Anthracycline-mediated Cardiotoxicity Research Articles

Statins as preventive therapy for anthracycline cardiotoxicity: a meta-analysis of randomized controlled trials

BackgroundCardiotoxicity occurs in 5–20% of cancer patients who receive anthracyclines. The aim of this study was to pool all the randomized controlled trials (RCTs) investigating the cardio-protective role of statins in patients treated with anthracyclines. MethodsPubMed and Scopus electronic databases were scanned for eligible studies up to May 3rd, 2023. A total of 5 RCTs with 808 patients were included. Efficacy endpoints were the rate of anthracycline-mediated cardiotoxicity, the incidence of hospitalization for heart failure (HF), left ventricular ejection fraction (LVEF) value after anthracycline treatment, and ∆LVEF calculated as the difference in LVEF before and after anthracycline therapy. Safety endpoints [i.e., the incidence of muscle pain and serious adverse events (SAE)] were also assessed. ResultsOn pooled analysis, the statin-treated group had a lower incidence of cardiotoxicity compared to the placebo group [risk ratio (RR) 0.52, 95% confidence Interval (CI) 0.33–0.83, P = 0.01; I2 = 0%], as well as higher mean LVEF [Mean difference (MD) 1.88, 95% CI 0.66–3.1, P < 0.01; I2 = 57.3%)] and a more favorable ∆LVEF during follow-up (MD 2.38, 95% CI -0.03 – +4.79, P = 0.05; I2 = 99%), despite no significant difference in terms of hospitalization for HF and rate of adverse events. Of note, severe heterogeneity affected the analyses for both LVEF and ΔLVEF. ConclusionsThe current meta-analysis of all RCTs conducted so far shows an overall beneficial effect of statins on the risk of anthracyclines-induced cardiotoxicity and LVEF preservation. No difference was observed in the rate of HF hospitalization. More powered RCTs are needed to fully investigate the impact of statins on prognosis in patients receiving anthracyclines therapy.

Polymorphism rs4673 and plasma paraoxonase 1 level for prediction and early diagnosis of anthracycline-mediated cardiotoxicity in patients with breast cancer.

12077 Background: Anthracyclines are highly effective chemotherapeutic agents, used for a wide variety of malignancies. Despite their antitumor efficacy there is a risk of cardiotoxic manifestations that reduce the time and quality of life of patients. The purpose was to study the effectiveness of molecular genetic tests based on rs4673 CYBA genotyping (c.242C &gt; T) and measurement of plasma paraoxonase 1 (PON1) level in patients with breast cancer (BC) for predicting and diagnosing anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer normal cardiovascular system parameters at baseline, who were treated with anthracyclines in 2019-2020. For rs4673 genotyping, DNA was extracted from the blood by using DNA-sorb-B (AmpliSens, Russia). HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by the Sanger method on a Genetic Analyzer 3500 (ABI, USA). The concentration of PON1 in blood plasma was measured at baseline and after 4 course of chemotherapy with anthracyclines using ELISA kits (Cloud-Clone Corp., China/USA). Results: During the follow-up period 21 (8.2%) patients developed signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic AMC (changes developed within a year after completion of anthracycline therapy). In the group of patients without AMC the frequency of the minor allele rs4673 (c.214C &gt; T CYBA) was 0.38, the frequency of genotypes C/C was 0.4, C/T - 0.43, and T/T - 0.17. The risk of AMC increased by 6.49 times in the presence of the rs4673 polymorphic allele (p = 0.002). The area under the ROC curve of the test based on rs4673 genotyping was 71.9%. The concentration of PON1 after the 4 courses of chemotherapy increased by 19.57% in the group of patients without cardiotoxic manifestations (p = 0.018) and in the group of patients with AMC by 20.23% (p = 0.007) as compared to the initial level. Besides, after 4 courses of chemotherapy the PON1 level was higher in patients with AMC by 25.08% (p = 0.026) than in patients without cardiovascular complications. The sensitivity of the test based on the measurement of the PON1 level in the blood plasma after 4 courses of chemotherapy was 100%, the specificity was 70.8% with a cut-off value of 2.9 ng/ml. Conclusions: This study has showed that genotyping of patients for the rs4673 polymorphism allows pre-stratification of the risk group white determination of the PON1 level in blood plasma after 4 courses of chemotherapy gives the opportunity to identify patients with AMC and promptly correct the chosen treatment.

