ABSTRACT

BACKGROUND: Elevated pre-treatment baseline inflammation has been associated with cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer. Monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio and systemic immune-inflammation index (NLR × platelets) have emerged in clinical context as markers of disease-related inflammation.

OBJECTIVES: To evaluate development of CTRCD according to pre-treatment blood inflammatory biomarkers in patients with breast cancer.

METHODS: Pilot cohort study including consecutive female patients ≥ 18 years with HER2-positive early breast cancer who consulted at the institution's breast oncology outpatient clinic between march/2019 and march/2022. CTRCD: absolute reduction in LVEF > 10% to below 53% (2D-echocardiogram). Survival analysis was performed using Kaplan-Meier curves, compared by the log-rank test, and discrimination ability was evaluated through AUC-ROC.

RESULTS: Forty-nine patients (53.3 ± 13.3 y) were included and followed-up for a median of 13.2 months. CTRCD was observed in 6 (12.2%) patients. Patients with high blood inflammatory biomarkers had lower CTRCD-free survival (P < 0.050 for all). MLR showed statistically significant AUC (0.802; P = 0.017). CTRCD was observed in 27.8% of patients with high MLR versus 3.2% with low MLR (P = 0.020); negative predictive value was 96.8% (95%CI 83.3-99.4%).

CONCLUSION: In patients with breast cancer, elevated pre-treatment inflammatory markers were associated with increased risk of cardiotoxicity. Among these markers, MLR had good discriminatory performance and high negative predictive value. The incorporation of MLR might improve risk evaluation and selection of patients for follow-up during cancer therapy.

PMID:37273150 | DOI:10.1007/s10549-023-06979-z

05:27

PubMed articles on: Cardio-Oncology

Long COVID syndrome after SARS-CoV-2 survival in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Pulm Circ. 2023 May 31;13(2):e12244. doi: 10.1002/pul2.12244. eCollection 2023 Apr.

ABSTRACT

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients have a more severe COVID-19 course than the general population. Many patients report different persistent symptoms after SARS-CoV-2 infection. The aim of our study is to analyze the prevalence of long COVID-19 symptoms and assess if COVID-19 affects pulmonary hypertension (PH) prognosis. PAH/CTEPH patients who survived COVID-19 for at least 3 months before visiting the PH centers were included in the study. The patients were assessed for symptoms in acute phase of SARS-CoV-2 infection and persisting in follow-up visit, WHO functional class, 6-min walk distance, NT-proBNP concentration. The COMPERA 2.0 model was used to calculate 1-year risk of death due to PH at baseline and at follow-up. Sixty-nine patients-54 (77.3%) with PAH and 15 (21.7%) with CTEPH, 68% women, with a median age of 47.5 years (IQR 37-68)-were enrolled in the study. About 17.1% of patients were hospitalized due to COVID-19 but none in an ICU. At follow-up (median: 155 days after onset of SARS-CoV-2 symptoms), 62% of patients reported at least 1 COVID-19-related symptom and 20% at least 5 symptoms. The most frequently reported symptoms were: fatigue (30%), joint pain (23%), muscle pain (17%), nasal congestion (17%), anosmia (13%), insomnia (13%), and dyspnea (12%). Seventy-two percent of PH patients had a low or intermediate-low risk of 1-year death due to PH at baseline, and 68% after COVID-19 at follow-up. Over 60% of PAH/CTEPH patients who survived COVID-19 suffered from long COVID-19 syndrome, but the calculated 1-year risk of death due to PH did not change significantly after surviving mild or moderate COVID-19.

PMID:37266140 | PMC:PMC10232226 | DOI:10.1002/pul2.12244

05:27

PubMed articles on: Cardio-Oncology

An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis

Circ Res. 2023 Jun 2. doi: 10.1161/CIRCRESAHA.122.322017. Online ahead of print.

ABSTRACT

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) KI (knock in) 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 WT (wild type) 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.

PMID:37264926 | DOI:10.1161/CIRCRESAHA.122.322017

05:27

PubMed articles on: Cardio-Oncology

Vascular Inflammation, Cancer, and Cardiovascular Diseases

Curr Oncol Rep. 2023 Jun 1. doi: 10.1007/s11912-023-01426-0. Online ahead of print.