Citations

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment’s effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.

Abstract Aims Radiation therapy (RT) is an integral component of cancer therapy but associated with adverse events. Our goal was to establish risk prediction models for major adverse cardiovascular and cerebrovascular events (MACCE) after chest RT. Methods and results A retrospective study of lung/breast cancer patients who had chest RT with planning CT at Mayo Clinic between 01/2010 and 01/2014. Predictive models were developed based on weighted independent predictors using a derivation (406 lung and 711 breast cancer) and validation cohort (179 lung and 234 breast cancer). Patient characteristics, pre-RT CT for coronary artery calcification (CAC), and post-RT MACCE data were reviewed. Post-RT MACCE occurred in 6.1 and 5.6% in the derivation and validation cohort over a mean follow-up of 42 ± 13 months. Post-therapy model (C2AD2) included CAC (two points), MACCE history (two points), age ≥74 (three points), DM (two points), and mean heart radiation dose ≥ 850 mGy (two points), and pre-therapy model (C2AD) included post-therapy model parameters minus mean heart radiation dose. Both models stratified patients into three risk groups: low (0–2), intermediate (3–5), and high (≥6). Post-RT MACCE across these groups were 2.7, 8.9, and 19.8% in the derivation, and 3.9, 6.6, and 16.4% in the validation cohort for post-therapy model (C2AD2) and 2.8, 9.2, and 20.4% in the derivation and 3.7, 9.2, and 13.2% in the validation cohort for pre-therapy model. Both models showed statistically significant graded survival outcome. Conclusion Post-therapy (C2AD2) and pre-therapy (C2AD) models are simple, easy to use and effective tools to stratify breast and lung cancer patients undergoing chest radiation for post-RT MACCE.

BACKGROUND: Global collaboration in cardio-oncology is needed to understand the prevalence of cancer therapy-related cardiovascular toxicity in different risk groups, practice settings, and geographic locations. There are limited data on the socioeconomic and racial/ethnic disparities that may impact access to care and outcomes. To address these gaps, we established the Global Cardio-Oncology Registry, a multinational, multicenter prospective registry. METHODS: We assembled cardiologists and oncologists from academic and community settings to collaborate in the first Global Cardio-Oncology Registry. Subsequently, a survey for site resources, demographics, and intention to participate was conducted. We designed an online data platform to facilitate this global initiative. RESULTS: A total of 119 sites responded to an online questionnaire on their practices and main goals of the registry: 49 US sites from 23 states and 70 international sites from 5 continents indicated a willingness to participate in the Global Cardio-Oncology Registry. Sites were more commonly led by cardiologists (85/119; 72%) and were more often university/teaching (81/119; 68%) than community based (38/119; 32%). The average number of cardio-oncology patients treated per month was 80 per site. The top 3 Global Cardio-Oncology Registry priorities in cardio-oncology care were breast cancer, hematologic malignancies, and patients treated with immune checkpoint inhibitors. Executive and scientific committees and specific committees were established. A pilot phase for breast cancer using Research Electronic Data Capture Cloud platform recently started patient enrollment. CONCLUSIONS: We present the structure for a global collaboration. Information derived from the Global Cardio-Oncology Registry will help understand the risk factors impacting cancer therapy-related cardiovascular toxicity in different geographic locations and therefore contribute to reduce access gaps in cardio-oncology care. Risk calculators will be prospectively derived and validated.

Background: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. Methods: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow–derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. Results: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow–derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)–induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. Conclusions: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

Introduction: Global collaboration in cardio-oncology (CO) is needed to understand the prevalence of cancer treatment related cardiovascular disease (CTRCD) in different risk groups, practice settings and geographic locations. Furthermore, socio-economic and ethnic disparities may impact access to care. Methods: We assembled cardiologists (CA) and oncologists from academic and community settings to collaborate in the first global cardio-oncology registry (G-COR). US and international CO physicians participated in the first global virtual meeting to assess feasibility and structure for G-COR. Subsequently, a survey for sites resources, demographics and intention to participate was conducted. Results: Responses with sites demographics from 104/140 sites invited: 43 US sites from 23 states and 61 international sites from 5 continents indicated decision to participate in G-COR. Sites were more commonly led by CA (74/99) than CA and oncologists (25/99) and were more often University/teaching (68/101) than community based (33/101). Significant minorities/disadvantaged CO patient population were reported by 32/43 US sites versus 16/60 international sites. Average number CO patients treated per month was 83, range (5-1,000). Breast cancer was the first or second G-COR priority for 84 centers, hematological malignancies (HEM) for 66 centers, and immune check point inhibitors (ICI) for 36 centers. Echocardiography with strain imaging is available in 92/95 participating sites and cardiac MRI in 80/86 sites. Biomarkers are used only in suspected or confirmed CTRCD in 56/96 sites and for risk stratification in high risk patients in 40/96 sites. Subsequently, scientific committee and topic committees for breast cancer, HEM, ICI, and disparities in CO were established. A pilot phase utilizing a RedCap Cloud platform will start enrolling patients in the last quarter of 2021 and the registry for all main pillars will launch in early 2022. Conclusions: We present a global initiative for conducting collaborative research. Information learned G-COR will help understanding risk factors impacting CTRCD in different geographic locations and therefore help reducing access gaps in CO care. Additionally, mitigating strategies can be devised for the future.

