ABSTRACT

Genetic cardiomyopathies are a group of inherited disorders in which myocardial structure and function are damaged. Many of these pathologies are rare and present with heterogenous phenotypes, thus personalized models are required to completely uncover their pathological mechanisms and develop valuable therapeutic strategies. Both cardiomyocytes and fibroblasts, differentiated from patient-specific human induced pluripotent stem cells, represent the most studied human cardiac cell models in the context of genetic cardiomyopathies. While endothelial dysfunction has been recognized as a possible pathogenetic mechanism, human induced pluripotent stem cell-derived endothelial cells are less studied, despite they constitute a suitable model to specifically dissect the role of the dysfunctional endothelium in the development and progression of these pathologies. In this review, we summarize the main studies in which human induced pluripotent stem cell-derived endothelial cells are used to investigate endothelial dysfunction in genetic-based cardiomyopathies to highlight new potential targets exploitable for therapeutic intervention, and we discuss novel perspectives that encourage research in this direction.

PMID:37538375 | PMC:PMC10394630 | DOI:10.3389/fphys.2023.1237101

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PubMed articles on: Cardio-Oncology

Accelerated cystogenesis by dietary protein load is dependent on, but not initiated by kidney macrophages

Front Med (Lausanne). 2023 Jul 19;10:1173674. doi: 10.3389/fmed.2023.1173674. eCollection 2023.

ABSTRACT

BACKGROUND: Disease severity of autosomal dominant polycystic kidney disease (ADPKD) is influenced by diet. Dietary protein, a recognized cyst-accelerating factor, is catabolized into amino acids (AA) and delivered to the kidney leading to renal hypertrophy. Injury-induced hypertrophic signaling in ADPKD results in increased macrophage (MФ) activation and inflammation followed by cyst growth. We hypothesize that the cystogenesis-prompting effects of HP diet are caused by increased delivery of specific AA to the kidney, ultimately stimulating MФs to promote cyst progression.

METHODS: Pkd1flox/flox mice with and without Cre (CAGG-ER) were given tamoxifen to induce global gene deletion (Pkd1KO). Pkd1KO mice were fed either a low (LP; 6%), normal (NP; 18%), or high (HP; 60%) protein diet for 1 week (early) or 6 weeks (chronic). Mice were then euthanized and tissues were used for histology, immunofluorescence and various biochemical assays. One week fed kidney tissue was cell sorted to isolate tubular epithelial cells for RNA sequencing.

RESULTS: Chronic dietary protein load in Pkd1KOmice increased kidney weight, number of kidney infiltrating and resident MФs, chemokines, cytokines and cystic index compared to LP diet fed mice. Accelerated cyst growth induced by chronic HP were attenuated by liposomal clodronate-mediated MФ depletion. Early HP diet fed Pkd1KO mice had larger cystic kidneys compared to NP or LP fed counterparts, but without increases in the number of kidney MФs, cytokines, or markers of tubular injury. RNA sequencing of tubular epithelial cells in HP compared to NP or LP diet group revealed increased expression of sodium-glutamine transporter Snat3, chloride channel Clcnka, and gluconeogenesis marker Pepck1, accompanied by increased excretion of urinary ammonia, a byproduct of glutamine. Early glutamine supplementation in Pkd1KO mice lead to kidney hypertrophy.

CONCLUSION: Chronic dietary protein load-induced renal hypertrophy and accelerated cyst growth in Pkd1KO mice is dependent on both infiltrating and resident MФ recruitment and subsequent inflammatory response. Early cyst expansion by HP diet, however, is relient on increased delivery of glutamine to kidney epithelial cells, driving downstream metabolic changes prior to inflammatory provocation.

PMID:37538309 | PMC:PMC10394241 | DOI:10.3389/fmed.2023.1173674

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PubMed articles on: Cardio-Oncology

Artificial intelligence modelling to assess the risk of cardiovascular disease in oncology patients

Eur Heart J Digit Health. 2023 May 8;4(4):302-315. doi: 10.1093/ehjdh/ztad031. eCollection 2023 Aug.

ABSTRACT

AIMS: There are no comprehensive machine learning (ML) tools used by oncologists to assist with risk identification and referrals to cardio-oncology. This study applies ML algorithms to identify oncology patients at risk for cardiovascular disease for referrals to cardio-oncology and to generate risk scores to support quality of care.

