bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ivabradine prevents doxorubicin-induced cardiotoxicity via attenuating mitochondrial dysfunction and mitochondrial dynamic imbalance in H9C2 cells and rats
Authors: Sripusanapan A , Piriyakunthorn C , Apaijai N , Chattipakorn S , Chattipakorn N 
Published: October 2024

Abstract

Background
Doxorubicin (DOX) is a widely used chemotherapeutic agent, and cardiotoxicity is one of its well-known side effects, which is mediated by cardiac mitochondrial dysfunction. Ivabradine (IVA), a heart rate reduction drug, exerts benefits in various cardiac diseases as shown in both preclinical and clinical studies. However, its roles on DOX-induced cardiotoxicity have never been investigated.

Purpose
We determined whether IVA reduces DOX-induced cardiotoxicity by directly promoting mitochondrial function and maintaining mitochondrial dynamic balance.

Methods
H9C2 cells were divided into 4 groups: 1) Control, 2) DOX (10 μM, 25 h), 3) IVA (3 μM, 25 h), 4) Pretreatment with IVA (3 μM, 1 h), followed by DOX treatment (10 μM, 24 h). Then, cell viability and mitochondrial function were determined. In animal study, male Wistar rats were divided into 4 groups: 1) Control, 2) IVA (10 mg/kg/d, PO), 3) DOX (3 mg/kg/d, 6 doses, IP), 4) Co-treatment with IVA (10 mg/kg/d, PO) and DOX (3 mg/kg/d, 6 doses, IP) for 30 days. Then, heart rate, cardiac function, and cardiac mitochondrial dynamic proteins were determined.

Result
DOX reduced %cell viability of H9C2 cells via increasing cellular and mitochondrial oxidative stress, and reducing mitochondrial respiration (Figure 1A, B). Under DOX-induced cellular injury condition, pretreatment with IVA resulted in increasing %cell viability by 11%, decreasing cellular and mitochondrial oxidative stress; however, IVA did not affect mitochondrial respiration. Consistent with in vitro study, DOX induced cardiac dysfunction as indicated by reduced heart rate and ejection fraction, impaired mitochondrial function and mitochondrial dynamics balance (Figure 1C, D). Co-treatment with DOX and IVA had no further impact on heart rate. DOX-IVA attenuated cardiac mitochondrial dysfunction and mitochondrial dynamics imbalance, thus prevented cardiac dysfunction.

Conclusion
IVA effectively protected against DOX-induced cardiotoxicity through improvement of mitochondrial function, mitochondrial dynamics, and reduction of oxidative stress. These findings suggest the therapeutic potential of IVA in preventing Dox-induced cardiotoxicity.
Clinical validated risk prediction model for development of heart failure after contemporary breast cancer treatment
Authors: Barac A , Chou J , Shara N , Chen L , Shi J , Chlebowski R , Haque R , Potosky A 
Published: October 2024

Abstract

Background
Patients receiving breast cancer (BC) treatment are at risk for heart failure and cardiomyopathy (HF/CM). European Society of Cardiology (ESC) cardio-oncology guidelines recommend baseline cardiovascular (CV) assessment, however, there is limited data about cardiotoxicity risk specific to patients with BC. Our aim was to develop and validate model for prediction of HF/CM in women receiving contemporary treatment for invasive early-stage BC.

Methods
We assembled a cohort women diagnosed with Stage I-III BC from 2008-2020 and followed through 2021 in a large health care plan. Women age &gt;80, with history of HF/CM, and women who received both anthracyclines and trastuzumab were excluded, leaving N=26,044 for analysis. Study cohort was randomly split into derivation (60%) and validation (40%) datasets. Elastic-net penalized Cox proportional hazard model was created using the derivation dataset to select risk factors and to calculate the panelized coefficient which defined the HF/CM risk score. Risk score system was assessed by Hosmer-Lemeshow goodness-of-fit test and area under the ROC curve (AUC). Event rates of &lt;5% constituted low risk; 5-14% moderate; and &gt;15% high risk category. Incident HF/CM events were examined using Kaplan-Meier approach in derivation and validation datasets.

