bluuebunny/crossref_metadata_2025 huggingface dataset:
HECT domain containing-3 (HECTD3) E3 ubiquitin ligase attenuates cardiac ischemia and hypertrophy in mice
Authors: Rangrez A , Borlepawar A , Schmiedel N , Deshpande A , Helbig A , Tholey A , Mueller O J , Frank D , Frey N
Published: October 2024

HECT domain containing 3 (HECTD3) is one of the E3 ubiquitin ligases, the cardiac function of which is not completely understood yet. We aimed here to understand the role of HECTD3 in cardiomyocytes using loss- and gain-of-function approaches in in vitro and in vivo models.

Interestingly, we found that HECTD3 was significantly downregulated in cardiac tissue obtained from human patients suffering from cardiac hypertrophy and ischemia. We thus employed loss- and gain-of-function approaches in neonatal rat cardiomyocytes (NRVCMs) to get further insights into potential cardiac function of HECTD3. Overexpression of HECTD3 in NRVCMs attenuated cardiomyocyte hypertrophy and lipopolysaccharide (LPS) or interferon-γ (IFN- γ) induced cellular inflammation; its knockdown on the other hand aggravated these effects. Mechanistically, using Yeast two-hybrid screen, mass-spectrometry, and transcriptomics analyses, we identified Small Ubiquitin like Modifier 2 (SUMO2) Signal Transducer and Activator of Transcription-1 (STAT1) as novel substrates for HECTD3, regulation of which resulted into attenuation of hypertrophy and inflammation, respectively. To translate these in vitro results in vivo, we employed Adeno-associated virus-9 (AAV-9) mediated gene therapy approach to overexpress HECTD3 specifically in the heart of mouse models of cardiac ischemia due to permanent ligation of the left anterior descending artery (LAD), and cardiac hypertrophy due to transverse aortic constriction (TAC). Overexpression of HECTD3 in mice, though moderate but significantly improved cardiac function upon ischemic or hypertrophic stress compared to respective control groups. Importantly, in vitro findings were consistent in vivo, where AAV-9 mediated overexpression of HECTD3 substantially reduced cardiac hypertrophy and fibrosis, improved cardiac function as assessed by echocardiography, inhibited activation of STAT1-mediated downstream signaling, and attenuated infiltration of inflammatory cells to the heart after TAC or LAD ligation. This data indicates that HECTD3 is a novel modulator of cardiac ischemia, hypertrophy, and inflammation via regulation of SUMO2 and STAT1-signaling.

In conclusion, we report here a novel cardioprotective mechanism involving the E3 ubiquitin ligase HECTD3, which exerts anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and its SUMOylating target STAT1. We believe that this "dual pathway" inhibition exhibits translational importance and could further be exploited for the prevention and/or therapy of heart failure due to cardiac ischemia or hypertrophy.
The essential role of the miRNA-208a/TARBP2/Sox6 axis in myosin expression in the end stage human heart failure
Authors: Kyselovic J , Cervenak Z , Hulman M , Gazova A
Published: October 2024

Despite diverse aetiologies, failing human hearts (HF) of various origins (coronary artery disease (CAD), dilated cardiomyopathy (DCM), restrictive cardiomyopathy, and hypertrophic cardiomyopathy (HCM)) exhibit impaired contractility and share alterations in MYH6, MYH7, and MYH7B gene expression. Here, we explore the miRNA-208a/TARBP2/Sox6 axis in regulating myosin expression within left ventricles of explanted human hearts.

Methods

Samples of left ventricles were obtained from explanted hearts of patients with terminal HF (NYHA III-IV) and reduced left ventricle ejection fraction (LVEF <25%) due to CAD (n=10), DCM (n=10), HCM (n=6), and controls (n=5). We analysed the expression of cardiac myosin heavy chains (MYH6, MYH7, MYH7B), cardiac damage markers (ANP, BNP), and heart-related MyoMiRs using quantitative real-time PCR.

Results

Pre-transplant data for the 31 subjects (25 male, 3 female) included: age 54.4±8.2y, BP 112±18/67±11 mmHg, HR 79±16 min-1, LVEF 27±14%, LVEDD 8.8±15.8mm, RVEDD 32.8±5.1mm, QRS 0.140±0.05s, QT 0.42±0.04s, NT-proBNP 5551±4259 ng/l.

In all diseased groups, MYH6 mRNA was downregulated, while MYH7 and MHRT ncRNA were upregulated. We observed strong positive correlations between MYH7, MYH7B, and MHRT transcription, suggesting coordinated expression. The miRNA-208a/miRNA-208b ratio shifted heavily towards miRNA-208b in controls, with a similar effect for miRNA-499 and MYH7B. A strong negative correlation existed between miRNA-499 and MYH7B expression across HF samples. TARBP2 expression decreased slightly in all pathological groups, while Sox6 mRNA increased.

Conclusion

Elevated Sox6 expression may contribute to MYH6 downregulation and MYH7/MYH7B upregulation. Altered TARBP2 expression could promote cardiomyopathy via Sox6-mediated repression of cardiac slow-twitch myofiber proteins. Changes in miRNA-208a processing leading to Sox6 upregulation may inhibit Sox6-dependent myosin transcript expression.
Association of long-term visit-to-visit glycemic variability with risk of adverse clinical outcomes in diabetic patients with heart failure with preserved ejection fraction
Authors: Hsu J , Yang Y Y , Chuang S L , Lin T T , Huang K C , Lee J K , Wu C K , Juang J M , Lin L Y
Published: October 2024

Background

Previous research has linked glycemic variability (GV) with cardiovascular issues in type 2 diabetes mellitus. However, its impact on patients with heart failure with preserved ejection fraction (HFpEF) remains understudied.

