Chemotherapy-induced Cardiomyopathy Research Articles

Left ventricular ejection fraction and myocardial fibrosis in survivors of ventricular fibrillation and ventricular tachycardia

Abstract Background Primary prevention implantable cardioverter defibrillator (ICD) therapy is indicated in patients with a LVEF<35%. Increasing evidence suggests that LVEF is a poor predictor or ventricular arrhythmias, such as ventricular tachycardia (VT) or fibrillation (VF). Methods Patients hospitalized for VF (55.4%) or VT with hemodynamic compromise underwent late gadolinium enhancement cardiovascular magnetic resonance (CMR). Patients with congenital heart disease, channelopathies, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and chemotherapy-induced cardiomyopathy were excluded. Results Among patients (n=111, aged 62.1 ± 14.6 years [mean ± SD]) hospitalized for VF (55.4%) or VT with hemodynamic compromise (44.5%) only 29/111 (43.6%) had a history of cardiac disease. At the index hospitalization, an ischemic cause was identified in 69.3%, a non-ischemic cause in 24.8% and no cause emerged in 5.9%. The LVEF (39.1 ± 17.2%) was ≤35% in 55.4% and >35% in 44.6%. Myocardial fibrosis was present in 85.1% (LVEF≤35%: 91.1%; LVEF>35%: 77.8%; p = 0.0619). Conclusions A large proportion of sustained VT or VF survivors would not have previously met LVEF primary prevention criteria for ICD therapy. In this 'ICD treatment gap', myocardial fibrosis was more prevalent than a LVEF≤35%. Further studies are needed to determine whether myocardial scar rather than LVEF≤35% should be used as an indication for primary prevention ICD therapy.

(325) - The Long-Term Outcomes of Patients with Chemotherapy-Induced Cardiomyopathy Undergoing Heart Transplantation

(325) - The Long-Term Outcomes of Patients with Chemotherapy-Induced Cardiomyopathy Undergoing Heart Transplantation

“Inherited cardiovascular disease mindset” can identify concealed inherited conditions at cardio-oncology evaluation: An opportunistic screening.

IntroductionBaseline cardiovascular (CV) risk stratification is recommended in all cancer patients. Integrating all clinical information (personal/family history, ECG and echocardiogram) can properly identify high-risk patients. We aimed to evaluate the concealed inherited CV conditions detected in mandatory CV screening performed at a Cardio-Oncology Unit. Methodsretrospective study of all consecutive cancer patients referred to the Cardio-Oncology Unit for CV evaluation (2020−2023). Inherited CV conditions diagnosis and genetic testing was performed according to guidelines. Results1984 cancer patients underwent CV screening. Sanger sequencing was indicated in 1 patient, excluding the genetic family disease. NGS sequencing was performed in 11 cancer patients with normal left ventricular ejection fraction (LVEF): 2 due to aortic syndrome evaluation (identifying 1 vascular Ehrler-Danlos syndrome due to COL3A1 p.Arg242Ter), 4 channelopathies (2 Long QT syndrome and 2 Brugada's), 4 hypertrophic cardiomyopathies and 1 non-dilated left ventricular cardiomyopathy (NDLVC). Among the 12 patients with reduced LVEF, one was diagnosed with NDLVC, and chemotherapy-induced dilated cardiomyopathy was only ascribable in 3 of them. ConclusionIntegrating clinical information at mandatory baseline CV toxicity risk cardio-oncology evaluation, can identify high-risk cancer patients with concealed inherited conditions. Keeping an “inherited cardiovascular disease-oriented mindset” to implement opportunist screenings is encouraged.

Comparison of Cardioprotective Effects of Dapagliflozin and Trimetazidine in the Model of Doxorubicin-Cyclophosphamide Cardiotoxicity