Results
HF/CM risk score had high discrimination ability and sufficiently good model of fit regarding HF/CM events (P value=0.163 and 0.667 from Hosmer–Lemeshow test;AUC 0.751 and 0.764, in derivation and validation sets, respectively). There were 10% of women in the high risk; 30% in moderate; and 60% in low-risk group. Variables associated with the higher HF/CM risk score included age, receipt of anthracycline-based chemotherapy or anti-HER2 therapy, presence of hypertension, diabetes, or history of other CV conditions at baseline. The score pattern showed major effect of age, with anthracycline and anti-HER2 therapy increasing the risk across all age groups (Figure 1). Kaplan-Meier analysis of incident HF/CM over 14 years after BC diagnosis showed significantly lower number of HF/CM events in low risk compared to moderate and high-risk score groups (p&lt;0.0001, Figure 2).

Conclusion
Our robust risk prediction model for HF/CM among women with early-stage BC provides a new tool to identify women at higher CV risk and inform cardiac function monitoring during and after BC treatment. Our findings may guide further validation studies and build evidence for the cardiotoxicity risk stratification in patients with BC.Risk Score for HF/CM by Age/ChemoTxK-M curves of freedom from HF/CM
Latent cytomegalovirus infection associates with impairments in myocardial reperfusion, left-ventricular function, and quality of life after ST-elevation myocardial infarction
Authors: Spray L , Mcintosh A , Mccartney P J , Berry C , Spyridopoulos I 
Published: October 2024

Abstract

Introduction
Cytomegalovirus (CMV) is a ubiquitous herpesvirus affecting the majority of adults in European countries. CMV influences T-lymphocyte biology throughout life. We have previously associated CMV status with adverse left ventricular (LV) remodeling after ST-elevation myocardial infarction (STEMI) in a single-centre study. In this study, we aimed to assess the external validity of these findings.

Methods
This study is a retrospective analysis of 354 patients presenting with STEMI, who were recruited to A Trial of Low-Dose Adjunctive Alteplase During Primary PCI (T-TIME) and had blood samples archived. The participants underwent immediate coronary angiography and percutaneous coronary intervention (PCI), serial cardiovascular magnetic resonance (CMR) imaging at 2-7 days and 3 months post-STEMI, and serial assessment of health-related quality of life with the standardised EQ-5D visual analogue scale (VAS). CMV IgG titre was measured in cryopreserved samples from each patient, and patients were categorised as CMV negative, low-positive or high-positive. All analyses were adjusted for infarct location.

Results
Of 354 patients, 175 (49.4%) were CMV IgG titre negative, 89 (25.1%) were low-positive and 90 (25.4%) were high-positive. CMV+ patients were older (62.5 vs 58.7 years) and more likely to be non-White (6.7% vs 2.3%). CMV+ patients displayed several adverse outcomes. First, myocardial reperfusion was impaired. Thrombolysis in myocardial infarction (TIMI) flow grade 3 after PCI, indicating complete reperfusion, was less common in CMV+ patients (76.0% vs 84.6%; p=0.042). CMV+ patients also had a higher TIMI frame count after PCI (p=0.021), and non-significantly less ST-segment resolution at 60 minutes (38.8% vs 48.4%; p=0.066). Impaired myocardial reperfusion appeared to lead to impaired LV function, with LV ejection fraction (LVEF) measured on early CMR lower in CMV+ patients (42.6% vs 45.3%, p=0.004). At 3 months, LV function remained impaired in CMV+ patients (LVEF: 47.8% vs 49.7%; p=0.035). This was mirrored by CMV+ patients displaying higher NT-pro BNP levels at 2-7 days (1381 vs 1172pg/mL, p=0.097) and 3 months (575 vs 338pg/mL, p=0.021). Finally, impaired LV function appeared to affect quality of life. Over 3 months, in contrast to CMV-negative patients, those with the highest CMV IgG experienced almost no improvement in quality of life, measured by change in the EQ-5D VAS (negative: +9.93; high-positive: +0.70; p=0.0002).

Conclusion
CMV+ patients with STEMI experience worse outcomes, with impaired reperfusion, persistently reduced LV function and less improvement in health-related quality of life over 3 months. We hypothesise that the effect of CMV is mediated through immune activation. Future research should explore the mechanisms by which CMV-specific lymphocytes interact with myocardial reperfusion and repair post-STEMI.
Relationships between 18-month kinetics and functional capacity and left ventricular remodeling and cardiac fibrosis in dilated cardiomyopathy
Authors: Wisniowska-Smialek S , Wypasek E , Szymanska M , Dziewiecka E , Banys P , Urbanczyk- Zawadzka M , Krupinski M , Rubis P 
Published: October 2024

Abstract

Introduction
Myocardial fibrosis is a primary pathogenetic process in dilated cardiomyopathy (DCM) that is responsible for progressive cardiac remodeling and functional capacity impairment. We sought to verify whether there were differences between 18-month kinetics of functional capacity and left ventricular remodeling in DCM patients with different types and advancement of fibrosis who were up-titrated with guideline directed pharmacotherapy (GDMT).

