Onset Of Cardiotoxicity Research Articles

New onset of left ventricular dysfunction and diastolic dysfunction are uncommon in patients with her2+ breast cancer after completion of cancer therapy

Abstract Background Cardiotoxicity from anthracyclines and trastuzumab is common among patients with breast cancer during therapy. However, there are limited data on new onset of cardiotoxicity (systolic or diastolic dysfunction) after completion of therapy. This knowledge has implications to guide long-term follow-up. Purpose The aim of this study was to evaluate the incidence of cancer therapy related cardiac systolic dysfunction (CTRCD) and diastolic dysfunction (DD) in women with HER2+ breast cancer after completion of cancer therapy and compare to incidence during cancer therapy. Methods We conducted a prospective cohort study of women with HER2+ breast cancer who were treated with sequential anthracycline and trastuzumab therapy, with or without radiation therapy (The EMBRACE-MRI trial, NCT02306538). Comprehensive surveillance echocardiograms were performed at baseline and every 3 months during treatment, early post-trastuzumab, then at years 1, 2, and 3 post trastuzumab completion. CTRCD was defined as a reduction in 3D-left ventricular ejection fraction (LVEF) by ≥ 10% from baseline to < 55%. Diastolic dysfunction was defined as per the American Society of Echocardiography guidelines. Results A total of 136 female patients, with a mean age of 51.1 ± 9.2 years were recruited. Among them, 15.4% had hypertension, 3.7% had diabetes mellitus, and 10.3% had dyslipidemia. The mean cumulative doxorubicin equivalent dose was 203.9 ± 12.5 mg/m2, 120 patients received radiation therapy with the mean heart dose of 170.8 ± 75.9 cGy. During cancer treatment, 27 out of 136 patients (19.9%) developed CTRCD. In long-term follow-up, due to death or interruption due to the COVID-19 pandemic, follow-up was available in 128 patients at 1 year, 117 at 2 years and 111 at 3 years. 5 of the 27 patients still had persistent LV dysfunction (3 at 1 year, 1 at 2 year and 1 at 3 year), however, there were no new diagnosis of CTRCD post completion of therapy. Of 129 patients with baseline normal or indeterminate diastolic function, new DD was identified in 25/129 patients (19.4%) during cancer treatment (17 grade I, 2 grade II, 6 unable to grade). After completion of cancer therapy, 5 patients had persistent DD. In patients with no DD during therapy and completed 3 year follow-up, 5 patients developed new DD after therapy (2 grade I, 3 unable to grade). Figure 1 illustrates the percentage of patients with new CTRCD or new diastolic dysfunction at each timepoint. None of the patients developed clinical heart failure. Conclusion Although both CTRCD and diastolic dysfunction are common during sequential therapy with anthracyclines and trastuzumab in women with HER2+ breast cancer, new onset after treatment completion is rare during a careful follow-up. These findings have implications for long-term surveillance.

Amla (Emblica officinalis) alleviates doxorubicin-induced cardiotoxicity and nephrotoxicity in rats

IntroductionDoxorubicin (DOX) is a widely used anticancer drug known for its significant cardiotoxic and nephrotoxic effects. Seeking remedies to mitigate these adverse effects is crucial. This study investigates the potential of Emblica officinalis (Amla) extract, a prominent component in Chinese and Indian traditional medicine systems, in alleviating DOX-induced cardiotoxicity and nephrotoxicity. MethodsDOX (20 mg/kg i.p., once) was given to rats to cause acute cardiotoxicity and nephrotoxicity. Rats received 16 similar and cumulative doses of DOX (1.25 mg/kg, i.p.) on alternate days for chronic cardiotoxicity and nephrotoxicity. Biochemical and histological evaluations were done to confirm the onset of cardiotoxicity and nephrotoxicity. ResultsThe cardioprotective and nephroprotective effects of Amla extract (AE) (150 mg/kg p.o. and 300 mg/kg p.o) were evaluated in comparison to Vitamin E (25 mg/kg p.o.). The treatment with AE (300 mg/kg/day, p.o.) considerably prevented DOX-induced cardiotoxicity, nephrotoxicity, and oxidative stress by positively altering the integrity of glomeruli, restoring the tissue GSH and decreasing serum TBARS. AE (300 mg/kg) was found to be more cardioprotective and nephroprotective than Vitamin E (25 mg/kg p.o.). DiscussionIt may be concluded that the induction of cardiotoxicity and nephrotoxicity in rats may be due to DOX-induced oxidative stress, and chronic treatment with AE (300 mg/kg) is an effective way to alleviate the cardiotoxic and nephrotoxic adverse effects of DOX in rats. Moreover, given Amla's historical and contemporary significance in Chinese and Indian traditional medicine systems, its potential therapeutic role merits further exploration in clinical settings.

