Identification Drug Targets for Oxaliplatin-Induced Cardiotoxicity without Affecting Cancer Treatment through Inter Variability Cross-Correlation Analysis (IVCCA).

The successful treatment of side effects of chemotherapy faces two major limitations: the need to avoid interfering with pathways essential for the cancer-destroying effects of the chemotherapy drug, and the need to avoid helping tumor progression through cancer promoting cellular pathways. To address these questions and identify new pathways and targets that satisfy these limitations, we have developed the bioinformatics tool Inter Variability Cross-Correlation Analysis (IVCCA). This tool calculates the cross-correlation of differentially expressed genes, analyzes their clusters, and compares them across a vast number of known pathways to identify the most relevant target(s). To demonstrate the utility of IVCCA, we applied this platform to RNA-seq data obtained from the hearts of the animal models with oxaliplatin-induced CTX. RNA-seq of the heart tissue from oxaliplatin treated mice identified 1744 differentially expressed genes with False Discovery Rate (FDR) less than 0.05 and fold change above 1.5 across nine samples. We compared the results against traditional gene enrichment analysis methods, revealing that IVCCA identified additional pathways potentially involved in CTX beyond those detected by conventional approaches. The newly identified pathways such as energy metabolism and several others represent promising target for therapeutic intervention against CTX, while preserving the efficacy of the chemotherapy treatment and avoiding tumor proliferation. Targeting these pathways is expected to mitigate the damaging effects of chemotherapy on cardiac tissues and improve patient outcomes by reducing the incidence of heart failure and other cardiovascular complications, ultimately enabling patients to complete their full course of chemotherapy with improved quality of life and survival rates.

Moving towards establishing centres of excellence in cardiac amyloidosis: an International Cardio-Oncology Society statement.

The prevalence of amyloidosis has been increasing, driven by a combination of improved awareness, evolution of diagnostic pathways, and effective treatment options for both transthyretin and light chain amyloidosis. Due to the complexity of amyloidosis, centralised expert providers with experience in delineating the nuances of confirmatory diagnosis and management may be beneficial. There are many potential benefits of a centre of excellence designation for the treatment of amyloidosis including recognition of institutions that have been leading the way for the optimal treatment of this condition, establishing the expectations for any centre who is engaging in the treatment of amyloidosis and developing cooperative groups to allow more effective research in this disease space. Standardising the expectations and criteria for these centres is essential for ensuring the highest quality of clinical care and community education. In order to define what components are necessary for an effective centre of excellence for the treatment of amyloidosis, we prepared a survey in cooperation with a multidisciplinary panel of amyloidosis experts representing an international consortium. The purpose of this position statement is to identify the essential elements necessary for highly effective clinical care and to develop a general standard with which practices or institutions could be recognised as a centre of excellence.

Advances in Screening for Radiation-Associated Cardiotoxicity in Cancer Patients.

PURPOSE OF REVIEW: Radiation is foundational to the treatment of cancer and improves overall survival. Yet, it is important to recognize the potential cardiovascular effects of radiation therapy and how to best minimize or manage them. Screening-both through imaging and with biomarkers-can potentially identify cardiovascular effects early, allowing for prompt initiation of treatment to mitigate late effects. RECENT FINDINGS: Cardiac echocardiography, magnetic resonance imaging (MRI), computed tomography, and measurements of troponin and natriuretic peptides serve as the initial screening tests of choice for RICD. Novel imaging applications, including positron emission tomography and specific MRI parameters, and biomarker testing, including myeloperoxidase, growth differentiation factor 15, galectin 3, micro-RNA, and metabolomics, hold promise for earlier detection and more specific characterization of RICD. Advances in imaging and novel applications of biomarkers have potential to identify subclinical RICD and may reveal opportunities for early intervention. Further research is needed to elucidate optimal imaging screening modalities, biomarkers, and surveillance strategies.

Cardiovascular toxicities after anthracycline and VEGF-targeted therapies in adolescent and young adult cancer survivors.