Background: Data published by task groups of the Ministry of Health of the Russian Federation, the European Society of Cardiology, and other medical associations and institutions show that chemotherapy-induced cardiomyopathy is still a challenging issue that requires further research.Objective: To compare the cardioprotective potential of trimetazidine and dapagliflozin in a rat model of doxorubicin-cyclophospha-mide cardiomyopathy.Materials and methods: Our randomized in vivo experimental study included 80 Wistar female rats. Doxorubicin and cyclophosphamide were administered at a dose of 15 mg/kg and 150 mg/kg, respectively. Trimetazidine (42 mg/kg) and dapagliflozin (14 mg/kg) were additionally administered to groups 3 and 4, respectively. The total duration of the experiment was 14 days.Results: Doxorubicin+cyclophosphamide mode of chemotherapy induces the development of toxic-ischemic cardiomyopathy. The trimetazidine and dapagliflozin administration was accompanied by stabilization of cardiovascular parameters. Comparison of both drugs’ cardioprotective properties revealed a clear advantage of dapagliflozin over trimetazidine, especially in terms of such an important indicator as N-terminal pro-B-type natriuretic peptide.Conclusions: Further research aimed at exploring the cardioprotective potential of dapagliflozin against cardiovascular complications of chemotherapy is justified from a pathogenetic point of view.

Effect of vitamin D receptor genetic polymorphism on the clinical response to angiotensin converting enzyme inhibitors therapy among breast cancer patients with chemotherapy induced cardiomyopathy

Abstract Background Blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone treatment of chemotherapy induced cardiomyopathy (CIC) yet, variability in response to angiotensin converting enzyme inhibitors (ACEIs) acting on the RAAS is well-documented. Vitamin D was found to play a role in regulating RAAS. Previous studies revealed an inverse relationship between levels of vitamin D in serum and RAAS activation. Purpose The current study is primarily to evaluate the association between genetic variants in the vitamin D receptor (VDR) and clinical response to ACEIs among breast cancer patients receiving chemotherapy with CIC. Methods A total of 60 breast cancer patients with CIC (mean ejection fraction 30%) on β-blocker therapy were started on a ACEIs and followed for 6 months. Post-ACEIs-treatment changes in ejection fraction (EF) and serum potassium (K) were evaluated. We genotyped VDR gene polymorphisms including; ApaI (rs7975232), TaqI (rs731236), BsmI (rs1544410) and FokI (rs2228570) variants using TaqMan technique. Stepwise linear regression was performed to identify genetic and clinical factors associated with variability in ACEIs response, with adjustment for all potential confounding covariates. Results BsmI (rs1544410) (CT) heterozygous and TaqI (rs731236) (GA) genotypes had a significant increase in EF (12.8% and 10.8 %, respectively) and serum K (1.1 mEq/L and 0.91 mEq/L respectively); adjusted-p = 0.0001 and 0.004 for ∆EF and adjusted-p = 0.005 and 0.002 for ∆K. In contrast, (AA) homozygous carriers of the ApaI SNP (rs7975232) had a smaller increase in EF (∆EF = 1.2%) and K (∆K = 0.1 mEq/L) compared to (CA) (∆EF = 6.5%, ∆K = 0.73mEq/L) and (CC) (∆EF = 9%, ∆K = 0.9mEq/L) carriers; adjusted-p = 0.003 for ∆EF, adjusted-p = 0.004 for ∆K. Finally, for the FokI SNP (rs2228570), there was no significant change in EF and serum K level. Conclusion The results from this study highlight that BsmI (rs1544410) and TaqI (rs731236) are strong predictors of response to ACEIs therapy in chemotherapy-induced cardiomyopathy (CIC).

Possibilities of dapagliflozin-induced cardioprotection on doxorubicin + cyclophosphamide mode of chemotherapy-induced cardiomyopathy

RationaleThe global burden of cardiovascular (CV) and oncological diseases continues to increase. In this regard, the prevention of CV diseases (CVD) before and after cancer treatment is an urgent and unsolved problem in medicine. For this reason, our research group aimed to investigate the possibility of dapagliflozin-related cardioprotection, using an experimental model of chronic Doxorubicin (Adriamycin) + Cyclophosphamide (AC)-mode of chemotherapy-induced cardiomyopathy. ObjectiveThe redox balance, lipid metabolism, endothelial dysfunction, and myocardial damage parameters were measured to evaluate the pathways of dapagliflozin-induced stabilization of CV homeostasis. MethodsFor this study, 80 inbred Wistar rats were randomly assigned to four equally sized groups. A model of chronic cardiotoxicity was attained by using doxorubicin and cyclophosphamide co-administration. In the case, the markers of redox-balance, cholesterol metabolism, endothelial dysfunction, myocardial alteration, and morphological examination were assessed. ResultsFor all parameters, statistically significant deviations were obtained, emphasizing the sequel of AC-mode chemotherapy-related detergent effect on CV system (group 2). Moreover, the data obtained from dapagliflozin-treated groups (group 3) showed that this strategy provide limitation of lipid peroxidation, cholesterol metabolism and endothelial function normalization, with subsequent morphological preservation of myocardium. ConclusionDapagliflozin has a broad spectrum of pleiotropic influences, namely cholesterol-lowering, anti-inflammatory, and endothelium-stabilizing properties. These properties provide a favorable environment for the prevention of chemotherapy-related cardiomyopathy.

