Anthracycline Cardiomyopathy Research Articles

Abstract Mo023: Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy

Background: Anthracyclines such as doxorubicin (Dox) are highly effective anti-tumor agents, but their use is limited by dose-dependent cardiomyopathy. Our laboratory previously reported that activation of cytochrome P450 family 1 (Cyp1) enzymes contributes to acute doxorubicin (Dox) cardiotoxicity in zebrafish and in mice, and that potent Cyp1 inhibitors prevent cardiotoxicity. However, the role of Cyp1 enzymes in chronic Dox cardiomyopathy, as well as the mechanisms underlying cardioprotection associated with Cyp1 inhibition, have not been fully elucidated. Objective: This study aims to define the role of Cyp1 inhibition in mouse models that more accurately recapitulates the chronic cardiomyopathy seen in patients. Methods: The function of Cyp1 enzymes was evaluated using a small molecule Cyp1 inhibitor in wild-type (WT) mice, or Cyp1-null mice ( Cyp1a1/1a2 -/- , Cyp1b1 -/- , and Cyp1a1/1a2/1b1 -/- ). Low-dose Dox was administered by serial intraperitoneal or intravenous injections, respectively. Expression of Cyp1 isoforms was measured by RT-qPCR, and myocardial tissue was isolated from the left ventricle for RNA sequencing. Cardiac function was evaluated by transthoracic echocardiography. Results: In WT mice, Dox treatment was associated with a decrease in Cyp1a2 and an increase in Cyp1b1 expression in the heart and in the liver. Co-treatment of WT mice with Dox and the potent Cyp1 inhibitor YW-130 protected against cardiac dysfunction compared to Dox treatment alone. Cyp1a1/1a2 -/- and Cyp1a1/1a2/1b1 -/- mice were protected from Dox cardiomyopathy compared to WT mice. Male, but not female, Cyp1b1 -/- mice had increased cardiac dysfunction following Dox treatment compared to WT mice. RNA sequencing of myocardial tissue showed upregulation of Fundc1 and downregulation of Ccl21c in Cyp1a1/1a2 -/- mice treated with Dox, implicating changes in mitophagy and chemokine-mediated inflammation as possible mechanisms of Cyp1a-mediated cardioprotection. Conclusions: Taken together, this study highlights the potential therapeutic value of Cyp1a inhibition in mitigating anthracycline cardiomyopathy.

Cardiovascular and hematologic complications of Hodgkin vs non-Hodgkin lymphoma and readmission trends: A National Readmission Database analysis from years 2016-2020.

e19034 Background: Cardiovascular complications are a leading cause of non-malignant death in lymphoma survivors. We sought to analyze the national readmission trends and evaluate the in-hospital mortality as well as the cardiovascular and hematological complications in lymphoma patients using the National Readmission Database (NRD). Methods: We selected patients aged >=18 years of age, from the NRD between the years 2016-2020 to generate a cohort of Hodgkin's Lymphoma (HL) and Non-Hodgkin's Lymphoma (NHL) patients using ICD-10 codes. The primary outcome was in-hospital mortality, and the secondary outcome was cardiovascular and hematologic complications of HL vs NHL after adjusting for demographic confounders. We used multivariate logistic regression and propensity score matching (PSM) using STATA v.18. We also analyzed the 30-day readmission trends in these patients. Results: A total of 1,016,338 NHL and 83,036 HL patients were included in the analysis. After matching for demographics confounders, on PSM analysis we found that in-hospital mortality was higher in NHL vs HL (5.9% vs 4.42%; p-value 0.001). The cardiovascular complications that were studied included cardiac tamponade (0.69% in NHL vs 0.4% in HL; p-value 0.001), pericarditis (0.13% in NHL vs 0.14% in HL; p-value 0.717) and anthracycline cardiomyopathy (0.47% in HL vs 0.85% in NHL; p-value 0.001). The hematological outcomes studied included myelodysplastic syndrome (0.71% in NHL vs 0.64% in HL; p-value 0.210), acute leukemia (0.48% in NHL vs 0.44% in HL; p-value 0.43), and myelosuppression (18.59% vs 13.73%; p-value 0.001). A 30-day readmission trend analysis showed a longer length of stay in NHL vs HL (5.34 days vs 4.77 days) while the total inflation-adjusted cost was higher in HL vs NHL (20,989 dollars vs 17176 dollars). Conclusions: An NRD analysis of NHL and HL patient populations from 2016-2020 reflected a slightly increased mortality rate, higher incidence of cardiovascular complications and a longer length of stay in NHL patients. [Table: see text]