SNP-SNP interactions and a 4-locus model for prediction the risk of anthracycline-mediated cardiotoxicity in patients with breast cancer.

12076 Background: Numerous pharmacogenetic studies have identified genetic polymorphisms (SNPs) associated with an increased risk of anthracycline-mediated cardiotoxicity (AMC). The purpose was to search for SNP-SNP interactions associated with the risk of cardiotoxic manifestations caused by anthracycline therapy in breast cancer patients. Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer with normal cardiovascular system parameters at baseline, who were treated with anthracyclines in 2019-2020. For SNP genotyping of c.4544G &gt; A rs8187710 (ABCC2), c.1744C &gt; T rs11549465 ( HIF1A), g.22125504G &gt; C rs1333049 ( CDKN2A/ B) and c.214T &gt; C rs4673 ( CYBA). DNA was extracted from blood by using DNA-sorb-B (AmpliSens, Russia). HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by the Sanger method on a Genetic Analyzer 3500 (ABI, USA). Results: During the follow-up period 21 (8.2%) patients developed signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic anthracycline mediated cardiotoxicity (changes developed within a year after completion of anthracycline therapy). Using the multifactorial dimension reduction method. We obtained a 4-locus model of SNP-SNP interactions c.4544G &gt; A rs8187710 ( ABCC2) x g.22125504G &gt; C rs1333049 ( CDKN2A/B) x c.214T &gt; C rs4673 ( CYBA) x g.23708527G &gt; A rs28714259 which has high prognostic properties. The specificity of the test based on the 4-locus model was 68%, the sensitivity was 100%, and the overall accuracy was 71%. The results of the analysis of SNP-SNP interactions indicate the greatest contribution of rs4673 and rs28714259 to the predisposition to AMC. The first ones yet into antagonistic interactions with rs28714259, rs1333049 and rs11549465, the second with rs8187710, rs11549465 and rs4673. On the contrary rs11549465 and rs1333049 contribute to a synergistic effect. Conclusions: The 4-locus model discovered in this study can form the basis of prognostic tests that predict early the risks of developing AMC in cancer patients, which in the future allow to personalize and select the most optimal treatment regimen.

Value of Left Ventricular Global Longitudinal Strain Assessed by Two-Dimensional Strain Imaging in Early Detection of Anthracycline Mediated Cardiotoxicity

Value of Left Ventricular Global Longitudinal Strain Assessed by Two-Dimensional Strain Imaging in Early Detection of Anthracycline Mediated Cardiotoxicity

RS4673 and pon1 level in blood plasma - new prospects in prediction and early diagnostics of anthracycline-mediated cardiotoxicity.

The purpose of this study was to research the effectiveness of molecular genetic tests based on the determination of the rs4673 CYBA polymorphism (c.242C>T) and the level of paraoxonase 1 (PON1) in the blood plasma of patients with breast cancer (BC) for predicting and diagnosing anthracycline-mediated cardiotoxicity (AMC). The genotyping of rs4673 CYBA (c.242C>T) and the study of the PON1 level in the blood plasma of 280 patients of the Caucasian type with a histologically verified diagnosis of breast cancer, who received complex treatment on the basis of the National Medical Research Center of Oncology, were carried out. Based on the results of observation for at least 8 months, two groups were identified: group 1 (257 people) without diagnosed cardiovascular changes; group 2 (23 people) - patients with subacute and early chronic AMC. It was found that carriers of the rs4673 polymorphism increase the likelihood of developing AMC by 6.8 times (p = 0.001). In the blood plasma of both groups of patients, an increase in the level of PON1 was described after the fourth course compared to the initial level (group 1 - p = 0.036, group 2 - p = 0.048). The level of the studied enzyme was higher in the blood plasma of patients with diagnosed AMC compared with patients without cardiovascular complications (before chemotherapy - p = 0.001, after the fourth course - p = 0.023). The test based on the measurement of the concentration of PON1 in the blood plasma of patients after the fourth course of chemotherapy was distinguished by high quality metrics: sensitivity - 100%, specificity - 70.8%, area under the ROC-curve (AUC) - 0.825 with a threshold level of PON1 equal to 2, 9 ng/μL. The presence of the T/T genotype caused a high level of PON1 in the blood plasma after the fourth course of chemotherapy (p = 0.012). The results of our work are of undoubted practical importance, since they allow us to obtain data on the prognosis and diagnosis of a patient in a short time, which can later be verified using clinical and instrumental methods.

