New advances in medical imaging technology for the evaluation of anthracycline-induced cardiotoxicity.
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ABSTRACT:
SUBMITTER: Su N
PROVIDER: S-EPMC9521788 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
Publications
New advances in medical imaging technology for the evaluation of anthracycline-induced cardiotoxicity.
Su Nan N Sun Jing J Zhang Guirong G Meng Yiming Y
Chinese medical journal 20220805 15
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Project description:Anthracyclines are highly potent anti-cancer drugs, but their clinical use is limited by severe cardiotoxic side effects. The impact of anthracycline-induced cardiotoxicity (AIC) on left ventricular (LV) microarchitecture and diffusion properties remains unknown. This study sought to characterize AIC by cardiovascular magnetic resonance diffusion tensor imaging (DTI). Mice were treated with Doxorubicin (DOX; n = 16) for induction of AIC or saline as corresponding control (n = 15). Cardiac function was assessed via echocardiography at the end of the study period. Whole hearts (n = 8 per group) were scanned ex vivo by high-resolution DTI at 7 T. Results were correlated with histopathology and mass spectrometry imaging. Mice with AIC demonstrated systolic dysfunction (LVEF 52 ± 3% vs. 43 ± 6%, P < 0.001), impaired global longitudinal strain (-19.6 ± 2.0% vs. -16.6 ± 3.0%, P < 0.01), and cardiac atrophy (LV mass index [mg/mm], 4.3 ± 0.1 vs. 3.6 ± 0.2, P < 0.01). Regional sheetlet angles were significantly lower in AIC, whereas helix angle and relative helicity remained unchanged. In AIC, fractional anisotropy was increased (0.12 ± 0.01 vs. 0.14 ± 0.02, P < 0.05). DOX-treated mice displayed higher planar and less spherical anisotropy (CPlanar 0.07 ± 0.01 vs. 0.09 ± 0.01, P < 0.01; CSpherical 0.89 ± 0.01 vs. 0.87 ± 0.02, P < 0.05). CPlanar and CSpherical yielded good discriminatory power to distinguish between mice with and without AIC (c-index 0.91 and 0.84, respectively, P for both < 0.05). AIC is associated with regional changes in sheetlet angle but no major abnormalities of global LV microarchitecture. The geometric shape of the diffusion tensor is altered in AIC. DTI may provide a new tool for myocardial characterization in patients with AIC, which warrants future clinical studies to evaluate its diagnostic utility.
| S-EPMC11790774 | biostudies-literature
Project description:Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease. Anthracycline induced cardiotoxicity (AIC) ranges from asymptomatic LV dysfunction to highly morbid end- stage heart failure. As cancer survivorship improves, the detection and treatment of AIC becomes more crucial to improve patient outcomes. Current treatment modalities for AIC have been largely extrapolated from treatment of conventional heart failure, but developing effective therapies specific to AIC is an area of growing research interest. This review summarizes the current evidence behind the use of neurohormonal agents, dexrazoxane, and resynchronization therapy in AIC, evaluates the clinical outcomes of advanced therapy and heart transplantation in AIC, and explores future horizons for treatment utilizing gene therapy, stem cell therapy, and mechanism-specific targets.
| S-EPMC9072636 | biostudies-literature
Project description:Background: Several cardiovascular risk factors have been suggested to be associated with anthracycline-induced cardiotoxicity, but their quantitative effects have not reached a consensus. Methods: We searched PubMed, EMBASE, and Cochrane Library databases for manuscripts published from inception to February 2021, which reported the results of cardiotoxicity due to anthracycline chemotherapy without trastuzumab. Cardiotoxicity defined by any reduction of left ventricular eject fraction (LVEF) to below 50% or a >10% reduction from baseline was defined as the primary endpoint. Odd ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model meta-analysis. Results: A total of 7,488 patients receiving anthracycline chemotherapy without trastuzumab were included, who had at least one risk factor at baseline. Hypertension (OR: 1.99; 95% CI: 1.43-2.76), diabetes mellitus (OR: 1.74; 95% CI: 1.11-2.74), and obesity (OR: 1.72; 95% CI: 1.13-2.61) were associated with increased risk of cardiotoxicity. In addition, the relative reduction of global longitudinal strain (GLS) from baseline after anthracycline treatment could significantly improve the detection ability of cardiotoxicity (28.5%, 95% CI: 22.1-35.8% vs. 16.4%, 95% CI: 13.4-19.9%) compared with LVEF. The early detection rate of anthracycline-induced cardiotoxicity (3 months after chemotherapy) by GLS was 30.2% (95% CI: 24.9-36.1%), which is similar with the overall result of GLS. Conclusions: Hypertension, diabetes mellitus, and obesity are associated with increased risk of anthracycline-induced cardiotoxicity, which indicates that corresponding protective strategies should be used during and after anthracycline treatment. The findings of higher detection rate and better early detection ability for cardiotoxicity than LVEF added new proofs for the advantages of GLS in detection of AIC.
