bluuebunny/crossref_metadata_2025_split huggingface dataset:
Worse long term prognosis in new onset HFpEF treated in HF clinics compared to HFrEF and HFmrEF patients; reflecting need for effective treatment in HFpEF. Results from the Stockholm PREFERS Study
Authors: Ekstrom M , Hage C , Lynga P , Arslan T , Persson B , Eriksson M J , Wallen H , Linde C , Persson H 
Published: November 2023

Abstract

Background/Introduction
Few contemporary studies are available for long term outcome in patients with new onset heart failure (HF) of the three 3 phenotypes; HF with preserved ejection fraction (HFpEF), mildly reduced (HFmrEF) and reduced EF (HFrEF). The Stockholm PREFERS study (Preserved and Reduced Ejection Fraction Epidemiological Regional Study) included new onset HF patients between 2014-18.

Purpose
To report and compare long term outcomes for patients with new onset HFpEF, vs HFmrEF and HFrEF.

Methods
Totally 547 patients, HFpEF n = 137 (25%), HFmrEF n = 61 (11%) and HFrEF n = 349 (64%) were included and followed to end of August 2021. Time to total and cardiovascular (CV) mortality and CV mortality and first HF hospitalizations were compared by log rank test and Cox regression models. All patients were followed at hospital-based HF clinics for guideline directed information and treatment. HFpEF patients were recommended optimal treatment for comorbidities including hypertension, diabetes, ischemic heart disease and atrial fibrillation, and RAAS-inhibition or diuretics. Primary endpoint: CV mortality and HF hospitalizations.

Results
Mean age was 76 (HFpEF), 71 (HFmrEF) and 67 (HFrEF) years (p&lt;0.001). Female sex 49% (HFpEF), 30% (HFmrEF) and 30% (HFrEF) (p&lt;0.001). Median follow up was 3.8 years (IQR 3.0;4.7). Median EF was 55%, 45% and 30% in HFpEF, HFmrEF, and HFrEF, respectively (p&lt;0.001). All-cause mortality was 13% (n = 70), and CV mortality 7.3% (n = 40). The overall CV hospitalization rate was 13.9% (n = 76). The combined endpoint of CV mortality and HF hospitalizations was 21.2% (n = 116) and higher in HFpEF compared to HFrEF (Univariate Hazard ratio (HR) 2.3 (95% CI 2.0-2.5, p&lt;0.001) and vs HFmrEF (HR 2.5; 2.1-2.6, p&lt;0.001). In analysis adjusted for age, sex and diabetes, HFpEF had worse outcome vs HFrEF and HFmrEF (HR 1.5; 0.2-2.0, p&lt;0.05).

Conclusions
New onset HFpEF patients have worse long term outcome vs new onset HFrEF and HFmrEF patients. There is a need for effective evidence based treatment in HFpEF.Figure 1
Exercise-induced pulmonary congestion is a promising marker to diagnose early stage heart failure in patients referred to rule out myocardial ischemia
Authors: Granger C , Legrand L , Allali Y , Wallet T , Guedeney P , Pousset F , Berman E , Helft G , Le Feuvre C , Isnard R , Collet J P , Montalescot G , Hammoudi N 
Published: November 2023

Abstract

Backgrounds
Pulmonary congestion assessed by B-lines using lung ultrasound (LUS) is a hallmark of heart failure (HF). Latent HF at rest can be unmasked during exercise but the diagnosis remains challenging. Exercise-induced B-lines could help diagnose HF with preserved left ventricular ejection fraction (LVEF) at an early stage. The patients in whom coronary artery disease is suspected are also at risk of HF.

Objectives
To assess exercise-induced pulmonary congestion in patients referred to rule out myocardial ischemia.

Methods
Data of stress echocardiography combined with LUS at rest and immediately after exercise in patients with LVEF≥50% referred for investigation of inducible myocardial ischemia in a tertiary center of cardiology, during a 3-years period of time, were retrospectively analyzed. Patients with induced myocardial ischemia, hypertrophic cardiomyopathy or moderate to severe valvular disease were excluded. B-lines were assessed by scanning 2 chest sites. Exercise-induced pulmonary congestion was defined as an increase of B-lines ≥ 2 between baseline and exercise.