Background: There is a paucity of data regarding the association between radiation exposure of heart substructures and the incidence of major coronary events (MCEs) in patients with esophageal cancer (ESOC) undergoing chemoradiation therapy. We studied radiation dosimetric determinants of MCE risk and measured their impact on patient prognosis using a cohort of ESOC patients treated at a single institution. Methods: Between March 2005 and October 2015, 355 ESOC patients treated with concurrent chemoradiotherapy were identified from a prospectively maintained and institutional-regulatory-board-approved clinical database. Dose-distribution parameters of the whole heart, the atria, the ventricles, the left main coronary artery, and three main coronary arteries were extracted for analysis. Results: Within a median follow-up time of 67 months, 14 patients experienced MCEs at a median of 16 months. The incidence of MCEs was significantly associated with the left anterior descending coronary artery (LAD) receiving ≥30 Gy (V30Gy) (p = 0.048). Patients receiving LAD V30Gy ≥ 10% of volume experienced a higher incidence of MCEs versus the LAD V30Gy < 10% group (p = 0.044). The relative rate of death increased with the left main coronary artery (LMA) mean dose (Gy) (p = 0.002). Furthermore, a mutual promotion effect of hyperlipidemia and RT on MCEs was observed. Conclusion: Radiation dose to coronary substructures is associated with MCEs and overall survival in patients with ESOC. In this study, the doses to these substructures appeared to be better predictors of toxicity outcomes than mean heart dose (MHD) or whole-heart V30Gy. These findings have implications for reducing coronary events through radiation therapy planning.

Abstract In response to the coronavirus disease 2019 (COVID-19) pandemic, the Cardio-Oncology and Imaging Councils of the American College of Cardiology offers recommendations to clinicians regarding the cardiovascular care of cardio-oncology patients in this expert consensus statement. Cardio-oncology patients—individuals with an active or prior cancer history and with or at risk of cardiovascular disease—are a rapidly growing population who are at increased risk of infection, and experiencing severe and/or lethal complications by COVID-19. Recommendations for optimizing screening and monitoring visits to detect cardiac dysfunction are discussed. In addition, judicious use of multimodality imaging and biomarkers are proposed to identify myocardial, valvular, vascular, and pericardial involvement in cancer patients. The difficulties of diagnosing the etiology of cardiovascular complications in patients with cancer and COVID-19 are outlined, along with weighing the advantages against risks of exposure, with the modification of existing cardiovascular treatments and cardiotoxicity surveillance in patients with cancer during the COVID-19 pandemic.

Background— The ROSE AHF trial (Renal Optimization Strategies Evaluation in Acute Heart Failure) found that when compared with placebo, neither low-dose dopamine (2 µg/kg per minute) nor low-dose nesiritide (0.005 μg/kg per minute without bolus) enhanced decongestion or preserved renal function in AHF patients with renal dysfunction. However, there may be differential responses to vasoactive agents in AHF patients with reduced versus preserved ejection fraction (EF). This post hoc analysis examined potential interaction between treatment effect and EF (EF ≤40% versus >40%) on the ROSE AHF end points. Methods and Results— ROSE AHF enrolled AHF patients (n=360; any EF) with renal dysfunction. The coprimary end points were cumulative urine volume and the change in serum cystatin-C in 72 hours. The effect of dopamine (interaction P =0.001) and nesiritide (interaction P =0.039) on urine volume varied by EF group. In heart failure with reduced EF, urine volume was higher with active treatment versus placebo, whereas in heart failure with preserved EF, urine volume was lower with active treatment. The effect of dopamine and nesiritide on weight change, sodium excretion, and incidence of AHF treatment failure also varied by EF group (interaction P <0.05 for all). There was no interaction between vasoactive treatment’s effect and EF on change in cystatin-C. Compared with placebo, dopamine was associated with improved clinical outcomes in heart failure with reduced EF and worse clinical outcomes in heart failure with preserved EF. With nesiritide, there were no differences in clinical outcomes when compared with placebo in both heart failure with reduced EF and heart failure with preserved EF. Conclusions— In this post hoc analysis of ROSE AHF, the response to vasoactive therapies differed in patients with heart failure with reduced EF and heart failure with preserved EF. Investigations of AHF therapies should assess the potential for differential responses in AHF with preserved versus reduced EF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01132846.