bluuebunny/crossref_metadata_2025_split huggingface dataset:
Importance of familial predisposition to heart failure to the risk of anthracycline related cardiotoxicity: a nationwide study
Authors: Banke A , D'Souza M , Andersson C , Nielsen D , Torp-Pedersen C , Gislason G.H , Moller J.E , Kober L , Madelaire C , Schou M 
Published: November 2020

Abstract

Background/Introduction
Anthracycline-based chemotherapy has improved the prognosis in cancer and hematological malignancies but is associated with the development of heart failure (HF). Besides well-known cardiac risk factors and cumulative dose of anthracycline, recent research has suggested that genetic variations associated with cardiomyopathies may increase the risk of HF associated with anthracycline. However, the importance of familial predisposition for the risk of developing anthracycline associated cardiotoxicity is unknown.

Purpose
To evaluate the risk of anthracycline related HF in patients with vs. without a first-degree relative with HF.

Methods
In the nationwide Danish registries, patients treated with anthracycline from 2004–2016 were identified. Primary outcome was a subsequent diagnosis of HF. Follow-up was 10 years or December 31, 2017. Familial relations were identified in the Danish Family Registry, which hold all persons born since 1942. Exposure was a first-degree biological relative (parent or sibling) with a diagnosis of HF. Risk of HF was evaluated in a cumulative incidence function with death as competing event and in a Fine and Grey model adjusted for age, sex, prevalent ischemic heart disease, atrial fibrillation, hypertension and chronic obstructive pulmonary disease.

Results
A total of 11.651 patients (mean age 48.0 (SD±8.6), 12.2% male gender) were evaluated after exclusion of 46 with pre-anthracycline HF. Mean follow-up was 4.4 years (SD±2.9). In the group with a first-degree relative with HF (n=1.608) 35 patients (2.2%) was diagnosed with HF vs. 133 (1.3%) in the group without a first-degree relative with HF (n=10.043) corresponding to incidence rates per 1000 patient years of 5.2 (95% CI: 3.8–7.3) vs. 3.0 (95% CI: 2.5–3.5). The cumulative incidence of HF was higher in the first-degree relative HF group (Figure 1a), yielding an adjusted hazard ratio of 1.53 (95% CI: 1.05–2.24, p=0.03) for HF associated with anthracycline. All-cause mortality showed a trend towards higher risk in the later 5 years of follow-up in the first-degree relative HF group with a 10-year risk of 32.4% (95% CI: 28.4–36.5) vs. 26.1% (95% CI: 24.9–27.4) but no significant difference in the Kaplan-Meier estimate (p=0.08) (Figure 1b).

Conclusion
In this nationwide register-based study having a first-degree relative with HF was associated with a small but increased risk of anthracycline related HF, yielding attention towards the family predisposition, when estimating the risk of cancer therapy related cardiotoxicity.
Figure 1

Funding Acknowledgement
Type of funding source: Public hospital(s). Main funding source(s): Odense University Hospital
Cardioprotective effect of Trimetazidine in patients with early breast cancer receiving anthracycline-based chemotherapy
Authors: Delle Donne M.G , Iannielli A , Capozza P , De Caterina R , Marzilli M 
Published: November 2020

Abstract

Background
Anthracyclines, alone or in combination with other drugs, are among the most effective chemotherapeutic agents to treat breast cancer both in the adjuvant and neoadjuvant settings. Unfortunately, anthracycline-associated dose-dependent cardiotoxicity is a limiting factor in clinical use. Extensive efforts have been devoted to identifying strategies to prevent anthracycline-induced cardiotoxicity. However, most cardioprotective agents have shown little efficacy in clinical trials. We hypothesized that myocardial damage by anthracyclines could be rationally prevented by using trimetazidine (TMZ), previously reported to interfere with anthracycline- and trastuzumab-induced cardiotoxicity. Therefore, we planned a randomized, controlled, open trial to determine whether TMZ may prevent the development of left ventricular (LV) dysfunction in patients receiving standard treatment for breast cancer.

Methods
The trial included 73 patients (41.2±8.1 years) undergoing surgery for breast cancer, who were scheduled for adjuvant epirubicin-containing chemotherapy and, if indicated, trastuzumab. Patients were randomly allocated in a 1:1 ratio to receive TMZ or baseline therapy only (control group). The main study endpoint was a reduction in the deterioration of left ventricular ejection fraction (LVEF), as evaluated by serial echocardiography performed at randomization and then every 3 months after the start of chemotherapy and for 1 year after its completion. Secondary outcome measures included echocardiographic indices of LV diastolic dysfunction, structural myocardial alterations, as assessed by speckle tracking echocardiography, and changes in cardiac biomarkers (troponin and brain natriuretic peptide).