Therapeutic potential of extracellular vesicles derived from cardiac progenitor cells in rodent models of chemotherapy-induced cardiomyopathy.

Current treatments of chemotherapy-induced cardiomyopathy (CCM) are of limited efficacy. We assessed whether repeated intravenous injections of human extracellular vesicles from cardiac progenitor cells (EV-CPC) could represent a new therapeutic option and whether EV manufacturing according to a Good Manufacturing Practices (GMP)-compatible process did not impair their bioactivity. Immuno-competent mice received intra-peritoneal injections (IP) of doxorubicin (DOX) (4 mg/kg each; cumulative dose: 12 mg/kg) and were then intravenously (IV) injected three times with EV-CPC (total dose: 30 billion). Cardiac function was assessed 9-11 weeks later by cardiac magnetic resonance imaging (CMR) using strain as the primary end point. Then, immuno-competent rats received 5 IP injections of DOX (3 mg/kg each; cumulative dose 15 mg/kg) followed by 3 equal IV injections of GMP-EV (total dose: 100 billion). Cardiac function was assessed by two dimensional-echocardiography. In the chronic mouse model of CCM, DOX + placebo-injected hearts incurred a significant decline in basal (global, epi- and endocardial) circumferential strain compared with sham DOX-untreated mice (p = 0.043, p = 0.042, p = 0.048 respectively) while EV-CPC preserved these indices. Global longitudinal strain followed a similar pattern. In the rat model, IV injections of GMP-EV also preserved left ventricular end-systolic and end-diastolic volumes compared with untreated controls. Intravenously-injected extracellular vesicles derived from CPC have cardio-protective effects which may make them an attractive user-friendly option for the treatment of CCM.

Nanotechnology Approaches for Prevention and Treatment of Chemotherapy-Induced Neurotoxicity, Neuropathy, and Cardiomyopathy in Breast and Ovarian Cancer Survivors.

Nanotechnology has emerged as a promising approach for the targeted delivery of therapeutic agents while improving their efficacy and safety. As a result, nanomaterial development for the selective targeting of cancers, with the possibility of treating off-target, detrimental sequelae caused by chemotherapy, is an important area of research. Breast and ovarian cancer are among the most common cancer types in women, and chemotherapy is an essential treatment modality for these diseases. However, chemotherapy-induced neurotoxicity, neuropathy, and cardiomyopathy are common side effects that can affect breast and ovarian cancer survivors quality of life. Therefore, there is an urgent need to develop effective prevention and treatment strategies for these adverse effects. Nanoparticles (NPs) have extreme potential for enhancing therapeutic efficacy but require continued research to elucidate beneficial interventions for women cancer survivors. In short, nanotechnology-based approaches have emerged as promising strategies for preventing and treating chemotherapy-induced neurotoxicity, neuropathy, and cardiomyopathy. NP-based drug delivery systems and therapeutics have shown potential for reducing the side effects of chemotherapeutics while improving drug efficacy. In this article, the latest nanotechnology approaches and their potential for the prevention and treatment of chemotherapy-induced neurotoxicity, neuropathy, and cardiomyopathy in breast and ovarian cancer survivors are discussed.