Biomarkers and Strain Echocardiography for the Detection of Subclinical Cardiotoxicity in Breast Cancer Patients Receiving Anthracyclines.

The optimal surveillance and management strategies for breast cancer patients receiving anthracycline therapy are limited by our incomplete understanding of the role of biomarkers heralding the onset of cardiotoxicity. The purpose of this study was to determine whether there is a temporal correlation between cardiac biomarkers and subclinical left ventricular dysfunction in breast cancer patients receiving anthracycline chemotherapy. Thirty-one females between 46 and 55 years old with breast cancer treated with anthracycline chemotherapy were prospectively enrolled. Cardiac biomarkers were correlated with echocardiography with speckle tracking at baseline, post-anthracycline therapy, and 6 months post-anthracycline chemotherapy. Subclinical cardiotoxicity was defined as ≥ 10% reduction in global longitudinal strain (GLS). There was a relative reduction in left ventricular ejection fraction (LVEF) ≥ 10% in 5/30 (17%) and 7/27 (26%) patients post-anthracycline therapy and 6 months post-anthracycline therapy, respectively. Subclinical cardiotoxicity was noted in 8/30 (27%) and 10/26 (38%) patients post-anthracycline and 6 months post-anthracycline therapy, respectively. Baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) was the strongest predictor of LVEF (ρ = -0.45; p = 0.019), with post-therapy NT-proBNP values illustrating similar predictive value (ρ = -0.40; p = 0.038). Interim changes in suppression of tumorigenicity 2 (ST2) and galectin-3 correlated with a 6-month change in LVEF (ρ = -0.48; p = 0.012 and ρ = -0.45; p = 0.018, for ST2 and galectin-3, respectively). Changes in galectin-3 from baseline to mid-therapy paralleled changes in GLS. NT-proBNP, ST2, and galectin-3 correlate with reduced LVEF among breast cancer patients receiving anthracycline therapy. Additional trials focusing on a cardiac biomarker approach may provide guidance in the early diagnosis and management of anthracycline-induced cardiotoxicity.

Three-Year Outcomes Following Permissive Cardiotoxicity in Patients on Trastuzumab.

Cardiotoxicity, manifest by reduced left ventricular ejection fraction (LVEF), is the most common reason for the premature discontinuation of trastuzumab. While permissive cardiotoxicity (where mild cardiotoxicity is accepted to enable ongoing trastuzumab) has been shown feasible, the longer-term outcomes are unknown. We aimed to study the intermediate-term clinical outcomes of patients who underwent permissive cardiotoxicity. We performed a retrospective cohort study of patients referred to the cardio-oncology service at McMaster University from 2016 to 2021 for LV dysfunction following trastuzumab administration. Fifty-one patients underwent permissive cardiotoxicity. The median (25th-75th percentile) follow-up time from cardiotoxicity onset was 3 years (1.3-4 years). Forty-seven (92%) patients completed trastuzumab; 3 (6%) developed severe LV dysfunction or clinical heart failure (HF) while on trastuzumab and prematurely discontinued therapy. One discontinued trastuzumab by patient choice. At final follow-up after therapy completion, 7 (14%) patients still had mild cardiotoxicity, including 2 who had clinical heart failure and stopped trastuzumab early. Among those with recovered LV function, 50% had normalized LVEF or GLS by 6 and 3 months, respectively, after initial cardiotoxicity. There was no difference in characteristics between those who did or did not recover their LV function. Among patients exposed to permissive trastuzumab cardiotoxicity for HER2-positive breast cancer, 6% were unable to complete planned trastuzumab due to severe LV dysfunction or clinical HF. Although most patients recover their LV function after trastuzumab discontinuation or completion, 14% still have persistent cardiotoxicity by 3-year follow-up.

Biomarker panel for early screening of trastuzumab -induced cardiotoxicity among breast cancer patients in west virginia.

Cardiotoxicity is a well-known pathophysiological consequence in breast cancer patients receiving trastuzumab. Trastuzumab related cardiotoxicity typically results in an overall decline in cardiac function, primarily characterized by reduction in left ventricular ejection fraction (LVEF) and development of symptoms associated with heart failure. Current strategies for the monitoring of cardiac function, during trastuzumab therapy, includes serial echocardiography, which is cost ineffective as well as offers limited specificity, while offering limited potential in monitoring early onset of cardiotoxicity. However, biomarkers have been shown to be aberrant prior to any detectable functional or clinical deficit in cardiac function. Hence, this study aims to develop a panel of novel biomarkers and circulating miRNAs for the early screening of trastuzumab induced cardiotoxicity. Patients with clinical diagnosis of invasive ductal carcinoma were enrolled in the study, with blood specimen collected and echocardiography performed prior to trastuzumab therapy initiation at baseline, 3- and 6-months post trastuzumab therapy. Following 6-months of trastuzumab therapy, about 18% of the subjects developed cardiotoxicity, as defined by reduction in LVEF. Our results showed significant upregulation of biomarkers and circulating miRNAs, specific to cardiac injury and remodeling, at 3- and 6-months post trastuzumab therapy. These biomarkers and circulating miRNAs significantly correlated with the cardiac injury specific markers, troponin I and T. The findings in the present study demonstrates the translational applicability of the proposed biomarker panel in early preclinical diagnosis of trastuzumab induced cardiotoxicity, further allowing management of cardiac function decline and improved health outcomes for breast cancer patients.

Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection.

Chemotherapy and targeted therapies have significantly improved the prognosis of oncology patients. However, these antineoplastic treatments may also induce adverse cardiovascular effects, which may lead to acute or delayed onset of cardiac dysfunction. These common cardiovascular complications, commonly referred to as cardiotoxicity, not only may require the modification, suspension, or withdrawal of life-saving antineoplastic therapies, with the risk of reducing their efficacy, but can also strongly impact the quality of life and overall survival, regardless of the oncological prognosis. The onset of cardiotoxicity may depend on the class, dose, route, and duration of administration of anticancer drugs, as well as on individual risk factors. Importantly, the cardiotoxic side effects may be reversible, if cardiac function is restored upon discontinuation of the therapy, or irreversible, characterized by injury and loss of cardiac muscle cells. Subclinical myocardial dysfunction induced by anticancer therapies may also subsequently evolve in symptomatic congestive heart failure. Hence, there is an urgent need for cardioprotective therapies to reduce the clinical and subclinical cardiotoxicity onset and progression and to limit the acute or chronic manifestation of cardiac damages. In this review, we summarize the knowledge regarding the cellular and molecular mechanisms contributing to the onset of cardiotoxicity associated with common classes of chemotherapy and targeted therapy drugs. Furthermore, we describe and discuss current and potential strategies to cope with the cardiotoxic side effects as well as cardioprotective preventive approaches that may be useful to flank anticancer therapies.

Role of myocardial work index in early detection of cardiotoxicity in breast cancer patient

Abstract Introduction Breast cancer patients receiving anthracyclines are particularly prone to develop cancer therapeutics-related cardiac dysfunction. Early detection of cardiotoxicity onset is required for optimal timing of cardio protection treatment. The latest guidelines consider a relative reduction of 15% in global longitudinal strain (GLS) from baseline as risk for cardiotoxicity. Nevertheless, the more recent Myocardial Work Index (MWI) offers a load-independent tool for detection of subclinical heart failure (HF). However, data in cancer patients are still scarce. Purpose This study analyses the predictive value of MWI for cardiotoxicity diagnosis after 6 months chemotherapy. Methods The study population consists of breast cancer patients referred for chemotherapy with anthracyclines and taxanes. Patients with a history of HF previous to chemotherapy or depressed LV function at baseline were excluded. Echocardiography was performed before onset of the chemotherapy (baseline) and after 6 months follow-up. LVEF, GLS and MWI were assessed offline using EchoPAC software. The values at baseline and 6 months follow-up were pairwise compared to detect subclinical cardiac dysfunction. LVEF, GLS and MWI means at baseline were taken as cut-off to compare the predictive value of each parameter. Moreover, patients were categorized in one group with GLS reduction >15% (Group 1) and one group with GLS reduction <15% (Group 2). Results From April 2016 to July 2020, 28 women with breast cancer were included (age 54±11 years, LVEF 58±4%, GLS −21±2%, MWI 2160±308 mmHg). All patients underwent the same standard chemotherapy protocol (4xEC, 12xTaxol). No difference in baseline characteristics between group 1 (n=13) and group 2 (n=15) was observed. At 6 months follow up a significant decrease in LVEF (53±8%, p=0.003), GLS (−19±3%, p=0.002) and MWI (1920±391 mmHg, p=0.005) was shown without any change in blood pressure. However, while mean LVEF and GLS at baseline did not predict any significant change, patients with MWI under the mean value at baseline (n=15) presented significant lower LVEF (50±8 vs 57±6% p=0.006), GLS (−17±3 vs −20±2%, p=0.01), MWI (1733±320 vs 2136±362 mmHg, p=0.005) after 6 months. Additionally, both groups had similar MWI at baseline (2148±335 mmHg vs 2170±294 mmHg, p=0.85), whereas those patients with GLS reduction >15% showed significant lower MWI after 6 months (1694±332 mmHg vs 2116±334 mmHg, p=0.003, Figure 1). Conclusions At 6 months follow up, a decline of the LV systolic function as side effect of chemotherapy can be seen. MWI at baseline shows the best predictive value for development of cardiotoxicity, in comparison to LVEF and GLS. Further studies are warranted to better understand the role of MWI for early detection of cardiotoxicity and its clinical relevance. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Onze-Lieve-Vrouw hospital in Aalst (Belgium)