Results
We found no significant differences between the two groups regarding baseline clinical and echocardiographic parameters. The two groups reached a similar cumulative dose of doxorubicin. No patient died during the study and no patients withdrew from chemotherapy. Three months after the start of chemotherapy, nonsignificant changes were observed in LVEF, shortening fraction, and LV diameters. No significant changes in cardiac biomarkers were observed in either group. Tissue Doppler imaging detected a significant decrease in myocardial velocities (P=0.001) in the control group, indicating LV diastolic dysfunction. In the same group, speckle tracking imaging revealed a statistically significant alteration in ventricular deformation (P=0.01), which means a decrease in LV systolic function. In the TMZ group, no significant alterations in LV diastolic function were observed.

Conclusions
Tissue Doppler imaging and speckle tracking imaging are more sensitive than conventional echocardiograms in the early diagnosis of cardiac dysfunction and TMZ seems to have an important role in the prevention of cardiotoxicity.

Funding Acknowledgement
Type of funding source: None
Pathological assessment of osimertinib-associated cardiotoxicity in EGFR-mutated non-small cell lung cancer patients
Authors: Oka T , Kamada R , Kunimasa K , Oboshi M , Nishikawa T , Yasui T , Shioyama W , Miyashita Y , Koyama T , Kumagai T , Fujita M 
Published: November 2020

Abstract

Background
Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), inhibits both EGFR-TKI sensitizing mutations and resistant T790M mutations detected in non-small cell lung cancer (NSCLC) patients. Cardiac adverse events (AEs) induced by osimertinib are infrequent; however, cases of severe associated cardiac dysfunction have been reported and remain poorly understood.

Purpose
To assess pathogenesis of osimertinib-associated cardiac AEs, we analyzed myocardial specimens of three NSCLC cases with osimertinib-associated cardiac dysfunction.

Results
Analysis of LVEF prior to and after osimertinb administration in 36 NSCLC patients showed significant decrease of LVEF from 69% to 63%. Within this cohort, right ventricular (RV) biopsy was performed in 2 cases to further understand the pathophysiology of cardiac dysfunction. Case 1 was 78-year-old female with advanced NSCLC harboring an EGFR L858R mutation was treated with osimertinib as second line therapy. After 3 moths of osimetinib treatment, she presented with dyspnea, high NT-proBNP and troponin I, and significantly decreased left ventricular ejection fraction (LVEF) at 28%. RV biopsy showed moderate cardiomyocyte hypertrophy without inflammatory cell infiltration. Case 2 was 52-year-old female with advanced NSCLC harboring L858R mutation. She was treated with osimertinib as first line therapy. After 2 weeks of osimertinib, screening echocardiography revealed a reduction of LVEF from 63% to 41% without cardiac symptom. RV biopsy showed mild cardiomyocyte hypertrophy with infiltration of a few inflammatory cells in interstinum. We further analyzed death case of NSCLC. Case 3 was 63-year-old female with advanced NSCLC harboring EGFR ex. 19 del. and T790M mutations. After 6 months of osimertinib, she suffered from severe respiratory failure and severely reduced LVEF at 27%. She died on the 44th day after admission. Pathological autopsy revealed mild to moderate cardiomyocyte hypertrophy without inflammatory cell infiltration in both ventricles. These pathological findings may indicate neither myocyte injury nor myocarditis was induced by osimertinib in myocardium.

Conclusion
Although additional data collection of advanced NSCLC patients will be important in understanding the pathophysiology of cardiac AEs with osimertinib, osimertinib-associated cardiotoxicity may result from functional inhibition of myocyte contractility by osimertinib without induction of cell death or inflammation.

Funding Acknowledgement
Type of funding source: None
Intracoronary autologous bone marrow mononuclear cells for the compassionate treatment of advanced heart failure
Authors: Jones D.A , Baca G.L , Hussain M , Jardim V , Davies L.C , Veerapen J.V , Martin J.E , Lowdell M.V , Mathur A 
Published: November 2020

Abstract

Background
Intracoronary delivery of autologous bone marrow-derived mononuclear cells (BMCs) has been shown to be beneficial in the treatment of patients with ischaemic (IHD) and non-ischaemic dilated cardiomyopathy (DCM). Given the results of phase II clinical trials in this population, our centre initiated the only programme to offer intracoronary BMCs to patients with advanced heart failure due to IHD or DCM in the UK. Clinical data and outcomes in these patients were maintained as part of a registry, the results of which are reported herein.