| S-EPMC8511483 | biostudies-literature
Project description:In this retrospective observational study, we aimed to investigate the potential of natural language processing (NLP) for drug repositioning by analyzing the preventive effects of cardioprotective drugs against anthracycline-induced cardiotoxicity (AIC) using electronic medical records. We evaluated the effects of angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors (ARB/ACEIs), beta-blockers (BBs), statins, and calcium channel blockers (CCBs) on AIC using signals extracted from clinical texts via NLP. The study included 2935 patients prescribed anthracyclines at a single hospital, with concomitant prescriptions of ARB/ACEIs, BBs, statins, and CCBs. Upon propensity score matching, groups with and without these medications were compared, and expressions suggestive of cardiotoxicity, extracted via NLP, were considered as the outcome. The hazard ratios for ARB/ACEIs, BBs, statins, and CCBs were 0.58 [95% CI: 0.38-0.88], 0.71 [95% CI: 0.35-1.44], 0.60 [95% CI 0.38-0.95], and 0.63 [95% CI: 0.45-0.88], respectively. ARB/ACEIs, statins, and CCBs significantly suppressed AIC, whereas BBs did not demonstrate statistical significance, possibly due to limited statistical power. NLP-extracted signals from clinical texts reflected the known effects of these medications, demonstrating the feasibility of NLP-based drug repositioning. Further investigation is needed to determine if similar results can be replicated using electronic medical records from other institutions.
| S-EPMC11850854 | biostudies-literature
Project description:Advances in cancer treatment have significantly improved the survival of patients with cancer, but, unfortunately, many of these treatments also have long-term complications. Cancer treatment-related cardiotoxicities are becoming a significant clinical problem that a new discipline, Cardio-Oncology, was established to advance the cardiovascular care of patients with growing cancer populations. Anthracyclines are a class of chemotherapeutic agents used to treat many cancers in adults and children. Their clinical use is limited by anthracycline-induced cardiotoxicity (AIC), which can lead to heart failure. Early-onset cardiotoxicity appears within a year of treatment, whereas late-onset cardiotoxicity occurs > 1 year and even up to decades after treatment completion. The pathophysiology of AIC was hypothesized to be caused by generation of reactive oxygen species that lead to lipid peroxidation, defective mitochondrial biogenesis, and DNA damage of the cardiomyocytes. The accumulation of anthracycline metabolites was also proposed to cause mitochondrial damage and the induction of cardiac cell apoptosis, which induces arrhythmias, contractile dysfunction, and cardiomyocyte death. This paper will provide a general overview of cardiotoxicity focusing on the effect of anthracyclines and their epigenetic molecular mechanisms on cardiotoxicity.
| S-EPMC7877852 | biostudies-literature
Project description: Not available
| S-EPMC11234563 | biostudies-literature
Project description:ObjectivesTo identify anthracycline-induced acute (within 1 month) and early-onset chronic progressive (within 1 year) cardiotoxicity in children younger than 16 years of age with childhood malignancies at a tertiary care centre of Pakistan.DesignProspective cohort study.SettingAga Khan University, Karachi, Pakistan.Participants110 children (aged 1 month-16 years).InterventionAnthracycline (doxorubicin and/or daunorubicin).Outcome measurementsAll children who received anthracycline as chemotherapy and three echocardiographic evaluations (baseline, 1 month and 1 year) between July 2010 and June 2012 were prospectively analysed for cardiac dysfunction. Statistical analysis including systolic and diastolic functions at baseline, 1 month and 1 year was carried out by repeated measures analysis of variance.ResultsMean age was 74±44 months and 75 (68.2%) were males. Acute lymphoblastic leukaemia was seen in 70 (64%) patients. Doxorubicin alone was used in 59 (54%) and combination therapy was used in 35 (32%). A cumulative dose of anthracycline <300 mg/m(2) was used in 95 (86%). Fifteen (14%) children developed cardiac dysfunction within a month and 28 (25%) children within a year. Of these 10/15 (66.6%) and 12/28 (43%) had isolated diastolic dysfunction, respectively, while 5/15 (33.3%) and 16/28 (57%) had combined systolic and diastolic dysfunction. Seven (6.4%) patients expired due to severe cardiac dysfunction. Eight of 59 (13.5%) children showed dose-related cardiotoxicity (p=<0.001). Cardiotoxicity was also high when the combination of doxorubicin and daunorubicin was used (p=0.004).ConclusionsIncidence of anthracycline-induced cardiotoxicity is high. Long-term follow-up is essential to diagnose its late manifestations.