Results
A total of 1114 patients were included. Mean age was 63±11 years, 54% of patients had hypertension and 27% diabetes. Exercise-induced pulmonary congestion was identified in 131 (12%) patients. Age, left atrial volume index (LAVi), resting and 20W septal E/e’&gt;15 and peak tricuspid regurgitation velocity (TRV) were associated with exercise-induced B-lines. In a multivariate logistic regression analysis, LAVi (Odds ratio (OR) = 1.03; 95%confidence interval (CI): 1.01–1.06; p = 0.003) and peak TRV (OR = 3.8; 95%CI: 1.4–10.1; p = 0.009) were independent predictors of exercise-induced pulmonary congestion.

Conclusion
Exercise-induced pulmonary congestion could be diagnosed in patients with preserved LVEF referred to rule out inducible myocardial ischemia. Exercise B-lines are linked with left ventricular diastolic dysfunction indices.
Tristetraprolin in cardiomyocytes has a protective role in pressure-overloaded hearts
Authors: Omiya S , Otsu K 
Published: November 2023

Abstract

Background
Elevated circulating levels of TNFα, IL-6 and the soluble TNF receptors predict adverse outcomes in patients with heart failure. However, the targeted anti TNF approaches resulted in worsening heart failure or death. The entire scenario of how the expression levels of inflammatory cytokines are maintained in failing hearts must be elucidated to develop novel and effective treatments for heart failure. Although transcriptional control is a determinant of the kinetics of proinflammatory cytokine gene expression, the stability of the mRNA also has a key function in coordinating immune responses. Tristetraprolin (TTP) has been shown to control mRNA decay by associating with the 3’- untranslated region and critical for the decay of the mRNAs for cytokines. The role of TTP in nonimmune cells such as cardiomyocytes remains to be elucidated.

Purpose
The purpose of this study is to examine the in vivo role of proinflammatory cytokine degradation by TTP in cardiomyocytes during cardiac remodelling under pressure overload.

Methods
Cardiomyocyte-specific TTP–deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) to induce heart failure. Cardiac remodelling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Cytokine mRNA levels were examined by quantitative PCR.

Results
Cardiomyocyte-specific TTP–deficient mice showed no cardiac phenotypes under baseline conditions. However, the mice exhibited severe systolic dysfunction, indicated by left ventricular fractional shortening, after 4 weeks of pressure overload by means of TAC compared with control littermates (fractional shortening, control littermates 35.8% versus cardiomyocyte-specific TTP-deficient mice 19.9%, p = 0.000). In addition, those hearts showed increases in collagen deposition and the mRNA levels of Col1a2 and Nppb (1.4 times (p = 0.023), 1.5 times (p = 0.033), and 2.0 times (p = 0.020), respectively) compared to corresponding control hearts. Four weeks after TAC, the Il6 mRNA level was upregulated 2.7 times (p = 0.000), but not other cytokine mRNAs, including Tnfα, in cardiomyocyte-specific TTP–deficient hearts compared to controls.

Conclusions
The degradation of cytokine mRNA by TTP in cardiomyocytes plays a protective role in failing hearts and the TTP–mediated pathway in cardiomyocytes might be a therapeutic target to treat patients with heart failure.
PDE2 is cardioprotective in chronic heart failure
Authors: Groener M , Firneburg R , Cachorro E , Rentzsch P , Bantel A , El-Armouche A , Kaemmerer S 
Published: November 2023

Abstract

Background
Patients with chronic heart failure (HF) often develop life-threatening arrhythmia due to structural and electrophysiological cardiac remodelling. The chronic activation of the sympathetic nervous system is initially able to compensate the reduced myocardial contraction. Finally, long-term activation of the β-adrenergic pathway leads to deleterious activation of cAMP-dependent kinases and dysregulation of intracellular Ca2+ handling promoting HF progression and development of arrhythmia. Interestingly, phosphodiesterase 2 (PDE2), an enzyme to hydrolyze cAMP, is upregulated in human HF. Thus, PDE2 might reduce enhanced cAMP levels and pro-arrhythmic Ca2+ releases in HF.

Purpose
We investigated the effects of genetic PDE2 deletion on cardiac function, cellular contraction and arrhythmia occurrence in murine HF model.

Methods
HF was induced via high fat (60 %) diet (HFD) and the treatment with NO-synthase inhibitor L-NAME (0.5 g/l) for 5 weeks in cardiomyocyte-specific PDE2-knockout mice (KO) and control mice (WT). We characterized cardiac function by echocardiography, arrhythmia development by ECG-telemetry, cellular contraction by video-based analysis of sarcomere-shortening and cellular Ca2+ releases using Ca2+ imaging techniques.

