bluuebunny/crossref_metadata_2025_split huggingface dataset:
SGLT2i Dapagliflozin decreases NLRP3, IL-1 and PCSK9 expression in preclinical models of short-term doxorubicin cardiotoxicity
Authors: Maurea N , Canale M L , Scherillo M , Bisceglia I , Palma G , Luciano A , Bruzzese F , Paccone A , Iovine M , Florio F , Grimaldi S , Giordano V , Maurea F , Quagliariello V 
Published: November 2023

Abstract

Background
Anthracyclines are an effective and widely used chemotherapy agent in the treatment of multiple solid organ tumors and hematologic malignancies. The use of anthracyclines as a standard cancer therapy is limited by the potential for the development of cardiac dysfunction, arrhythmias, and clinical heart failure. In recent five years, it was demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), a lipid metabolism-related protein, is a key orchestrator of immune infiltration in myocardial and cancer tissues and could regulate cardiac fibrosis and inflammation. PCSK9 is a protein with key roles in hepatic low density lipoprotein (LDL) homeostasis. PCSK9 systemic levels are associated to HOMA score and high insulin levels. Dapagliflozin exerts systemic ant-inflammatory properties and cardioprotective effects in diabetic and non-diabetic patients.

Purpose
We hypothesized that Dapagliflozin, administered during doxorubicin, could reduce PCSK9 systemic levels in preclinical models.

Methods
Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). After treatments, plasma levels of PCSK9, IL-1β and CRP were analyzed through selective anti-mouse ELISA methods. Myocardial and liver expression of NLRP3-inflammasome and IL-1β were analyzed through ELISA method in tissue lysates after treatments.

Results
DAPA associated to DOXO reduces significantly systemic levels of PCSK9 ( -37,5% vs DOXO group, p&lt;0,001). IL-1β and CRP levels were also reduced ( -47,3 and – 28,5 %, respectively; p&lt;0.05 for both). Myocardial and liver IL-1β and NLRP3 inflammasome expression were also reduced in DAPA/DOXO group vs DOXO and control, indicated beneficial metabolic and anti-inflammatory effects of SGLT2i.

Conclusion
DAPA has been shown to reduce systemic levels of PCSK9 in preclinical models of short-term DOXO cardiotoxicity. To the best of our knowledge, this is the first evidence of SGLT-2/PCSK9 crass-talk in cardioncology therefore the overall picture of the study open a new window on the beneficial properties of DAPA against anthracyclines side effects.
Anti CTLA-4 and PD-1 monoclonal antibodies increases systemic SDF-1 and galectin-3 levels and reduces myocardial strain through NLRP3 and MyD-88 pathways
Authors: Maurea N , De Lorenzo C , Passariello M , Di Mauro A , Cipullo C , Bisceglia I , Paccone A , Iovine M , Florio F , Grimaldi S , Giordano V , Bruzzese F , Palma G , Luciano A , Quagliariello V 
Published: November 2023

Abstract

Background
Immune checkpoint inhibitors (ICIs) have significantly changed the oncology clinic in recent years, improving survival expectations in cancer patients. ICI therapy have a broad spectrum of side effects from endocrinopathies to cardiovascular diseases.

Purpose
In this study, pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models were analyzed.

Methods
Firstly, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (with CTLA-4 or PD-1 blocking agents, at 200 nM) for 72h. After treatment, production of DAMPs and 12 cytokines were analyzed in the supernatant through colorimetric and enzymatic assays. C57/Bl6 mice were treated with CTLA-4 or PD-1 blocking agents (15 mg/kg) for 10 days. Before (T0), after three days (T3) and after treatments (T10), ejection fraction, fractional shortening, radial and longitudinal strain were calculated by using bidimensional echocardiography (Vevo 2100,Fujfilm). Fibrosis, necrosis, hypertrophy and vascular NF-kB expression were analyzed through Immunohistochemistry. Myocardial expression of DAMPs (S100- Calgranulin, Fibronectin and Galectine-3), MyD88, NLRP3 and twelve cytokines have been analyzed. Systemic levels of SDF-1, IL-1β and IL-6 were analyzed before, during and after ICIs therapy.