| S-EPMC3840341 | biostudies-literature
Project description:The administration of anthracycline drugs induces progressive and dose-related cardiac damage through several cytotoxic mechanisms, including endoplasmic reticulum (ER) stress. The unfolded protein response plays a crucial role for mitigating misfolded protein accumulation induced by excessive ER stress. We aimed to clarify whether endoplasmic reticulum-selective autophagy machinery (ER-phagy) serves as an alternative system to protect cardiomyocytes from ER stress caused by anthracycline drugs. Primary cultured cardiomyocytes, H9c2 cell lines, and cardiomyocyte-specific transgenic mice, all expressing ss-RFP-GFP-KDEL proteins, were used as ER-phagy reporter models. We generated loss-of-function models using RNA interference or gene-trap mutagenesis techniques. We assessed phenotypes and molecular signaling pathways using immunoblotting, quantitative polymerase chain reaction, cell viability assays, immunocytochemical and histopathological analyses, and cardiac ultrasonography. The administration of doxorubicin (Dox) activated ER-phagy in ss-RFP-GFP-KDEL-transduced cardiomyocytes. In addition, Dox-induced cardiomyopathy models of ER-phagy reporter mice showed marked activation of ER-phagy in the myocardium compared to those of saline-treated mice. Quantitative polymerase chain reaction analyses revealed that Dox enhanced the expression of cell-cycle progression gene 1 (CCPG1), one of the ER-phagy receptors, in H9c2 cells. Ablation of CCPG1 in H9c2 cells resulted in the reduced ER-phagy activity, accumulation of proapoptotic proteins, and deterioration of cell survival against Dox administration. CCPG1-hypomorphic mice developed more severe deterioration in systolic function in response to Dox compared to wild-type mice. Our findings highlight a compensatory role of CCPG1-driven ER-phagy in reducing Dox toxicity. With further study, ER-phagy may be a potential therapeutic target to mitigate Dox-induced cardiomyopathy.
| S-EPMC10635891 | biostudies-literature
Project description:Simple Summary Anthracycline-induced cardiotoxicity (AIC) poses a significant clinical challenge in the management of cancer patients. Thus, the development of effective preventive measures for AIC is a heavily studied subject in the field of cardio-oncology. A new class of agents, namely angiotensin receptor/neprilysin inhibitors (ARNi; sacubitril/valsartan), recently incorporated into the management of heart failure with reduced ejection fraction, were found to possess robust cardioprotective effects in preclinical models of a wide range of cardiovascular pathologies. This review discusses the cardioprotective mechanisms of action of sacubitril/valsartan in relation to the pathophysiologic processes involved in the cardiotoxicity of anthracyclines: myocardial remodeling, cardiomyocyte DNA damage, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory response, and renin-angiotensin-aldosterone system dysregulation. Additionally, the available data on the effectiveness of sacubitril/valsartan administration in the prevention of AIC were summarized. Several reports on sacubitril/valsartan administration in animal models of AIC published at the time of writing have shown promising results, as ARNi prevented anthracycline-induced myocardial systolic dysfunction and remodeling by alleviating oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and the inflammatory response. Human data remain limited—an ongoing PRADAII trial, aimed to assess the efficacy of sacubitril/valsartan in patients receiving chemotherapy for breast cancer, is expected to be completed in 2025. Abstract Anthracycline-induced cardiotoxicity (AIC) poses a clinical challenge in the management of cancer patients. AIC is characterized by myocardial systolic dysfunction and remodeling, caused by cardiomyocyte DNA damage, oxidative stress, mitochondrial dysfunction, or renin-angiotensin-aldosterone system (RAAS) dysregulation. In the past decade, after positive results of a PARADIGM-HF trial, a new class of drugs, namely angiotensin receptor/neprilysin inhibitors (ARNi), was incorporated into the management of patients with heart failure with reduced ejection fraction. As demonstrated in a variety of preclinical studies of cardiovascular diseases, the cardioprotective effects of ARNi administration are associated with decreased oxidative stress levels, the inhibition of myocardial inflammatory response, protection against mitochondrial damage and endothelial dysfunction, and improvement in the RAAS imbalance. However, data on ARNi’s effectiveness in the prevention of AIC remains limited. Several reports of ARNi administration in animal models of AIC have shown promising results, as ARNi prevented ventricular systolic dysfunction and electrocardiographic changes and ameliorated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and the inflammatory response associated with anthracyclines. There is currently an ongoing PRADAII trial aimed to assess the efficacy of ARNi in patients receiving breast cancer treatment, which is expected to be completed by late 2025.
| S-EPMC9818213 | biostudies-literature
Project description:Cancer diagnostics and therapies have improved steadily over the last few decades, markedly increasing life expectancy for patients at all ages. However, conventional and newer anti-neoplastic therapies can cause short- and long-term cardiotoxicity. The clinical implications of this cardiotoxicity become more important with the increasing use of cardiotoxic drugs. The implications are especially serious among patients predisposed to adverse cardiac effects, such as youth, the elderly, those with cardiovascular comorbidities, and those receiving additional chemotherapies or thoracic radiation. However, the optimal strategy for preventing and managing chemotherapy-induced cardiotoxicity remains unknown. The routine use of neurohormonal antagonists for cardioprotection is not currently justified, given the marginal benefits and associated adverse events, particularly with long-term use. The only United States Food and Drug Administration and European Medicines Agency approved treatment for preventing anthracycline-related cardiomyopathy is dexrazoxane. We advocate administering dexrazoxane during cancer treatment to limit the cardiotoxic effects of anthracycline chemotherapy.
| S-EPMC7048046 | biostudies-literature