Dynamin-Related Protein 1 Binding Partners MiD49 and MiD51 Increased Mitochondrial Fission In Vitro and Atherosclerosis in High-Fat-Diet-Fed ApoE-/- Mice.

Novel components of the mitochondrial fission machinery, mitochondrial dynamics proteins of 49 kDa (MiD49) and 51 kDa (MiD51), have been recently described, and their potential therapeutic targets for treating cardiovascular disease have been shown, including acute myocardial infarction (AMI), anthracycline cardiomyopathy and pulmonary arterial hypertension (PAH). Here, we examined the role of MiD49 and MiD51 in atherosclerosis. MiD49/51 expression was increased in the aortic valve endothelial cells (ECs) of high-fat diet-induced atherosclerosis in ApoE-/-mice and IL-8-induced human umbilical vein endothelial cells (HUVECs), which accelerated dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Silencing MiD49/51 reduced atherosclerotic plaque size, increased collagen content, and decreased the IL-8-induced adhesion and proliferation of HUVECs. MiD51 upregulation resulted from decreased microRNA (miR)-107 expression and increased hypoxia-inducible factor-1a (HIF-1a) expression. Treatment with miR-107 mimics decreased atherosclerotic plaque size by reducing HIF-1α and MiD51 production. Both MiD49 and MiD51 were involved in atherosclerotic plaque formation through Drp1-mediated mitochondrial fission, and the involvement of MiD51 in this process was the result of decreased miR-107 expression and increased HIF-1α expression. The miR-107-HIF-1α-MiD51 pathway might provide new therapeutic targets for atherosclerosis.

Initial Phase of Anthracycline Cardiotoxicity Involves Cardiac Fibroblasts Activation and Metabolic Switch.

The application of doxorubicin (DOX) is hampered by cardiotoxicity, with diastolic dysfunction as the earliest manifestation. Fibrosis leads to impaired relaxation, but the mechanisms that operate shortly after DOX exposure are not clear. We asked whether the activation of cardiac fibroblasts (CFs) anticipates myocardial dysfunction and evaluated the effects of DOX on CF metabolism. CFs were isolated from the hearts of rats after the first injection of DOX. In another experiment, CFs were exposed to DOX in vitro. Cell phenotype and metabolism were determined. Early effects of DOX consisted of diastolic dysfunction and unchanged ejection fraction. Markers of pro-fibrotic remodeling and evidence of CF transformation were present immediately after treatment completion. Oxygen consumption rate and extracellular acidification revealed an increased metabolic activity of CFs and a switch to glycolytic energy production. These effects were consistent in CFs isolated from the hearts of DOX-treated animals and in naïve CFs exposed to DOX in vitro. The metabolic switch was paralleled with the phenotype change of CFs that upregulated markers of myofibroblast differentiation and the activation of pro-fibrotic signaling. In conclusion, the metabolic switch and activation of CFs anticipate DOX-induced damage and represent a novel target in the early phase of anthracycline cardiomyopathy.