Redox Signaling in Doxorubicin-Induced Ferroptosis

Doxorubicin is among the most widely used anticancer drugs; however, its clinical use is associated with cardiomyopathy and heart failure. Studies show ferroptosis as a pivotal form of cell death underlying doxorubicin cardiomyopathy. Recently, multiple redox signaling pathways have been discovered to underly doxorubicin-induced ferroptosis. This Cutting-Edge Research Highlights discusses these latest advances, focusing on pathways involving Nrf2/HO-1, GPx4, and Alas1/heme synthesis. (First online: February 19, 2023) REFERENCES Zhu H, Sarkar S, Scott L, Danelisen I, Trush MA, Jia Z, et al. Doxorubicin Redox biology: redox cycling, topoisomerase inhibition, and oxidative stress. React Oxyg Species (Apex) 2016; 1(3):189–98. doi: https://dx.doi.org/10.20455/ros.2016.835 Higgins AY, O'Halloran TD, Chang JD. Chemotherapy-induced cardiomyopathy. Heart Fail Rev 2015; 20(6):721–30. doi: https://dx.doi.org/10.1007/s10741-015-9502-y Page RL, 2nd, O'Bryant CL, Cheng D, Dow TJ, Ky B, Stein CM, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation 2016; 134(6):e32–69. doi: https://dx.doi.org/10.1161/CIR.0000000000000426 Fang X, Wang H, Han D, Xie E, Yang X, Wei J, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci USA 2019; 116(7):2672–80. doi: https://dx.doi.org/10.1073/pnas.1821022116 Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5):1060–72. doi: https://dx.doi.org/10.1016/j.cell.2012.03.042 Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 2016; 113(34):E4966–75. doi: https://dx.doi.org/10.1073/pnas.1603244113 Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 2017; 13(1):81–90. doi: https://dx.doi.org/10.1038/nchembio.2238 Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Naga Prasad SV, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 2014; 124(2):617–30. doi: https://dx.doi.org/10.1172/JCI72931 Tadokoro T, Ikeda M, Ide T, Deguchi H, Ikeda S, Okabe K, et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 2020; 5(9). doi: https://dx.doi.org/10.1172/jci.insight.132747 Abe K, Ikeda M, Ide T, Tadokoro T, Miyamoto HD, Furusawa S, et al. Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis. Sci Signal 2022; 15(758):eabn8017. doi: https://dx.doi.org/10.1126/scisignal.abn8017

Hippo pathway activation mediates chemotherapy-induced anti-cancer effect and cardiomyopathy through causing mitochondrial damage and dysfunction.

Rationale: Chemotherapy is a common clinical strategy for cancer treatment. However, the accompanied cardiomyopathy renders cancer patients under risk of another life-threatening condition. Whereas Hippo pathway is known to play key roles in both cancerogenesis and heart disease, it remains unclear whether Hippo pathway activation mediates chemotherapy-induced cardiomyopathy. Methods and Results: In human breast cancer cells, doxorubicin (DOX) significantly induced upregulation of Hippo kinase Mst1, inhibitory phosphorylation of YAP, mitochondrial damage, reduced cell viability and increased apoptosis. Hippo pathway inactivation by Mst1-siRNA transfection effectively improved cell survival and mitigated mitochondrial damage and cell apoptosis. Another anti-cancer drug YAP inhibitor verteporfin also induced lower cancer cell viability, apoptosis and mitochondrial injury. Chronic treatment with DOX in vivo (4 mg/kg/week for 6 weeks) caused mitochondrial damage and dysfunction, oxidative stress and cardiac fibrosis, while acute DOX treatment (16 mg/kg single bolus) also induced myocardial oxidative stress and mitochondrial abnormalities. Chronic treatment with verteporfin (2 months) resulted in cardiomyopathy phenotypes comparable to that by chronic DOX regimen. In transgenic mice with cardiac overexpression of kinase-dead mutant Mst1 gene, these adverse cardiac effects of DOX were significantly attenuated relative to wild-type littermates. Conclusions: Anti-cancer action of both DOX and verteporfin is associated with Hippo pathway activation. Such action on cardiac Hippo pathway mediates mitochondrial damage and cardiomyopathy.

Association of Neurohormonal Antagonists on Incident Cardiotoxicity in Patients With Breast Cancer