Purpose
To report outcomes of the first 20 patients with DCM treated at the compassionate stem cell unit.

Methods
A total of 45 patients with advanced heart failure (left ventricular ejection fraction (LVEF) at referral of ≤45%, New York Heart Association (NYHA) classification ≥2 and no secondary cause for the cardiomyopathy) despite optimal medical therapy (OMT) were accepted into the programme and received treatment with intracoronary BMCs, manufactured and supplied as Advanced Therapy Medicinal Products, with adjunctive granulocyte colony stimulating factor (G-CSF). All patients received 5 days of G-CSF followed by bone marrow aspiration and IC infusion of cells (∼10ml of BMCs) on Day 6. LVEF was assessed by cardiac CT.

Results
Of the 20 patients with DCM, 80% were male with a mean age of 64.6±10.6 years (range 45–81 years old). Baseline LVEF was 36.1%±10.6. Baseline NYHA class distributions were 70% NYHA class II (n=14), NYHA class III 25% (n=5), and NYHA class IV – 5% (n=1). All procedures were performed successfully with no procedural complications (100% radial). One year after treatment, 71.4% of people improved by 1 or more NYHA classes with 28.6% noting no change (1 year NYHA classes I (60%), II (27%) and III (13%)). No patients felt worse. A mean increase of 3.4% (±9.6%) was seen in LVEF at 1 year compared to baseline with a corresponding mean reduction in NT-pro-BNP of 18.9% (mean 1012pmol/l vs 1250pmol/l). In terms of clinical events, at 1 year all treated patients were alive, with no reported MACE events and no admissions for heart failure.

Conclusion
IC autologous BMC injections are a novel therapy for patients with advanced HF despite OMT. These data indicate this therapy is safe and results in significant improvement in symptoms of heart failure. An improvement in the LVEF is seen at levels which support initial findings of phase II clinical trials.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Heart Cell Foundation; Barts Heart Centre, St Bartholomew's Hospital
Age-related differences in ventricular remodeling and long-term heart failure outcomes following acute coronary syndrome
Authors: Adamson P.D , Verryt T , Frampton C.M , Troughton R , Doughty R.N , Richards A.M 
Published: November 2020

Abstract

Background
Older patients are at increased risk of heart failure hospitalization following acute coronary syndrome (ACS).

Purpose
We sought to determine whether this increased hazard was related to differing patterns in left ventricular (LV) remodeling over the first 12 months after ACS.

Methods
In a prospective multi-centre observational cohort study, 2,140 patients with ACS underwent echocardiography at 1, 4, and 12 months following the index event. Long-term heart failure hospitalisation events were captured for a median 4.8 (IQR 3.4–6.5) years and the relative risk compared between individuals ≤65 years and those &gt;65 years using a multivariable Cox model adjusted for baseline clinical (sex, blood pressure, coronary revascularisation) and echocardiographic (LV end diastolic and end systolic volumes, LV ejection fraction, interventricular septal wall thickness, and E/e') variables recorded at baseline and 12 months.

Results
The 1177 (55%) participants who were &gt;65 years were more likely to be women (34% versus 22%), had higher blood pressure, were more likely to present with non-ST elevation ACS, demonstrated smaller increases in peak myocardial biomarkers and were less likely to undergo coronary revascularization during the index admission (43.2% versus 72.3%; p&lt;0.001 for all comparisons). At the 1 month visit, after indexing for body surface area, older patients had similar LV end diastolic but larger end systolic volumes (p=0.029), lower LV ejection fractions, and greater left ventricular mass and diastolic filling pressure estimates (E/e' 14 versus 10; p&lt;0.001 for all) compared with the young. Systolic volumes appeared to further diverge at 12 months (p=0.064) however LV mass did not change in either group. In unadjusted analysis older patients were at increased risk of future heart failure hospitalization (HR 4.1, 95% CI 3.2–5.3). This increased risk persisted after adjustment for differences in baseline clinical and echocardiography data, and LV remodeling (adjusted HR 2.4, 95% CI 1.5–3.9).