Initial phase of anthracycline cardiotoxicity involves metabolic switch and activation of cardiac fibroblasts

Abstract Background Doxorubicin (DOX) is an effective anticancer drug, but its application is hampered by cardiotoxicity with asymptomatic diastolic dysfunction as the earliest manifestation. Interstitial fibrosis leads to impaired relaxation, but the timing of fibrotic process and the mechanisms that operate shortly after DOX exposure are not clear. While changes in energy metabolism by DOX is recognized in cardiomyocytes, the effects of DOX on cardiac fibroblasts (CFs) metabolism are unknown.Thus, in a model of anthracycline cardiomyopathy, we asked whether the activation of CFs anticipates the onset of DOX-induced early diastolic dysfunction and evaluated the effects of DOX on the activation and metabolism of CFs. Methods Fischer 344 rats were exposed to 6 injections of 2.5 mg/kg of DOX over 2 weeks. Heart function was assessed by echocardiography and left ventricular catheterization. To test the very early in vivo effects of DOX on CFs, primary CFs were isolated from hearts of DOX-treated rats after the first injection of DOX. In another set of experiments, CFs were exposed to DOX in vitro. Cell metabolism was measured by a Seahorse-XF Real-Time ATP assay and cell phenotype was determined by immunocytochemistry and molecular biology. Results Early effects of DOX consisted of unchanged ejection fraction and the evidence of diastolic dysfunction. Markers of pro-fibrotic remodeling and histological evidence of CFs transformation were present in the heart immediately after treatment completion. Importantly, at the very beginning of the DOXO exposure, when cardiac function was normal and there was no histological evidence of increased fibrosis, the conversion of CFs to myofibroblasts, evidenced by SMA, was detected. Oxygen consumption rate and extracellular acidification, revealed the increased metabolic activity of CFs after DOX exposure and the switch to the glycolytic energy production. These effects were consistent in CFs isolated from the hearts of DOX-treated animals and in naive CFs exposed to DOX in vitro. The metabolic switch was paralleled with the phenotype change of CFs towards extracellular matrix-producing cells. Upon DOX, CFs upregulated markers of myofibroblast differentiation and the activation of pro-fibrotic signaling (aSMA, TGFb and phospho-SMAD). CFs maintained their functional properties in scratch assay. CFs upregulated also NOX2, indicating these cells as an intramyocardial source of reactive oxygen in the initial phase of the disease. Conclusion The metabolic switch and activation of CFs anticipate the onset of DOX-induced early diastolic dysfunction. The effect of DOX on the metabolic profile in CFs represents a novel and potentially targetable component of the very early phase of the pathogenesis of anthracycline cardiomyopathy.

Anthracycline-induced cardiac injuries and the effect of placenta cryoextract on the myocardium in doxorubicin cardiomyopathy

Background. Doxorubicin is the most widely used drug among anthracyclines. However, despite its clinical effectiveness, the cardiotoxic effect is observed in approximately 25,0% of patients, thus limiting its use. Although significant success in understanding individual pathogenetic elements of the cardiotoxic effect of this drug has been achieved, cancer patients who have doxorubicin-induced cardiac complications are currently treated mostly with drugs for cardiac insufficiency because there is no specific treatment for anthracycline cardiomyopathy.
 Purpose – to characterize the effect of placenta cryoextract on the course of doxorubicin myocardial injury on the model of chronic doxorubicin cardiomyopathy compared to reference drug vinboron according to the data of biochemical analyses of the heart tissues.
 Materials and methods. Chronic doxorubicin cardiomyopathy was modeled by the means of injection of doxorubicin hydrochloride at the rate of 5 mg/kg of body weight once a week for 4 weeks (on days 7, 14, 21, 28). The placenta cryoextract was injected on days 1, 7, 14, 21, 28. The animals were withdrawn from the experiment on day 35. The content of adenylic nucleotides, glycogen, pyruvate, lactate, and reactants with thiobarbituric acid was studied in the homogenates of the heart tissues.
 Results and discussion. The development of doxorubicin cardiomyopathy is accompanied with impaired energy metabolism in the myocardium of animals, as indicated by a statistically significant decrease in the content of adenosine triphosphoric acid (ATP) (p < 0,01) in myocardium tissues by 42,4% and an increase in the content of adenosine diphosphoric acid (ADP) (р < 0,05) and adenosine monosphoric acid (AMP) (p < 0,001) by 45,4% and by 2,2 times respectively relative to the parameters of intact rats. The development of energy disbalance is accompanied with a statistically significant (p< 0,001) increase in the content of reactants with thiobarbituric acid. The use of placenta cryoextract leads to nullifying the energy deficit in myocardium of animals with doxorubicin cardiomyopathy – the level of ATP in the setting of injection of the studied cryoextract increased statistically significantly (p < 0,001) by 72,7%. In addition, in the setting of injection of the studied cryoextract, the «lactate/pyruvate» ratio decreased statistically significantly by 51,9% relative to the parameters of the animals with doxorubicin cardiomyopathy which did not receive treatment and the level of glycogen increased statistically significantly (р < 0,01) by 2 times relative to the parameters of the rats with doxorubicin cardiomyopathy which did not receive treatment, but the content of reactants with thiobarbituric acid decreased (p < 0,05) by 38,9%.
 Conclusions. Placenta cryoextract shows cardioprotective activity, which is compared to is meant to be used when you’re highlighting similarities, while compared with is supposed to be used when you’re focusing on the differences vinboron, on the model of doxorubicin cardiomyopathy. One of the mechanisms of the mentioned activity is the ability of the studied cryoextract to produce an energystabilizing effect on cardiomyocytes, and also its antioxidative activity.