Purpose

In this study, we aim to examine how glycemic variability influences on clinical cardiovascular outcomes in diabetic HFpEF patients.

Methods

We conducted a retrospective cohort analysis utilizing the electronic medical records of a tertiary medical center in Taiwan between 2014 and 2019. Diabetic patients diagnosed with HFpEF were included in the study. The coefficient of variability of fasting glucose (FGCV) was determined for each individual, and the FGCVs were categorized into tertiles. We analyzed the association between FGCV and the risks of hospitalization for heart failure (HHF), atrial fibrillation (AF), cardiac mortality, and overall mortality.

Results

A total of 74,835 patients were enrolled in this study. Among them, 753 diabetic patients with concomitant with HFpEF and measured FGCV were identified, with a median follow-up duration of 38.1 months. In the multivariable regression model, the third tertile of FGCV demonstrated a significant association with an elevated risk of HHF and overall mortality compared to the first tertile (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.03-1.50, p = 0.026; HR 1.64 [1.15-2.26], p = 0.006). Although a higher FGCV exhibited a trend towards increased AF and cardiac mortality, statistical significance was not reached (HR 1.19 [0.91-1.56], p=0.208; HR 1.64 [0.87-3.12], p=0.129). The Kaplan-Meier analyses revealed a significant association between higher FGCV and both HHF and overall mortality (log-rank p = 0.022 and <0.001, respectively).

Conclusions

Our study highlights a significant association between increased GV and a higher incidence of HHF as well as an overall mortality rate in diabetic individuals with HFpEF.
Prevalent and incident anemia in PARAGON-HF
Authors: Lu H , Claggett B , Packer M , Pfeffer M A , Lam C S P , Zile M R , Desai A S , Jhund P , Lefkowitz M , Mcmurray J J V , Solomon S D , Vaduganathan M
Published: October 2024

Background

Anemia is a common comorbidity in patients with heart failure (HF) and is associated with adverse prognosis. Renin-angiotensin system inhibitors (RASi) have been shown to lower hemoglobin levels, potentially related to direct reductions in erythropoetin levels and hematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anemia in patients with HF with mildly reduced or preserved ejection fraction.

Methods

PARAGON-HF was a global, multicenter randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction≥45%. Anemia was defined as hemoglobin <120 g/L in women and <130 g/L in men. We evaluated changes in hemoglobin, risks of incident anemia and new oral iron initiation during follow-up. We also assessed treatment effects on the primary composite endpoint of total HF hospitalizations (HFH) and cardiovascular (CV) death according to anemia status.

Results

Among 4,795 participants with a hemoglobin measurement available, 1,111 (23.2%) had anemia at randomization of which 3.5%, 77.7%, and 18.8% were characterized as micro-, normo-, and macrocytic anemia. 5.6% were treated with oral iron at baseline. Over a 2.7-year median follow-up period, patients with anemia were at nearly twice the risk of the primary outcome (21.6 vs. 11.5 per 100py; rate ratio 1.90; 95% CI: 1.62-2.21; P<0.001). Compared with valsartan, sacubitril/valsartan significantly slowed the decline in hemoglobin levels by 1.4 g/L (95% CI: 0.4-2.4 g/L; P = 0.005; Figure 1 Panel A). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anemia (30.3% vs. 37.6%; HR 0.76; 95% CI: 0.68-0.85; P<0.001; Figure 1 Panel B) and starting oral iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI: 0.67-0.97; P = 0.026; Figure 2). Treatment effects of sacubitril/valsartan vs. valsartan on the primary endpoint were consistent among patients with and without anemia (Pinteraction=1.00).

Conclusions

Among patients with HF with mildly reduced or preserved ejection fraction, treatment with sacubitril/valsartan resulted in slower declines in hemoglobin, lower rates of incident anemia, and fewer new initiations of iron therapy compared with RASi.
Beyond conventional measures: left atrial reservoir strain as a superior prognostic marker for all-cause mortality in HFpEF
Authors: Disabato G , Attanasio A , Guida G , Camporeale A , Tondi L , Castelvecchio S , Iannotta M , Paglione G , Spagnolo P , Lombardi M , Bandera F , Guazzi M , Piepoli M
Published: October 2024

Background

Considerable data are available concerning improvements in diagnostic approaches over recent years for the treatment of heart failure with reduced ejection fraction (HFrEF). Conversely, regarding heart failure with preserved ejection fraction (HFpEF), there has been relatively little change in terms of therapy and prognostic stratification. Many efforts have been made to phenotype HFpEF spectrum, aiming to identify simple and reliable tools for recognizing patients at high risk for mortality.

Purpose

The aim of the present study is to identify a prognostic tool for all-cause mortality in patients with HFpEF.

Methods

From 2013 to 2024 thirty-eight HFpEF patients who underwent both transthoracic echocardiography at rest and cardiopulmonary exercise test (CPET) combined with echocardiography have been enrolled. Patients with established cardiomyopathy, such as hypertrophic cardiomyopathy and cardiac amyloidosis, have been excluded from the analysis. Mean follow-up period was 3,7 years. Primary outcome was all-cause mortality.