Cardiotoxicity in breast cancer patients: the role of gated myocardial perfusion SPECT

Abstract Funding Acknowledgements Type of funding sources: None. Background Patients undergoing chemotherapy (CHT) for breast cancer (BC) need a monitoring of cardiac function due to the possible onset of cardiotoxicity. Cardiotoxicity may occur with heart failure but is often asymptomatic and is detectable only by assessing an increase in cardiac volumes (left ventricular end-diastolic (LV-EDV) and end-systolic (LV-ESV) volumes) and/or by a reduction of the left ventricular ejection fraction (LV-EF). The primary purpose of this study was to evaluate the role of gated SPECT myocardial perfusion imaging in this setting. Dosimetric evaluation was also assessed. Methods Seventeen BC patients (mean age 55.93 ± 11.04 years)with invasive ductal carcinoma HER2 + treated with surgery and with an anthracycline-based adjuvant CHT, were enrolled. The trend of cardiac function was assessed by evaluation of LV-EF, LV-EDV and LV-ESV using gSPECT in baseline conditions and at 12, 15 and 52 weeks during treatment and then at 6, 12, 24 and 48 months during follow-up. Each patient was studied 15-20 min after injection of 555 MBq of 99mTc-Tetrofosmin with gSPECT (16 frames/cardiac cycle) using an Infinia Hawkeye IV gamma-camera. Dosimetry was assed according to ICRP reports. Results Two out of the 17 patients enrolled left the protocol: one because of a second tumor and the other due to the appearance of cardiotoxicity. 15 patients completed the study: mean LVEF at baseline was 70.67 ± 5.68. The greatest modification occurred after 15th week of treatment, when mean LV-EF showed a significant decrease to 65.67 ± 8.27, while mean LV-EDV and mean LV-ESV increased from 73.60 ± 16.72 up to 84.73 ± 21.11 and from 21.93 ± 7.17 up to 30.27 ± 14.16, respectively. All parameters progressively returned similar to baseline values at the final examination (after 48th month): mean LV-EF 70.20 ± 5.65, LV-EDV 73.40 ± 16.15 and ESV 22.07 ± 7.50. In one case cardiotoxicity occurred at 15th week: LV-EF decreased from 69 to 47%, LV-EDV increased from 92 up to 142 ml and LV-ESV from 28 up to 75 ml. According to our image protocols, effective dose for gSPECT was 3.83 mSv (ICRP 106). The use of gSPET instead of MUGA (6.47 mSv–ICRP 80) allowed a dose effective saving of 2.64 mSv/each control with a total saving of 21.12 mSv/patient. Conclusions Although the small sample size, gSPECT was demonstrated to be an applicable tool for monitoring cardiac function because it correctly identified BC patient with cardiotoxicity. gSPECT also allowed a significant radiation dose saving compared to MUGA: this is particularly relevant in cardiotoxicity studies that require repeated and close evaluations.

Myocardial work index: a novel tool for detection of early cardiotoxicity in breast cancer patient

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Cardiovascular Research Center Aalst, (Aalst, Belgium) Introduction Breast cancer patients receiving anthracyclines are particularly prone to develop cancer therapeutics-related cardiac dysfunction (CTRCD). Early detection of cardiotoxicity onset is required for optimal timing of cardio protection treatment. The latest guidelines consider a relative reduction of 15% in global longitudinal strain (GLS) from baseline as risk for cardiotoxicity. Nevertheless, the more recent Myocardial Work Index (MWI) offers a load-independent tool for detection of subclinical heart failure (HF). Data in cancer patients are still scarce. Purpose This study analyses the predictive value of MWI for cardiotoxicity diagnosis after 6 months chemotherapy. Methods The study population consists of breast cancer patients referred for chemotherapy with anthracyclines and taxanes. Patients with a history of HF previous to chemotherapy or depressed LV function at baseline were excluded. Echocardiography was performed before onset of the chemotherapy (baseline) and after 6 months follow-up. LVEF, GLS and MWI were assessed offline using EchoPAC software. The values at baseline and 6 months follow-up were pairwise compared to detect subclinical cardiac dysfunction. Mean LVEF, GLS and MWI at baseline were taken as cut-off value to compare the predictive value of each parameter. Moreover, patients were categorized in one group with GLS reduction >15% (Group 1) and one group with GLS reduction <15% (Group 2). Results From April 2016 to January 2020, 24 women with breast cancer were included (age 54 ± 11 years, LVEF 58 ± 4%, GLS -21 ± 2%, MWI 2181 ± 325 mmHg). All patients underwent the same standard chemotherapy protocol (4xEC, 12xTaxol). No difference in baseline characteristics between group 1 (n = 9) and group 2 (n = 15) was observed. At 6 months follow up a significant decrease in LVEF (53 ± 8%, p = 0.003), GLS (-19 ± 3%, p = 0.002) and MWI (1933 ± 410 mmHg, p = 0.005) was shown without any change in blood systolic pressure. However, while mean LVEF and GLS at baseline did not predict any significant change, patients with MWI under the mean value at baseline (n = 13) presented significant lower LVEF (49 ± 8%, p = 0.006), GLS (-18 ± 4%, p = 0.045), MWI (1753 ± 341 mmHg, p = 0.018) after 6 months. Additionally, both groups had similar MWI at baseline (2199 ± 390 mmHg vs 2170 ± 294 mmHg, p = 0.85), whereas those patients with GLS reduction >15% showed significant lower MWI after 6 months (1626 ± 344 mmHg vs 2116 ± 334 mmHg, p = 0.003, Figure 1). Conclusions At 6 months follow up, a decline of the LV systolic function as side effect of chemotherapy can be seen. In comparison to LVEF and GLS, MWI shows the best predictive value for development of early cardiotoxicity. Further studies are warranted to better understand the role of MWI in predicting CTRCD and its clinical relevance. Abstract Figure. Change in MWI