Methods
Between May 2019 and September 2020, 99 DCM patients (88 male, mean age 45.2 ± 11.8 years, mean EF 29.7 ± 10%) underwent cardiac magnetic resonance with assessment of replacement fibrosis via late gadolinium enhancement (LGE) and interstitial fibrosis via extracellular volume (ECV). Each patient had serial (baseline, 6-, 12-, 18 month) functional assessment: NYHA class and 6- minute walking test (6-MWT) and follow-up echocardiography, including measurement of left ventricular end-diastolic volume (LVEDvol) and ejection fraction (EF). Patients were divided into LGE-negative and LGE-positive groups, whereas based on median ECV – they were divided into those with ECV below and above median values.

Results
Overall, LGE was identified in 44 (44%) of patients, whereas median ECV was 27.7%. NYHA class was significantly worse in patients with LGE (1.5±0.5 vs. 1.9±0.6) and with higher ECV (1.93±0.6 vs. 1.6±0.5) in comparison to those without LGE and lower ECV. However, NYHA class improved during observational period in all groups. There were no differences in 6-MWT distance in LGE positive and negative groups at all time points. Baseline 6-MWT distance in LGE positive group was 494.2±88.2 vs. 453.9±98.8 meters in LGE negative group. Baseline 6-MWT distance in upper median ECV group was (408.8±103.5 vs. 492.4±92.9 meter) was significantly lower ECV group (p=0.03). During 18 months 6-MWT distance increased only in LGE negative group but in both ECV groups (Figure 1 A-D). There were no differences in EF between patients with and without LGE and also with higher and lower ECV. Baseline EF in LGE positive group was 27.4±11.2% and 31.7±10.6% in LGE negative. Baseline indexed LVEDvol in LGE positive group was 107.7±40.7 vs. 91.8±37.8 ml/m2 (p=0.09) in LGE negative group. EF increased significantly in both groups, whereas indexed LVEDvol decreased only in LGE negative group (Figure 2 A-D).

Conclusions
Regardless of the presence of replacement and to some extent of interstitial fibrosis, functional and cardiac morphological improvement was observed during 18 months observation in DCM patients on GDMT. The greatest improvement occurred during the first 3 (occasionally 6) months which was associated with the greatest escalation of GDMT. Further dose escalation was not associated with a significant improvement in both functional and morphological parameters.
Determinants of changes in peak oxygen consumption in patients with new onset heart failure
Authors: Jensen M , Thunestvedt M T , Lamberts M L , Schou M S , Nielsen S N , Elmegaard M E , Nouhravesh N N , Holt A H , Shurenberg C S , Wolsk E W 
Published: October 2024

Abstract

Background
Patients with heart failure (HF) with reduced ejection fraction (HFrEF) have a high risk of mortality. Cardio-Pulmonary Exercise Test (CPET) assesses peak oxygen consumption (pVO2) which is considered a key predictor of mortality and morbidity in patients with HFrEF. Factors responsible for the changes in pVO2 could consequently be of interest, as optimizing these factors may improve prognosis and overall quality of life in patients with HFrEF.

Purpose
To investigate factors contributing to changes in pVO2 within a contemporary cohort of new-onset patients with HFrEF.

Methods
From December 2022 to September 2023, patients with new-onset HFrEF (European Society of Cardiology (ESC) criteria) were included from a HF outpatient clinic, who after referral to the clinic underwent 12 weeks of HF management according to ESC guidelines. This included physical training and optimization of pharmacological management of HFrEF. Baseline characteristics, CPET, medication and echocardiography were collected at referral and after 12 weeks. Changes in pVO2 were investigated according to baseline characteristics, changes in medication, and changes in echocardiographic parameters in both uni- and multivariable linear regression models. Significant independent variables were identified using stepwise selection (p&lt;0.1), adjusted for age and sex. A p-value of 0.05 was considered significant.