Conclusions
Older patients experience a more eccentric remodeling pattern over the 12 months following ACS. Older individuals remain at increased risk of long-term heart failure hospitalization after accounting for clinical and echocardiographic characteristics.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): New Zealand Heart Foundation, New Zealand Health Research Council
Association of leptin serum concentration with heart adipose tissue and parameters of systolic and diastolic function in heart failure patients
Authors: Shomanova Z , Ohnewein B , Froeb E.J , Pogoda C , Granitz C , Jirak P , Lichtenauer M , Hoppe U , Reinecke H , Motloch L.J , Pistulli R 
Published: November 2020

Abstract

Aims
Leptin has recently been related to myocardial remodeling in animal experimentation studies on heart failure (HF). Furthermore, leptin has been reported to be related to diastolic dysfunction, however only in healthy population. With the emergence of new medical therapies targeting cardiac remodeling, there needs to be a better understanding of the metabolic pathways involving leptin. Our study aims to investigate leptin's correlation to parameters of systolic and diastolic heart function, as well as epicardial and pericardial adipose tissue (EAT and PAT) in heart failure (HF) patients.

Methods
The study included 51 patients with chronic heart failure with reduced ejection fraction (HFrEF) of ischemic (n=22) and non-ischemic (n=29) origin (NYHA II-III, mean EF 29.56%, SD 8.1; mean BMI 28.08, SD 5.8). Serum concentrations of leptin, NT-proBNP, HbA1c, LDL, and total cholesterol were also measured. Global longitudinal strain (GLS) and other LV function parameters were assessed in transthoracic echocardiography, as well as EAT and PAT in parasternal long and short-axis views.

Results
We found a significant correlation between leptin serum concentration and epicardial, as well as pericardial adipose tissue (EAT r=0.336, p=0.030; PAT r=0.565, p&lt;0.001). There was a significant negative correlation between leptin and GLS (r=−0.332; p=0.045), as well a positive correlation between Leptin and E/E' ration (r=0.373; p=0.039). There was no significant difference between ischemic and non-ischemic HF patients.

Conclusion
We provide evidence of serum leptin correlation to remodeling parameters, as well as epicardial and pericardial fat tissue in HF patients. Whether leptin has positive effects on reversing or preventing remodeling in heart failure, needs further investigation.
Correlation of leptin vs. GLS

Funding Acknowledgement
Type of funding source: None
An epigenetic circuit linking oxidative stress and DNA hydroxymethylation in heart failure
Authors: Elbeck Z , Hossain M.B , Franzen O , Siga H , Karlsson F , Walentinsson A , Moosmang S , Milting H , Lund L.H , Vegvari A , Knoll R 
Published: November 2020

Abstract

Background
Heart failure is a major cause of morbidity and mortality worldwide, but the underlying molecular mechanisms remain not well defined. Reactive oxygen species (ROS) in heart failure (HF) alter multitudes of mitochondrial enzymes and metabolites, such as α-ketoglutarate and its oxidised form L-2-hydroxyglutarate (L-2HG). These metabolites are cofactors for ten eleven translocation (TET) enzymes that convert DNA's 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).

Aim
We hypothesize that oxidative stress during heart failure alters mitochondrial function through epigenetic remodeling, and that reduction of oxidative stress will improve cardiac function.

Methods and results
Targeted LC-MS/MS analysis of dilated cardiomyopathy (DCM) hearts obtained from MLP−/− and WT littermate controls showed a significant increase in the oxidized metabolite L-2HG (∼30%, p=0.004), with significant reduction of multiple TCA cycle intermediates. RNA sequencing revealed a significant reduction in mRNA levels of IDH2 in human TTN related DCM and MLP−/− HF mice. The altered activity of IDH2 contributes to ROS production in these hearts and to the production of L-2HG. No alteration in the mitochondria structures was observed. HF biopsies show decreased TET activity most likely due to increased L-2HG levels. Whole genome single base pair 5mC and 5hmC deep sequencing of gDNA from explanted human DCM heart biopsies and MLP−/− mouse model revealed significantly altered global distribution of both 5mC and 5hmC in comparison to control samples. Genes involved in hypertrophy, such as Myh7 and Fhl2 were among the top genes with differential 5mC levels. Global loss of 5hmC level was observed, especially in the intronic regions of genes involved in redox hemostasis. Reducing oxidative stress in vivo in MLP−/− using a small molecule (AZ14117925) improves heart function (EF) by 13% [EF=(Treated:47,44%, Placebo: 34,54%), n=5 (males per group), p=0.0373, unpaired t-test]. Additional bioinformatic analysis revealed that reduction of ROS most likely leads to activation of TET and activation of pro-survival pathways, anti-oxidative stress response, and significantly less activation of apoptotic pathways.