Results
Radial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 inflammasome and MyD88 and induced both in vitro and in vivo the secretion of IL-1β, TNF-α and IL-6. Systemic levels of SDF-1, IL-1β and IL-6 were increased during and after treatment with ICIs.

Conclusions
Short therapy with PD-1 and CTLA-4 blocking agents increases vascular expression of NF-kB, systemic SDF-1, IL-1β, IL-6 levels and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A pro-inflammatory cytokine storm was induced in myocardial tissues and in cultured cardiac cells after ICIs therapy. The overall picture of the study suggests new putative biomarkers of ICIs-mediated systemic and myocardial damages potentially useful in clinical cardioncology.
Immune checkpoint inhibitors and atherosclerotic cardiovascular events: a retrospective cohort study
Authors: Tan S , Spear E , Sane N , Chan J , Nelson A J , Nerlekar N , Segelov E , Nicholls S J 
Published: November 2023

Abstract

Background
Immune checkpoint inhibitors (ICI) are cancer therapies that have improved the prognoses of over 20 different tumour types (1). However, ICIs have been increasingly recognised to associate with major atherosclerotic cardiovascular events (MACE) in cancer survivorship (2).

Purpose
This study aimed to determine the incidence and predictors for MACE among cancer patients treated with ICIs.

Methods
We performed a single-centre retrospective analysis of consecutive ambulatory cancer patients treated with ICIs between 2018 and 2020. Demographics, baseline cardiovascular risk factors (CVRF), medication history, cancer history and ICI regimen were determined from electronic medical records. The primary endpoint of MACE, defined as a composite of acute myocardial infarction, coronary revascularization, ischaemic stroke, and acute limb ischaemia, was determined from case note review. Cox proportional multivariable modelling was performed to determine predictors for MACE using significant variables on univariate analysis (p&lt;0.20) and variables of clinical relevance including CVRFs and use of dual ICI therapy. Time to first MACE analysis was undertaken; in those without MACE, date of death or last follow-up was used as the censoring date. Subgroup analysis was performed among patients with stage 1-3 cancer who were treated with (neo)adjuvant ICI therapy and expected to have favourable long-term prognoses.

Results
The study cohort included 366 patients (median age 66 years (58,73), 63% male). There were 238 patients (65%) with non-small cell lung cancer and 65 (17.8%) had prior history of atherosclerotic cardiovascular disease (ASCVD). A total of 26 patients (7.1%) experienced 27 MACE (7 myocardial infarction, 1 coronary revascularization, 13 ischaemic stroke, 6 acute limb ischaemia) over median follow up of 1.9 years (0.6,3.2). During the study, there were 226 (61.8%) cancer-related deaths; there were no cardiac deaths. On multivariable analysis, MACE was independently associated with history of ASCVD (hazard ratio [HR] 4.49, 95% CI 1.92-10.49, p&lt;0.01) and hypertension (HR 2.57, 95% CI 1.07-6.17, p=0.04). When limited to those with stage 1-3 cancer, 16 patients (11.0%) developed MACE among a cohort of 145 patients. History of ASCVD was the only variable associated with MACE on subgroup analysis (HR 3.79, 95% 1.25-11.49, p=0.02).

Conclusion
Among an unselected cohort of cancer patients treated with ICIs, an increased risk of MACE was observed among patients with a history of ASCVD or hypertension. Patients undergoing ICI therapy with concomitant ASCVD or hypertension should be identified and their modifiable CVRFs aggressively treated.
Reg3 dependent accumulation of macrophages in aging related atrial fibrillation
Authors: Wang Z , Liu D , Jia Z , Li G , Tse G , Bao Q , Liu T 
Published: November 2023

Abstract

Background
The mechanisms underlying the high prevalence of AF in the elderly population are not well understood. Inflammation induced aging related AF need to be further elucidated.

Purpose
The aim of this study was to explore new mechanisms that inflammation induced aging related AF and provide new directions for the clinical management of the occurrence, development and recurrence of AF in the elderly.