METHODS AND RESULTS: De-identified patient data were obtained from Vanderbilt University Medical Center. Patients with breast, kidney, and B-cell lymphoma cancers were targeted. Additionally, the study included patients who received immunotherapy drugs for treatment of melanoma, lung cancer, or kidney cancer. Random forest (RF) and artificial neural network (ANN) ML models were applied to analyse each cohort: A total of 20 023 records were analysed (breast cancer, 6299; B-cell lymphoma, 9227; kidney cancer, 2047; and immunotherapy for three covered cancers, 2450). Data were divided randomly into training (80%) and test (20%) data sets. Random forest and ANN performed over 90% for accuracy and area under the curve (AUC). All ANN models performed better than RF models and produced accurate referrals.

CONCLUSION: Predictive models are ready for translation into oncology practice to identify and care for patients who are at risk of cardiovascular disease. The models are being integrated with electronic health record application as a report of patients who should be referred to cardio-oncology for monitoring and/or tailored treatments. Models operationally support cardio-oncology practice. Limited validation identified 86% of the lymphoma and 58% of the kidney cancer patients with major risk for cardiotoxicity who were not referred to cardio-oncology.

PMID:37538144 | PMC:PMC10393891 | DOI:10.1093/ehjdh/ztad031

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PubMed articles on: Cardio-Oncology

Modulatory effect of amifostine (WR-1065) against genotoxicity and oxidative stress induced by methotrexate in human umbilical vein endothelial cells (HUVECs)

Toxicol Mech Methods. 2023 Aug 3:1-11. doi: 10.1080/15376516.2023.2238069. Online ahead of print.

ABSTRACT

Amifostine is used in chemotherapy and radiotherapy as a cytoprotective adjuvant alongside DNA-binding chemotherapeutic agents. It functions by reducing free radicals and detoxifying harmful metabolites. Methotrexate, as an antimetabolite drug has been considered for treating various cancers and autoimmune diseases. However, the cytotoxic effects of methotrexate extend beyond tumor cells to crucial organs, including the heart. This study applied the HUVEC cell line as a reference in vitromodel for researching the characteristics of vascular endothelium and cardiotoxicity. The current study aimed to assess amifostine's potential cytoprotective properties against methotrexate-induced cellular damage. Cytotoxicity was measured using the MTT assay. Apoptotic rates were evaluated by Annexin V-FITC/PI staining viaflow cytometry. The genoprotective effect of amifostine was determined using the comet assay. Cells were exposed to various amifostine doses (10-200 μg/mL) and methotrexate (2.5 μM) in pretreatment culture condition. Methotrexate at 2.5 μM revealed cytotoxicity, apoptosis, oxidative stress and genotoxicity while highlighting amifostine's cyto/geno protective properties on HUVECs. Amifostine significantly decreased the levels of ROS and LPO while preserving the status of GSH and SOD activity. Furthermore, it inhibited genotoxicity (tail length, %DNA in tail, and tail moment) in the comet assay. Amifostine markedly attenuated methotrexate-induced apoptotic cell death (early and late apoptotic rates). These findings convey that amifostine can operate as a cytoprotectant agent.

PMID:37537746 | DOI:10.1080/15376516.2023.2238069

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PubMed articles on: Cardio-Oncology

Homotypic targeted nanoplatform enable efficient chemoimmunotherapy and reduced DOX cardiotoxicity in chemoresistant cancer via TGF-β1 blockade

J Control Release. 2023 Aug 1:S0168-3659(23)00486-8. doi: 10.1016/j.jconrel.2023.07.063. Online ahead of print.