Results

Sixteen patients (42%) died during the study's follow-up period. No statistically significant differences were found for clinical, demographic, and therapeutic variables. Among all echocardiographic parameters, both at rest and during exertion, E/e' at rest (12 [8.9-19] vs. 17 [12-33], p-value 0.023), SPAP at rest and during exertion (31 ± 7 vs. 43 ± 16, p-value 0.021 and 51 ± 10 vs. 66 ± 17, p-value 0.019), TAPSE/SPAP at rest and during exertion (0.67 ± 0.15 vs. 0.47 ± 0.20, p-value 0.005 and 0.48 ± 0.15 vs. 0.33 ± 0.12, p-value 0.019), and left atrial reservoir function (22 [15-29] vs. 9.4 [6-15], p-value 0.001) were significantly associated with all-cause mortality (Table 1). Among CPET variables, respiratory exchange rate and oxygen pulse were associated with all-cause mortality (1.1 ± 0.13 vs. 1.18 ± 0.15, p-value 0.021 and 10 [7-11] vs. 8.1 [5.4-8.7], p-value 0.008) (Table 1). In multivariate analysis, the only independent predictor of mortality was left atrial reservoir function (p-value 0.026, OR 1.17 [1.02-1.35]). The optimal cutoff was identified using the Youden Index analysis (cut-off: 16.4%, sensitivity 85%, specificity 68%; AUC 0.839 [0.710-0.969]) (Figure 1). Survival curves based on the optimal cutoff are reported in Figure 1.

Conclusions

In a cohort of patients with HFpEF the left atrial reservoir function remains an important prognostic determinant for all-cause mortality. These results highlight the importance of estimating left ventricular filling pressures which are higher in patients diagnosed with HFPEF due to diminished ventricular compliance. Further studies with a larger cohort are needed to confirm these preliminary data.
The Triglycerides - Glucose Index: An independent predictor of late subclinical cardiotoxicity in adult survivors of childhood, adolescent and young adult cancer
Authors: Ouabdesselam S , Ait Mokhtar O , Benkhedda S
Published: October 2024

Introduction

The Triglycerides - Glucose index (TyG index) has been identified as a reliable alternative for estimating insulin resistance (IR). Numerous recent studies have provided strong statistical evidence suggesting that this index is associated with the development and prognosis of cardiovascular pathologies.

Objectives

The aim of this study was to investigate the predictive role of the TyG index on the decrease in left ventricular longitudinal global strain (GLS) assessed on two-dimensional echocardiography in asymptomatic adult survivors of childhood, adolescent and young adult cancer.

Methods

The study included patients aged 18 years and older, asymptomatic cardiovascular survivors of childhood, adolescent and young adult cancer treated with anthracyclines with or without mediastinal radiotherapy. Anthropometric characteristics, cardiovascular risk factors and cancer treatment-related characteristics were collected. The TyG index was calculated using the formula: ln [fasting triglycerides (mg/dl) × fasting glucose (mg/dl)/2]. GLS was assessed and expressed as an absolute value. A GLS equal to 17.3% was retained as the threshold value after calculation in a referent group matched to patients according to age and gender. Cardiac biomarkers GDF 15, ultra-sensitive troponin I and NT-proBNP levels were measured in addition to fasting blood glucose and lipid profiles. Multivariate analysis using linear regression was performed to identify associations between these different parameters.

Results

A total of 105 cancer survivors from childhood, adolescence and young adulthood were included. The sex ratio was 1.3. The mean age of the patients was 25 years, the mean time since completion of cancer treatment was 10.6 years, the mean cumulative doses of anthracyclines and mediastinal radiotherapy were successively 245.75 ± 75.14 mg/m2 and 34.6 ± 6.19 Gy. Mean GLS was 18.5 ± 2.83%, mean LVEF 60.6 ± 5.69%. None of the patients had any known diabetes or treatment to lower blood glucose or triglyceride levels. No patient had a history of cardiovascular disease. In the univariate study, the factors associated with lower GLS were patient age at recruitment (p = 0.03), mean time since completion of cancer treatment when this was greater than ten years (p = 0.005), dyslipidemia (p = 0.012), obesity (p = 0.037) and TyG (p = 0.037). In multivariate analysis, lower GLS was related to mean time since completion of cancer treatment (p = 0.015) and TyG index (p = 0.002).

Conclusion

Our results suggest that the TyG index, as a simple and inexpensive marker of insulin resistance, could help identify cancer survivors from childhood, adolescence and young adulthood who would be at risk of subclinical cardiac dysfunction. Prospective studies with larger numbers are needed to confirm these findings.
Chronotropic incompetence as a critical predictor for cardiovascular outcomes in heart failure with preserved ejection function
Authors: Lin T , Chen T Y C , Wu C K W , Lin L Y L
Published: October 2024

Background

Chronotropic incompetence (CI), linked with exercise intolerance, is a prevalent feature of heart failure with preserved ejection fraction (HFpEF). Our study aimed to explore the impact of CI on cardiovascular outcomes in HFpEF patients.

Methods

From November 2019 to December 2022, we enrolled 359 subjects who underwent invasive cardiopulmonary exercise testing (iCPET) due to heart failure symptoms. After excluding individuals without HFpEF (those with resting pulmonary capillary wedge pressure [PCWP] < 15mmHg or exercise PCWP < 25mmHg), we identified 113 patients for long-term follow-up. Our assessment of cardiovascular outcomes encompassed hospitalization for heart failure (HHF) and cardiovascular death. We employed Cox regression analysis to evaluate the associations between exercise hemodynamic parameters and outcomes.

Results

Among the cohort, 85 (75.2%) subjects with CI were older (71 vs. 66 years) and more frequently women (61 vs. 28%) compared to those without CI. At peak exercise, patients with CI exhibited significantly reduced left atrial booster strain, impaired right ventricle-arterial coupling, decreased systemic vascular resistance, cardiac output (CO), stroke volume, VO2, respiratory exchange ratio, and minute ventilation/carbon dioxide production (VE/VCO2) slope. A significant increase in PCWP (36 ± 10 vs. 26 ± 11mmHg, p=0.012) was noted in patients with CI. Over a median follow-up of 22.6 months, 20 (17.7%) subjects experienced cardiovascular events. Multivariate Cox proportional analyses revealed that CI (Hazard ratio [HR] 1.725, 95% confidence intervals [CI] 1.212-2.413) and an elevated PCWP/CO slope (HR 1.829, 95% CI 1.331-2.382) were predictive of outcomes.