The possible role of genetic testing in the early identification of patients at increased risk of developing anthracycline-induced cardiotoxicity

Abstract Background In the last years prognosis of cancer patients (pts) has been improved, but the develop of cardiotoxicity (CTX) in pts with low CV risk treated with cumulative doses of Anthracycline (ANT) considered safe, led to investigate the possible role of the genetic profile in the onset of CTX. Purpose To study the role of some single nucleotide polymorphisms (SNPs) as predictive genetic markers of individual susceptibility to CTX induced by anticancer treatment. Methods We have enrolled women with non-metastatic breast cancer who had to start a therapy with ANT. The presence of a known heart disease, a previous mediastinal irradiation and a previous treatment with ANT, were the main exclusion criteria. All pts underwent complete cardiological evaluation (ECG, echo) before the beginning of the therapy (T0), after each ANT cycle and every 3 months up to 1 year of follow-up after the end of treatment. During each visit, we performed the determination of troponin I (TnI) and NT-proBNP. The genetic profile of each pts was also investigated, analyzing 6 SNPs belonging to 3 different genes (two for each genes) coding for enzymes or enzyme systems involved in the metabolism of ANT. DNA extraction from blood samples was performed using the QIAamp DNA Mini kit (QIAGEN). The DNA extracted was genotyped (by performing TaqMan SNP Genotyping assays) identifying 3 possible variants for each SNPs: homozygosity for the protective and “at risk” variant and heterozygosity. Results 179 pts finished the follow-up and from the analysis of the trend of biomarkers we found that 53 pts (30%) showed a significant increase in TnI (>0.04ng/mL) or less than this cut-off but persistently >0.015ng/mL in at least 2 measurements (“TnI+ group”), in the remaining 126 pts the TnI remained non-measurable (“TnI− group”); 76 pts (43%) showed NT-proBNP values ≥125 ng/L in at least two consecutive determinations (“NT-proBNP + group”),in the remaining 57% of pts this increase was not detected (“NT-proBNP - group”). Comparing “TnI+ group” to “TnI− group” we observed that only the genotyping of the SNPs rs1149222 (G/T) belonging to the ABCB4 gene is distributed differently in the two groups, in particular the homozygosity for the “at risk” variant (G/G) was present in 13% of the pts of the “TnI+ group” vs 5% in the “TnI− group” (p 0.06). The results of the comparison of “NT-proBNP+ group” vs “NT-proBNP− group”, showed that the genotyping of the SNPs rs6759892 (G/T) belonging to the UGT1A6 gene was distributed differently, the homozygosity for the “at risk” variant (G/G) was present in 28% of the “NT-proBNP+ group” vs 17% in the “NT-proBNP− group” (p 0.07). Conclusion Together with the baseline clinical evaluation, genetic markers could contribute to the early identification of pts at high risk of developing CTX especially following treatment with ANT and they could support future therapeutic decisions and the planning of taylored strategies for the prevention of the CTX development. Funding Acknowledgement Type of funding source: None

Association of body mass index and cardiotoxicity related to anthracyclines and trastuzumab in early breast cancer: French CANTO cohort study