The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy.

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the development of anthracycline cardiomyopathy, but its efficacy is insufficient. Carvedilol (CVD) is another product being tested in clinical trials for the same indication. This study's objective was to evaluate anthracycline cardiotoxicity in rats treated with CVD in combination with DEX. The studies were conducted using male Wistar rats receiving DOX (1.6 mg/kg b.w. i.p., cumulative dose: 16 mg/kg b.w.), DOX and DEX (25 mg/kg b.w. i.p.), DOX and CVD (1 mg/kg b.w. i.p.), or a combination (DOX + DEX + CVD) for 10 weeks. Afterward, in the 11th and 21st weeks of the study, echocardiography (ECHO) was performed, and the tissues were collected. The addition of CVD to DEX as a cardioprotective factor against DOX had no favorable advantages in terms of functional (ECHO), morphological (microscopic evaluation), and biochemical alterations (cardiac troponin I and brain natriuretic peptide levels), as well as systemic toxicity (mortality and presence of ascites). Moreover, alterations caused by DOX were abolished at the tissue level by DEX; however, when CVD was added, the persistence of DOX-induced unfavorable alterations was observed. The addition of CVD normalized the aberrant expression of the vast majority of indicated genes in the DOX + DEX group. Overall, the results indicate that there is no justification to use a simultaneous treatment of DEX and CVD in DOX-induced cardiotoxicity.

Anthracycline-induced cardiomyopathy in the long-term period after chemotherapy: clinical case

Background. As is known, the treatment of the oncological process leads either to the occurrence of cardiovascular pathology, or to an increase in the risk of death from cardiovascular diseases. Currently, the concept of ˝cardiovascular toxicity˝ has been introduced, which is associated with the treatment of cancer (CTR-CVT). Systemic drug anthracycline-containing anticancer therapy can cause a number of cardiovascular complications, such as myocardial systolic dysfunction, coronary heart disease, cardiac arrhythmias, arterial hypertension. Particular attention is paid to anthracycline drugs, because they are still included in combinations of many adjuvant therapy regimens and first-line treatment of both the most common cancers and rarer ones.
 Clinical Case Description. The article presents a clinical case of a patient who received adjuvant polychemotherapy for breast cancer in 2017 with AC 4 D 4 regimen, in which chronic anthracycline-induced cardiomyopathy manifested years after completion of antitumor therapy. The development of anthracycline cardiomyopathy is possible even in patients with initially low cardiac risk.
 Conclusion. The clinical case highlights the importance of monitoring patients after the end of anthracycline antitumor therapy, in particular, they are shown to periodically perform an echocardiographic study in order to detect delayed asymptomatic myocardial dysfunction.

RBL2 Regulates Cardiac Sensitivity to Anthracycline Chemotherapy

BackgroundAnthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2). ObjectivesThe aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart. MethodsRbl2−/− mice and Rbl2+/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies. ResultsThe loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors. ConclusionsRbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy.