Polymorphisms rs4673 and rs28714259 in predicting anthracycline-mediated cardiotoxicity in patients with breast cancer.

Against the background of significant progress in anticancer therapy, which makes it possible to improve the quality of life and life expectancy of patients with cancer, anthracycline antibio-tics retain their relevance, both for scientific research and for clinical practice. However, the therapeutic efficacy of anthracyclines is associated with the development of various complications, among which the most common is cardiotoxicity. Our study was dedicated to searching for possible associations between rs4673 and rs28714259 single nucleotide polymorphisms (SNPs) and the risk of cardiotoxicity in breast cancer patients who underwent anthracycline-containing chemotherapy. The study included 256 patients with a dia-gnosis of breast cancer without dia-gnosed cardiovascular changes who were treated at the National Medical Research Center of Oncology in Rostov-on-Don in 2019-2020. For SNP genotyping, DNA was extracted from blood and high resolution melting analysis was performed. The presence of SNPs was confirmed by Sanger sequencing. The presence of the T-allele rs4673 increased the risk of cardiotoxicity in breast cancer patients 6.49x (95% CI 1.48-28.53; P = 0.002), and the presence of the A-allele rs28714259 increased the risk 3.27x (95% CI 1.23-8.75; P = 0.026). For tests based on genotyping rs4673 and rs28714259 SNPs, the areas under the receiver operating characteristic (ROC) curves were equal to 71.9% and 76.3%, respectively. The two-locus SNP-SNP model turned out to be statistically significant: the training balanced accuracy was 0.77; similarly, the testing balanced accuracy, and the cross-validation consistency was 10/10. Our study confirmed the predictive value of genetic tests based on the determination of the rs4673 and rs28714259 SNPs. Genotyping of both SNPs will significantly improve the accuracy of predicting the development of cardiotoxicity against the background of anthracycline-containing therapy and timely identify the risk group of breast cancer patients for whom it is necessary to adjust the therapeutic strategy.

Exercise to Reduce Anthracycline-Mediated Cardiovascular Complications in Breast Cancer Survivors.

While developments in cancer therapeutics have greatly reduced morbidity and mortality in females with breast cancer, it comes at a cost of an increased risk of cardiovascular complications. In particular, anthracyclines, like doxorubicin, which are a mainstay of current chemotherapy regimens, are associated with dose-dependent cardiotoxicity. Exercise has been widely accepted as an effective intervention in reducing cardiovascular risk in a variety of different clinical conditions. However, the benefits of exercise in anthracycline-mediated cardiotoxicity are not clearly understood. First, this review discusses the pre-clinical studies which have elucidated the cardioprotective mechanisms of aerobic and resistance exercise in improving cardiovascular function in the setting of anthracycline treatment. Next, it aims to summarize the results of aerobic and resistance exercise clinical trials conducted in females with breast cancer who received anthracycline-based chemotherapy. The review further discusses the current exercise guidelines for women undergoing chemotherapy and contraindications for exercise. Finally, the review addresses gaps in research, specifically the need for further clinical trials to establish a recommended exercise prescription within this patient population.

Polymorphisms rs4673 and rs28714259 as predictors of anthracycline-mediated cardiotoxicity in patients with breast cancer.