Methods
SD rats fed normally until 20 months of age were constructed as the aging group.The young group (control) was SD rats fed normally until 3 months of age. Electrophysiological examination detected atrioventricular conduction circumference (AVWCL), sinus node recovery time (SNRT), refractory period (ERP) and AF inducibility. Aging rats were also divided into aging prone and non-prone AF according to AF inducibility. RNA-seq was performed on atrium. We overexpressed Reg3γ in both young and aging hearts by AAV-viurs to evaluate electrical and structural remolding, AF inducibility as well as inflammation. Bone marrow-derived macrophages (BMDMs) were isolated and induced. Migration assays, qPCR and cytokine array panel were performed to observe the effects of Reg3γ on BMDMs recruitment, production and secretion of inflammatory factors. RNA-seq and siRNA were performed on BMDMs with or without Reg3γ to investigate the mechanism of macrophage activation by Reg3γ.

Results
AVWCL, SNRT, AERP, AF inducibility and atrial fibrosis were increased in aging rats compared with young controls. RNA-seq analysis of AF-prone atrium in the aging group compared with those in the young group showed the differential genes were mainly concentrated in inflammation-related pathways. The mRNA level of TNFα, CCL2, CCL10 were significantly increased in aging rats. In addition, CD68+ macrophages markedly infiltrated in aging atrium, including cardiac-resident macrophages (CCR2- MCHIIlow and CCR2- MCHIIhi macrophages) and monocytes-migrated macrophages (CCR2+ macrophages). RNA-seq analysis showed Reg3γ was themost significantly varied differential gene, and the expression of Reg3γ was higher in atrium prone to AF with aging than in those non-prone to AF with aging. After overexpression of Reg3γ, both aging and young rats showed great atrial electrical and structural remolding, AF inducibility as well as inflammatory infiltration. In addition, we found that Reg3γ promoted the recruitment of BMDMs, production and secretion of inflammatory factors by qPCR and cytokine array panel. Then, we found Reg3γ regulated macrophages probably through JAK-STAT signaling pathway by GSEA analysis of RNA-seq. And the siRNA results confirmed that Reg3γ activated macrophages through the gp130-JAK1-STAT3 pathway.

Conclusion
Reg3γ recruits macrophages and activates them through the gp130-JAK1-STAT3 pathway, then promoting production and release of inflammatory factors, ultimately contributing to the development of aging related Atrial fibrillation.
Increased incidence of cancer metastasis in young patients with ischaemic heart disease
Authors: Caller T , Fardman A , Naftali Shani N , Leor J , Maor E 
Published: November 2023

Abstract

Background
Heart disease has been linked to an increased risk of developing certain types of cancer. However, while cancer metastasis is the primary determinant of cancer prognosis, the association between heart disease and cancer metastasis has never been studied in humans.

Methods
We evaluated 22,057 self-referred adults, free of cancer and IHD at baseline, who were screened in preventive healthcare as private individuals. To eliminate the cases of silent cancer, we implicated a one-year blanking period at the start of the follow-up. Cancer and mortality data were available for all subjects from national registries. Then, multivariable Cox regression model with IHD as a time-dependent covariate was used to evaluate the association of IHD with metastatic cancer during follow-up. Finally, we implicated the same models in evaluating the differences in risk between young (age&lt;55) and old adults.

Results
During a median follow-up of 6.5 years (Interquartile range 3-13 years), 913 subjects developed IHD and 929 subjects developed metastatic cancer. Compared with subjected who did not develop IHD during follow-up, subjects who developed IHD during follow-up were 64% more likely to develop metastatic cancer during follow-up, in a univariate model (95% CI 1.15-2.36, p=0.0006). Multivariable analysis with adjustment for common risk factors yielded consistent results such that IHD was associated with 50% increased risk of metastatic cancer (Fig-A, p=0.005). Moreover, IHD was associated with poor survival of cancer patients with and without metastasis (HR=1.75 and 1.65, p&lt;0.001 for both). Subgroup analysis demonstrated that the association of IHD with the risk of metastatic cancer was age-dependent: the association was more significant among younger subjects below 55 years of age (Fig-B, n=17,433, n(IHD)=433, HR=2.24, p=0.011), compared with older subjects (n=4624, n(IHD)=480, HR=0.91, p=0.711; p for interaction = 0.085). Notably, IHD emerged as a risk factor for metastatic cancer in younger adults (&lt;55) despite lower rate of cardiovascular risk factors.