Conclusions

Patients with CI demonstrated heightened filling pressure, a steeper VE-VCO2 slope, and reduced VO2 compared to those without CI. These factors likely contribute to adverse cardiovascular outcomes in HFpEF patients with CI.
Novel method in mice to evaluate left atrial (LA) systolic contribution to left ventricular volume (LV) using pressure-volume (PV) loops
Authors: Baker H , Christie R M , Sam F
Published: October 2024

Background

LA myopathy is a critically important non-LV contributor to the progression of HFpEF (heart failure with preserved ejection fraction) in patients and is associated with a severe phenotype, leading to impaired cardiac output reserve and reduced exercise capacity. In normal humans LA systole contributes ~20% of total LV filling, but with HFpEF, this contribution decreases to <16% with a greater reliance on this contribution to LV filling.

Purpose

We sought to investigate LA function as a critical component of cardiac function analysis by utilizing the LV pressure signal to identify and quantify the contribution of volume during LA systole to the total LV volume in mice with HFpEF.

Methods

Hypertension (HTN)-associated HFpEF C57BL/6J mice were subjected to chronic aldosterone infusion and 1% NaCl for 4 weeks (SAUNA model). Obesity after a high fat diet (HFD: 60% fat diet) for 16 weeks followed by the SAUNA protocol, induced HTN and obesity associated HFpEF. Blood pressure was monitored weekly. Mice were anesthetized with isoflurane, intubated, chest opened to expose the heart and allow placement of a PV catheter (Transonic) which was introduced into the LV via apical stab with a 27G needle. Calibration of the PV catheter was performed according to the manufacturer’s instructions. Atrial systole was identified using 2nd order derivative of the LV pressure signal. Contribution of LA systole was calculated using volume at the beginning of LA systole identified by the 2nd order derivative of the LV pressure signal and subtracting from the LV end diastolic volume. The % of LA systole contribution was calculated as a % of the total LV stroke volume. Data was analyzed with LabChart pro software (AD Instruments).

Results

SAUNA mice had normal LVEF, moderate HTN and lung congestion. PV relationships demonstrated Tau was impaired in HFpEF vs. control mice (14±1 vs. 10±0.5 ms) with a shift of the PV loop to the left (Fig. A.) In control mice, the atrial systole contributed 39± 4% to LV volume and was impaired in HFpEF mice 20± 3% a 1.95-fold reduction (P<0.01). Importantly atrial systole contribution was increased in obese mice 53±5 %. However, the combination of obesity and HTN, both common comorbidities in HFpEF, resulted in a reduced LA systole contribution by 1.43-fold to 37± 9%, (P<0.005; Fig B).

Conclusion

A novel method of % atrial systole from LV PV loop using 2nd order derivative to quantify the volume contribution of atrial systole to total LV stroke volume was identified in mice. LA dysfunction was present in murine HTN-associated HFpEF with/without obesity.
Transpulmonary proteome gradients identify inflammatory pathways involved in the development of pulmonary vasculopathy in heart failure
Authors: Melenovsky V , Jarolim P , Kutilkova E , Jenca D , Binova J , Benes J , Al-Hiti H , Miklovic M , Borlaug B A
Published: October 2024

Background

Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. Unbiased analysis of transpulmonary gradients may identify not only markers but also mediators of PVD by identifying proteins that may be consumed or elaborated across the lungs.

Purpose

Examine hemodynamics and transpulmonary proteome gradients in HFrEF and controls.

Methods

21 non-HF controls and 160 patients with advanced HFrEF underwent pulmonary artery (PA) catheterization with blood sampling from the PA catheter in the wedged position (02sat > 90%, indicating pulmonary venous blood) and the un-wedged position to obtain transpulmonary proteome gradients. Samples from controls and HF from the highest quartile (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using proteomic PEA assay of 275 proteins (Olink Target 96, panels CVII, CVIII, Inflammation). Pulmonary artery concentrations ("markers") or transpulmonary fold-change gradients (i.e. putative "mediators") of normalized protein expression (NPX) were plotted against significance; Benjamini–Hochberg FDR<0.05 considered as significant.

Results

Patients displayed typical characteristics of HFrEF (age 56±8y, NYHA 3.0 ±0.6, 87% males, LVEF 24±9.6%), Controls had similar anthropometrics, gender and age. Comparing all HF to Con, 38 markers of HF were identified (NPX fold-change>2), including 33 up (top 5: NTproBNP, BNP, GDF15, FGF23, IL8) and 5 down. HF patients in Q1 had median PVR 1.5 (IQR: 0.3-1.7) WU and those in Q4 had PVR 5.4 (4.3-6.6) WU. Comparison of Q1 and Q4 identified 3 protein markers of high PVR in PA blood from HF: chemokine CCL3, TNFRSF13B and surfactant protein-D (PSP-D). Examination of protein gradients from HF lungs (Figure) showed significant uptake of 14 protein mediators, most of which were associated with inflammatory responses (top 5: OSM, MMP9, CCL19, BNP, TR), and release of 8 mediators (top 4: IL-6, IL33, CCL4, CXCL10). In contrast, protein gradients were negligible in controls. Patients in Q4 PVR group were characterized by the highest pulmonary uptake of OSM (Oncostatin-M), lymphatic chemokine CCL19, BNP, MMP9, and had more significant transpulmonary release of IL6 and IL33. Across all patients, OSM lung uptake was the strongest correlate of transpulmonary pressure gradient (r=-0.3, p<0.001).

