bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring criteria for active surveillance of perioperative myocardial infarction/injury following noncardiac surgery
Authors: Puelacher C , Weder S , Glarner N , Strebel I , Burri K , Pargger M , Gualandro D M , Osswald S , Mueller C
Published: November 2023

Introduction

Recent cardiology guidelines on perioperative management of cardiovascular diseases during noncardiac surgery include recommendations concerning perioperative screening for perioperative myocardial infarction/injury (PMI) to improve patient care. However, little evidence exists on the optimal population to be screened.

Methods

In this post-hoc analysis of our ongoing prospective multicenter observational study BASEL-PMI which included consecutive high-risk patients undergoing major noncardiac surgery, who 1) were ≥45 years with a history of coronary artery disease, peripheral arterial disease, or stroke/TIA, summarized as established atherosclerotic disease (EAD) OR 2) were ≥65 years old. For these two groups, we calculated univariable incidences of PMI stratified by risk factors, surgical specialties, and surgical risk estimates . A Conway-Maxwell Poisson regression model was used to obtain multivariable adjusted incidence rates.

Results

Between 2014-2018 9290 patients were included, of which 13.3% developed a PMI. The incidence rates of PMI were higher in patients with EAD than in patients without EAD, but in both groups the incidence of PMI was >10%. In both groups, patients with chronic heart failure (CHF, 19 and 27%, respectively) and chronic kidney disease < 30 ml/min (19 and 29%, respectively) were associated with the highest incidences of PMI. In multivariable analysis, high surgical risk classification, anemia, and a metabolic equivalent of task (MET) <4 showed the highest incidence rate of PMI (high-risk surgery: 8.08/100 patients, intermediate-risk surgery 7.63/100 patients, anemia: 6.73/100 patients, MET <4: 6.25/100 patients), while cardiovascular comorbidities were evenly distributed.

Conclusions

Patients undergoing noncardiac surgery with established EAD or aged >65 years all show an incidence of PMI >10%, hence screening seems warranted in those patients. Established atherosclerotic disease, established CHF, higher risk of surgery, anaemia, and poor MET are associated with high rates of PMI.Poisson adjusted PMI Incidence Rate
Impact of beta blockers on perioperative complications in patients undergoing major noncardiac surgery
Authors: Glarner N C , Puelacher C , Menosi Gualandro D , Pargger M , Burri K , Bolliger D , Mueller C
Published: November 2023

Introduction

Beta blockers (BB) are broadly used in patients with cardiovascular disease because they are known to decrease myocardial oxygen consumption by decreasing heart rate and myocardial contractility. Pilot studies have shown conflicting results. Therefore, we aimed to evaluate the impact of preoperative BB therapy on (1) the incidence of cardiac perioperative myocardial injury/infarction (PMI) within 48 hours after surgery and (2) long-term MACE within 365 days in patients after major noncardiac surgery.

Methods

We prospectively included consecutive high-risk patients undergoing inpatient major noncardiac surgery at a university hospital and a hospital, both in Switzerland, who were eligible for the institutional active PMI surveillance and response program. The primary endpoint was PMI due to cardiac causes (type 1 myocardial infarction (MI), tachyarrhythmia, acute heart failure, or type 2 MI) within 3 days after surgery, centrally adjudicated by two independent experts. The secondary endpoint was the occurrence of MACE, defined as a composite of acute myocardial infarction, acute heart failure, life-threatening arrhythmia, and cardiovascular death, within 365 days. We used inverse probability of treatment weighting to account for differences between BB and non-BB users and then performed a univariable logistic regression with cardiac PMI and a univariable Cox proportional hazard model with MACE as a dependent variable.