ABSTRACT

Doxorubicin (DOX) with broad-spectrum antitumor activity has been reported to induce effective immunogenic cell death (ICD) effect. However, the serious cardiotoxicity and chemoresistance severely restrict the widely clinical application of DOX. Herein, for the first time, a bio-inspired nanoplatform via co-assembly of DOX-conjugated polyethyleneimine (PEI-DOX), cancer cell membrane (CCM) and TGF-β1 siRNA (siTGF-β1) was rationally designed, which can not only overcome the drawbacks of DOX but also display high capability to modulate the tumor microenvironment and prevent the tumor progressing and metastasis. Experimental studies confirmed the pH-sensitivity of PEI-DOX and the homotypic-targeting and immuno-escapable ability of CCM, resulting an enhanced accumulation of DOX and siTGF-β1 in tumor sites. In addition to this, the bio-inspired nanoplatform could also improve the stability and facilitate the endosomal escape of siTGF-β1. All these effects ensured the silence efficiency of siTGF-β1 in tumor sites, which could further modulate the chemoresistant and immunosuppressive tumor microenvironment, resulting a synergistic effect with DOX to prevent tumor progressing and metastasis. Additionally, even trapped in cardiac tissues, siTGF-β1 could inhibit the production of TGF-β1 and ROS induced by DOX, resulting a reduced myocardial damage. Therefore, our newly designed bio-inspired nano-delivery system may be a promising nanoplatform with efficient chemoimmunotherapy to ameliorate DOX-induced cardiotoxicity and combat tumor growth and metastasis in chemoresistant cancer.

PMID:37536544 | DOI:10.1016/j.jconrel.2023.07.063

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PubMed articles on: Cardio-Oncology

Patient mortality following new-onset heart failure stratified by cancer type and status

Eur J Heart Fail. 2023 Aug 3. doi: 10.1002/ejhf.2984. Online ahead of print.

ABSTRACT

AIM: Expected 1-year survival is essential to risk stratification of patients with heart failure (HF); however, little is known about the 1-year prognosis of patients with HF and cancer. Thus, the objective was to investigate the 1-year prognosis following new-onset HF stratified by cancer status in patients with breast-, gastrointestinal-, or lung cancer.

METHODS AND RESULTS: All Danish patients with new-onset HF from 2000-2018 were included. Cancer status was categorized as history of cancer (no cancer-related contact within five years of HF diagnosis), non-active cancer (curative intended procedure administered) and active cancer. Standardized 1-year all-cause mortality was reported using G-computation. Age-stratified 1-year all-cause mortality was estimated using the Kaplan-Meier estimator. In total, 193 359 patients with HF were included, 7.3% had either a breast-, gastrointestinal or lung cancer diagnosis. Patients with cancer were older and more comorbid than patients without cancer. Standardized 1-year all-cause mortalities (95% confidence intervals) were 24.6% (23.0%-26.2%), 27.1% (25.5%-28.6%), and 29.9% (25.9%-34.0%) for history of breast-, gastrointestinal-, and lung cancer, which was comparable to patients with non-active cancers. For active breast-, gastrointestinal-, and lung cancer, standardized 1-year all-cause mortalities were 36.2% (33.8%-38.6%), 49.0% (47.2%-50.9%), and 61.6% (59.7%-63.5%), respectively. One-year all-cause mortality increased incrementally with age, except for active lung cancer.

CONCLUSION: Standardized 1-year all-cause mortality were comparable for patients with history of cancer and non-active cancer regardless cancer type, but varied comprehensively for active cancers. Prognostic impact of age was limited for active lung cancer. Thus, granular stratification of cancer is necessary for optimized management of new-onset HF. This article is protected by copyright. All rights reserved.

PMID:37534618 | DOI:10.1002/ejhf.2984

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PubMed articles on: Cardio-Oncology

Cancer Therapy-Related Cardiotoxicity: A Comprehensive Retrospective Analysis at Najran Cancer Center, Saudi Arabia

Cureus. 2023 Jul 2;15(7):e41287. doi: 10.7759/cureus.41287. eCollection 2023 Jul.

