bluuebunny/crossref_metadata_2025 huggingface dataset:
Adverse prognostic implications of increased left ventricular force in hypertrophic cardiomyopathy
Authors: Wierzbowska-Drabik K , Palinkas E D , Peteiro Vazquez J , Tesic M , Re F , Palinkas A , Aguiar Rosa S , Cortigiani L , Losi M A , Cotrim C , Nemes A , Ciampi Q , Pellikka P A , Olivotto I , Picano E
Published: October 2024

Background

The left ventricular (LV) force, also known as elastance, serves as a load-independent indicator of contractility and can be noninvasively assessed through echocardiography. In hypertrophic cardiomyopathy (HCM), the heightened presence of the active state of myosin heads results in an increased LV force.

Purpose

To assess the prognostic value of increased LV elastance at rest in patients with HCM.

Methods

We enrolled 1420 HCM patients (age 50±16 years, 907 males, 64%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 10 quality-controlled labs from 7 countries. TTE assessment included peak left ventricular outflow tract gradient (LVOTG), EF, and LV force (systolic blood pressure + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/mL). All patients were followed up. All-cause death was the outcome measure.

Results

At a median follow-up of 83 months, 150 deaths occurred (Group 1). At study entry, Group 1 patients had the same ESC-Sudden cardiac death score compared to survivors (Group 2). In Group 1 compared to Group 2, TTE showed higher values of MR severity, E/e’ , left atrial volume index, estimated systolic pulmonary artery pressure, and force (see table). At multivariable Cox analysis, only age (HR =1.08, 95% CI=1.03-1.14, p=0.001) and force > median value of 5.3 mmHg/mL (HR = 2.14, 95% CI 1.53-2.99, p=0.020) were independent predictors of mortality. Ten-year survival was 95% in the pooled first (<3.8 mmHg/mL) and second (3.8-5.2 mmHg/mL) quartiles vs 80% in the pooled third (5.3-7.8 mmHg/mL) and fourth quartiles (>7.8 mmHg/mL), see figure.

Conclusion

HCM patients with higher values of resting LV elastance show a worse survival, highlighting the dark prognostic side of an excess of force in these patients.

Table Legends

E/e’, early mitral inflow to early mitral annulus motion ratio, EF, left ventricular ejection fraction, LAVI, left atrial volume index; LVOTG, left ventricular outflow tract peak gradient, MR, mitral regurgitation; MWT, maximal wall thickness, NYHA, New York Heart Association classification, RWT, relative wall thickness; SCD risk, risk score for sudden cardiac death in hypertrophic cardiomyopathy, SPAP, systolic pulmonary arterial pressure.Table.Clinical and TTE findingsFigure.Survival in the force quartiles
Long-term clinical course of heart failure across left ventricular ejection fraction phenotypes
Authors: Teramoto K , Nochioka K , Sakata Y , Nishimura K , Shimokawa H , Yasuda S
Published: October 2024

Background

Studies examining changes in cardiac features and long-term outcomes across heart failure (HF) phenotypes, particularly for normal and supranormal left ventricular ejection fraction (LVEF), are limited.

Objectives

Our objective was to assess changes in echocardiographic parameters and biomarkers over three years and investigate long-term outcomes across LVEF phenotypes in chronic HF.

Methods

Patients from the SUPPORT trial (mean age 66 years, 25% female, mean LVEF 54%), a prospective, randomized, open-label blinded endpoint study performed in Japan to determine the additional benefit of olmesartan on top of standard therapy in hypertensive patients with HF, were classified into four HF phenotypes based on baseline LVEF: reduced (HFrEF [LVEF ≤40%], n=200 [17.6%]), mildly reduced (HFmrEF [41% ≤ LVEF <50%], n=229 [20.1%]), normal (HFnEF [51% ≤ LVEF <65%], n=403 [35.4%]), and supranormal (HFsnEF [LVEF ≥65%], n=306 [26.9%]). Changes in echocardiographic parameters and biomarkers were assessed in patients with data available at baseline and three years. The composite outcome of HF hospitalization or all-cause death was analysed from baseline and three years (landmark analysis).