12005 Background: Numerous pharmacogenetic studies have led to the identification of genetic polymorphisms associated not only with the development of cardiovascular disease, but also increase the risk of complications due to the use of anthracycline drugs, widely used in the treatment of cancer. The purpose of this study was to study the frequency of rs4673 and rs28714259 and possible associations with the risk of cardiovascular changes in patients with breast cancer during anthracycline therapy (anthracycline-mediated cardiotoxicity — AMC). Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer without diagnosed cardiovascular changes, who were treated with anthracyclines at the National Medical Research Center of Oncology in 2019-2020. For genotyping of rs4673 and rs28714259, DNA was extracted from blood using DNA-sorb-B (AmpliSens, Russia) and HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphisms was confirmed by Sanger sequencing on a Genetic Analyzer 3500 (ABI, USA). Results: During the follow-up period 21 (8.2%) patients were diagnosed with signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic AMC (changes developed within a year after completion of anthracycline therapy). In the group of patients without AOC the allelic frequency of rs4673 (c.214T &gt; C CYBA) was 0.38, the frequency of genotypes C/C – 0.4, C/T – 0.43, and T/T – 0.17. In the same group, the frequency of the A allele rs28714259 was 0.07, the frequency of the G/G genotypes – 0.87, G/A – 0.13, and A/A – 0. The prevalence of genotypes T/T rs4673 and allele G rs28714259 in a cohort of Russian patients differed from the European population (p = 0.014 and p = 0.05, respectively). The risk of cardiovascular changes on the background of anthracycline therapy increased in the presence of the rs4673 polymorphic allele by 6.49 times, in the case of the G/A and A/A rs28714259 genotypes - by 3.27 times. The results of the ROC-analysis suggested high quality of the tests based on the dominant models rs4673 and rs28714259 (AUC was 71.9% and 76.3% correspondingly). Conclusions: In this study the prognostic efficiency of the genetic markers rs4673 and rs28714259 was shown for the prompt detection of the risks of AMC development in the management of cancer patients. However, population characteristics should be taken into consideration for risk assessment.

Mechanisms of anthracycline-mediated cardiotoxicity and preventative strategies in women with breast cancer.

While anthracyclines (ACs) are a class of chemotherapeutic agents that have improved the prognosis of many women with breast cancer, it is one of the most cardiotoxic agents used to treat cancer. Despite their reported dose-dependent cardiotoxicity, AC-based chemotherapy has become the mainstay of breast cancer therapy due to its efficacy. Elucidating the mechanisms of anthracycline-mediated cardiotoxicity and associated therapeutic interventions continue to be the main focus in the field of cardio-oncology. Herein, we summarized the current literature surrounding the mechanisms of anthracycline-induced cardiotoxicity, including the role of topoisomerase II inhibition, generation of reactive oxygen species, and elevations in free radicals. Furthermore, this review highlights the molecular mechanisms of potential cardioprotective interventions in this setting. The benefits of pharmaceuticals, including dexrazoxane, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, statins, and antioxidants in this setting, are reviewed. Finally, the mechanisms of emerging preventative interventions within this patient population including nutraceuticals and aerobic exercise are explored.

Cardiovascular complications in patients with cancer: focus on anthracycline-induced cardiotoxicity

The article describes prevalence and risk factors of cardiovascular in patients with cancer. The problems of anthracycline-induced cardiotoxicity, the deleterious effects of doxorubicin on the heart, as well as the cardioprotective effects of beta-blockers and agents acting on the renin-angiotensin-aldosterone system pathway are discussed. By cardiotoxicity is implied the development of various adverse cardiovascular events against the background of drug therapy for cancer patients. Depending on the severity of myocardial damage, there are type I (anthracycline-mediated cardiotoxicity, myocardial damage is irreversible) and type II (trastuzumab-mediated cardiotoxicity, myocardial dysfunction is reversible) cardiotoxicity. Anthracycline-induced cardiotoxicity, in turn, is divided into acute, early-onset chronic and late-onset chronic. At the same time, the main mechanisms of anthracycline cytotoxicity in relation to healthy cardiomyocytes are stimulation of intracellular oxidative stress, a decrease in reduced glutathione concentration, inhibition of cell redox potential, and a change in iron metabolism. The article discusses in detail the risk factors (age, hypertension, diabetes, asymptomatic left ventricular dysfunction, documented cardiovascular diseases, heart failure, etc.), as well as the mechanisms and treatment of anthracycline-mediated cardiotoxicity.