Results
We included 48 patients with new-onset HFrEF with a median age of 73 (interquartile range (IQR): 60-77) years, 10 (20.8%) women, a baseline median left ventricular ejection fraction (LVEF) of 30% (IQR: 25-35), and a baseline median pVO2 of 17.3 ml/min/kg (IQR: 14.1-21.9). After 12 weeks, pVO2 improved with a mean of +2.18 ml/min/kg (95% confidence interval (CI) 1.25 to 3.10, p&lt;0.01) and LVEF improved with a mean of +11.7% (95% CI 7.9 to 15.6, p&lt;0.01). In univariable analyses increasing age were negatively associated with pVO2 changes (p=0.04) and increasing minute ventilation (MV) and initiation of sodium-glucose cotransporter (SGLT2) inhibitors were all positively associated with pVO2 changes (p&lt;0.01 and p=0.03, respectively). Other clinical variables included in the analysis were not significantly associated with a change in pVO2. In the multivariable analysis, body mass index emerged as an independent variable negatively associated with pVO2 changes, and MV and initiation of SGLT2 inhibitors remained significantly positively associated with pVO2 changes.

Conclusion
Optimal pharmacological management and physical training in patients with new-onset HFrEF, induce a significant recovery of cardiorespiratory performance and ejection fraction. Furthermore, our results suggest that the initiation of SGLT2 inhibitors in patients with new-onset HFrEF appears to improve their pVO2 already after 12 weeks of optimal HF management.Table 1:BaselineTable 2:Associations
Use and associations with mortality/morbidity of guideline-directed medical therapy use in heart failure with improved ejection fraction: a PS-matched analysis from the swedish heart failure registry
Authors: Basile C , Benson L , Lindberg F , Guidetti F , Dahlstrom U , Lund L , Savarese G 
Published: October 2024

Abstract

Background
Guideline-directed medical therapy reduces mortality/morbidity in heart failure (HF) with reduced ejection fraction (EF). However, evidence about its use and prognostic role once EF has improved is limited.

Purpose
To assess use and associations with mortality/morbidity of renin-angiotensin system inhibitors (RASi), angiotensin-receptor neprilysin inhibitors (ARNi), beta-blockers (BBL), and mineralocorticoid receptor antagonists (MRA) in patients with HF and improved EF (HFimpEF).

Methods
We analyzed patients with HFimpEF, defined as a first recorded EF &lt;40% and a subsequent EF ≥40%, registered in the Swedish HF registry between 2004 and 2021. Index date was the SwedeHF registration reporting the second (i.e. improved) EF assessment. To reduce the bias related to the initial recommendation for MRA limited to more severe HF (NYHA III-IV), the assessment of MRA was restricted to patients with index date 2016 or later, when Swedish guidelines on HF included a recommendation for MRA in patients with NYHA class II–IV. The association between treatment use and the composite outcome cardiovascular mortality (CVM)/HF hospitalization (HHF) (with censoring &gt;3 years) was assessed by Cox proportional hazard models in a 2:1 propensity score-matched cohort. Propensity scores for treatment use were calculated by a logistic regression model including 38 variables, achieving a standardized mean difference &lt;0.1 for all evaluated variables. Since matching reduces the sample size and may limit generalizability, a Cox proportional hazard model was fitted in the overall cohort adjusting, rather than matching, for the propensity score (Overall HR).

Results
Of 4700 patients with HFimpEF (mean age 68±12 yrs, 70% male), 94%, 95%, and 50% received RASi/ARNi, BBL, and MRA, respectively. Regardless of the specific treatment, non-users had lower BMI, education level and use of other HF medications, but older age, higher EF at improvement, higher NT-proBNP, and more likely peripheral artery disease, anemia, and valvular disease. In the matched cohorts, RASi/ARNi use was associated with a statistically significant lower risk of CVM/HHF [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.53–0.95] (Figure). There was no statistically significant association between CVM/HHF and beta-blockers (HR 0.75, (95% CI 0.53-1.08), and MRA (HR 1.16, 95% CI 0.90-1.49). These results were consistent after adjustment for the propensity score in the overall cohort (Figure).