BackgroundIn patients treated with cardiotoxic chemotherapies, the presence of cardiovascular risk factors and previous cardiac disease have been strongly correlated to the onset of cardiotoxicity. The influence of overweight and obesity as risk factors in the development of treatment-related cardiotoxicity in breast cancer (BC) was recently suggested. However, due to meta-analysis design, it was not possible to take into account associated cardiac risk factors or other classic risk factors for anthracycline (antineoplastic antibiotic) and trastuzumab (monoclonal antibody) cardiotoxicity.Methods and findingsUsing prospective data collected from 2012–2014 in the French national multicenter prospective CANTO (CANcer TOxicities) study of 26 French cancer centers, we aimed to examine the association of body mass index (BMI) and cardiotoxicity (defined as a reduction in left ventricular ejection fraction [LVEF] > 10 percentage points from baseline to LVEF < 50%). In total, 929 patients with stage I–III BC (mean age 52 ± 11 years, mean BMI 25.6 ± 5.1 kg/m2, 42% with 1 or more cardiovascular risk factors) treated with anthracycline (86% epirubicin, 7% doxorubicin) and/or trastuzumab (36%), with LVEF measurement at baseline and at least 1 assessment post-chemotherapy were eligible in this interim analysis. We analyzed associations between BMI and cardiotoxicity using multivariate logistic regression. At baseline, nearly 50% of the study population was overweight or obese. During a mean follow-up of 22 ± 2 months following treatment completion, cardiotoxicity occurred in 29 patients (3.2%). The obese group was more prone to cardiotoxicity than the normal-weight group (9/171 versus 8/466; p = 0.01). In multivariate analysis, obesity (odds ratio [OR] 3.02; 95% CI 1.10–8.25; p = 0.03) and administration of trastuzumab (OR 12.12; 95% CI 3.6–40.4; p < 0.001) were independently associated with cardiotoxicity. Selection bias and relatively short follow-up are potential limitations of this national multicenter observational cohort.ConclusionsIn BC patients, obesity appears to be associated with an important increase in risk-related cardiotoxicity (CANTO, ClinicalTrials.gov registry ID: NCT01993498).Trial registrationClinicalTrials.gov NCT01993498.

Hyaluronated liposomes containing H2S-releasing doxorubicin are effective against P-glycoprotein-positive/doxorubicin-resistant osteosarcoma cells and xenografts.

Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a H2S-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma. HA-Lsdox showed favorable drug-release profile and higher toxicity in vitro and in vivo than dox or the FDA-approved liposomal dox Caelyx® against Pgp-overexpressing osteosarcoma, displaying the same cardiotoxicity profile of Caelyx®. Differently from dox, HA-Lsdox delivered the drug within the endoplasmic reticulum (ER), inducing protein sulfhydration and ubiquitination, and activating a ER stress pro-apoptotic response mediated by CHOP. HA-Lsdox also sulfhydrated the nascent Pgp in the ER, reducing its activity. We propose HA-Lsdox as an innovative tool noteworthy to be tested in Pgp-overexpressing patients, who are frequently less responsive to standard treatments in which dox is one of the most important drugs.

Surviving Cancer without a Broken Heart.

Chemotherapy-associated myocardial toxicity is increasingly recognized with the expanding armamentarium of novel chemotherapeutic agents. The onset of cardiotoxicity during cancer therapy represents a major concern and often involves clinical uncertainties and complex therapeutic decisions, reflecting a compromise between potential benefits and harm. Furthermore, the improved cancer survival has led to cardiovascular complications becoming clinically relevant, potentially contributing to premature morbidity and mortality among cancer survivors. Specific higher-risk populations of cancer patients can benefit from prevention and screening measures during the course of cancer therapies. The pathobiology of chemotherapy-induced myocardial dysfunction is complex, and the individual patient risk for heart failure entails a multifactorial interaction between the selected chemotherapeutic regimen, traditional cardiovascular risk factors, and individual susceptibility. Treatment with several specific chemotherapeutic agents, including anthracyclines, proteasome inhibitors, epidermal growth factor receptor inhibitors, vascular endothelial growth factor inhibitors, and immune checkpoint inhibitors imparts increased risk for cardiotoxicity that results from specific therapy-related mechanisms. We review the pathophysiology, risk factors, and imaging considerations as well as patient surveillance, prevention, and treatment approaches to mitigate cardiotoxicity prior, during, and after chemotherapy. The complexity of decision-making in these patients requires viable discussion and partnership between cardiologists and oncologists aiming together to eradicate cancer while preventing cardiotoxic sequelae.

Cardiovascular safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients: a prospective evaluation.

The aim of this study is to evaluate cardiotoxicity of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer patients (pts) with cardiovascular comorbidities or coronary artery disease (CAD) risk factors. We prospectively analyzed pts receiving AA in order to evaluate correlations between cardiotoxicity onset and CAD risk factors or cardiovascular comorbidities. Eighty-seven pts were enrolled, with median treatment duration of 9months (1-44). At baseline, 84pts (96%) had CAD risk factors. During treatment four pts (4;6%) developed hypertension and 26pts (30%) worsened the preexisting hypertension. Median left ventricular ejection fraction were 64 and 63% at baseline and after treatment, respectively. AA appears to be safe in pts with cardiovascular comorbidities or CAD risk factors.