Genetics of Anthracycline-Mediated Cardiotoxicity: Current Status and Challenges

Anthracyclines are potent and widely used anti-cancer compounds which carry a significant risk of cardiotoxicity. Genetic background is a key determinant of risk susceptibility and identifying causal genes and polymorphisms is an area of intense and growing interest. In this review, we provide an overview of the strategies employed to identify causal alleles and key findings stemming from recent studies. We describe candidate gene association studies and genome-wide association studies of anthracycline cardiotoxicity and summarize key findings. The importance of data robustness is discussed, as well as the largely untapped potential of stem cell–based strategies for both validation and discovery purposes. Multi-disciplinary and coordinated efforts will be vital to fully understand the link between genetic background and anthracycline cardiotoxicity risk. Doing so will enhance understanding of pathological mechanisms and enable more personalized and nuanced treatment strategies for patients undergoing anthracycline chemotherapy.

Association of rs28714259 polymorphism with a risk of early-onset chronic anthracycline-mediated cardiotoxicity in patients with breast cancer.

e13504 Background: Numerous pharmacogenetic studies have led to the identification of genetic polymorphisms associated not only with the development of cardiovascular disease, but also increase the risk of complications due to the use of anthracycline drugs, widely used in the treatment of cancer. The purpose of this study was to assess the prevalence of rs28714259 polymorphism and to study possible correlation with anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 173 Caucasian patients (median age 55 years) with a diagnosis of breast cancer without diagnosed cardiovascular pathology who underwent treatment in the RRIO, Rostov-on-Don in 2019. For genotyping of SNP rs28714259, DNA was extracted from blood using DNA-sorb-B (AmpliSens, Russia) and HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by Sanger sequencing with a Genetic Analyzer 3500 (ABI, USA). The obtained results were compared with European population (1000 Genome). Results: 13 patients (7.5%) with an early-onset of chronic AMC were founded after three courses of chemotherapy. The allelic frequency rs28714259 was 0.079, the frequency of AG genotypes was 0.135, and AA was 0.012. It was shown that the presence of this SNP leads to an increase risk of cardiovascular pathology at an early stage by more than 4 times (OR = 4.186, p = 0.006). In addition, when comparing with the European population, the highest probability of developing early-onset chronic AMC was determined for patients with the AA genotype (more than 22 times, p = 0.001). Conclusions: In this study, a statistically significant association of rs28714259 presence with developing early-onset chronic AMC was revealed, which seems promising for the early determination of the risk group in the management of cancer patients.

Updates in Anthracycline-Mediated Cardiotoxicity.

Cardiotoxicity is one of the main adverse effects of chemotheraphy, affecting the completion of cancer therapies and the short- and long-term quality of life. Anthracyclines are currently used to treat many cancers, including the various forms of leukemia, lymphoma, melanoma, uterine, breast, and gastric cancers. World Health Organization registered anthracyclines in the list of essential medicines. However, anthracyclines display a major cardiotoxicity that can ultimately culminate in congestive heart failure. Taking into account the growing rate of cancer survivorship, the clinical significance of anthracycline cardiotoxicity is an emerging medical issue. In this review, we focus on the key progenitor cells and cardiac cells (cardiomyocytes, fibroblasts, and vascular cells), focusing on the signaling pathways involved in cellular damage, and the clinical biomarkers in anthracycline-mediated cardiotoxicity.