Conclusions
We show, for the first time, that ischaemic heart disease is associated with increased and independent risk of metastatic cancer. Furthermore, we demonstrated that the risk is age-dependent and more pronounced among patients younger than 55. Understanding this relationship could lead to advances in cardiovascular and cancer treatment and could ultimately help to improve patient outcomes.
Relation between coronary artery calcium score and cardiovascular events in Hodgkin lymphoma survivors: a cross-sectional matched cohort study
Authors: Polomski E A S , Heemelaar J C , De Graaf M A , Krol A D G , Louwerens M , Stoger J L , Schalij M J , Jukema J W , Antoni M L 
Published: November 2023

Abstract

Introduction
Long-term survival after Hodgkin lymphoma (HL) has improved significantly over the past years, due to enhanced treatment options. Thoracic radiotherapy is still one of the corner stones of HL treatment, but is associated with increased risk of cardiovascular events. As HL is often diagnosed at young age, long-term follow-up including screening for coronary artery disease (CAD) is recommended.

Purpose
This study aims to evaluate the presence and distribution of coronary artery calcium in relation to cardiovascular events in HL patients treated with thoracic radiotherapy compared to a non-cancer control group.

Methods
Consecutive HL patients treated with thoracic radiotherapy, who underwent evaluation for asymptomatic CAD with coronary computed tomography angiography (CCTA) &gt; 10 years after irradiation between 2002 and 2022 were included. HL patients were matched 1:1 to non-cancer patients on gender, age, cardiovascular risk factors and statin use. Differences in coronary artery calcium score (CACS), stenosis severity and cardiovascular events between the two groups were compared.

Results
The total study population consisted of 194 patients of whom 97 patients had a prior HL diagnosis and 97 patients had no history of cancer. Elevated CACS was seen in 50.5% of the HL patients (N=49) and 30.9% of the control patients (N=30). HL survivors had an odds ratio of 2.28 [95% CI: 1.22 – 4.28] for having a CACS &gt; 0 compared to the matched non-cancer population (p=0.006). Distribution pattern of coronary calcium differed significantly with the prevalence of a CACS above the 90th percentile (17.5% in HL survivors versus 4.7% in the matched population, p=0.005). Also coronary artery stenosis was more prevalent in the HL population than in the control population (39.2% versus 15.5% respectively, p=&lt;0.001). Nine HL patients experienced an event during the follow-up period including two patients with a CACS of zero. No events were observed in the control population.

Conclusion
This study shows that in a matched study population, HL survivors have a higher prevalence of a CACS &gt; 0 and an increased risk of cardiovascular events after thoracic irradiation compared to a matched non-cancer control group.Distribution of CACS percentiles
The correlation between cardiac biomarkers and serum cytokines after CAR-T therapy
Authors: Sunayama I , Min K D , Orihara Y , Oboshi M , Yoshihara S , Yoshihara K , Tamaki H , Teramoto M , Nishimura K , Eguchi A , Naito Y , Higasa S , Asakura M , Ishihara M 
Published: November 2023

Abstract

Introduction
As Chimeric Antigen Receptor T cell (CAR-T) therapy gains its clinical advantage in the management of diffuse large B cell lymphoma (DLBCL), accumulating evidence shows that it often accompanies cardiac dysfunction. Previous retrospective studies indicated the potential involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy. Inflammatory cytokines such as IL1βand IL-6 are generally considered as cytokines involved in CRS after CAR-T therapy, but no prospective study has reported which cytokines correlated with change of cardiac biomarkers after CAR-T therapy.

Purpose
The objectives of this study are to prospectively examine the sequential changes in cardiac biomarkers and serum cytokines overtime after CAR-T therapy and to clarify the association between cardiac biomarkers and serum cytokines.