Conclusions

Lungs of patients with HF, and particularly those with high PVR, display abnormal uptake and release of proinflammatory CC and CXC chemokines and cytokines from IL1 and IL6 family, along with increased pulmonary uptake of IL6-type cytokine Oncostatin-M, a known mediator of lung inflammation and fibrosis, that acts via gp130/JAK/STAT, suggesting a novel role in PVD due to HF.Transpulmonary proteome in HF patients
Telomere shortening and cardiac alterations in asymptomatic type 2 diabetes patients: impact of sex
Authors: Balfanz P , Riccardi B , El Mernissi K , Zhang Y , Alassaad L , Thibault H , Moulin P , Bergerot C , Audureau E , Derumeaux G
Published: October 2024

Background

Telomere shortening is associated with the occurrence of deleterious events in the context of cardiometabolic disorders, including type 2 diabetes mellitus (T2DM). However, no evidence is available on the link between leukocyte telomere length (LTL) and subclinical cardiac alterations in T2DM patients.

Purpose

Our aim is to evaluate the relation between LTL and cardiovascular function in asymptomatic T2DM patients, taking into consideration the impact of the sex.

Methods

We analyzed a cohort of asymptomatic T2DM patients free from any overt cardiovascular disease (including coronary artery disease) and other T2DM comorbidities. A detailed metabolic and echocardiographic evaluation was performed together with LTL measurements at inclusion and after 2 years of follow-up. Univariate analyses in regard of the comparison of three graded LTL tertiles and different gender were used to test individual relationships betweenbioclinical and echocardiographic parameters and LTL measures. Subsequently, an unsupervised clustering method (self-organizing maps [SOM]) was used to identify cluster at risk of cardiomyopathy.

Results

We studied 89 T2DM patients aged 50±4 years (43% female) with a mean T2DM duration of 10±5.8 years and an average follow-up of 2.1±0.2 years. Leukocyte TL analysis demonstrated a slight but significant attrition after 2 years. The analysis of echocardiographic variables (transmitral flow velocities, velocity of mitral annular motion, left ventricular ejection fraction) did not show any evidence for ouvert cardiomyopathy. However, in the lower LTL tertile a higher proportion of patients with global longitudinal strain [GLS]<18% was found [41.6% vs. 22.8% vs. 21.6%]. Interestingly, leukocyte TL was associated with T2DM duration, FIB-4, a noninvasive indice used to assess fibrosis associated with non-alcoholic fatty liver disease (NAFLD), and usage of GLP-1 agonists. Comparison of men and women by univariate analysis did not show any differences in both LTL and echocardiographic parameters. However, unsupervised cluster method (SOM) unmasked a subgroup of female T2DM patients with diastolic alterations (e’ mean) and systolic alteration (GLS) both linked with lower LTL, whereas no specific subgroup in male T2DM patients could be distinguished.

Conclusion

Our study identifies subclinical diastolic and systolic dysfunction together with shorter LTL in a subgroup of female T2DM patients. These findings raise the importance of considering sex effect in the understanding of diabetic cardiomyopathy.
Comparing the anti-remodeling effect of sacubitril/valsartan and angiotensin-converting enzyme inhibition on myocardial samples of advanced heart failure patients undergoing heart transplantation
Authors: Nagy D , Balint T , Kocsis-Balogh P , Horvath Z , Olah A , Sayour A A , Barta B A , Merkely B , Radovits T , Ruppert M
Published: October 2024

Background

In decreasing heart failure (HF) hospitalization and cardiovascular death in HF patients with reduced ejection fraction, Sacubitril/Valsartan (SAC/VAL) treatment was proved to be superior to angiotensin-converting enzyme inhibition (ACEi). According to recent experimental results and clinical data based on echocardiography and circulating biomarkers, this benefit might be at least partially attributed to a greater anti-remodeling effect. However, there is a lack of direct evidence from human myocardial samples for this assumption.

Purpose

Therefore, we aimed to compare the anti-remodeling effect of SAC/VAL treatment to ACEi on myocardial samples of HF patients undergoing heart transplantation (HTX).

Methods

We studied left ventricular (LV) samples of seventy advanced HF patients who underwent HTX and received either SAC/VAL (SAC/VAL group, N=32) or ACEi treatment (ACEi group, N=38) for at least three months prior to HTX. Furthermore, all patients received beta-blockers and mineralocorticoid receptor antagonists titrated to maximally tolerated or target dose. Our groups were matched for age, sex, ejection fraction and other clinical parameters. Patients with liver or kidney failure, mechanical circulatory support, systemic inflammatory/fibrotic diseases or positive inotrope treatment were excluded. Myocardial mRNA expression of fibrotic markers and B-type natriuretic peptide (BNP) were measured with qRT-PCR and normalized to glyceraldehyde 3-phosphate dehydrogenase expression. Interstitial fibrosis area was assessed histologically.

Results

Preoperative plasma N-terminal pro-BNP levels were similar in the two groups (SAC/VAL: 4363±752 pg/mL vs. ACEi: 4616±1020 pg/mL; p=0.911). In contrast, the mRNA level of BNP in the myocardium was lower in patients treated with SAC/VAL (SAC/VAL: 2.2±1.05 vs. ACEi: 5.2±1.74; p=0.006). TIMP metallopeptidase inhibitor 1 (SAC/VAL: 0.07±0.01 vs. ACEi: 0.13±0.02; p=0.011), TIMP metallopeptidase inhibitor 2 (SAC/VAL: 0.06±0.01 vs. ACEi: 0.11±0.01; p<0.001), collagen type I alpha 1 chain (SAC/VAL: 0.02±0.00 vs. ACEi: 0.08±0.02; p<0.001) and collagen type III alpha 1 chain (SAC/VAL: 0.12±0.02 vs. ACEi: 0.27±0.04; p<0.001) relative gene expressions were also decreased in the LV of SAC/VAL-treated patients. Histology analysis confirmed reduced interstitial myocardial fibrosis area in the SAC/VAL group as well (SAC/VAL: 7.2±0.4% vs. ACEi: 8.6±0.5%; p=0.031).