Doxorubicin enhances oxysterol levels resulting in a LXR-mediated upregulation of cardiac cholesterol transporters

The anthracycline-mediated cardiotoxicity is still not completely understood. To examine the impact of cholesterol metabolism and transport in this context, cholesterol and oxysterol levels as well as the expression of the cholesterol transporters ABCA1 and ABCG1 were analyzed in doxorubicin-treated HL-1 murine cardiomyocytes as well as in mouse model for acute doxorubicin-induced cardiotoxicity. Doxorubicin-treated HL-1 cells exhibited enhanced cholesterol (153±20% of control), oxysterol (24S-hydroxycholesterol: 206±29% of control) and cholesterol precursor levels (lathosterol: 122±12% of control; desmosterol: 188±10% of control) indicating enhanced cholesterol synthesis. Moreover, abca1 and abcg1 were upregulated on mRNA, protein and functional level caused by a doxorubicin-mediated activation of the nuclear receptor LXR. In addition, the oxysterols not only induced the abca1 and abcg1 in HL-1 cells but also enhanced the expression of endothelin-1 and transforming growth factor-β, which have already been identified as important factors in doxorubicin-induced cardiotoxicity. These in vitro findings were verified in a murine model for acute doxorubicin-induced cardiotoxicity, demonstrating elevated cardiac (2.1±0.2vs. 3.6±1.0ng/mg) and systemic cholesterol levels (105.0±8.4vs. 130.0±4.3mg/dl), respectively, as well as enhanced oxysterol levels such as cardiac 24S-hydroxycholesterol (2.1±0.2vs. 3.6±1.0ng/mg). In line with these findings cardiac mRNA expression of abca1 (303% of control) and abcg1 (161% of control) was induced.Taken together, our data demonstrate enhanced cholesterol and oxysterol levels by doxorubicin, resulting in a LXR-dependent upregulation of abca1 and abcg1. In this context, the cytotoxic effects of oxysterols and their impact on cardiac gene expression should be considered as an important factor in doxorubicin-induced cardiotoxicity.

The Future of Onco-Cardiology: We Are Not Just "Side Effect Hunters".

Cancer treatments in general share various detrimental effects in common, especially upregulation of cardiovascular risk factors. Therefore, the science of onco-cardiology should not be restricted in scope to the side effects of each specific cancer drug. In particular, premature aging induced by cancer treatment may contribute to the chronic health problems of cancer survivors. About 1 660 000 people, including more than 12 000 children below the age of 18 years, are newly diagnosed with a malignancy in the United States every year.1 The American Cancer Society reported that in 2016 there are 15.5 million cancer survivors in the United States (http://www.cancer.org/cancer/news/news/report-number-of-cancer-survivors-continues-to-grow). At present, the 5-year survival rate of patients treated for cancer is 67%. Seventy-five percent of children in whom cancer is diagnosed today will live for at least 10 years; 20% will survive for longer than 35 years.1 Although these numbers are impressive compared with those from decades ago, further improvement of cancer survivors’ life span as well as quality of life and functional status is still necessary. Approximately 75% of cancer survivors have some form of chronic health problem. Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in this population, particularly after recurrent or second malignancy. The risk of CVD in cancer survivors is 8× higher than that of the general population. The relative risks of coronary artery disease and heart failure in cancer survivors are 10× and 15× higher, respectively, than their siblings without cancer.1 Cancer treatments, including chemotherapy and radiation, can lead to both short- and long-term cardiovascular complications. Evidence of subclinical cardiac and vascular damage was observed in more than 50% of survivors 5 to 10 years after chemotherapy.1 Onco-cardiology is a medical subspecialty concerned with the diagnosis and treatment of CVDs and organ failure mediated by microcirculatory or macrocirculatory …