Methods
In this prospective observational study, 30 DLBCL patients who underwent CAR-T therapy were enrolled and classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely the low-CRS group (CRS&lt;2) and the high-CRS group (CRS≧2). Before and after the treatment, the level of cardiac biomarkers and cytokines levels were sequentially collected.

Results
The average age of participants was 59.6 years, and 9 patients (30%) were female. The average duration of DLBCL was 2.7 years. The number of patients in the low- and high-CRS groups was 13 and 17, respectively. The high-CRS group showed significantly higher NT-proBNP levels compared to the low-CRS group on days 3 and 7 after CAR-T therapy (p&lt;0.001 and p=0.003, respectively), whereas troponin T level did not show any differences. The levels of IL-6 and IL-1β on day 3 were significantly higher in the high-CRS group compared to those of the low-CRS group (p=0.001 and p=0.008, respectively). After day 3, the serum level of IL-6 reduced to near the baseline value, whereas the serum level of IL-1β increased further from day 3 to day 7. Given that the significant increase of NT-proBNP level on days 3 was a consequence of CRS, the correlation between culprit cytokine and NT-proBNP levels at the prior time point was expected. Therefore, we analyzed the correlation between NT-proBNP and serum cytokine levels on day 3. NT-proBNP levels were significantly correlated with serum IL-6 (r=0.644, p&lt;0.001) and IL-1β levels (r=0.628, p&lt;0.001).

Conclusion
In the patients who underwent CAR-T therapy for DLBCL, the elevation of NT-proBNP level and IL-6 level were observed on day3 and they were strongly correlated. These data supported the hypothesis that IL-6 was central to the causal mechanisms of CRS cardiotoxicity after CAR-T therapy.Sequential changes in IL-6 and IL-1βCorrelation of NT-proBNP and cytokines
Gender differences in cardio-oncology care of patients treated with immune checkpoint inhibitor therapy
Authors: Mincu R I , Lampe L F , Margraf S M , Michel L , Pohl J , Rassaf T , Totzeck M 
Published: November 2023

Abstract

Background
Immune checkpoint inhibitor (ICI) therapy has significantly improved survival in patients with different cancer entities. It is estimated that nearly half of the patients with advanced cancer will be eligible for immunotherapy in the near future. Cancer therapy-related cardiovascular toxicity (CTR-CVT) could significantly increase morbidity and mortality in this patient population. There is limited knowledge regarding the impact of gender on the development of CTR-CVT under ICI therapy, since there are studies suggesting different immune responses between females and males.

Aim
To identify gender differences in the incidence of CTR-CVT and survival rates in patients with cancer under ICI therapy from the local Essen cardio-oncology Registry (EcoR) database.

Results
1443 cardio-oncology patients were included in the EcoR from 2018 until 2021. 353 patients (24.4%, evaluated through 864 consultations) were treated with ICI therapy. The study population included 38% females vs. 62% males (p &lt; 0.001), 61 ± 13 years vs. 63 ± 13 years (p = 0.077), 72.4% vs. 72.6% metastatic disease (p = 0.802) respectively. 74.2% patients presented with malignant melanoma (78.4% females vs. 71.7% males, p = 0.169), 7.1% with non-small cell lung cancer, 6.5% with squamous cell carcinoma, 5.4% with Merkel cell carcinoma, 3.4% with hepatocellular carcinoma, 1.1% with oropharynx carcinoma and 2.4% with other cancer entities. Male patients showed a higher incidence of arterial hypertension, coronary artery disease, atrial fibrillation and permanent pacing. Additionally, LVEF at baseline was reduced in the male population (Table 1). There was no difference in the ICI regimen between males and females (Table 2). Females and males showed the same incidence of CTR-CVT, including myocarditis (Figure 1) and the same one-year survival rate (87.3% survival in females vs. 84.5% survival in males, p = 0.531).

Conclusion
Females showed similar rates of CVR-CVT and one-year survival compared to male population, despite higher incidence of cardiovascular risk factors and pre-existent cardio-vascular disease in the male population. Further studies should assess gender-specific causes of this difference.Figure 1Tables 1 and 2