Molecular mechanisms of anthracycline induced cardiotoxicity: Zebrafish come into play.

Anthracyclines are among the most potent chemotherapeutics; however, cardiotoxicity significantly restricts their use. Indeed, anthracycline-induced cardiotoxicity (AIC) fares among the worst types of cardiomyopathy, and may only slowly and partially respond to standard heart failure therapies including β-blockers and ACE inhibitors. No therapy specifically designed to treat anthracycline cardiomyopathy at present, and neither is it known if any such strategy could be developed. To address this gap and to elucidate the molecular basis of AIC with a therapeutic goal in mind, zebrafish has been introduced as an in vivo vertebrate model about a decade ago. Here, we first review our current understanding of the basic molecular and biochemical mechanisms of AIC, and then the contribution of zebrafish to the AIC field. We summarize the generation of embryonic zebrafish AIC models (eAIC) and their use for chemical screening and assessment of genetic modifiers, and then the generation of adult zebrafish AIC models (aAIC) and their use for discovering genetic modifiers via forward mutagenesis screening, deciphering spatial-temporal-specific mechanisms of modifier genes, and prioritizing therapeutic compounds via chemical genetic tools. Several therapeutic target genes and related therapies have emerged, including a retinoic acid (RA)-based therapy for the early phase of AIC and an autophagy-based therapy that, for the first time, is able to reverse cardiac dysfunction in the late phase of AIC. We conclude that zebrafish is becoming an important in vivo model that would accelerate both mechanistic studies and therapeutic development of AIC.

Modeling Doxorubicin-Induced Cardiomyopathy With Fibrotic Myocardial Damage in Wistar Rats.

Cardiovascular complications, arising after anthracycline chemotherapy, cause a significant deterioration in the life quality and expectancy of those patients who were previously successfully treated for malignant neoplasms. A number of clinical studies have demonstrated that patients with cardiotoxicity manifested during anthracyclines therapy also have extensive fibrotic changes in the cardiac muscle in the long term. Given the lack of an unambiguous understanding of the mechanisms of fibrotic changes formation under doxorubicin treatment in the myocardium, there is the obvious necessity to create a relevant experimental model of chronic doxorubicin-induced cardiomyopathy with fibrotic myocardial lesions and delayed development of diastolic dysfunction. The study was divided into two stages: first stage (creation of acute doxorubicin cardiomyopathy) - 35 male Wistar rats; second stage (creation of chronic doxorubicin cardiomyopathy) - 40 male Wistar rats. The animals were split into eight groups (two control ones and six experimental ones), which determined the doxorubicin dose (first stage: 25, 20.4, 15 mg/kg; second stage: 5, 10, 15 mg/kg, intraperitoneally) and the frequency of injection. Echocardiographic, hematological, histological, and molecular methods were used to confirm the successful modeling of acute and chronic doxorubicin-induced cardiomyopathy with fibrotic lesions. A model of administration six times every other day with a cumulative dose of doxorubicin 20 mg/kg is suitable for evaluation of acute cardiotoxicity. The 15 mg/kg doxorubicin dose is highly cardiotoxic; what's more, it correlates with progressive deterioration of the clinical condition of the animals after 2 months. The optimal cumulative dose of doxorubicin leads to clinical manifestations confirmed by echocardiographic, histological, molecular changes associated with the development of chronic doxorubicin-induced cardiomyopathy with fibrotic lesions of the left ventricular of the cardiac muscle and ensure long-term survival of animals is 10 mg/kg doxorubicin. A dose of 5 mg/kg of the doxorubicin does not ensure the development of fibrous changes formation. We assume that cumulative dose of 10 mg/kg with a frequency of administration of six times in 2 days can be used to study the mechanisms of anthracycline cardiomyopathy development.

Ischemic stroke as the first manifestation of anthracycline cardiomyopathy

This article is devoted to the discussion of cardioembolic complications of anthracycline cardiomyopathy. The article describes a clinical case of cardiotoxicity caused by aggressive neoadjuvant chemotherapy in a patient with breast cancer and complicated by the development of cardioembolic ischemic stroke.