Results
After 5 weeks HFD and L-NAME, mice gained weight, displayed increased blood pressure and reduced systolic and diastolic cardiac function. Interestingly, PDE2 KO showed reduced contractility and ejection fraction compared to WT mice after 5 weeks HF. On cellular level, the contraction of isolated cardiomyocytes slightly increased in HF indicating cardiac hypertrophy. However, the β-adrenergic stimulation with isoprenaline (ISO) enhanced cellular contraction only in non-failing WT mice, but was blunted in cells from failing WT hearts reflecting a desensitization of the β-adrenergic pathway. In contrast, the ISO-induced increase in cellular contraction was preserved in failing hearts from KO mice. Interestingly, PDE2 inhibition with BAY 60-7550 increased the ISO-induced cellular contraction in HF from WT, which was not observed in cells from non-failing mice. In HF, the expression of Ca2+ cycling proteins like phospholamban (PLB) were affected. Failing PDE2 KO mice showed higher phosphorylation levels of PLB compared to WT mice with HF. In diseased hearts, pro-arrhythmic triggers like spontaneous Ca2+ waves and Ca2+ sparks were increased. Importantly, diseased PDE2 KO mice developed more arrhythmia in-vivo upon arrhythmia provocation than WT animals.

Conclusion
Cardiac PDE2 deletion was detrimental in HF showing reduced cardiac function and higher number of arrhythmia. PDE2 stimulation might serve as potential therapeutical target in HF limiting the consequences of chronic β-adrenergic hyperactivation.
Association between vitamin D receptor gene polymorphism and cardiomyopathy in response to adriamycin treatment among breast cancer patients
Authors: Mokhtar R , Al-Ansary I , Hassan S , Schaalan M , Sarhan N 
Published: November 2023

Abstract

Background
Chemotherapy-induced cardiomyopathy (CIC) is a common side effect affecting patients with breast cancer treated with anthracyclines chemotherapeutic agents. Vitamin D receptor gene polymorphism seemed to play a crucial role in developing CIC, as vitamin D deficiency was found to increase the risk of many diseases including colon, breast, prostate and ovarian cancer.

Purpose
The current study is primarily to investigate the effect of vitamin D receptor gene polymorphism (ApaI, TaqI, BsmI and FokI) on the incidence of CIC in adult patients with local/advanced or metastatic breast cancer on anthracyclines. Another aim is to detect the association of the gene polymorphism with the response to treatment with chemotherapeutic agents. Moreover, the current study investigated the expression of miR-155 in patients and analyzed its relationship with CIC occurrence.

Methods
This case-control study recruited 60 breast cancer patients with CIC and 30 breast cancer patients without CIC from cardiology and oncology clinics between February 2017 and November 2021. Genomic DNA was extracted from peripheral blood samples and VDR gene polymorphisms were detected using TaqMan techniques.

Results
For the ApaI (rs7975232) and TaqI (rs731236) single-nucleotide polymorphisms (SNPs), the heterozygous (CA) and heterozygous (GA) genotypes increased the risk of CIC among breast cancer patients compared to the control group (OR = 4.31, P &lt; 0.001; OR = 3.2, P = 0.015, respectively). In contrast, homozygous (CC) carriers of the BsmI SNP (rs1544410) had a significantly lower risk for CIC among breast cancer patients (P &lt; 0.001). Finally, for the FokI SNP (rs2228570), there was no significant association with CIC risk. Levels of miR-155 were significantly increased in CIC group compared to the control group (P = 0.015).

Conclusion
The C allele carriers of ApaI SNP and A allele carriers of TaqI SNP are at higher risk of CIC among breast cancer patients; in contrast, the homozygous (CC) carriers of the BsmI SNP are protective against CIC among breast cancer patients. Additionally, higher levels of miR-155 are associated with CIC increased risk among breast cancer patients.
Usefulness of the baseline risk assessment guidelines to predict cancer therapy-related cardiac dysfunction in early-stage HER2 positive breast cancer
Authors: Oristrell Santamaria G , Vila-Sanjuan S , Vila R , Alvarez C , Aguilar R , Arumi M , Escriva-De-Romari S , Saura C , Miranda B , Valente F , Ferreira-Gonzalez I 
Published: November 2023

Abstract

Introduction
Treatment of HER 2-positive breast cancer (HER2+BC) with anthracyclines and HER2-targeted therapy is associated with a high incidence of cancer therapy-related cardiac dysfunction (CTRCD). Baseline risk assessment is crucial to determine patients at high risk of developing CTRCD. Heart Failure Association-International Cardio-Oncology (HFA-ICOS) risk stratification has recently been developed but validation with the new definition of CTRCD is needed (1).

Purpose
To investigate whether the HFA-ICOS baseline risk stratification is useful to identify patients at risk for CTRCD in patients with early-stage HER2+BC.