Cardiovascular disease is the leading cause of mortality among breast cancer survivors. Anthracyclines and trastuzumab have been associated with an increased risk of cardiotoxicity, requiring close follow-up for signs of clinical heart failure or asymptomatic left ventricular systolic dysfunction. Whether neurohormonal antagonism with angiotensin-converting enzyme inhibitor (ACE-I), angiotensin receptor blockers (ARBs), or β-blockers can prevent the development of chemotherapy-induced cardiomyopathy in this population remains unknown. We studied 459 women who were diagnosed with breast cancer at our medical center from January 2014 to December 2021 and evaluated baseline characteristics, oncologic treatment, and outcomes. The primary end point was the development of cardiotoxicity, defined as symptomatic decline in ejection fraction of ≥5% below 55% or an asymptomatic decline of ≥10% after treatment with chemotherapy. Patients who were exposed to neurohormonal antagonists were more likely to have hypertension, hyperlipidemia, and diabetes. There was an increased risk of cardiotoxicity noted for patients who were older (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.01 to 1.1), smokers within the past 10years (HR 2.54, 95% CI 1.41 to 4.6), or who received a combination of both trastuzumab and anthracycline therapy (HR 2.52, 95% CI 1.01 to 6.3). Over a median follow-up of 12months, there were no significant protective benefits noted for patients who were taking ACE-I/ARBs (HR 0.49, 95% CI 0.17 to 1.4), β-blockers (HR 0.50, 95% CI 0.16 to 1.6), or both (HR 1.30, 95% CI 0.44 to 3.9). In conclusion, previous use of ACE-I/ARBs and β-blockers, separately or in combination, was not associated with a reduction in the development of cardiotoxicity in patients receiving anthracycline or trastuzumab therapies. Older age, smoking, and combination chemotherapy were found to be associated with an increased risk.

Abstract 15276: Polygenic Susceptibility to Dilated Cardiomyopathy Underlies Peripartum, Alcoholic, and Chemotherapy-Induced Cardiomyopathies

Introduction: Rare (monogenic) variants linked to dilated cardiomyopathy (DCM) are enriched among individuals with peripartum (PPCM), alcoholic (ACM), and chemotherapy-induced cardiomyopathies (CCM), but are present in <15% of cases. Whether a common-variant (polygenic) susceptibility to DCM is also shared across these secondary cardiomyopathies is unknown. Methods: Cases of DCM, PPCM, ACM, and CCM were adjudicated using hospital billing codes only (in UK Biobank), or with additional chart reviews conducted by 2 medical doctors blinded to the genetic data (in Mass General Brigham [MGB] Biobank). A DCM polygenic score predicated on imaging-based measures of left ventricular structure and function was tested for association with each condition. In a subset of MGB Biobank participants with whole exome sequencing data, we determined the proportion of cases with a monogenic variant and/or a high (≥90 th percentile) polygenic score. Results: In MGB Biobank (n=30,837) and UK Biobank (n=304,687), 193 cases of PPCM (n=18), ACM (n=127) or CCM (n=48) were identified. A DCM polygenic score comprising 2.3 million common genetic variants associated comparably with DCM and all three secondary cardiomyopathies (meta-analyzed p<0.001 for all) ( Figure ). Among chart-validated phenotypes in MGB Biobank, cases had higher median polygenic score percentiles than controls (Controls=50; DCM=68; PPCM=86; ACM=70; CCM=59), and a high polygenic score conferred 3.3-fold odds of any secondary cardiomyopathy (p<0.001). In the whole exome sequencing subset (N=21,378; n=65 secondary cardiomyopathy cases), 9.2% of secondary cardiomyopathy cases harbored a monogenic variant, while 21.5% had a high polygenic score (including 1.5% who had both). Conclusion: Individuals with PPCM, ACM, and CCM are enriched for a high DCM polygenic score, further suggesting that these conditions arise from unique, extrinsic insults acting in the context of a common, underlying genetic susceptibility.

Abstract 15243: Incidence and Predictors of Chemotherapy-Induced Cardiomyopathy in African Americans: A Single-Center Experience