Results

Between October 2014 and February 2018, we included 7751 high-risk patients undergoing major inpatient noncardiac surgery. The median age was 74 years and 45% were female. 2856 of 7751 patients (36.8%) received preoperative BB therapy. Patients receiving BB therapy had more cardiovascular comorbidities like known coronary artery disease, atrial fibrillation, or hypertension. After IPTW, we achieved a good balance between patients receiving BB therapy and those who did not. 812 patients (10.5%) had a cardiac PMI within 3 days after surgery. When comparing the patients receiving BB to those that did not, we did not see any difference in the occurrence of cardiac PMI, resulting in a weighted odds ratio of 0.99 (95% Confidence interval [CI] 0.89-1.10). The composite secondary endpoint MACE within 365 days occurred in 9% of all patients. In multivariable analysis, there was no difference between patients receiving BB and those that did not, with a weighted hazard ratio of 1.07 (95% CI 0.86-1.33).

Conclusion

In our patient cohort, we could not see any difference in cardiac PMI between patients receiving BB therapy and those who did not, suggesting that continuing BB perioperatively is safe but not associated with any benefit. Also after 1 year, we saw no difference in MACE between patients receiving BB therapy versus those who did not.MACE within 365 days
Body composition in elderly with myocardial infarction
Authors: Kanic V , Kompara G , Suran D , Naji F H
Published: November 2023

Background

Body mass index may differ significantly from true fatness and cannot distinguish between excess body fat (BF) and an increase in fat-free mass (FFM) (a surrogate for skeletal muscle mass). Both FFM and BF have been shown to influence prognosis. Greater skeletal muscle strength enables better mobility and cardiorespiratory fitness, both of which are known prognostic factors for better outcome. There are no data on a possible association between body composition and prognosis in the elderly with myocardial infarction.

Purpose

We aimed to evaluate the effects of FFM and BF on 30-day and one-year all-cause mortality in patients ≥ 65 years of age with MI who underwent PCI.

Methods

This retrospective study was conducted at a tertiary referral hospital with a 24/7 PCI service. We screened 8348 MI patients, of whom 3946 were ≥ 65 years old. We formed four groups of patients with different body composition: HighFFM-LowBF (22 patients), HighFFM-HighBF (2165 patients), LowFFM-LowBF (1165 patients), and LowFFM-HighBF (594 patients). These groups were compared. Data were analyzed using descriptive statistics.

Results

The lowest mortality was observed in the HighFFM-LowBF group (4.5%), followed by the HighFFM-HighBF group (9.3%), LowFFM-LowBF and LowFFM-HighBF (13.0% and 13.1%, respectively; p=0.002 (Figure 1). After one year, mortality was 18.2% in the HighFFM-LowBF group, 16.1% in the HighFFM-HighBF group, 22.6% in the LowFFM-LowBF group, and 26.4% in the LowFFM-HighBF group; p< 0.0001. (Figure 2). After adjustment for confounders, body composition groups were not associated with 30-day mortality (p=0.14), but were independently associated with one-year mortality risk (p=0.012).

Conclusion

Our result suggests that body composition is important in elderly patients with MI. We found that elderly patients with greater FFM (≈ muscle mass) survived better. The highest mortality was observed in sarcopenic obese elderly (low muscle mass and high body fat percentage).All-cause mortality in 30 daysOne-year all-cause mortality
Short and long-term renal function changes with direct oral anticoagulants in elderly patients with atrial fibrillation
Authors: Armentaro G , D'arrigo G , Bo M , Cassano V , Miceli S , Pitino A , Tripepi G , Sesti G , Lip G Y H , Pastori D , Gori M , Sciacqua A
Published: November 2023

Background

Atrial Fibrillation (AF) and chronic kidney disease (CKD) frequently coexist in elderly patient. Previous evidence showed that vitamin K antagonists (VKAs) may be associated with an accelerated decrease of estimated glomerular filtration rate (eGFR) compared to direct oral anticoagulants (DOACs). However, there is little evidence on DOACs in the elderly population and in real life settings; the evidence available to us comes from randomized clinical trials with younger populations.

Purpose

The main objective of this study was to investigate the medium to long term renal function changes in older AF patients treated with DOACs and VKAs.