BACKGROUND: Cancer survival rates have been steadily improving in the adolescent and young adult (AYA) population, but survivors are at increased risk for cardiovascular disease (CVD). The cardiotoxic effects of anthracycline therapy have been well studied. However, the cardiovascular toxicity associated with newer therapies, such as the vascular endothelial growth factor (VEGF) inhibitors, is less well understood. OBJECTIVE: This retrospective study of AYA cancer survivors sought to gain insight into their burden of cardiovascular toxicities (CT) following initiation of anthracycline and/or VEGF inhibitor therapy. METHODS: Data were extracted from electronic medical records over a fourteen-year period at a single institution. Cox proportional hazards regression modeling was used to examine risk factors for CT within each treatment group. Cumulative incidence was calculated with death as a competing risk. RESULTS: Of the 1,165 AYA cancer survivors examined, 32%, 22%, and 34% of patients treated with anthracycline, VEGF inhibitor, or both, developed CT. Hypertension was the most common outcome reported. Males were at increased risk for CT following anthracycline therapy (HR: 1.34, 95% CI 1.04-1.73). The cumulative incidence of CT was highest in patients who received both anthracycline and VEGF inhibitor (50% at ten years of follow up). CONCLUSIONS: CT was common among AYA cancer survivors who received anthracycline and/or VEGF inhibitor therapy. Male sex was an independent risk factor for CT following anthracycline treatment. Further screening and surveillance are warranted to continue understanding the burden of CVD following VEGF inhibitor therapy.

Adding Pharmacist-Led Home Blood Pressure Telemonitoring to Usual Care for Blood Pressure Control: A Systematic Review and Meta-Analysis.

Health systems have been quickly adopting telemedicine throughout the United States, especially since the onset of the COVID-19 pandemic. However, there are limited data on whether adding pharmacist-led home blood pressure (BP) telemonitoring to office-based usual care improves BP. We searched PubMed/MEDLINE and Embase for randomized controlled trials from January 2000 until April 2022, comparing studies on pharmacist-led home BP telemonitoring with usual care. Six randomized controlled trials, including 1,550 participants, satisfied the inclusion criteria. There were 774 participants in the pharmacist-led telemonitoring group and 776 in the usual care group. The addition of pharmacist-led telemonitoring to usual care was associated with a significant decrease in systolic BP (mean difference -8.09, 95% confidence interval -11.15 to -5.04, p <0.001, I2 = 72%) and diastolic BP (mean difference -4.19, 95% confidence interval -5.58 to -2.81, p <0.001, I2 = 42%) compared with usual care. In conclusion, this meta-analysis showed that adding pharmacist-led home BP telemonitoring to usual care achieves better BP control than usual care alone.

Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with a human equivalent dosage of intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified that oxaliplatin induces strong changes in the heart and affects the heart's energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such as Nmrk2. Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage.

Clinicopathological classification of immune checkpoint inhibitor-associated myocarditis: possible refinement by measuring macrophage abundance.

BACKGROUND: Immune checkpoint inhibitor (ICI) myocarditis is associated with high morbidity and mortality. While endomyocardial biopsy (EMB) is considered a gold standard for diagnosis, the sensitivity of EMB is not well defined. Additionally, the pathological features that correlate with the clinical diagnosis of ICI-associated myocarditis remain incompletely understood. METHODS: We retrospectively identified and reviewed the clinicopathological features of 26 patients with suspected ICI-associated myocarditis based on institutional major and minor criteria. Seventeen of these patients underwent EMB, and the histopathological features were assessed by routine hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for CD68, a macrophage marker. RESULTS: Only 2/17 EMBs obtained from patients with suspected ICI myocarditis satisfied the Dallas criteria. Supplemental IHC staining and quantification of CD68+ macrophages identified an additional 7 patients with pathological features of myocardial inflammation (> 50 CD68+ cells/HPF). Macrophage abundance positively correlated with serum Troponin I (P = 0.010) and NT-proBNP (N-terminal pro-brain natriuretic peptide, P = 0.047) concentration. Inclusion of CD68 IHC could have potentially changed the certainty of the diagnosis of ICI-associated myocarditis to definite in 6/17 cases. CONCLUSIONS: While the Dallas criteria can identify a subset of ICI-associated myocarditis patients, quantification of macrophage abundance may expand the diagnostic role of EMB. Failure to meet the traditional Dallas Criteria should not exclude the diagnosis of myocarditis.

Recent Advances in Serum Biomarkers for Risk Stratification and Patient Management in Cardio-Oncology.

PURPOSE OF REVIEW: Following significant advancements in cancer therapeutics and survival, the risk of cancer therapy-related cardiotoxicity (CTRC) is increasingly recognized. With ongoing efforts to reduce cardiovascular morbidity and mortality in cancer patients and survivors, cardiac biomarkers have been studied for both risk stratification and monitoring during and after therapy to detect subclinical disease. This article will review the utility for biomarker use throughout the cancer care continuum. RECENT FINDINGS: A recent meta-analysis shows utility for troponin in monitoring patients at risk for CTRC during cancer therapy. The role for natriuretic peptides is less clear but may be useful in patients receiving proteasome inhibitors. Early studies explore use of myeloperoxidase, growth differentiation factor 15, galectin 3, micro-RNA, and others as novel biomarkers in CTRC. Biomarkers have potential to identify subclinical CTRC and may reveal opportunities for early intervention. Further research is needed to elucidate optimal biomarkers and surveillance strategies.