Abstract P3114: Intermittent Fasting Potentiates Anthracycline Cardiotoxicity

Background: Anthracyclines such as doxorubicin (Dox) cause cardiotoxicity and associated autophagic impairment, though controversy exists increasing autophagy ameliorates or exacerbates Dox cardiotoxicity. Because intermittent fasting (IF), a potent stimulus of autophagy, is presently under clinical investigation in multiple human clinical trials of cancer patients receiving chemotherapy, we tested whether IF would ameliorate or exacerbate Dox cardiotoxicity in multiple murine models. Methods: Chow-fed C57BL/6 mice (n=150) were randomized to ad libitum feeding ( adlib ) or IF (every other day) and treated with vehicle or Dox (5 mg/kg IP x 4 doses). Alternatively, to stimulate autophagy and lysosomal biogenesis transcriptionally, we employed adeno-associated virus 9 (AAV9)-driven overexpression of transcription factor EB (TFEB) vs null, followed by vehicle or Dox (n=40). We further analyzed TFEB nuclear content in myocardial tissue from patients with anthracycline cardiomyopathy vs non-failing donors and patients with other non-ischemic cardiomyopathies (n=17). Results: In Dox-treated mice (but not in vehicle controls), IF significantly reduced survival (18% absolute reduction or AR) ( figure A ), left ventricular ejection fraction (LVEF) (8% AR) ( figure B ) and heart weight index (12% relative reduction) ( figure C ) compared to adlib group. Mechanistically, in Dox-treated mice, IF significantly decreased phosphorylation of mammalian target of rapamycin, increased active, nuclear TFEB content, and increased levels of the atrophy factor muscle RING-finger protein-1. In myocardial tissue from patients with anthracycline cardiomyopathy, we observed a 3.5-fold increase (p<0.01) in nuclear TFEB content compared to both tissues from donors without heart failure and tissues from patients with other non-ischemic cardiomyopathies. Overexpression of TFEB exacerbated Dox-induced cardiotoxicity, including significant decreases in LVEF, left ventricular mass index, and survival. Conclusions: IF exacerbates Dox-related mortality and cardiomyopathy, likely by stimulating the autophagy-lysosomal transcriptional regulator TFEB. Our data raise concerns about the safety of IF and augmentation of TFEB activity in the context of anthracycline chemotherapy.

New advances in medical imaging technology for the evaluation of anthracycline-induced cardiotoxicity.

New advances in medical imaging technology for the evaluation of anthracycline-induced cardiotoxicity.

Health-Related Quality of Life in Adolescents and Young Adults with Heart Failure

<h3>Purpose</h3> In adult heart failure populations, health-related quality of life (HRQOL) is predictive of changes in health status and outcomes including mortality and hospitalization. Despite a growing population of pediatric and young adult patients with heart failure, HRQOL in this population has not been well described. This study aimed to describe self- and proxy-reported HRQOL in adolescents and young adults (AYA) with heart failure. <h3>Methods</h3> AYAs (12-24 years) with heart failure or a significant post-heart transplant complication and a caregiver were enrolled at a single center. AYA/parent dyads completed a self- or proxy-reported version of the PedsQL 4.0 Generic Core. Group comparisons based on primary cardiac diagnosis leading to heart failure were conducted. Patient demographic and disease characteristics were examined as correlates of HRQOL. <h3>Results</h3> 53 patient-caregiver dyads participated. Patients were 64% male; 76% White. Post-transplant with life threatening complication (26%), single ventricle heart disease (SVHD) (23%), anthracycline induced cardiomyopathy (21%) and dilated cardiomyopathy (DCM) (17%) were the most common diagnoses. Disease burden was high with 42% experiencing extra-cardiac disease and 34% having >11 hospitalizations. AYAs with transplant complications, SVHD, and DCM and their caregivers endorsed significantly impaired total HRQOL when compared to population norms. Conversely, AYAs with anthracycline cardiomyopathy and their caregivers reported normative HRQOL that was significantly better than the other diagnostic groups (p=0.04). Across all diagnostic groups, female sex (p=0.01) and white race (p=0.01) were associated with poorer physical functioning HRQOL. <h3>Conclusion</h3> Many AYAs with heart failure and their caregivers report impaired HRQOL, however certain cardiac diagnoses and demographic groups were associated with better reported HRQOL. Further studies are needed to understand mediators of risk for poor HRQOL in this population, as well as the role of potential resiliency focused interventions to improve HRQOL.