Conclusions

SAC/VAL treatment decreased the myocardial expression of BNP and fibrosis-related genes to a greater extent compared with ACEi in LV samples of patients undergoing HTX. Histological analysis also verified the differences in fibrosis. Thus, the anti-remodeling effect of SAC/VAL might be superior to ACEi even in advanced HF.
Clinical characteristics of patients with raised BNP referred from primary care to an outpatient heart failure with potential heart failure using NICE guidelines
Authors: Bain R , Walters M , Whickham K , Jones R
Published: October 2024

Introduction

UK NICE guidelines (1) mandate the referral of patients with potential heart failure (signs, symptoms and raised BNP) for specialist opinion including diagnostic echocardiography. We have analysed the demographic and clinical characteristics of 233 consecutive referrals over a nine month period of such patients from primary care to our outpatient cardiology service.

Purpose

To identify any differences between those who are subsequently identified as having reduced LV systolic function (HFrEF) and those with preserved LV systolic function. We have further explored any potential differences between those with moderately raised (>440 <2000ng/L) and those with grossly raised levels (>2000ng/L) of BNP as NICE guidance proposes a difference in urgency of assessment for these two patient cohorts.

Methods

All patients had diagnostic echocardiography following the British Society of Echocardiography guidelines (2) and were clinically assessed by a consultant cardiologist and specialist heart failure nurse.

Results

Of the 233 patients, 64 (27%) were identified as having HFrEF with the remaining 169 having preserved LV systolic function. In patients with HFrEF the majority had grossly raised BNP (62.5%) whereas with preserved LV systolic function the majority had moderately raised BNP (70.5%); Table 1.

Within the referred population, demographics and clinical characteristics were broadly similar for patients with HFrEF and those with preserved LV systolic function for age and cardiovascular comorbidities (IHD, diabetes mellitus, hypertension) but were different for gender and heart rhythm. Patients with HFrEF and moderately raised BNP were twice as likely to be in sinus rhythm (75%) than those with grossly raised BNP (37.5%). In patients with moderately raised BNP those with preserved LV systolic function were more likely to be in AF than those with HFrEF (41% v. 25%). No gender difference was seen in patients with preserved LV systolic function whereas patients with HFrEF were twice as likely to be male; Table 2.

Conclusions

1. The majority of patients with raised BNP and potential heart failure referred from primary care do not have HFrEF (72.5%)

2. Regardless of their LV systolic function those patients with the highest BNP levels are more likely to be in AF

3. Of patients with a raised BNP and HFrEF twice as many are male whereas no gender difference is seen in those with a raised BNP and preserved LV systolic

4. Whilst the mean age of both groups (preserved and reduced LV systolic function) is the same, in both groups those with grossly raised BNP are on average 5 years older than those with moderately raised BNP.
A new heart transplant resource: DBD donor with out-of-hospital cardiac arrest
Authors: Fischetti G , Giovannico L , Parigino D , Ramirez A D , Santeramo V , Savino L , Mazzone F , Silva A M , Di Bari N , Bottio T , Milano A D
Published: October 2024

The aim of the present study is to analyze the differences in terms of cardiac transplant survival in organ recipients from a DBD (donor with brain death) donor characterized by out-of-hospital cardiac arrest (OHCA) and from a DBD donor not characterized by OHCA, in order to find new strategies to expand the donor pool. We analyzed the differences in mortality 30 days and 120 days after transplantation between the two groups of recipients, the length of stay in the ICU, the length of post-operative stay in the hospital, mechanical ventilation, the use of ECMO, the use of CVVH and the possible occurrence of ischemic and/or haemorrhagic stroke. 78 patients were compared: 13 recipients from a donor with OHCA with an average age of 55.18 (44.35 - 63.1) and 65 recipients from a donor without OHCA with an average age of 57.74 (50.9 - 66). The populations under study presented almost the same characteristics in terms of initial diagnosis, risk factors, comorbidities and list status. Comparing the results, no statistically significant differences were found between the two groups for ICU stay (p=1.000), for in-hospital stay (p=0.920) and for mechanical ventilation (p=0.95 ). No statistically significant difference was detected between the two groups even in terms of ECMO support (p=0.90), ischemic stroke (p=0.70), hemorrhagic stroke (p=0.781). From the analysis of the survival curves it can be seen that there is no statistically significant difference between the two groups either with regard to 30-day mortality (p=0.905) or 120-day mortality (p=0.957). The use of a DBD donor with OHCA represents a valid resource in the field of heart transplantation. In the present study it does not affect the recipient's survival rate. 30 days after heart transplantation mortality is conditioned by the intrinsic characteristics of the recipients.Kaplan-Meier 30 day survivalKaplan-Meier 30 day survival
Effects of body mass index on worsening of heart failure and all-cause death in patients with heart failure and reduced left ventricular ejection fraction: a 10-year follow-up study
Authors: Malmborg M , Fuchs Andersen A , Elmegaard M , Garred C , Zahir D , Butt J , Christensen D , Nouhravesh N , Videbaek L , Kober L , Gustafsson F , Schou M
Published: October 2024

Background/Introduction

Obesity in patients with heart failure (HF) with reduced ejection fraction (HFrEF) is common, and with the emergence of effective anti-obesity drugs, a better understanding of the relation between BMI and clinical outcome in HFrEF is needed.

Purpose

This study aimed to analyse whether a body mass index (BMI) above 27 kg/m2 (cut-off used in trials) is associated with a greater rate of all-cause death and HF hospitalization in patients with HFrEF.