In-hospital mortality of heparin-induced thrombocytopenia in end-stage kidney disease. A retrospective national population-based cohort study.

AIM: Heparin induced thrombocytopenia (HIT) and end stage kidney disease (ESKD) are independent conditions associated with increased mortality and morbidity, however, whether ESKD is an independent risk factor for increased mortality in HIT admissions is not well studied. Therefore, we aimed to compare in-hospital mortality in HIT admissions based on their ESKD status. METHODS: This is a retrospective cohort study of HIT hospitalizations aged 18 and older using the 2016-2019 national inpatient sample (NIS) database. RESULTS: From 2016 to 2019 we had 12 161 admissions for HIT among 28 484 087 total hospitalizations. The annual incidence rate for HIT admissions per 100 000 admissions were: 47, 46, 41.1, and 36.6, respectively (p < .001) in 2016, 2017, 2018, and 2019 respectively. Among HIT admissions, the mean age was 64.3 years, 46.8% were females, 68% were Whites and 16% were Blacks. Black patients have a significantly higher likelihood of in-hospital mortality than White patients (aOR 1.25; 95% CI: 1.06, 1.48; p = .007). Patients who did not have any insurance or self-pay had higher mortality compared to Medicare (aOR 1.64; 95% CI: 1.13, 2.38; p = .009). ESKD status was not associated with higher or lower in-hospital mortality among HIT admissions (aOR 1.002; 95% CI: 0.84, 1.19; p = .981) after adjusting for age, sex, race, and insurance status. CONCLUSION: There are no higher or lower odds of in-hospital mortality in the ESKD subgroup in HIT admissions in adults. Decreasing incidence of HIT hospitalizations was seen over the years from 2016 to 2019.

Sex-based disparities and in-hospital outcomes of patients hospitalized with atrial fibrillation with and without dementia.

Study objective: We sought to evaluate the sex-based disparities and comparative in-hospital outcomes of principal AF hospitalizations in patients with and without dementia, which have not been well-studied. Design: This is a non-interventional retrospective cohort study. Setting and participants: We identified principal hospitalizations of AF in the National Inpatient Sample in adults (≥18 years old) between January 2016 and December 2019. Main outcome measure: In-hospital mortality. Results: Of 378,230 hospitalized patients with AF, 49.2 % (n = 186,039) were females and 6.1 % (n = 22,904) had dementia. The mean age (SD) was 71 (13) years. Patients with dementia had higher odds of in-hospital mortality {adjusted odds ratio (aOR): 1.48, 95 % confidence interval (CI): 1.34, 1.64, p < 0.001} and nontraumatic intracerebral hemorrhage (aOR: 1.60, 95 % CI: 1.04, 2.47, p = 0.032), but they had lower odds of catheter ablation (0.39, 95 % CI: 0.35, 0.43, p < 0.001) and electrical cardioversion (aOR: 0.33, 95 % CI: 0.31, 0.35, p < 0.001). In patients with AF and dementia, compared to males, females had similar in-hospital mortality (aOR: 1.00, 95 % CI: 0.93, 1.07, p = 0.960), fewer gastrointestinal bleeds (aOR: 0.92, 95 % CI: 0.85, 0.99, p = 0.033), lower odds of getting catheter ablation (aOR: 0.79, 95 % CI: 0.76, 0.81, p < 0.001), and less likelihood of getting electrical cardioversion (aOR: 0.78, 95 % CI: 0.76, 0.79, p < 0.001). Conclusions: Patients with AF and dementia have higher mortality and a lower likelihood of getting catheter ablation and electrical cardioversion.

All-cause and in-hospital mortality after aspirin use in patients hospitalized with COVID-19: a systematic review and meta-analysis.