Introduction: African Americans (AA) have largely been under-represented in randomized clinical trials investigating chemotherapy-induced cardiomyopathy (CICM) associated with doxorubicin and trastuzumab. Limited and conflicting evidence has linked higher incidence of CICM among AA patients to a higher prevalence of underlying co-morbidities. Hypothesis: African Americans have a higher incidence of CICM which is associated with higher prevalence of underlying co-morbidities in these patients. Methods: We retrospectively identified and included AA patients who underwent treatment with doxorubicin and trastuzumab at our institution. CICM was defined as a decline in ejection fraction (EF) to <50% OR >/=10% decline in baseline EF post-treatment. A univariate analysis was performed to study the association of common co-morbidities with CICM. JMP software (SAS v 9.4) was used for statistical analysis. Results: A total of 121 patients were included for analysis, out of which, 52.1% (63/121) and 47.9% (58/121) were treated with trastuzumab and doxorubicin respectively. Majority (85.1%, 103/121) were females and the mean age was 62.4±5.2 years. Median EF pre- and post-treatment were 65% (IQR 60%,65%) and 60% (IQR 55%,65%) respectively. The cumulative incidence of CICM in our cohort was 24% (29/121). There was no statistically significant association of CICM with female sex [OR=0.79 (0.25-2.99), p=0.68], age [OR=0.99 (0.96-1.02), p=0.88], pre-treatment EF [OR=1.09 (0.96-1.94), p=0.27], hypertension [OR=1.27 (0.51-3.18), p=0.60], diabetes [OR=1.91 (0.89-4.95), p=0.13], hyperlipidemia [OR=1.19 (0.44-2.92), p=0.78] or coronary artery disease [OR=1.93 (0.68-5.93), p=0.21]. Conclusions: Per existing literature, the incidence of CICM in our cohort of AA patients is higher than general population. As historically postulated, CICM was not found to be associated with pre-existing co-morbidities. Further clinical and translational research is needed to study genetic and pathophysiological mechanisms driving CICM in AA patients.

Abstract 9563: Intravenously Infused Extracellular Vesicles Preserve Function of Anthracycline-Treated Hearts

Introduction: Current treatments of chemotherapy-induced cardiomyopathy (CCM) are of limited efficacy. Hypothesis: Extracellular vesicles (EV) might represent a new therapeutic option. Methods: Male immunocompetent mice were subjected to 3 intraperitoneal (IP) injections of doxorubicin (DOX, 4mg/kg) followed by 3 sequential intravenous injections of EV (10x10 9 /injection) collected from human induced pluripotent stem cell (hiPSC)-differentiated cardiovascular progenitor cells. Outcomes were assessed 8-11 weeks after the onset of DOX treatment on MRI and compared with those of mice injected with saline (controls) or DOX-untreated (sham). Explanted hearts were subjected to transcriptomics. Next, female rats received 5 IP injections of DOX (3mg/kg) followed by 3 IV injections of EV (33x10 9 /injection) similar to those of the mouse study except that they had been GMP-manufactured to be of clinical grade. Control rats were saline-injected or DOX-untreated (sham). Outcomes were assessed 1 month after the onset of DOX treatment on echocardiography. In additional in vitro experiments, hiPSC-derived cardiomyocytes were stressed by DOX w/wo EV and assessed for ATP content. Results: In mice, DOX+saline-injected hearts (n=14) incurred a significant decline in basal (global, epi- and endocardial) circumferential strain compared with the 14 sham mice (p=0.04 for each) while EV (n=11) preserved these indices which did not significantly differ from those of sham mice. Global longitudinal strain followed a similar pattern. EV also upregulated genes involved in the limitation of cardiac remodeling and preservation of contractile function. In rats, LV endsystolic volumes were significantly increased in saline-injected hearts (n=11) compared with the 6 sham (p=0.03) but were preserved after EV injections (n=12). Likewise, the percentages of "responder" rats which did not increase their enddiastolic LV volumes by more than 5% from their post-DOX pre-treatment values were 58% vs . 28% in EV- and saline-injected hearts, respectively. In vitro , EV increased ATP levels of DOX-stressed cardiomyocytes by 30% compared to placebo. Conclusions: The cardioprotective effects of IV-injected EV make them an attractive user-friendly option for the treatment of CCM.

Natural history and clinical parameters of chemotherapy-induced dilated cardiomyopathy