ABSTRACT

Background Cardiotoxicity, produced as an adverse effect of anticancer therapy, is a common issue during cancer treatment. Acute coronary syndrome, myocarditis, arrhythmias, or heart failure can all be symptoms of this issue. Little is known about its occurrence among Saudi Arabian cancer patients. This study aims to investigate factors linked to anticancer therapy-related cardiotoxicity. Methods A retrospective study was conducted from April 2020 to May 2022 at the King Khalid Hospital, Najran, Saudi Arabia. The study included adult cancer patients receiving anticancer therapy, regardless of their cardiovascular disease history. Univariate analysis was used to investigate factors associated with the occurrence of cardiotoxicity related to anticancer therapy. Results Of 78 patients receiving anticancer therapy, cardiotoxicity occurred in 12 (15.4%) patients. The mean age was 56.5 ± 13.4 years, with 33.3% aged over 65 years. Comorbidities included hypertension (44; 56.4%), diabetes (41; 52.6%), dyslipidemia (13; 16.7%), smoking (16; 20.5%), heart disease (6; 7.7%), trastuzumab use (9; 11.5%), and chronic kidney disease (2; 2.6%). The most common cancers were breast cancer and gastrointestinal cancer (27.6% each). Monoclonal anticancer agents 35 (46.1%) and alkylating agents 29 (38.2%) were commonly used chemotherapies. Cardiac protective agents were used in 16 (21.1%) of patients, with angiotensin-converting enzyme (ACE) inhibitors 15 (19.7%) and statins (13; 17.1%) being the most prescribed. Baseline ejection fraction (EF) was normal in 69 (90.8%) of cases. The follow-up duration was 1.93 ± 1.90 years. A drop in EF occurred in five (6.6%) of cases. Dyslipidemia (OR: 0.12; 95% CI: 0.03-0.47, p=0.002), previous heart disease (OR: 0.14; 95% CI: 0.02-0.81, p=0.029), and impaired baseline EF (p=0.029) were associated with increased risk of cardiotoxicity. Statin (OR: 0.22; 95% CI: 0.05 to 0.84, p=0.028) and antiplatelet agents (OR: 0.19; 95% CI: 0.03 to 1.01, p=0.051) were protective agents against cardiac toxicity. Conclusion Effective anti-cancer therapy may be accompanied by an increased risk of cardiotoxicity. In this study, a history of prior heart disease, dyslipidemia, low baseline ejection fraction, and the administration of multiple anticancer therapy agents was associated with cardiotoxicity. Proactive management strategies aimed at mitigating the potential cardiotoxic effects of anti-cancer therapies are crucial.

PMID:37533611 | PMC:PMC10393428 | DOI:10.7759/cureus.41287

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PubMed articles on: Cardio-Oncology

The protective effect of thiolutin on doxorubicin-induced H9c2 cardiomyocyte injury

J Toxicol Sci. 2023;48(8):469-479. doi: 10.2131/jts.48.469.

ABSTRACT

The use of doxorubicin (DOX) may contribute to cardiotoxicity, limiting its clinical application. Thiolutin (THL) has been found to exert protective roles in various biological activities, while its effects on DOX-induced cardiotoxicity are still uncovered. Cell counting kit 8 assay was utilized to detect cell viability and half maximal inhibitory concentration of THL in H9c2 cardiomyocytes. The level of lactate dehydrogenase (LDH), adenosine triphosphate (ATP), interleukin (IL)-18 and IL-1 beta (IL-1β) were measured using the corresponding detection kits, and flow cytometry determined cell apoptosis rate. The reactive oxygen species (ROS) accumulation was evaluated by utilizing immunofluorescence or flow cytometry assay. The protein levels of NLR family Pyrin domain 3 (NLRP3), pro-Caspase1, cleaved-Caspase1, gasdermin D (GSDMD) and cleaved-GSDMD (GSDMD-N) in H9c2 cells were detected by immunoblotting assay. The treatment of THL reduced H9c2 cell viability in a gradient-dependent manner. THL treatment reversed the DOX-induced inhibition of proliferation, decrease of ATP, up-regulation of LDH, IL-18, IL-1β and production of ROS, activation of NLRP3 and inflammasome-mediated pyroptosis in H9c2 cells. Additionally, NLRP3 knockdown abolished the effects of THL in DOX-treated H9c2 cells remarkably. This investigation proved that THL notably ameliorated DOX-induced apoptosis, oxidative stress, and pyroptosis in H9c2 cardiomyocytes. Besides, THL effectively inactivated DOX-induced NLRP3 inflammasome in H9c2 cells. These findings revealed a promising drug to assist DOX in its anti-cancer effects and protect the heart of patients.

PMID:37532580 | DOI:10.2131/jts.48.469

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PubMed articles on: Cardio-Oncology

Non-coding RNAs, cancer treatment and cardiotoxicity: A triad of new hope

Cancer Treat Res Commun. 2023 Jul 28;36:100750. doi: 10.1016/j.ctarc.2023.100750. Online ahead of print.