Methods

Enrolled patients underwent 3 eGFR measurements during follow-up, and the between arms difference in eGFR lost over time was investigated by 1) the Linear Mixed Models (LMM) and 2) group-based trajectory model (GBTM) analyses. Analysis was done according to short-term (3.2 years) and long-term follow-up (6.7 years). During the study period 420 enrolled AF patients (77.0±6.0 years, 136 on VKAs and 284 on DOACs) underwent 1260 eGFR assessments.

Results

After a median follow-up of 4.9 years, in the whole sample eGFR decreased from 67.4±18.2 ml/min/1.73 m2 to 47.1±14.3 ml/min/1.73 m2, p<0.001. Patients on DOACs experienced a significantly lower eGFR decrease that those treated with VKAs (-21.3% vs -45.1%, p<0.001). The benefit of DOACs compared with VKAs was evident both in the short term (eGFR decline -6.6 (95% CI: -9.1 to -4.0) ml/min/1.73 m2 vs -19.9 (95% CI: -23.6 to -16.2) ml/min/1.73 m2 respectively) and in the long-term, (eGFR -13.5 (95% CI: -16.1 to -11.0) ml/min/1.73 m2 in DOACs group vs -34.2 (95% CI: -37.9 to -30.5) ml/min/1.73 m2), respectively). After stratifying our study population into 5 groups according to trajectories of renal function decline, from the first (lowest decline in eGFR) to the fifth (greatest decline in eGFR), the first trajectory consisted of 80% patients on DOACs therapy. Logistic regression showed that the group on DOACs therapy was 3.03- to 4.24-fold more likely to belong to the trajectory with less eGFR decline than the VKAs group.

Conclusions

In conclusion, DOACs were associated with less long term decline in renal function in elderly patients with AF compared with VKAs.
The effect of anthracycline-based chemotherapy on endothelial function and arterial stiffness in breast cancer patients
Authors: Anastasiou M , Oikonomou E , Theofilis P , Papamikroulis G A , Gazouli M , Pesiridis T , Goliopoulou A , Papatheodoridi D , Psyrri A , Zagouri F , Siasos G , Tousoulis D
Published: November 2023

Introduction

Cardiotoxicity restricts anthracycline and trastuzumab treatment of Human Epidermal Growth Factor Receptor 2 positive early breast cancer. Endothelial dysfunction and arteriosclerosis are significant cardiovascular risk factors.

Purpose

We studied the effect of anthracycline-based chemotherapy, with or without trastuzumab, on endothelium and arteriosclerosis in patients with breast cancer.

Methods

In this case-control study, 52 women with breast cancer and 104 women without breast cancer were examined longitudinally up to 15 months following (in the breast cancer group) initiation of chemotherapy. Arterial stiffness was evaluated through pulse wave velocity (PWV), while endothelial function via flow-mediated dilatation (FMD) at baseline (T0), 3 (T1), 6 (T2), and 15 (T3) months later.

Results

There was no difference between subjects with breast cancer and control in PWV and FMD at baseline. Longitudinally, participants with breast cancer exhibited considerable impairment of PWV and FMD compared to the control group (p for interaction < 0.001 for both parameters). In breast cancer patient there was a significant increase from T0 to T3 in PWV (7.43 ± 1.68 m/sec vs. 8.18 ± 2.00 m/sec, p = 0.01) and decrease in FMD (6.95 ± 2.86 % vs. 5.03 ± 2.83 %, p = 0.006). The addition of trastuzumab in the treatment did not have any effect on PWV (p = 0.74) or FMD (p = 0.91).