Abstract Background Chemotherapy-induced dilated cardiomyopathy (CI-DCM) is a well-recognized phenotype of non-ischemic dilated cardiomyopathy (DCM), characterized by poor outcomes. However, a detailed comparison between idiopathic DCM (iDCM) and CI-DCM is still lacking. Methods All consecutive DCM patients enrolled in the Trieste Muscle Heart Disease Registry were analyzed. CI-DCM and iDCM were defined according to current recommendations. The primary study outcome measure was all-mortality death and secondary outcomes were a) a composite of cardiovascular death/heart-transplantation/ventricular-assist-device implantation, and b) major ventricular arrhythmias. Results The study included 551 patients (499 iDCM and 52 CI-DCM). At enrolment, compared to iDCM, CI-DCM patients were older (51±14 years vs 58±3 years respectively, p<0.001) and had a higher left ventricular ejection fraction (35%±10 vs 32%±9, p=0.03). Over a median follow-up of 90 months (IQR 54–140 months), CI-DCM patients had a higher incidence of all-cause mortality compared to iDCM (36.5% vs 8.4% in CI-DCM and iDCM respectively, p<0.001), while the incidence of major ventricular arrhythmias was higher in the iDCM group compared to CI-DCM (4% vs 0%, in CI-DCM and iDCM respectively, p=0.03). The risk of the composite outcome was comparable between the two groups (p=0.91). At Cox multivariable analysis, the diagnosis of CI-DCM emerged as independently associated to primary outcome (HR 6.42, 95% CI 2.52–16.31, p<0.001). Conclusions In a well-selected DCM cohort, patients with a chemotherapy-induced aetiology had a higher incidence of all-cause mortality compared to iDCM. Conversely, the incidence of life-threatening ventricular arrhythmic events was higher among patients with iDCM. Funding Acknowledgement Type of funding sources: None.

The International thoracic organ transplant registry of the international society for heart and lung transplantation: Thirty-ninth adult heart transplantation report-2022; focus on transplant for restrictive heart disease.

This 39th annual international adult heart transplant report focuses on transplantation for heart disease with restrictive physiology, that is, restrictive cardiomyopathies and hypertrophic cardiomyopathy, based on data submitted to the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant (TTX) Registry between January 1992 and June 2018. Restrictive cardiomyopathy (RCM) refers to a heterogeneous group of cardiomyopathies that includes amyloid, sarcoid, radiation and/or chemotherapy-induced cardiomyopathy, and other types of heart disease that all share restrictive physiology, and reduced or normal diastolic and systolic volumes in 1 or both ventricles.

Clinical characterization and natural history of chemotherapy-induced dilated cardiomyopathy.

Chemotherapy-induced dilated cardiomyopathy (CI-DCM) is a well-recognized phenotype of non-ischemic dilated cardiomyopathy (DCM), characterized by poor outcomes. However, a detailed comparison between idiopathic DCM (iDCM) and CI-DCM is still lacking. All consecutive DCM patients enrolled in the Trieste Muscle Heart Disease Registry were analysed. CI-DCM and iDCM were defined according to current recommendations. The primary study outcome measure was all-mortality death and secondary outcomes were a) a composite of cardiovascular death/heart-transplantation/ventricular-assist-device implantation, and b) major ventricular arrhythmias. The study included 551 patients (499 iDCM and 52 CI-DCM). At enrolment, compared with iDCM, CI-DCM patients were older (51±14years vs. 58±3years, respectively, P<0.001) and had a higher left ventricular ejection fraction (32%±9 vs. 35%±10, respectively, P=0.03). Over a median follow-up of 90months (IQR 54-140months), CI-DCM patients had a higher incidence of all-cause mortality compared with iDCM (36.5% vs. 8.4% in CI-DCM and iDCM respectively, P<0.001), while the incidence of major ventricular arrhythmias was higher in the iDCM group compared with CI-DCM (4% vs. 0%, in CI-DCM and iDCM respectively, P=0.03). The risk of the composite outcome was comparable between the two groups (P=0.91). At Cox multivariable analysis, the diagnosis of CI-DCM emerged as independently associated to primary outcome (HR 6.42, 95% C.I. 2.52-16.31, P<0.001). In a well-selected DCM cohort, patients with a chemotherapy-induced aetiology had a higher incidence of all-cause mortality compared with iDCM. Conversely, the incidence of life-threatening ventricular arrhythmic events was higher among patients with iDCM.