ABSTRACT

The global health landscape has experienced a shift towards non-communicable diseases, with cardiovascular diseases and cancer as leading causes of mortality. Although advancements in healthcare have led to an increase in life expectancy, they have concurrently resulted in a greater burden of chronic health conditions. Unintended consequences of anticancer therapies on various tissues, particularly the cardiovascular system, contribute to elevated morbidity and mortality rates that are not directly attributable to cancer. Consequently, the field of cardio-oncology has emerged to address the prevalence of CVD in cancer survivors and the cardiovascular toxicity associated with cancer therapies. Non-coding RNAs (ncRNAs) have been found to play a crucial role in early diagnosis, prognosis, and therapeutics within the realm of cardio-oncology. This comprehensive review evaluates the risk assessment of cancer survivors concerning the acquisition of adverse cardiovascular consequences, investigates the association of ncRNAs with CVD in patients undergoing cancer treatment, and delves into the role of ncRNAs in the diagnosis, treatment, and prevention of CVD in patients with a history of anti-cancer therapy. A thorough understanding of the pathogenesis of cancer therapy-related cardiovascular disease and the involvement of ncRNAs in cardio-oncology will enable healthcare professionals to provide anticancer treatment with minimized cardiovascular side effects, thereby improving patient outcomes. Ultimately, this comprehensive analysis aims to provide valuable insights into the complex interplay between cancer and cardiovascular diseases, facilitating the development of more effective diagnostic, therapeutic, and preventive strategies in the burgeoning field of cardio-oncology.

PMID:37531735 | DOI:10.1016/j.ctarc.2023.100750

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PubMed articles on: Cardio-Oncology

Anthracycline induced left ventricular dysfunction in AML: A focus on the molecularly defined future of cardio-oncology

Leuk Res. 2023 Jul 29;133:107366. doi: 10.1016/j.leukres.2023.107366. Online ahead of print.

NO ABSTRACT

PMID:37531679 | DOI:10.1016/j.leukres.2023.107366

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PubMed articles on: Cardio-Oncology

Diagnostic Value of Three-Dimensional Speckle Tracking Imaging Strain Parameters for Detection of Cancer Chemotherapy-Related Cardiac Dysfunction: A Meta-Analysis

Arq Bras Cardiol. 2023 Jul;120(8):e20220370. doi: 10.36660/abc.20220370.

ABSTRACT

BACKGROUND: Chemotherapeutic agents (e.g., anthracyclines, trastuzumab) commonly used for treating malignant tumors have been demonstrated to have cardiotoxic effects, which is associated with poor prognosis. Three-dimensional echocardiography has been used to predict cancer chemotherapy-induced cardiac dysfunction.

OBJECTIVES: Evaluation of the diagnostic performance of strain parameters, global area strain (GAS), longitudinal strain (GLS), circumferential strain (GCS), and radial strain (GRS) by meta-analysis.

METHODS: Relevant studies were searched from the Embase, PubMed, and Web of Science databases. Statistical analysis was performed using Stata 12. The summary receiver operating characteristic curve, sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and corresponding 95% confidence interval for the four strain parameters were pooled. P<0.05

RESULTS: Nine studies involving 650 participants were included. GAS and GLS showed significant diagnostic advantages over GCS and GRS. For GAS, the sensitivity was 0.85 (0.70, 0.93) and specificity was 0.82(0.78, 0.86) with PLR of 4.76 (3.55, 6.39) and NLR of 0.18 (0.09, 0.39) and an area under the curve (AUC) of 0.85 (0.82, 0.88). For GLS, the sensitivity was 0.81 (0.74, 0.86) and specificity was 0.81(0.68, 0.90) with PLR of 4.35(2.42, 7.80) and NLR of 0.23 (0.17, 0.33) and an AUC of 0.85 (0.82, 0.88). The GCS showed a sensitivity of 0.63 and a specificity of 0.79 with an AUC of 0.77. The GRS showed a sensitivity of 0.74 and a specificity of 0.66 with an AUC of 0.73.

CONCLUSION: 3D-STI strain parameters GAS and GLS showed good performance in detecting early cardiac dysfunction in patients with tumors receiving chemotherapy.

PMID:37531470 | DOI:10.36660/abc.20220370

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PubMed articles on: Cardio-Oncology

Cardiorenal Syndrome: A Literature Review

Cureus. 2023 Jul 1;15(7):e41252. doi: 10.7759/cureus.41252. eCollection 2023 Jul.