Conclusions

In patients with breast cancer, there is progression of endothelial dysfunction and arteriosclerosis up to 15 months following initiation of anthracycline-based chemotherapy. Trastuzumab has no additive effect on endothelial function or arterial stiffness.Figure 1Figure 2
Monocyte-to-lymphocyte ratio as predictor of cancer therapy-related cardiotoxicity in patients with breast cancer
Authors: Saffi M , Pivatto Junior F , Barreto Santiago Santos A , Foresti Englert E , Mazzutti G , Oliveira Magalhaes Costa G , Emanuel Rubini Liedke P , Henrique Fritsch V , Biolo A
Published: November 2023

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 (PLR), and systemic immune-inflammation index [SII = (neutrophil × platelets)/ lymphocyte] are inflammation markers easily obtained through of the blood count.

Purpose

To evaluate the development of CTRCD according to pre-treatment blood inflammatory biomarkers in patients with breast cancer. To evaluate the development of CTRCD in patients with HER2+ early breast cancer according to MLR, NLR, PLR, and SII inflammatory markers obtained from pre-cancer therapy blood count.

Methods

Prospective cohort study including consecutive female patients ≥ 18 years with HER2+ early breast cancer who consulted at the institution's breast oncology outpatient clinic between march/2019 and march/2022. This study was approved by the Institutional Review Board (protocol No. 2019-0010). Furthermore, it was conducted in accordance with Resolution no.466/12 of the National Health Council. 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 area under the ROC curve (AUC-ROC). P < 0.05 was considered statistically significant.

Results

Forty-nine patients (53.3±13.3y) were included and followed up for a median of 13.2 (IQR 25-75%: 10.8-16.1) 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, Figure A-D). MLR showed statistically significant AUC-ROC (0.802; P = 0.017). CTRCD was observed in 27.8% of patients with high MLR vs. 3.2% with low MLR (P = 0.020); negative predictive value was 96.8% (95%CI: 83.3-99.4%).

Conclusions

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.Figure (A-D)
Modeling familial sinus node dysfunction with a large intergenic deletion between PITX2 and ANK2 using iPS cell-derived sinoatrial nodal-like cardiomyocytes
Authors: Aizawa T , Makiyama T , Murata H , Takaki T , Baudic M , Gao J , Imamura T , Ohno S , Yoshida Y , Shimizu W , Makita N , Barc J , Schott J J , Horie M , Kimura T
Published: November 2023

Background

Pituitary homeobox 2 (PITX2) encoded by PITX2, is one of the transcription factors and plays an important role in establishing the left-right axis during development. In the heart, PITX2 inhibits the development of the sinoatrial node (SAN) in the left atrium, whereas the absence of PITX2 allows the development of SAN in the right atrium. In a multicenter study, we recently identified a sizeable intergenic deletion between PITX2 and ANK2 on chromosome 4q25 in familial sinus node dysfunction (SND). The deletion contains a CTCF-binding motif (19 bps) which forms a topologically associating domain (TAD) involved in PITX2, and putatively disrupts the TAD. In order to investigate how the intergenic deletion causes SND, we analyzed iPS cells (iPSCs) by specifically differentiating them into SAN cardiomyocytes.

Methods and results

We identified an intergenic heterozygous deletion of 30k bps in a Japanese family with SND by whole genome sequencing. In the SND family, all 11 genetically affected patients developed SND since childhood, and seven of them underwent pacemaker implantation (the mean age was 26). To elucidate the pathology, we utilized 3 iPSC lines: an iPSC line from a patient, a homozygous CTCF-binding motif knockout line by gene editing, and a control line from a healthy volunteer. We modified the previously reported SAN differentiation protocol1 and generated SAN-like iPSC-derived cardiomyocytes (SANLCMs). SANLCMs showed a higher beating rate than ventricular-like cardiomyocytes (VLCMs), and exhibited SAN-like action potential morphology recorded using a patch-clamp technique. SANLCMs contained lesser NKX2-5 positive cells than VLCMs by immunostaining analysis and their gene expression patterns were compatible with SAN cardiomyocytes: higher expression levels of SHOX2, TBX18, TBX3, and HCN4, and lower expression levels of PITX2, NKX2-5, and MYL2 compared with VLCMs. Then, we analyzed the gene expression profiles during the SAN differentiation. SANLCMs from CTCF-binding motif knockout iPSC lines showed lower beating rates than controls. We also found that the levels of PITX2 expression in SANLCMs from patient-derived and CTCF-binding motif knockout iPSC lines were significantly higher compared to those from the control.