β-Adrenergic Blockade for Anthracycline- and Trastuzumab-Induced Cardiotoxicity

Breast cancer is the second leading cause of cancer-related death among women in the United States.1 Approximately 25% to 30% of breast cancers have overexpression of human epidermal growth factor receptor 2 (HER2), which is associated with an adverse prognosis.2 Adjuvant chemotherapy with trastuzumab, the humanized monoclonal antibody that directly targets HER2, significantly improves disease-free and overall survival in these patients.3 However, trastuzumab, especially when given in combination with anthracyclines, has been associated with asymptomatic and symptomatic left ventricular (LV) dysfunction3 that can lead to premature discontinuation of trastuzumab therapy and significant cardiac morbidity. Article see p 420 In this issue of Circulation: Heart Failure , Seicean et al4 retrospectively evaluated the incidence of new symptomatic heart failure (HF) in patients with breast cancer treated with anthracyclines, trastuzumab, or both, at the Cleveland Clinic between 2005 and 2010. Using 1:2 propensity matching, they compared patients on continuous β-blockers during cancer treatment to those not on β-blockade, and assessed the effect of incidental β-blocker use on new symptomatic HF and noncardiac mortality during a median follow-up of ≈3 years. The results of this study show that trastuzumab, when given alone or in combination with anthracyclines, substantially increased the risk of symptomatic HF compared with anthracyclines alone (hazard ratio, 9.5; 95% confidence interval, 3.9–23.1). Furthermore, incidental β-blocker use significantly reduced the incidence of symptomatic HF (hazard ratio, 0.2; 95% confidence interval, 0.1–0.7) but did not affect noncardiac mortality in patients with breast cancer treated with trastuzumab, anthracyclines, or both. This article highlights 2 important issues: (1) it emphasizes the magnitude of trastuzumab cardiotoxicity in the real world, and (2) it provides support for the hypothesis that prophylactic β-blocker use may be cardioprotective in patients receiving trastuzumab, anthracyclines, or both. Anthracyclines cause a dose-dependent toxicity that is felt …

Early detection of anthracycline-mediated cardiotoxicity: the value of considering both global longitudinal left ventricular strain and twist

Anthracyclines are important anticancer drugs, but their use is limited by cardiotoxicity. Left ventricular ejection fraction (LVEF) is often inadequate to detect myocardial disease induced by chemotherapy. Tissue Doppler and bidimensional-strain imaging could detect LV myocardial dysfunction earlier than LVEF. In drug-induced cardiotoxicity, torsional and longitudinal LV deformations [LV twist (LVtw), radial strain (GRS), global longitudinal strain (GLS)] are damaged. We assessed whether a new index, GLS×LVtw, could predict future anthracycline-induced cardiomyopathy. Echocardiography, troponin, and natriuretic peptide determination were prospectively performed in 74 patients before and after 6, 12, 24, and 52 weeks of anthracycline treatment. These patients were treated for breast cancer, Hodgkin's or non-Hodgkin's lymphoma, acute lymphoblastic or myeloblastic leukaemia, or osteosarcoma. At 6 weeks after initiation of chemotherapy, isovolumic relaxation time, systolic mitral annular velocity, LVGLS, LVGRS, LV apical rotation, LVtw, and GLS×LVtw deteriorated, and troponin levels became elevated (all p < 0.05 by ANOVA) before LVEF decreased. The receiver operating characteristic curves identified early deterioration of GLS×LVtw as the best predictor of later cardiotoxicity (area under curve = 0.93), followed by GLS (0.84) and LV apical rotation (0.81) deterioration. In conclusion, early change in the GLS×LVtw index seems to be a good predictor of future development of anthracycline-induced cardiotoxicity.

Auto-acetylation stabilizes p300 in cardiac myocytes during acute oxidative stress, promoting STAT3 accumulation and cell survival

The nuclear acetyltransferase p300 is rapidly and stably induced in the heart during hemodynamic stress, but the mechanism of this induction is unknown. To determine the role of oxidative stress in p300 induction, we exposed neonatal rat cardiac myocytes to doxorubicin (DOX, 1 μM) or its vehicle, and monitored p300 protein content and stability for 24 h. Levels of p300 rose substantially within 1 h and remained elevated for at least 24 h, while p300 transcript levels declined. In the presence of cycloheximide, the estimated half-life of p300 in control cells was approximately 4.5 h, typical of an immediate-early response protein. DOX treatment prolonged p300 t(1/2) to >24 h, indicating that the sharp rise in p300 levels was attributable to rapid protein stabilization. p300 stabilization was entirely due to an increase in acetylated p300 species with greatly enhanced resistance to proteasomal degradation. The half-life of p300 was dependent on its acetyltransferase activity, falling in the presence of p300 inhibitors curcumin and anacardic acid, and increasing with histone deacetylase (HDAC) inhibition. At the same time, acetyl-STAT3, phospho-STAT3-(Tyr 705) and -(Ser 727) increased, together with a prolongation of STAT3 half-life. SiRNA-mediated p300 knockdown abrogated all of these effects, and strongly enhanced DOX-mediated myocyte apoptosis. We conclude that DOX induces an acute amplification of p300 levels through auto-acetylation and stabilization. In turn, elevated p300 provides a key defense against acute oxidative stress in cardiac myocytes by acetylation, activation, and stabilization of STAT3. Our results suggest that HDAC inhibitors could potentially reduce acute anthracycline-mediated cardiotoxicity by promoting p300 auto-acetylation.