Oncologic emergencies and urgencies: A comprehensive review

Patients with advanced cancer generate 4 million visits annually to emergency departments (EDs) and other dedicated, high-acuity oncology urgent care centers. Because of both the increasing complexity of systemic treatments overall and the higher rates of active therapy in the geriatric population, many patients experiencing acute decompensations are frail and acutely ill. This article comprehensively reviews the spectrum of oncologic emergencies and urgencies typically encountered in acute care settings. Presentation, underlying etiology, and up-to-date clinical pathways are discussed. Criteria for either a safe discharge to home or a transition of care to the inpatient oncology hospitalist team are emphasized. This review extends beyond familiar conditions such as febrile neutropenia, hypercalcemia, tumor lysis syndrome, malignant spinal cord compression, mechanical bowel obstruction, and breakthrough pain crises to include a broader spectrum of topics encompassing the syndrome of inappropriate antidiuretic hormone secretion, venous thromboembolism and malignant effusions, as well as chemotherapy-induced mucositis, cardiomyopathy, nausea, vomiting, and diarrhea. Emergent and urgent complications associated with targeted therapeutics, including small molecules, naked and drug-conjugated monoclonal antibodies, as well as immune checkpoint inhibitors and chimeric antigen receptor T-cells, are summarized. Finally, strategies for facilitating same-day direct admission to hospice from the ED are discussed. This article not only can serve as a point-of-care reference for the ED physician but also can assist outpatient oncologists as well as inpatient hospitalists in coordinating care around the ED visit.

Factors associated with the recovery of chemotherapy induced cardiomyopathy in HER2 overexpressing breast cancer

Objective: Chemotherapy induced cardiomyopathy (CI-CMP) is an important and potentially deadly complication of chemotherapy. However, factors associated with the recovery of CI-CMP have not been studied adequately so far. In this study, determinants of the recovery of CI-CMP in HER2 overexpressing breast cancer patients who received a chemotherapy regimen consisting of Doxorubicin, Trastuzumab, Paclitaxel and Cyclophosphamide and developed CI-CMP were investigated. Material and Methods: 88 patients with CI-CMP among 1.410 HER2 positive breast cancer patients were enrolled and followed up for a median of 64 months. A multivariate logistic regression analysis model was used to assess the association between recovery of CI-CMP and other variables Results: The median age of the participants was 52, and similar between groups. CI-CMP was recovered in 52 patients (59.1 %). Hypertension, diabetes mellitus, clinical heart failure, ECG anomaly, visceral metastasis, heart rate and blood glucose were significantly lower in recovered patients. A multivariate logistic regression analysis revealed that diabetes mellitus (OR 0.030, CI 0.010-0.083, p&lt;0.001), heart rate (OR 0.799, CI 0.700-0.913, p&lt;0.001), minimum LVEF during follow-up (OR 1.115, CI 1.015-1.223, p=0.03), development of clinical heart failure (OR 0.238, CI 0.098-0.876, p=0.022) and visceral metastasis (OR 0.022, CI 0.002-0.226, p=0.001) were independent predictors of the recovery of CI-CMP. Conclusion: According to our results, Diabetes mellitus, heart rate, minimum LVEF during follow-up, development of clinical heart failure, and presence of visceral metastasis were independently associated with the recovery of CI-CMP. Particularly, relationship between diabetes and recovery of CI-CMP is notable and deserves further research.

Ventricular assist device support for children with chemotherapy-induced cardiomyopathy and advanced heart failure: Perspectives gained from a single-center experience.

Guidance and data on ventricular assist device (VAD) support for children with chemotherapy-induced cardiomyopathy, particularly within the first 2years after chemotherapy, are limited. We performed a single-center retrospective case series, reviewing medical records of children <18years of age with chemotherapy-induced cardiomyopathy and advanced heart failure (HF) who received durable VAD support. Six patients met inclusion criteria-5 HeartWare™ HVAD, 1 Berlin Heart EXCOR® . Median age at cancer diagnosis was 6years (IQR 4.5-10years). Median dose of anthracycline received was 540mg/m2 (IQR 450-630mg/m2 ). All patients developed HF within 1year after initiation of cancer treatment (median 8months, IQR 6-11.5months) and were initiated on durable VAD support at a median of 8months after completion of cancer treatment (IQR 3.3-43.5months). Four patients had significant right ventricular dysfunction needing oral pulmonary vasodilator therapy, one patient had a major bleeding complication, and two patients had thromboembolic strokes while on VAD support. Median duration of VAD support was 7.5months (IQR 3-11.3months). Two patients underwent VAD explant due to recovery of LV function, one died due to cancer progression, and three underwent heart transplantation. Durable VAD support should be considered as a therapeutic option for children who have advanced HF due to chemotherapy-induced cardiomyopathy, even within 2years of completing cancer treatment. A multi-disciplinary approach is essential for appropriate patient selection prior to implant and to ensure comprehensive care throughout the duration of VAD support.