Methods

We included 1,017 medically optimized according to existing HF guidelines at the time and clinically stable HF patients with a left ventricular ejection fraction of <45% from the NorthStar study. Patients were included between 2005 and 2009 and followed for 10 years using Danish nationwide registries. The outcomes of interest were all-cause death and hospital discharge for HF (overnight stay). Descriptive statistics were grouped according to tertiles of BMI. The association between BMI as a continuous variable and the outcomes of interest was analysed using restricted cubic splines in Cox proportional-hazards models. Reported were hazard ratios (HR) with 95% confidence intervals (CI) adjusted for relevant prognostic covariates (reference: BMI = 27 kg/m2).

Results

At enrolment, the median age was 69 years, 75% were men, and the median BMI was 26.3 kg/m2 (Table 1). Patients in the upper 3rd BMI tertile were younger (median age 67), had a lower level of NT-proBNP level (median 737.5 pg/ml) and a higher proportion of diabetes (29.9%). During 10 years of follow-up, HF hospitalization occurred in 683 patients (61.7%), and 623 patients died (56.3%). A BMI above 27 kg/m2 was associated with a higher rate of HF hospitalization (significantly from BMI 35.2 kg/m2: HR 1.30 [CI 1.00-1.68]; Figure 1). Similar findings were observed for all-cause mortality (significantly from BMI 35.7 kg/m2: HR 1.27 [CI 1.00-1.62])

Conclusion

In patients with HFrEF, a BMI above 27 kg/m2 was associated with a higher rate of HF hospitalization and all-cause death. Efforts to find effective and safe approaches to reducing weight in obese patients with HFrEF are warranted.Figure 1
The efficacy of catheter ablation compared to medical therapy in heart failure patients with concomitant atrial fibrillation: A meta-analysis of randomized controlled trials
Authors: Ishrak Khan M , Choi J , Reza Akbari A , Hart H , Goodfarb J , Subaita Zahir R , Z. Safdar N , Alam B , Jose Romeo F , Mahmood K
Published: October 2024

Introduction

The management of atrial fibrillation in patients with heart failure continues to be a topic of ongoing debate. We conducted a meticulous comparison between two primary treatment modalities: catheter ablation versus medical therapy. Our aim is to assess the efficacy of these interventions in patients presenting with both atrial fibrillation and heart failure, drawing from the randomized controlled trials.

Methods

A comprehensive literature search was conducted up to February 2024, utilizing databases including PubMed, EMBASE, and Clinicaltrials.gov. A total of 10 randomized studies were identified and their data were extracted and analyzed. The primary outcomes assessed included the impact of catheter ablation on all-cause mortality, cardiovascular death, left ventricular ejection fraction (LVEF %), and 6-minute walk test (6MWT) in meters. Data were analyzed utilizing a random-effects model to calculate weighted mean differences for LVEF and 6MWT, and risk ratios for all-cause mortality and cardiovascular death on Review Manager 5.3 (RevMan 5.3) software.

Results

In totality, data from 1944 heart failure patients (N = 966 on catheter ablation; N = 978 on medical therapy) with concomitant atrial fibrillation were included. Patients in the catheter ablation group exhibited a significant reduction in all-cause mortality (RR 0.63 [95% CI 0.48, 0.83]; P=0.001; I2 = 17%). Moreover, there was a notable decrease in cardiovascular death among patients undergoing catheter ablation (RR 0.53 [95% CI 0.34, 0.81]; P=0.004; I2 = 20%). Patients who underwent catheter ablation demonstrated a marked improvement in LVEF (MD 5.79 [95% CI 3.13, 8.44]; P <0.0001; I2 = 82%). The 6MWT revealed superior outcomes in the catheter ablation group (MD 22.69 [95% CI 9.87, 35.50]; P=0.0005; I2 = 38%).

Conclusion

Heart failure patients with concomitant atrial fibrillation undergoing catheter ablation therapy exhibited notable improvements in LVEF and 6MWT, alongside a significantly reduced risk of all-cause mortality and cardiovascular death compared to those receiving solely medical therapy. These findings shed light on the potential advantages and superior outcomes associated with catheter ablation therapy in preserving cardiac chamber function and mitigating mortality in such a patient cohort. However, further investigations are warranted to understand the long-term benefits and optimal management strategies for such individuals.
The effect of empagliflozin on right ventricular function in heart failure patients with reduced ejection fraction: analysis from the randomized empire hf clinical trial
Authors: Hansen M C , Jensen J , Ali M , Guststavsson F , Schou M , Moeller J E , Frederiksen P H , Omar M
Published: October 2024

Background

Reverse remodeling of the left ventricle (LV) has been proposed as a key mechanism to the cardio-protective effects of sodium-glucose-transporter-2 (SGLT2) inhibitors in patients with heart failure and reduced ejection fraction (HFrEF). Deterioration of the right ventricular (RV) function is associated with poor outcome, whereas improvement in RV dysfunction has been correlated with improved outcomes in HFrEF patients. The impact of SGLT2 inhibitors on the RV remains unclear.

Purpose

The aim of this post-hoc study of the Empire HF trial was to investigate the effect of Empagliflozin on RV function assessed by echocardiography in patients with HFrEF after 12 weeks of treatment compared to placebo.

Methods

The Empire HF trial was a double-blind, placebo-controlled, randomized clinical trial, in which 190 stable HFrEF patients with a LV ejection fraction (LVEF) ≤40% were randomized (1:1) to receive Empagliflozin 10 mg once daily or matching placebo for 12 weeks. Echocardiographic images were analysed blinded to treatment allocation. Exploratory outcomes were changes in right ventricular function. Statistical analyses were performed using mixed-effects linear models adjusted for age, sex and baseline variables.