Background: With the results of the largest randomized controlled trial (RECOVERY) and the most extensive retrospective cohort study on coronavirus disease 2019 (COVID-19) recently published, we performed a meta-analysis on the association of aspirin with mortality of COVID-19. We aimed to investigate the role of aspirin in COVID-19 hospitalizations. Materials and Methods: We searched PubMed, EMBASE and Cochrane databases for studies from 1 January 2020 until 20 July 2022, that compared aspirin versus non-aspirin use in hospitalized COVID-19 patients. We excluded case reports, review articles and studies on non-hospitalized COVID-19 infections. We used the inverse variance method and random effects model to pool the individual studies. Results: Ten observational studies and one randomized controlled trial met the criteria for inclusion. There were 136 695 total patients, of which 27 168 were in the aspirin group and 109 527 were in the non-aspirin group. Aspirin use was associated with a 14% decrease in all-cause mortality compared with non-aspirin use in patients hospitalized with COVID-19 [relative risk (RR) 0.86, confidence interval (95% CI) 0.76-0.97; P = 0.002; I 2 =64%]. Among subgroups of studies reporting in-hospital mortality in COVID-19 hospitalizations, aspirin use was associated with a 16% decrease in in-hospital mortality compared with non-aspirin use (RR 0.84, 95% CI 0.71-0.99; P = 0.007; I 2 =64%). Conclusion: Our study shows that aspirin decreases in-hospital mortality in patients hospitalized with COVID-19. Further studies are needed to assess which COVID-19 patient populations benefit most, such as patients on aspirin for primary versus secondary prevention of atherosclerotic disease. In addition, significant bleeding also needs to be considered when assessing the risk-benefit of aspirin use.

Implementing a Machine-Learning-Adapted Algorithm to Identify Possible Transthyretin Amyloid Cardiomyopathy at an Academic Medical Center.

Background: Wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) is a frequently under-recognized cause of heart failure (HF) in older patients. To improve identification of patients at risk for the disease, we initiated a pilot program in which 9 cardiac/non-cardiac phenotypes and 20 high-performing phenotype combinations predictive of wild-type ATTR-CM were operationalized in electronic health record (EHR) configurations at a large academic medical center. Methods: Inclusion criteria were age >50 years and HF; exclusion criteria were end-stage renal disease and prior amyloidosis diagnoses. The different Epic EHR configurations investigated were a clinical decision support tool (Best Practice Advisory) and operational/analytical reports (Clarity™, Reporting Workbench™, and SlicerDicer); the different data sources employed were problem list, visit diagnosis, medical history, and billing transactions. Results: With Clarity, among 45 051 patients with HF, 4006 patients (8.9%) had ⩾1 phenotype combination associated with increased risk of wild-type ATTR-CM. Across all data sources, 2 phenotypes (cardiomegaly; osteoarthrosis) and 2 combinations (carpal tunnel syndrome + HF; atrial fibrillation + heart block + cardiomegaly + osteoarthrosis) generated the highest proportions of patients for wild-type ATTR-CM screening. Conclusion: All EHR configurations tested were capable of operationalizing phenotypes or phenotype combinations to identify at-risk patients; the Clarity report was the most comprehensive.

Radiation-Induced Cardiovascular Toxicities.

OPINION STATEMENT: Several seminal papers over the last decade have furthered our recognition of radiation-induced heart disease (RIHD) as an important potential toxicity following radiation therapy (RT) to the chest. Investigators continue to evaluate the subacute and long-term effects of RT. In addition, studies are determining whether certain cardiac substructures are more sensitive to radiation, working to identify risk factors for the development of RIHD, and testing screening and mitigation strategies for RIHD. Multiple groups and expert consensus guidelines have published whole-heart and cardiac substructure dose constraints based on available data and cancer type. The authors recommend readers to familiarize themselves with the guidelines for screening and mitigating RIHD in adults and children, which advocate for cardiovascular risk assessment and reduction before and following RT, as well as cardiovascular imaging at appropriate follow-up intervals for early recognition of subclinical cardiovascular disease. Referrals to cardiology or cardio-oncology can also be helpful in prevention, screening, and mitigation strategies.

Radiation-Induced Cardiac Dysfunction: Optimizing Radiation Delivery and Postradiation Care.

Radiation therapy (RT) is part of standard-of-care treatment of many thoracic cancers. More than 60% of patients receiving thoracic RT may eventually develop radiation-induced cardiac dysfunction (RICD) secondary to collateral heart dose. This article reviews factors contributing to a thoracic cancer patient's risk for RICD, including RT dose to the heart and/or cardiac substructures, other anticancer treatments, and a patient's cardiometabolic health. It is also discussed how automated tracking of these factors within electronic medical record environments may aid radiation oncologists and other treating physicians in their ability to prevent, detect, and/or treat RICD in this expanding patient population.