Torsion analysis in the early detection of anthracycline-mediated cardiomyopathy

Anthracyclines have profound consequences on the structure and function of the heart, which over time cause a cardiomyopathy that leads to congestive heart failure. Early detection of subclinical left ventricular (LV) dysfunction following a low dose of anthracyclines may be a preventive strategy. The aim of this study was to determine torsion analysis using two-dimensional speckle-tracking imaging (STI), useful for detecting early anthracycline-mediated cardiotoxicity. Conventional and Doppler echocardiography images were obtained from 25 patients (mean age 58 ± 11 years) before chemotherapy and 1 and 3 months after treatment. The cumulative anthracycline doses were 98 ± 59 and 170 ± 87 g/m(2) at 1 and 3 months, respectively. After standard echocardiography, LV torsion and twisting velocity profiles from apical and basal short-axis images were analysed using STI. LV dimensions and ejection fraction did not change throughout follow-up. Although isovolumic relaxation time showed prolongation 3 months after chemotherapy, other Doppler indices did not show significant changes. However, significant deteriorations in torsion (P < 0.0001 by ANOVA), twisting rate (P < 0.0001 by ANOVA), and untwisting rate (P < 0.001 by ANOVA) were found 1 month after chemotherapy. A significant negative correlation was observed between cumulative anthracycline doses and torsion (r = -0.524, P < 0.0001). LV torsion analysis could be a useful non-invasive approach for early detection of subclinical anthracycline cardiotoxicity.

Examination of the mechanism(s) involved in doxorubicin-mediated iron accumulation in ferritin: studies using metabolic inhibitors, protein synthesis inhibitors, and lysosomotropic agents.

Anthracyclines are potent anticancer agents, but their use is limited by cardiotoxicity at high cumulative doses. The mechanisms involved in anthracycline-mediated cardiotoxicity are still poorly understood, but numerous investigations have indicated a role for iron in this process. Our previous studies using neoplastic and myocardial cells showed that anthracyclines inhibit iron mobilization from the iron storage protein, ferritin, resulting in marked accumulation of ferritin-iron. Although the process of ferritin-iron mobilization is little understood, catabolism of ferritin by lysosomes may be a likely mechanism. Because anthracyclines have been shown to accumulate in lysosomes, this latter organelle may be a potential target for these drugs. The present study demonstrated, using native polyacrylamide gel electrophoresis-59Fe autoradiography, that ferritin-59Fe mobilization is an energy-dependent process that also requires protein synthesis. Depression of lysosomal activity via the enzyme inhibitors E64d [(2S,3S)-trans-epoxysuccinyl-l-leucylamido-2-methylbutane ethyl ester] and leupeptin or the lysosomotropic agents ammonium chloride, chloroquine, and methylamine resulted in a 3- to 5-fold increase in 59Feferritin accumulation compared with control cells. In addition, the proteasome inhibitors N-benzoyloxycarbonyl (Z)-Leu-Leuleucinal (MG132) and lactacystin also significantly increased 59Fe-ferritin levels compared with control cells. These effects of lysosomotropic agents or inhibitors of lysosomal activity were comparable with that observed with the anthracycline doxorubicin. Collectively, our study indicates a role for lysosomes and proteasomes in ferritin-iron mobilization, and this pathway is dependent on metabolic energy and protein synthesis. Furthermore, the lysosome/proteasome pathway may be a novel anthracycline target, inhibiting iron mobilization from ferritin that is essential for vital iron-requiring processes such as DNA synthesis.