Cardiotoxicity of Cancer Treatments: Focus on Anthracycline Cardiomyopathy.

Significant progress has been made in developing new treatments and refining the use of preexisting ones against cancer. Their successful use and the longer survival of cancer patients have been associated with reports of new cardiotoxicities and the better characterization of the previously known cardiac complications. Immunotherapies with monoclonal antibodies against specific cancer-promoting genes, chimeric antigen receptor T cells, and immune checkpoint inhibitors have been developed to fight cancer cells, but they can also show off-target effects on the heart. Some of these cardiotoxicities are thought to be due to nonspecific immune activation and inflammatory damage. Unlike immunotherapy-associated cardiotoxicities which are relatively new entities, there is extensive literature on anthracycline-induced cardiomyopathy. Here, we provide a brief overview of the cardiotoxicities of immunotherapies for the purpose of distinguishing them from anthracycline cardiomyopathy. This is especially relevant as the expansion of oncological treatments presents greater diagnostic challenges in determining the cause of cardiac dysfunction in cancer survivors with a history of multiple cancer treatments including anthracyclines and immunotherapies administered concurrently or serially over time. We then provide a focused review of the mechanisms proposed to underlie the development of anthracycline cardiomyopathy based on experimental data mostly in mouse models. Insights into its pathogenesis may stimulate the development of new strategies to identify patients who are susceptible to anthracycline cardiomyopathy while permitting low cardiac risk patients to receive optimal treatment for their cancer.

Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician.

Today the pharmacological possibilities of treating cancer are expanding and as a result, life expectancy is increasing against the background of chemotherapy and supportive treatment. In the conditions of successful antitumor treatment, complications associated with its toxic effect on healthy tissues and organs began to come to the fore. Anthracycline cardiomyopathy was the first serious cardiovascular complication to draw the attention of oncologists and cardiologists around the world. Anthracycline drugs such as doxorubicin, epirubicin, idarubicin are still widely used in oncological practice to treat a wide range of solid and hematological malignancies. Doxorubicin-induced cardiomyopathy is closely associated with an increase in oxidative stress, as evidenced by reactive oxygen species (ROS) nduced damage such as lipid peroxidation, and decreased levels of antioxidants. Myofibrillar destruction and dysregulation of intracellular calcium are also important mechanisms, usually associated with doxorubicin-induced cardiotoxicity. Despite the abundance of data on various mechanisms involved in the implementation of doxorubicin-induced cardiotoxicity, a final understanding of the mechanism of the development of doxorubicin cardiomyopathy has not yet been formed. It poses the most significant challenges to the development of new methods of prevention and treatment, as well as to the unambiguous choice of a specific treatment regimen using the existing pharmacological tools. In order to resolve these issues new models that could reflect the development of the chemotherapy drugs effects are needed. In this review we have summarized and analyzed information on the main existing models of doxorubicin cardiomyopathy using small laboratory animals. In addition, this paper discusses further areas of research devoted to the development and validation of new improved models of doxorubicin cardiomyopathy suitable both for studying the mechanisms of its implementation and for the preclinical drugs effectiveness assessment.