Methods
95 patients with early-stage HER2+BC were consecutively included in a specialized cardio-oncology unit. In this cohort, patients with previous exposure to antineoplastic treatment, patients with left ventricular ejection fraction (LVEF) &lt; 50% and patients with moderate-severe valvular heart disease had been excluded. All patients underwent a baseline echocardiography study and every 3 months until the end of the chemotherapy. Ultrasensitive troponin I was determined before and immediately after each cycle of chemotherapy.

Results
In our cohort, 48.4% of patients received sequential treatment with anthracyclines and anti-HER2 therapy, while 51.6% received anti-HER2 therapy without anthracyclines. HFA-ICOS baseline risk assessment identified 40 (42,1%) patients with low risk, 27 (28,4%) with moderate risk and 28 (29,5%) with high risk of CTRCD. Table 1 showed the distribution of HFA-ICOS risk factors in our cohort. Only 1 patient with high risk and 3 patients with moderate risk received cardioprotective drugs. At a median follow-up of 13,6 months, 38 patients (40%) did not develop CTRCD, 53 (55,8%) mild-CTRCD, 3 (3,2%) moderate-CTRCD, 1 (1,1%) severe-CTRCD. 3 out of the 4 patients who presented with moderate or severe CTRCD were properly identified as moderate or high risk. However, 52,5% of patients with low risk of CTRCD developed some degree of CTRCD and 19 out of the 38 patients (69,4%) who did not present CTRCD were wrongly identified as moderate or high risk. Table 2 showed the relation between HFA-ICOS risk assessment and the development of CTRCD.

Conclusions
Treatment of early-stage HER2+BC was associated with a high incidence of CTRCD. In our cohort of early-stage HER2+BC, HFA-ICOS baseline risk assessment was useful in identifying patients at risk of developing moderate or severe CTRCD, but was not useful in identifying patients at low risk of CTRCD.HFA-ICOS risk factors and CTRCDHFA-ICOS risk assessment and CTRCD
CerS2 ko in vivo reduces pro-inflammatory ceramides and improves doxorubicin mediated cardiotoxicity
Authors: Kretzschmar T , Bekhite M , Gruen K , Mueller T , Graeler M , Nietzsche S , Westermann M , Schulze P C 
Published: November 2023

Abstract

Background
Ceramides and their role in various signaling pathways are believed to regulate distinct cellular effects. Accumulation of ceramides seems to be associated with an inflammatory phenotype negatively affecting cardiomyocyte vitality and mitochondrial homeostasis.

Aim
The purpose of our study is to identify underlying ceramide signaling pathways and characterize downstream effects on cell vitality of cardiomyocytes.

Methods
A CerS2 ko mouse model was generated and the animals were treated with 7 cumulative doses of 3 mg/kg BW Doxorubicin (Dox). Subsequently, hearts were extracted and analyzed, including mRNA (qPCR) and protein expression (WB) and ceramide level (mass spectrometry).

Results
The CerS2 ko was stable and Dox injection did not increase CerS2 protein expression. Mass spectrometry revealed an increase of long chain ceramides (C≤20) with the highest peak for C18:0 (5.08 ± 0.21, p&lt;0.001) but a decrease of the pro- inflammatory very long chain ceramides C24:0 (0.65 ± 0.20, p = 0.02) and C24:1 (0.23 ± 0.22, p&lt;0.001). qPCR showed a decrease of TNFα (0.18 ± 0.49, p&lt;0.001), IL-1β (0.43 ± 0.27, p&lt;0.001) and BNP (0.28 ± 0.53, p&lt;0.001). Furthermore, mitochondrial homeostasis improved by a reduction of the mitochondria fission related gene Mitochondrial fission factor (Mff) (0.74 ± 0.23, p = 0.007).

Conclusion
CerS2 ko and subsequent ceramide reduction improves cardiomyocyte vitality on a cellular level by a reduction of inflammation and an improvement of mitochondrial function. Thus, regulation of ceramide levels through control of CerS2 activity might represent a novel therapeutic option for the control of cardio toxicity.
Initial phase of anthracycline cardiotoxicity involves metabolic switch and activation of cardiac fibroblasts
Authors: Urbanek K , Donniacuo M , Cappetta D , Telesca M , Riemma M , Bellocchio G , Berrino L , Rossi F , Castaldo G , De Angelis A 
Published: November 2023

Abstract

Background
Doxorubicin (DOX) is an effective anticancer drug, but its application is hampered by cardiotoxicity with asymptomatic diastolic dysfunction as the earliest manifestation. Interstitial fibrosis leads to impaired relaxation, but the timing of fibrotic process and the mechanisms that operate shortly after DOX exposure are not clear. While changes in energy metabolism by DOX is recognized in cardiomyocytes, the effects of DOX on cardiac fibroblasts (CFs) metabolism are unknown.Thus, in a model of anthracycline cardiomyopathy, we asked whether the activation of CFs anticipates the onset of DOX-induced early diastolic dysfunction and evaluated the effects of DOX on the activation and metabolism of CFs.