Conclusion

Our findings suggest that the lack of CTCF-binding motif involved in a large intergenic deletion on chromosome 4q25 might be associated with a hypoplasia of SAN via PITX2 overexpression during cardiac development.
Echocardiographic signs of aortic valve dysfunction in patients with Philadelphia-negative myeloproliferative neoplasms
Authors: Solli C N , Chamat-Hedemand S , Elming H , Ngo A , Kjaer L , Skov V , Soerensen A L , Ellervik C , Hasselbalch H , Bruun N E
Published: November 2023

Background

Patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) have an increased prevalence of calcifications on the aortic valve, but the prevalence of aortic valve stenosis or regurgitation has only been reported in one small study based on outdated guidelines, and a few case reports. Chronic inflammation and increased shear stress on the aortic valve increase the risk of developing aortic valve dysfunction. The proliferation of mature blood cells in patients with MPNs leads to increased blood viscosity that increase shear stress on endothelial cells in the blood vessels, and likely also on the aortic valve. Furthermore, there is evidence of chronic inflammation in patients with MPNs.

Purpose

To investigate if patients with MPNs had a higher prevalence of aortic valve stenosis and/or regurgitation compared to the general population.

Methods

Patients with the MPN diagnosis were recruited between 2016 and 2018 and examined with echocardiography. The patients were matched 1:1 on sex and 5-year age span, with participants from CCHS, a large on-going population study. Aortic valve stenosis was defined as an AV Vmax >2.5 m/s measured by continuous wave Doppler and aortic valve regurgitation was defined as colour Doppler with a visible regurgitation jet.

Results

We included 167 patients with MPNs (mean age 66 years [SD ± 10]) and 167 controls (mean age 62 [SD ± 10]). There was a significantly higher median AV Vmax in the MPN cohort (1.4 vs 1.3 m/s, p<0.0001) and a significantly lower mean aortic valve area (2.2 vs 2.6 cm2, p<0.0001). There were nine patients (5%) in the MPN cohort who fulfilled the criterion for aortic valve stenosis while no one in the control group fulfilled this criterion (p=0.0035). Aortic valve regurgitation was found in 41 (25%) MPN patients and 8 (5%) controls (p<0.0001)

Conclusion

Patients with MPNs have a higher prevalence of aortic valve stenosis and aortic valve regurgitation compared to the general population.Graphical overviewTable 1
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

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<0,001). IL-1β and CRP levels were also reduced ( -47,3 and – 28,5 %, respectively; p<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

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

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<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<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

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

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<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<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 (<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

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) > 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 > 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=<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 > 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

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<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<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<0.001) and IL-1β levels (r=0.628, p<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

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 < 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
VCAM-1 accelerates atrial remodeling in TERT-/- mice
Authors: Wang Z , Zhao R , Zhou Z , Zhang X , Yuan J , Liu D , Wang F , Liu T
Published: November 2023

Background

Aging, an independent risk factor for AF, could significantly increase its morbidity and mortality. The mechanism of AF in the elderly population remains to be further elucidated. Atrial remodeling is considered to be an important mechanism of atrial fibrillation. Telomerase dysfunction and telomere shortening are important signs of aging, and the relationship and mechanism between telomerase dysfunction and atrial remodeling is not very clear.

Purpose

This study aims to explore the mechanism of atrial remodeling caused by telomerase dysfunction.

Methods

The atrial electrophysiology was used to detect refractory period (ERP) and atrial fibrillation inducibility, and the epicardial electrical mapping technique was used to detect the atrial conduction velocity, direction and conduction heterogeneity to evaluate the atrial electrical remodeling. HE and Masson staining were used to evaluate atrial structural remodeling. RNA-seq analysis screened out the differential genes and corresponding pathways in each model.

