocardiographic and cardiac sympathetic activity. In scintigraphic images, the ratio of 123I-mIBG uptake between the heart and mediastinum, and the washout rate were calculated. The variables were compared between patients who received anthracyclines and trastuzumab (Group 1) and only anthracyclines (Group 2).Results:Twenty patients, with mean age 57 ± 14 years, were studied. The mean left ventricular ejection fraction by echocardiography was 67.8 ± 4.0%. Mean washout rate was 28.39 ± 9.23% and the ratio of 123I-mIBG uptake between the heart and mediastinum was 2.07 ± 0.28. Of the patients, 82% showed an increased in washout rate, and the ratio of 123I-mIBG uptake between the heart and mediastinum decreased in 25%. Concerning the groups, the mean washout rate of Group 1 was 32.68 ± 9.30% and of Group 2 was 24.56 ± 7.72% (p = 0,06). The ratio of 123I-mIBG uptake between the heart and mediastinum was normal in all patients in Group 2, however, the Group 1, showed 50% the ratio of 123I-mIBG uptake between the heart and mediastinum ≤ 1.8 (p = 0.02).Conclusion:In women with breast cancer undergoing chemotherapy, assessment of cardiac sympathetic activity with 123I-mIBG appears to be an early marker of cardiotoxicity. The combination of chemotherapy showed higher risk of cardiac adrenergic hyperactivity.

Fundamento:A quimioterapia com antracíclicos e trastuzumabe pode causar cardiotoxicidade. A alteração da função adrenérgica cardíaca, avaliada pela metaiodobenzilguanidina marcada com iodo-123 (123I-mIBG), parece preceder a queda da fração de ejeção do ventrículo esquerdo.Objetivo:Avaliar e comparar a presença de alterações cardiovasculares entre pacientes com câncer de mama submetidas à quimioterapia com antracíclicos e trastuzumabe e apenas a antracíclico.Métodos:Foram analisadas variáveis clínicas, laboratoriais, eletro e ecocardiográficas, além de atividade simpática cardíaca. Nas imagens cintilográficas, foram calculadas a relação da captação do 123I-mIBG entre o coração e o mediastino, e a taxa de clareamento. As variáveis foram comparadas entre os pacientes que receberam antracíclicos e trastuzumabe (Grupo 1) e apenas antracíclicos (Grupo 2).Resultados:Vinte pacientes, com idade média 57 ± 14 anos, participaram deste estudo. A fração de ejeção do ventrículo esquerdo média pelo ecocardiograma foi 67,8 ± 4,0%. A taxa de clareamento média foi 28,39 ± 9,23%, e a relação da captação do 123I-mIBG entre o coração e o mediastino foi de 2,07 ± 0,28. Dentre as pacientes, 82% mostraram taxa de clareamento aumentada e 25%, uma relação da captação do 123I-mIBG entre o coração e o mediastino diminuída. Em relação aos grupos, a média da taxa de clareamento no Grupo 1 foi de 32,68 ± 9,30% e, no Grupo 2, de 24,56 ± 7,72% (p = 0,06). A relação da captação do 123I-mIBG entre o coração e o mediastino foi normal em todas as pacientes do Grupo 2, entretanto, no Grupo 1, 50% mostraram relação da captação do 123I-mIBG entre o coração e o mediastino ≤ 1,8 (p = 0,02).Conclusão:Em mulheres com câncer de mama submetidas à quimioterapia, a avaliação da atividade simpática cardíaca com 123I-mIBG pode ser um marcador precoce de cardiotoxicidade. A associação de quimioterápicos proporcionou maior risco de hiperatividade adrenérgica cardíaca.

Cardiac sympathetic hyperactivity after chemotherapy: early sign of cardiotoxicity?

BACKGROUND: Chemotherapy with anthracyclines and trastuzumab can cause cardiotoxicity. Alteration of cardiac adrenergic function assessed by metaiodobenzylguanidine labeled with iodine-123 (123I-mIBG) seems to precede the drop in left ventricular ejection fraction. OBJECTIVE: To evaluate and to compare the presence of cardiovascular abnormalities among patients with breast cancer undergoing chemotherapy with anthracyclines and trastuzumab, and only with anthracycline. METHODS: Patients with breast cancer were analyzed clinical, laboratory, electrocardiographic and echocardiographic and cardiac sympathetic activity. In scintigraphic images, the ratio of 123I-mIBG uptake between the heart and mediastinum, and the washout rate were calculated. The variables were compared between patients who received anthracyclines and trastuzumab (Group 1) and only anthracyclines (Group 2). RESULTS: Twenty patients, with mean age 57 ± 14 years, were studied. The mean left ventricular ejection fraction by echocardiography was 67.8 ± 4.0%. Mean washout rate was 28.39 ± 9.23% and the ratio of 123I-mIBG uptake between the heart and mediastinum was 2.07 ± 0.28. Of the patients, 82% showed an increased in washout rate, and the ratio of 123I-mIBG uptake between the heart and mediastinum decreased in 25%. Concerning the groups, the mean washout rate of Group 1 was 32.68 ± 9.30% and of Group 2 was 24.56 ± 7.72% (p = 0,06). The ratio of 123I-mIBG uptake between the heart and mediastinum was normal in all patients in Group 2, however, the Group 1, showed 50% the ratio of 123I-mIBG uptake between the heart and mediastinum ≤ 1.8 (p = 0.02). CONCLUSION: In women with breast cancer undergoing chemotherapy, assessment of cardiac sympathetic activity with 123I-mIBG appears to be an early marker of cardiotoxicity. The combination of chemotherapy showed higher risk of cardiac adrenergic hyperactivity.