The results of a single-center experience with HeartMate 3 in a biventricular configuration

Right ventricular (RV) failure after left ventricular assist device (VAD) implantation is a difficult problem. One solution is the implantation of continuous-flow VADs in a biventricular configuration. Disappointing survival and a concerning incidence of right-sided pump thrombosis have been previously reported. From May 2017 to April 2020, a total of 12 patients underwent implantation of HeartMate 3 (HM3) biventricular VADs (BiVADs) as a bridge to cardiac transplantation. The right-sided pump was implanted in the right atrium in all cases. Adverse events and patient outcomes were determined. Patients were male, and the mean age was 44 years. The etiology was dilated cardiomyopathy (6 patients), sarcoid heart disease (2 patients), ischemic cardiomyopathy (1 patient), anthracycline cardiomyopathy (1 patient), non-compaction cardiomyopathy (1 patient), and arrhythmogenic RV cardiomyopathy with biventricular involvement (1 patient). There was 1 death from multisystem failure. There were 3 episodes of right VAD thrombus (thrombosis or clot ingestion); 1 managed medically, 1 recognized intraoperatively treated with clot retrieval, and 1 requiring pump exchange. There were 3 driveline infections. At 18 months after the procedure, 5 patients (41.7%) had undergone cardiac transplantation, 5 patients (41.7%) were alive and on biventricular support, 1 patient had died (8.3%), and 1 patient had VAD explantation for myocardial recovery (8.3%). Actuarial survival at 18 months was 91.7%. In this small study, HM3 BiVAD in these critically ill patients was used with low mortality. This suggests that the timely deployment of biventricular support with HM3 can be associated with favorable outcomes.

Features of Myocardial Remodeling and Changes in the Blood Lipid Spectrum in Experimental Doxorubicin-Induced Cardiomyopathy and Atorvastatin Administration.

Structural myocardial reorganization and changes in the blood lipid spectrum in rats were studied after administration of a single sublethal dose of doxorubicin (15 mg/kg) alone and in combination with atorvastatin (20 mg/kg/day over 7 days). It was established that doxorubicin induced the development of dyslipidemia in experimental animals (the concentrations of total cholesterol, triglycerides, and VLDL increased by 2.2, 2.0, and 1.96 times, respectively; the atherogenic coefficient increased by 3.4 times by day 7 of the experiment). In animals with experimental anthracycline cardiomyopathy treated with atorvastatin, the concentrations of the main components of the blood lipid spectrum increased less markedly. Atorvastatin alone induces moderate myocardial remodeling in comparison with more pronounced changes in the structural organization of the myocardium in rats treated with doxorubicin alone. Course treatment with atorvastatin under conditions of doxorubicin-induced cardiomyopathy reduced the severity of myocardial remodeling: the decrease in the volume density of cardiomyocytes and the increase in the volume density of the connective tissue were less pronounced in the dynamics of the experiment.

Human-induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies.

Normal cardiac contractile and relaxation functions are critically dependent on a continuous energy supply. Accordingly, metabolic perturbations and impaired mitochondrial bioenergetics with subsequent disruption of ATP production underpin a wide variety of cardiac diseases, including diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, anthracycline cardiomyopathy, peripartum cardiomyopathy, and mitochondrial cardiomyopathies. Crucially, there are no specific treatments for preventing the onset or progression of these cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. Therefore, new treatments are needed to target the metabolic disturbances and impaired mitochondrial bioenergetics underlying these cardiomyopathies in order to improve health outcomes in these patients. However, investigation of the underlying mechanisms and the identification of novel therapeutic targets have been hampered by the lack of appropriate animal disease models. Furthermore, interspecies variation precludes the use of animal models for studying certain disorders, whereas patient-derived primary cell lines have limited lifespan and availability. Fortunately, the discovery of human-induced pluripotent stem cells has provided a promising tool for modelling cardiomyopathies via human heart tissue in a dish. In this review article, we highlight the use of patient-derived iPSCs for studying the pathogenesis underlying cardiomyopathies associated with metabolic perturbations and impaired mitochondrial bioenergetics, as the ability of iPSCs for self-renewal and differentiation makes them an ideal platform for investigating disease pathogenesis in a controlled in vitro environment. Continuing progress will help elucidate novel mechanistic pathways, and discover novel therapies for preventing the onset and progression of heart failure, thereby advancing a new era of personalized therapeutics for improving health outcomes in patients with cardiomyopathy.