Conclusion
In patients with HFimpEF use of GDMT was high. Treatment with RASi/ARNi was associated with lower morbidity and mortality, whereas no statistically significant association was observed with beta-blockers which might be explained by limited statistical power.Composite outcome.
MELD score as predictor of mortality in patients with advanced heart failure: a longitudinal evaluation
Authors: Cacciatore F , Curcio F , Chiappetti R , Amarelli C , Maiello C , Mattucci I , Flocco V , Gerundo G , Mazzella F , Abete P , Cacciatore F 
Published: October 2024

Abstract

Aims
Advanced heart failure (AHF) is characterized by recurrent episodes of hemodynamic instability, frequent hospitalizations leading to a progressive decline in quality of life, and high mortality rates. The objective of this study was to assess the clinical associations of the MELD score and its efficacy in predicting mortality among patients with AHF.

Methods
102 patients with AHF were enrolled, all patients included in the study were on top of tolerated medical therapy according to guidelines. The MELD score was measured at baseline, and every 6 months during follow-up. All patients underwent echocardiographic assessment, six-minute walking test, and cardiopulmonary testing with evaluation of VO2 max and VE/VCO2.

Results
The mean age of the study group was 57.8±11.9 years. There were 26 deaths during a follow-up period of 31.9±15.4 months. The mean NYHA class was 2.8±0.6, ejection fraction was 26.5±6.3%, TAPSE was 17.5±4.1 mm, and NT-pro-BNP was 2746.0±2475.9 pg/mL. The mean VO2 max was 11.7±3.5 ml/kg/min, and the distance covered in the six-minute walk test was 270.1±151.5 meters. Data stratified by mortality showed that deceased patients had higher NYHA class (2.7±0.6 vs. 3.2±0.3; p&lt;0.001), NT-pro-BNP levels (4767.2±2888.1 vs. 1884.0±1669.5 pg/mL; p&lt;0.001), and MELD score (19.3±3.8 vs. 11.9±5.1; p&lt;0.001) compared to those who were alive at follow-up. Multiple regression analysis revealed a positive correlation between MELD score and NT-pro-BNP (Beta = 0.300; p=0.010), and a negative correlation between MELD score and TAPSE (Beta = -0.236; p=0.026). Cox regression analysis identified MELD score as a predictor of mortality (HR = 1.113; 95%CI = 1.011-1.225; p=0.029), independently by the effect of age, NYHA class, NT-pro-BNP, ejection fraction, TAPSE, and VO2 max. Changes in MELD score percentage, considered as a dichotomous variable (≤100% and &gt;100%), were found to be predictors of mortality. Receiver operating characteristic (ROC) curves showed an area under the curve (AUC) of 0.897 for MELD score and mortality.

Conclusions
The MELD score and its longitudinal changes are effective predictors of mortality in patients with AHF, regardless of age, NYHA class, and NT-pro-BNP.
SGLT2 inhibitors are associated with development of heart failure with improved ejection fraction
Authors: Yang C D , Wang X Q 
Published: October 2024

Abstract

Background
Heart failure (HF) with improved ejection fraction (EF), termed HFimpEF, has been proposed as a new HF classification associated with better clinical outcomes. Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce cardiovascular death and hospitalization for HF irrespective of diabetes.

Purpose
Analyze the effect of SGLT2 inhibitors on the development of HFimpEF.

Methods
Consecutive HF with reduced EF (HFrEF) patients with follow-up echocardiogram at around 12 months were enrolled from 2017 to 2022. Patients were classified into HFimpEF (follow-up EF &gt; 40% and ≥ 10% absolute increase) or otherwise persistent HFrEF based on repeat echocardiograms after 12 months. A 1:2 propensity score matched analysis was performed.

Results
Of all the HFrEF patients in the cohort, 46.6% of patients developed HFimpEF. We matched 93 and 186 patients treated with or without SGLT2 inhibitors according to propensity score. In the matched cohort, treatment with SGLT2 inhibitors was associated with nearly a doubled likelihood of the development of HFimpEF (OR: 1.978 [95% CI 1.184~3.346]). Subgroup analysis revealed this association was only present in HF patients with an ischemic etiology (OR: 3.427 [95% CI 1.614~7.573], P for interaction=0.022). There was no significant interaction term between SGLT2 inhibitors and the presence of diabetes for the development of HFimpEF.

Conclusions
This study reveals that treatment with SGLT2 inhibitors is associated with increased likelihood of HFimpEF, especially in those with an ischemic etiology.