Assessment of the onset of radiation-induced cardiac damage after radiotherapy of breast cancer patients

ObjectivesThe study aimed to evaluate the dose delivered to the heart during radiotherapy of left-sided and right-sided breast cancer (BC) patients, correlate the dose and laterality of radiotherapy to the possible cardiac damage and evaluate whether Left-ventricular Ejection Fraction (LVEF), Troponin-I (TnI), Creatinine Kinase (CK), Creatine Kinase-MB Relative Index (CK-MBRI) or Lactic Dehydrogenase (LDH) could be used to detect the possible onset of radiotherapy-related cardiotoxicity. Subjects and methods80 females were assigned as; 30 left-sided BC patients, 30 right-sided BC patients and 20 healthy females. Patients were treated by radical mastectomy followed by FAC-based chemotherapy and radiotherapy. CT-based 3D-planning was used to generate cardiac dose-volume histograms to assess mean dose received by the heart.Echocardiography was done to all patients before and 1 year after completing radiotherapy. In serum, TnI and CK-MB concentration and CK and LDH activities were determined before and 1 year after radiotherapy. ResultsIn left-sided patients, mean dose delivered to the heart was significantly higher in left-sided patients with significant association with total radiotherapy dose in left- but not right-sided patients. LVEF before and after radiotherapy were statistically different only in left-sided patients. LVEF one year after radiotherapy dropped 20% or more (ΔLVEF) in 6 patients, all were left-sided.Using cut-off values 0.08 ng/mL for TnI and 1.4 for CK-MBRI; 11 left-sided patients had abnormal TnI and CK-MBRI vs 5 right-sided patients, the 6 patients identified with ΔLVEF ≥ 20 were all among them. Conclusionthe mean dose delivered to the heart is significantly higher in left-sided patients, and it was correlated to the total radiotherapy dose. One year after radiotherapy, ΔLVEF is possibly good marker of cardiotoxicity onset, however, the persistent elevation of both TnI and CK-MBRI could identify both patients with cardiotoxicity and patients that are thought to be in subclinical phase of cardiac damage.

Reliability of Left Ventricular Ejection Fraction from Three-Dimensional Echocardiography for Cardiotoxicity Onset Detection in Patients with Breast Cancer

Cardiotoxicity is a well-known adverse effect of various chemotherapeutic agents that can be monitored by echocardiography. A decrease in left ventricular ejection fraction (LVEF) triggers consideration for therapy modification or interruption. The aim of this study was to evaluate how variability in LVEF estimates computed using three-dimensional echocardiography could influence cardiotoxicity onset detection. One hundred eighty one patients with breast cancer treated with anthracycline and trastuzumab were analyzed. LVEF was computed using two commercial software packages. In a subgroup of 40 patients, three-dimensional echocardiographic data were reanalyzed to assess intra- and interobserver variability by two expert investigators using both packages. Global longitudinal strain (GLS) imaging was evaluated in 64 patients. End-diastolic volume, end-systolic volume, and LVEF measurements obtained applying the two software packages were in good agreement, with small bias and acceptable limits of agreement. Intra- and interobserver variability was smaller using one of the two software packages. However, for both packages, variability indexes were in the range of affecting LVEF estimates at a level that could lead to an inaccurate assessment of cardiac adverse effects of cancer therapeutic drugs. On the basis of LVEF, 11 of 181 patients (6.1%) had cardiotoxicity at 3-month follow-up. The absolute value of GLS was smaller in 16 of 64 patients (25%) thought to have cardiotoxicity on the basis of GLS results, including six of seven patients who had cardiotoxicity considering LVEF in this subgroup. Following clinical definition of cardiotoxicity onset, variability in LVEF computation by three-dimensional echocardiography could be a confounding factor for cardiotoxicity diagnosis, and different software packages should not be used interchangeably for LVEF monitoring. GLS confirms its predictive value for subsequent cardiotoxicity.

Rac1-mediated cardiac damage causes diastolic dysfunction in a mouse model of subacute doxorubicin-induced cardiotoxicity.

The anticancer efficacy of anthracyclines is limited by congestive heart failure. Clinically established markers of early onset of cardiotoxicity following anthracycline treatment and preventive measures are missing. Although statins are reported to alleviate anthracycline-induced cardiotoxicity in vivo, the molecular mechanisms involved remain elusive. In vitro data point to Rac1 as major target of the cytoprotective statin effects. Here we investigated whether specific inhibition of Rac1 by NSC23766 is as effective as lovastatin in preventing subacute cardiotoxicity following doxorubicin treatment. C57BL/6 mice were treated over 3weeks with multiple low doses of doxorubicin (6×3mg/kgBW, i.p.) and the level of DNA damage, apoptosis and regenerative proliferation as well as pro-inflammatory, pro-fibrotic and oxidative stress responses were investigated. Moreover, heart function was monitored by echocardiography. Doxorubicin induced subacute cardiotoxicity which was reflected on the level of residual DNA damage, frequency of apoptotic and mitotic cells as well as elevated mRNA expression of markers of heart failure, remodeling and mitochondrial biogenesis. These molecular markers of cardiotoxicity were mitigated to a similar extent by co-treatment with either lovastatin (10mg/kgBW, p.o.) or NSC23766 (5mg/kgBW, i.p.) three times a week. Moreover, doxorubicin caused diastolic dysfunction as reflected by increased E-wave acceleration time (EAT), which again was prevented by pharmacological inhibition of Rac1. Inhibition of Rac1 signaling is of major relevance for the cardioprotective effects of lovastatin in the context of anthracycline-induced cardiotoxicity. Moreover, EAT is a useful marker of subacute cardiotoxicity caused by persisting harmful effects of doxorubicin.