Distribution of Coronary Artery Calcium by Age, Sex, and Race Among Patients 30-45 Years Old.

BACKGROUND: Coronary artery calcium (CAC) is a measure of atherosclerotic burden and is well-validated for risk stratification in middle- to older-aged adults. Few studies have investigated CAC in younger adults, and there is no calculator for determining age-, sex-, and race-based percentiles among individuals aged <45 years. OBJECTIVES: The purpose of this study was to determine the probability of CAC >0 and develop age-sex-race percentiles for U.S. adults aged 30-45 years. METHODS: We harmonized 3 datasets-CARDIA (Coronary Artery Risk Development in Young Adults), the CAC Consortium, and the Walter Reed Cohort-to study CAC in 19,725 asymptomatic Black and White individuals aged 30-45 years without known atherosclerotic cardiovascular disease. After weighting each cohort equally, the probability of CAC >0 and age-sex-race percentiles of CAC distributions were estimated using nonparametric techniques. RESULTS: The prevalence of CAC >0 was 26% among White males, 16% among Black males, 10% among White females, and 7% among Black females. CAC >0 automatically placed all females at >90th percentile. CAC >0 placed White males at the 90th percentile at age 34 years compared with Black males at age 37 years. An interactive webpage allows one to enter an age, sex, race, and CAC score to obtain the corresponding estimated percentile. CONCLUSIONS: In a large cohort of U.S. adults aged 30-45 years without symptomatic atherosclerotic cardiovascular disease, the probability of CAC >0 varied by age, sex, and race. Estimated percentiles may help interpretation of CAC scores among young adults relative to their age-sex-race matched peers and can henceforth be included in CAC score reporting.

Radiation-induced cardiac dysfunction: Practical implications.

Radiation-induced cardiac dysfunction is a critical healthcare concern facing survivors of thoracic cancers treated with radiation therapy. Despite cardiac-sparing advances in radiation therapy delivery, many patients with thoracic cancers receiving modern radiation therapy will still have incidental radiation exposure to the heart. Therefore, it is imperative that cardiovascular healthcare providers take appropriate measures to prevent, screen, and manage radiation-induced cardiac dysfunction in patients with a history of thoracic radiation therapy. In this review, we aim to provide healthcare providers with foundational information about radiation-induced cardiac pathophysiology and a chronology of advances in radiation technology. Subsequently, we provide an up-to-date review of treatment- and host-related factors that can influence a patient's risk for radiation-induced cardiac dysfunction. Finally, we culminate our discussion by detailing current screening and management guidelines to aid healthcare providers in caring for their patients with a history of thoracic radiation therapy.

Cost-Effectiveness Analysis of Robotic-assisted Lobectomy for Non-Small Cell Lung Cancer.

BACKGROUND: Robot-assisted thoracic surgery has emerged as an alternative to video-assisted thoracic surgery (VATS) for treating patients with resectable non-small cell lung cancer. The objective of this study was to evaluate the cost effectiveness of robotic-assisted lobectomy (RAL) compared with VATS and open lobectomy for adults with NSCLC. METHODS: A decision analysis model was employed to compare the cost effectiveness of RAL, VATS, and open lobectomy with 1-year time horizon from both health care and societal perspectives. Health care costs (2020$) and quality-adjusted life-years were compared between the approaches. The incremental cost-effectiveness ratio was calculated in terms of cost per quality-adjusted life-years gained. Sensitivity analyses were performed to identify variables driving cost effectiveness across several willingness-to-pay thresholds. RESULTS: Open thoracotomy was not cost effective compared with both RAL and VATS lobectomy. From the health care sector perspective, RAL was $394.97 more expensive per case than VATS resulting in an incremental cost-effectiveness ratio of $180 755.10 per quality-adjusted life-year. From the societal perspective, RAL was $247.77 more expensive per case than VATS, resulting in an incremental cost-effectiveness ratio of $113 388.80 per quality-adjusted life-years. Robotic-assisted lobectomy becomes cost effective with marginally lower robotic instrument costs, shorter operating room times, lower conversion rates, shorter lengths of stay, higher hospital volumes, and improved quality of life. Robotic-assisted lobectomy is also cost effective if surgeons can increase the proportion of minimally invasive lobectomies using robotic technology. CONCLUSIONS: Compared with VATS, RAL is not cost effective for lung cancer lobectomy at lower willingness-to-pay thresholds. However, several factors may drive RAL to emerge as the more cost-effective approach for minimally invasive lung cancer resection.