Methods
Fischer 344 rats were exposed to 6 injections of 2.5 mg/kg of DOX over 2 weeks. Heart function was assessed by echocardiography and left ventricular catheterization. To test the very early in vivo effects of DOX on CFs, primary CFs were isolated from hearts of DOX-treated rats after the first injection of DOX. In another set of experiments, CFs were exposed to DOX in vitro. Cell metabolism was measured by a Seahorse-XF Real-Time ATP assay and cell phenotype was determined by immunocytochemistry and molecular biology.

Results
Early effects of DOX consisted of unchanged ejection fraction and the evidence of diastolic dysfunction. Markers of pro-fibrotic remodeling and histological evidence of CFs transformation were present in the heart immediately after treatment completion. Importantly, at the very beginning of the DOXO exposure, when cardiac function was normal and there was no histological evidence of increased fibrosis, the conversion of CFs to myofibroblasts, evidenced by SMA, was detected. Oxygen consumption rate and extracellular acidification, revealed the increased metabolic activity of CFs after DOX exposure and the switch to the glycolytic energy production. These effects were consistent in CFs isolated from the hearts of DOX-treated animals and in naive CFs exposed to DOX in vitro. The metabolic switch was paralleled with the phenotype change of CFs towards extracellular matrix-producing cells. Upon DOX, CFs upregulated markers of myofibroblast differentiation and the activation of pro-fibrotic signaling (aSMA, TGFb and phospho-SMAD). CFs maintained their functional properties in scratch assay. CFs upregulated also NOX2, indicating these cells as an intramyocardial source of reactive oxygen in the initial phase of the disease.

Conclusion
The metabolic switch and activation of CFs anticipate the onset of DOX-induced early diastolic dysfunction. The effect of DOX on the metabolic profile in CFs represents a novel and potentially targetable component of the very early phase of the pathogenesis of anthracycline cardiomyopathy.
Right ventricular dysfunction in the absence of pulmonary hypertension in HFpEF
Authors: Popovic D , Alogna A , Omar M , Sorimachi H , Kazunori O , Reddy Y N V , Borlaug B A 
Published: November 2023

Abstract

Background
Right ventricular (RV) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), portends worse prognosis, and is believed to be caused by contractile impairment and remodeling due to afterload mismatch from pulmonary hypertension (PH). The goal of this study was to examine the right heart in patients with HFpEF and resting mean pulmonary arterial (PA) pressure (MPAP)≤20 mmHg.

Methods and results
Among 621 patients with HFpEF undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing, 159 (26%) had resting MPAP≤20 mmHg (HFpEFMPAP≤20mmHg). In comparison to 73 controls, they were more obese, had more coronary disease and atrial fibrillation. After adjusting for BMI, there were no differences in plasma volume but NTproBNP was higher and peak oxygen consumption lower in HFpEFMPAP≤20mmHg than in controls (p = 0.002, &lt;0.001, respectively). While RV dimension was similar, tricuspid annular plane systolic excursion and RVs’ were lower in HFpEFMPAP≤20mmHg (18±5 vs. 22±4 mm, p = 0.005; 10±2 vs. 12±2 cm/s, p = 0.047, respectively). HFpEFMPAP≤20mmHg and controls displayed similar pulmonary vascular resistance, MPAP and right atrial pressure at rest, but during exercise, MPAP and right atrial pressure were higher in patients with HFpEFMPAP≤20mmHg (41±10 vs. 33±10 mmHg; 18±7 vs. 12±4 mmHg, p&lt;0.001, respectively). PA compliance was lower at both rest and exercise (rest 4.1±2.1 vs. 5.0±1.8; exercise 2.9±1.4 vs. 3.2±1.4 ml/mmHg, p&lt;0.001, for both).

Conclusion
Right heart dysfunction is present in patients with HFpEF even in the absence of frank PH. These patients display greater pulsatile RV loading by PA compliance even as resistance is not markedly elevated. These data support further study into novel therapies targeting pulsatile RV afterload in HFpEF.