Mechanisms of Fatal Cardiotoxicity following High-Dose Cyclophosphamide Therapy and a Method for Its Prevention

Observed only after administration of high doses, cardiotoxicity is the dose-limiting effect of cyclophosphamide (CY). We investigated the poorly understood cardiotoxic mechanisms of high-dose CY. A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). Cytotoxicity was then evaluated by 3-(4,5-dimethyl-2-thiazolyl)¬2,5-diphenyl¬2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase release, production of reactive oxygen species (ROS), and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC), antioxidant isorhamnetin (ISO), and CYP inhibitor β-ionone (BIO). Quantifying CY and CY metabolites by means of liquid chromatography coupled with electrospray tandem mass spectrometry, we assayed culture supernatants of CYS9 with and without candidate cardioprotectant agents. Assay results for MTT showed that treatment with CY (125–500 μM) did not induce cytotoxicity. CYS9, however, exhibited myocardial cytotoxicity when CY concentration was 250 μM or more. After 250 μM of CY was metabolized in S9 mix for 2 h, the concentration of CY was 73.6 ± 8.0 μM, 4-hydroxy-cyclophosphamide (HCY) 17.6 ± 4.3, o-carboxyethyl-phosphoramide (CEPM) 26.6 ± 5.3 μM, and acrolein 26.7 ± 2.5 μM. Inhibition of CYS9-induced cytotoxicity occurred with NAC, ISO, and BIO. When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein is likely to be an important mechanism for preventing cardiotoxicity.

Delayed bupropion cardiotoxicity associated with elevated serum concentrations of bupropion but not hydroxybupropion

Context. Bupropion overdose commonly causes generalized seizures and central nervous system depression. Less commonly, cardiotoxicity has been reported. The toxicity of the parent drug compared to its active metabolite hydroxybupropion is uncertain. Case details. A 31-year-old man presented to the emergency department with altered mental status after an intentional overdose of bupropion. Three hours after admission he developed status epilepticus requiring intubation, and 13 h after admission he developed marked widening of the QRS complex and prolongation of the QTc interval. Serial serum bupropion levels peaked with the onset of cardiotoxicity (334 ng/mL) and fell into the therapeutic range within 24 h, which coincided with normalization of his ECG intervals. Levels of the metabolite hydroxybupropion peaked later (4302 ng/mL) and remained elevated even after neurological and cardiotoxic symptoms resolved. Discussion. Cardiotoxicity appears to be caused primarily by bupropion rather than its active metabolite hydroxybupropion.

Trastuzumab-Related Cardiotoxicity in Early Breast Cancer: A Cohort Study

Concerns have been raised about the cardiac safety profile of trastuzumab for the adjuvant treatment of early stage breast cancer in clinical practice. We assessed trastuzumab-related cardiotoxicity and its predictors in a large cohort of Italian women. Through a record linkage between four regional health care databases, we identified the rate of severe cardiac adverse events among women treated with trastuzumab for early breast cancer in Lombardy. The cumulative risk of cardiotoxicity was estimated using the Kaplan-Meier method, and independent predictors were assessed using the Cox model. Of 2,046 trastuzumab users, 53 (2.6%) experienced at least one hospitalization for a cardiac event, and there were two cardiac deaths. The cumulative risk of cardiotoxicity increased up to 2 years after starting treatment, reaching a plateau at 2.8%. The risk was low (0.2%) among young women, whereas the incidence was approximately 10% in women aged ≥70 years, irrespective of cardiovascular risk factors. Age and history of cardiac disease were strong predictors of cardiotoxicity, with a hazard ratio of 11.3 (95% confidence interval [CI]: 3.5-36.6) for women aged ≥70 years as compared with those <50 years of age. Hazard ratio was 4.4 (95% CI: 2.1-9.5) for women with a history of cardiac disease compared with those without a history of cardiac disease. Cardiotoxicity of trastuzumab varies considerably across subgroups of patients. The long-term safety profile was less favorable than in the largest clinical trial. Strategies to reduce cardiotoxicity in high-risk women should be investigated.