Conclusion
Alterations in TCA cycle metabolites may underlie changes in DNA methylation and gene expression in end-stage human DCM and mouse models and indicate a role for epigenetic regulation of mitochondrial function in HF. NRF2 activation may pose a novel therapeutic approach to treat this devastating disease.

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): AstraZeneca
Metabolomics and a breath sensor identify acetone as a biomarker for heart failure
Authors: Gladding P.A , Young R , Cooper M , Holland U , Loader S , Chapman L , Chapman A , Smith K , Zarate E , Villas-Boas S , Green S , Thorstensen E , Keven C 
Published: November 2020

Abstract

Introduction
Metabolomics delivers more biological and clinical insight than targeted investigations. We applied metabolomics to patients with heart failure (HF) with reduced ejection fraction (HFrEF).

Methods
46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LC-MS/GC-MS), nuclear magnetic resonance (NMR) metabolomics and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudal strain (GLS) &lt;18%, ejection fraction &lt;50% and NTproBNP ≥35 pmol/L. A low cost consumer breath acetone (BrACE) sensor validated SPME results in 69 patients.

Results
34 metabolites were identified by GCMS, 33 by LCMS and 2 volatiles by SPME (acetone, 2-pentanone in plasma and urine). Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP (r=0.59, 95% CI 0.4 to 0.7), triacylglycerol (55:9), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE &gt;1.5 ppm discriminated HF from other cardiac pathology (AUC 0.88, 95% CI 0.77 to 0.99, P&lt;0.0001).

Conclusion
Breath acetone was detectable in HFrEF patients using a consumer sensor ($1/test) and although not cardiac specific, discriminated HF from other cardiac pathology.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): Health Research Council of New Zealand
Classification of HFrEF based on echocardiography using machine learning to predict future HFrecEF events
Authors: Sakamoto T , Ito S , Endo A , Yoshitomi H , Tanabe K 
Published: November 2020

Abstract

Background
In recent years, there have been sporadic reports of heart failure with recovered ejection fraction (HFrecEF), wherein the left ventricular EF (LVEF) has been improved by considering temporal changes in the LVEF. Although patients with HFrecEF are known to have a better prognosis than other groups, the type of heart failure associated with reduced EF (HFrEF) that subsequently transitions to HFrecEF is yet to be determined.

Purpose
In this study, we examined whether it is possible to predict future HFrecEF events by stratifying the HFrEF using machine learning based on previously recorded echocardiographic indices.

Methods
For 162 patients, with HFrEF and a history of hospitalization owing to heart failure, who underwent echocardiography in a stable hemodynamic state, stratification was performed via machine learning. Regarding temporal changes in the LVEF, 73 patients who underwent another echocardiography under stable conditions were investigated (52 with continued HFrEF and 21 with HFrecEF, with a median follow up of 397 days). HFrEF was defined as a condition for patients with an LVEF of less than 50%, and HFrecEF was defined as a condition for patients who initially had an LVEF of less than 50% but later improved. Patients with severe valvular disease, acute myocardial infarction, acute myocarditis, acute pulmonary embolism, post-cardiac surgery, and pericardial disease were excluded from this group. The random forest method was used as a classification method for machine learning.

Results
When 162 patients with HFrEF were stratified using machine learning, 63 were classified into Cluster 1 and 99 into Cluster 2. Cluster 1 patients showed a significantly higher tendency to transition to HFrecEF than Cluster 2 patients (p=0.001). The Gini coefficient was calculated to identify echocardiographic indices that are important for the purpose of stratification. As a result, LVEF, left ventricular endo-diastolic volume (LVEDV), the thickness of interventricular septum (IVSth), E/A ratio, and the maximum diameter of the inferior vena cava were found to be particularly important. Compared to Cluster 2 patients, Cluster 1 patients exhibited a significantly higher LVEF (41.5±5.9% vs 27.0±7.6%, p&lt;0.001), lower LVEDV (93.6±36.8 mL vs 141.1±51.7 mL, p&lt;0.001), and a higher IVSth (10.8±2.6 mm vs 9.4±2.5 mm, p&lt;0.001).

Conclusion
Stratifying HFrEF via machine learning based on echocardiographic indices can help predict temporal changes in the LVEF and deduce the echocardiographic indices useful for improving LVEF.

Funding Acknowledgement
Type of funding source: None