Results

Compared with wild-type (WT) mice, a third-generation of telomerase reverse-transcriptase knockout mice (F3 TERT-/-, hereafter as TERT-/-) showed a shortened atrial ERP, increased atrial fibrillation inducibility, slowed atrial conduction velocity,change in the direction of propagation, and increased atrial fibrosis, suggesting electrical and structural remodeling in TERT-/- mice. RNA-seq revealed significant changes in cell adhesion molecules (CAMs) of TERT-/- mice compared with the WT, among which vascular adhesion molecule (VCAM-1) changed most significantly. Then, TERT-/- mice were treated with anti-VCAM-1 neutralizing antibodies, atrial electrical and structural remodeling was partially relieved compared to untreated TERT-/- mice. RNA-seq and KEGG enrichment analysis were conducted on differential genes, which were mainly concentrated on extracellular matrix (ECM)-receptor interaction. Furthermore, we found that the extracellular matrix LAMC3, Collgen1 and myofibroblast marker α-SMA were reversed in TERT-/- mice treated with anti-VCAM-1 neutralizing antibodies compared with TERT-/- mice.

Conclusion

VCAM-1 could accelerate the production of extracellular matrix, and ultimately lead to atrial electricity and structural remodeling, and the occurrence of atrial fibrillation in TERT-/- mice.
Age- and sex- specific rate of venous thromboembolism in cancer survivors: a nationwide cohort study
Authors: Sun G L , Fosbol E L , Schou S , Nouravesh N , Lamberts M , Kober L , Butt J H
Published: November 2023

Background

Patients with cancer have an increased risk of venous thromboembolism (VTE) initially, then to decrease over time. VTE might be potentially preventable with pharmacologic prophylaxis, particularly in high-risk patients. The long-term risk of VTE among cancer survivors, however, has not been reported.

Purpose

We investigated the rate of VTE in survivors of various cancers 5 years out from diagnosis, overall and according to age and sex.

Methods

Using Danish nationwide registries, five-year survivors of 20 cancers (diagnosed between 1994 and 2013; >15 years at diagnosis) were matched on age and sex with four non-cancer controls from the general population. Rates of VTE in the cancer and non-cancer groups were compared with Cox regression models, overall and according to age (i.e., 15-39, 40-64, and >65 years) and sex.

Results

In total, 197,702 five-year cancer survivors (median age at diagnosis 63 years [IQR: 53 – 71 years]; 38.5% men) were matched with 790,808 non-cancer controls. During a median follow-up of 6.2 years, cancer survivors overall had a higher associated rate of incident VTE than non-cancer controls (incidence rate per 1,000 person-years 5.6 [95% CI, 5.5-5.8] and 3.3 [3.3-3.4] for cancer survivors and non-cancer controls, respectively; adjusted hazard ratio [aHR] 1.77 [1.72-1.83]). The increased rate of VTE in cancer survivors, compared with matched controls, was statistically significant for all 20 cancer subtypes and was more pronounced in multiple myeloma and lung cancer [Figure 1]. The relatively higher rate of VTE in cancer survivors was more pronounced in women, and the younger patients (age group: 15-39 years) (PInteraction<0.01). Though, VTE was more prevalent in men (per 1,000 person-years 6.7 [95% CI, 6.4-6.9]) than in women (5.2 [95% CI, 5.0-5.3]), and in older patients (8.5 [95% CI, 8.2-8.7]) compared with younger patients (2.2 [95% CI, 1.9-2.4]) [Figure 2].

Conclusions

Compared with the general population, five-year cancer survivors had higher associated rates of VTE, irrespective of age and sex. The increased relative rate of VTE was more pronounced in the younger individuals and women.Hazard ratios of venous thromboembolismVenous thromboembolism by age and sex