Results

Baseline characteristics were well balanced between the two groups; mean age 64 (SD±11) years; males: 85%; mean LVEF 29 (SD±8) %, RV free wall strain (RVFWS): -16.7 (SD±6)%, NYHA-functional class II: 78% and ischemic HFrEF etiology: 51%. No significant between-group differences were detected in RV free wall strain (RVFWS), tricuspid annular plane systolic excursion (TAPSE) or S’ RV free wall (all P>0.05), Figure 1. When stratified into baseline tertiles of RVFWS, patients in the lowest tertile showed a significant improvement in the Empagliflozin group compared to placebo (treatment effect: -4.4 % [95% CI: -8.0 to -0.8]; P=0.018), Figure 2. There was no correlation between the effect of Empagliflozin on RVFWS in the lowest RVFWS tertile and other changes such as LVEF (P=0.845), plasma volume (P=0.710) or weight loss (P=0.639).

Conclusion

In this randomized, short-term trial, Empagliflozin did exert a significant effect on RV function in stable HFrEF patients in the overall study population, but notably improved RVFWS in patients in the lowest tertile of RVFWS at baseline after 12 weeks of treatment. Additional research is required to confirm these explorative findings, and to better understand the impact of SGLT2i on RV function and identify patients who could potentially experience therapeutic and prognostic benefits by RV improvement.
Left ventricular myocardial work predicts clinical course in patients with heart failure with mildly reduced ejection fraction
Authors: Chilingaryan A L , Tunyan L G , Asatryan A A , Sisakyan J G
Published: October 2024

Heart failure with mildly reduced ejection fraction (HFmrEF) often represents a movable patients subset that changes its HF category by increasing or reducing EF. Course prediction is challenging due to insufficient evidence to date. We studied multiple newly established parameters in order to find predictors of clinical course of HFmrEF.

Methods

135 patients (61 women) 62±5 years with HFmrEF NYHA II-III on GDMT were enrolled. Longitudinal (GLS), circumferential (GCS) and radial strain (GRS), peak LV twist (LVTR) were measured by speckle tracking from apical and short axis views. Left ventricular (LV) global myocardial work (GW) index (GWI) was obtained from pressure-strain loops derived from LV GLS and supine systemic blood pressure measured right before the image acquisition. Then constructive GW (GCW) as the sum of positive work due to myocardial shortening during systole and negative work due to lengthening during isovolumic relaxation, wasted GW (GWW) as energy loss by myocardial lengthening in systole and shortening in isovolumic relaxation and GW efficiency (GWE) as the percentage ratio of constructive work to the sum of constructive work and wasted work were obtained by dedicated software. All parameters were analyzed offline by one experienced specialist. Patients were followed up for 1 year.

Results

38 (28%) patients improved EF to the value ≥50%, 31 (23%) reduced EF to ≤40%. Patients with improved EF had significantly higher absolute values of GLS (17.3±2.2 vs 15.8±3.1%, p<0.03), GCS (18.9±2.6 vs 16.1±1.9%, p<0.02), GRS (42.5±7.2% vs 31.3±4.7%, p<0.02), LVT (6.2±2.5° vs 5.3±2.3°, p<0.03), GCW (2253±121 vs 1872±132 mmHg%, p<0.001) and lower GWW (108±7 vs 128±12 mmHg%) compared with patients with later reduced EF. Multivariate analysis showed that lower GCW was associated with EF reduction (HR 0.982, 95% CI 0.969–0.996, p = 0.012). GCW was the powerful predictor of CV events (AUC 0.94) with cut off value of 1495 mmHg% that had 98% sensitivity and 86% specificity.

Conclusion

LV GCW predicts EF changes in patients with HFmrEF.
Comparative analysis of renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitor and mineralocorticoid receptor antagonists in heart failure with mildly reduced ejection fraction
Authors: Lin T , Kuan D W K , Lee C C L , Wu W C K
Published: October 2024

Background

Apart from sodium-glucose co-transporter 2 inhibitors, the efficacy of renin–angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI)j8788 as well as mineralocorticoid receptor antagonist (MRA) in patients with heart failure with mildly reduced ejection fraction remains uncertain. We assessed the association between these medications and outcomes in patients with heart failure with mildly reduced ejection fraction (HFmrEF).

Methods

Patients with HFmrEF from our university hospital-integrated Medical Database were included. Associations between the medications and cardiovascular mortality/heart failure hospitalization were evaluated using Cox regressions in a 1:1 propensity score-matched cohort. Inverse probability of treatment weighting was employed to balance baseline patient characteristics.

Results

Of 2584 patients with HFmrEF, 17% received MRA and 43% received RASI/ARNI. Predictors of MRA use included older age, slightly higher ejection fraction, lower NT-proBNP level, and eGFR >60 mL/min/1.73 m^2. Predictors of RASI/ARNI use included higher body mass index, lower NT-proBNP level, normal uric acid level, normal potassium level, and eGFR >60 mL/min/1.73 m^2. MRA use was not associated with a lower risk of cardiovascular death and hospitalization for heart failure (hazard ratio [HR] = 0.89, 95% confidence interval [CI]: 0.78–1.02 and HR = 1.01, 95% CI: 0.94–1.09, respectively). Conversely, RASI/ARNI use was associated with a lower risk of cardiovascular death but not hospitalization for heart failure (HR = 0.82, 95% CI: 0.71–0.94 and HR = 0.995, 95% CI: 0.924–1.07, respectively). Notably, landmark analysis revealed no significant difference in the risk of outcomes when the follow-up duration exceeded two years.

Conclusions

The effect of MRA on cardiovascular death and hospitalization for heart failure was neutral, whereas RASI/ARNI was associated with a lower risk of cardiovascular death. Our findings suggest that RASi use may be more beneficial than MRA use in patients with HFmrEF.