Results

Over three years, all-cause mortality rates were 15% in HFrEF, 10.0% in HFmrEF, 5.5% in HFnEF, and 4.2% in HFsnEF. The most significant decrease in left ventricular (LV) end-diastolic and -systolic diameter occurred in HFrEF (median percent change; LVDd -5.8% and LVDs -8.8%). Left atrial diameter did not change across HF phenotypes. N-terminal pro-brain natriuretic peptide (NT-proBNP) decreased in HFrEF (-35.7%) but increased in HFnEF and HFsnEF (12.5% and 18.2%, respectively). Troponin increased in all groups except for HFrEF. Growth differentiating factor-15 (GDF15) increased consistently across all HF phenotypes (18.5% in HFrEF, 18.0% in HFmrEF, 16.0% in HFnEF, 22.8% in HFsnEF) (Figure 1). Over a median follow-up of 8.6 years, compared to HFnEF, the risk of the composite outcome was higher in HFrEF (adjusted HR 1.40, 95% CI [1.08-1.82]), but was not different in HFmrEF (1.15, [0.90-1.47]). This trend persisted in the landmark analysis. Up to three years, the risk in HFsnEF compared to HFnEF was not different (1.13, [0.70-1.82]), but it was lower after three years (0.73, [0.55-0.95]). The incident curves show a diverging time point at around three years between HFnEF and HFsnEF (Figure 2).

Conclusions

In patients with chronic HF and three-year follow-up data, there was minimal decrease in LV dimension, most pronounced in HFrEF. Changes in biomarkers were more diverse, except for consistently elevated GDF15 across all HF phenotypes. The risk of HF hospitalization or all-cause death diverged between HFnEF and HFsnEF after three years.Figure 1Figure 2
Clinical and genetic profiles of patients with hereditary and wild type transthyretin amyloidosis: the transthyretin cardiac amyloidosis registry in the state of Sao Paulo, Brazil REACT-SP
Authors: Fernandes F , Luzuriaga G C J , Correia E B , Carvalho A V S , Macedo A V S , Coelho Filho O R , Scheinberg P , Antunes M O , Schwartzmann P V , Mangini S , Marques W , Simoes M V , Ubner C C
Published: October 2024

Introduction

Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous.

Purpose

We designed the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo (REACT-SP), aiming to describe the demographic, genetic, clinical, and diagnostic test results and treatment of patients with ATTR.

Methods

We present data on physical signs and symptoms, cardiac and neurological assessments, and genetics in patients enrolled in the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo, Brazil.

Results

Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Sixteen different mutations were detected, the most common being Val50Met (48.3%) and V142Ile (40.8%). Overall, more than half of the patients presented cardiological involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p<0.001). The neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p<0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between the forms of amyloidosis. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients. The median time between the onset of symptoms and diagnosis was 1,853 (IQR 1277–2997) days, which was longer in ATTRv patients than in ATTRwt patients (p<0.001). Sinus rhythm was reported in 74.2%, atrial fibrillation in 17.0%, low voltage in 28.6%, repolarization abnormalities in 39.8%, and pseudo infarction in 27.4%. Echocardiography showed median Left Ventricular Ejection Fraction (LVEF) was 60%, Interventricular Septum (IVS) 14 mm, Posterior Wall Thickness (PWT) 13 mm, Left Atrium (LA) 41 mm, Left Ventricular Diastolic Diameter (LVDD) 45 mm, Left Ventricular Systolic Diameter (LVSD) 30 mm, basal Right Ventricular Diastolic Diameter (RVDD) 35 mm and Left Ventricle (LV) longitudinal strain 9.1%. There was some degree of LV diastolic dysfunction in 38.4%, apical sparing in 31.3%, and thrombus or masses in 1.0%. Late Gadolinium Enhancement (LGE) was absent in 29% and was subendocardial in 35.5%, transmural in 13.7%, mesocardial in 13.7%, and epicardial in 8.2%.

Conclusions

This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.
The prognostic impact of renal dysfunction and anemia in japanese heart failure patients stratified by left ventricular ejection fraction
Authors: Moriki T , Hamada T , Kubo T , Takabayashi K , Kawai K , Furuno T , Yabe T , Yamasaki N , Kitaoka H
Published: October 2024

Background

Renal dysfunction and anemia have been reported to be important prognostic factors in heart failure (HF) patients, but the differences in their effects stratified by left ventricular ejection fraction (LVEF) are not clear. Therefore, we investigated the prognostic impact of renal dysfunction and anemia in Japanese HF patients stratified by LVEF.

Methods

We combined two registry studies of acute HF patients in Japan and examined major events and associated factors during 2-year observation period. The primary endpoint was defined as all-cause mortality or HF hospitalization. Renal dysfunction was defined as eGFR <60 mL/min/1.73 m2, and anemia was defined as hemoglobin <13 g/dl in men and 12 g/dl in women. Two groups were also analyzed by LVEF (LVEF >50% and LVEF <49%).

Results

A total of 2142 patients were enrolled and analyzed. The mean observation period was 623±244 days. Mean age was 78.7 years. Forty-nine percent were male. Coronary artery disease and atrial fibrillation were present in 31% and 44% of patients, respectively. Medications included beta-blockers in 61% of patients and RAS inhibitors in 53%. Renal dysfunction was present in 1676 patients (74%) and anemia in 1523 patients (67%). Combination of both was observed in 1190 patients (53%). The primary endpoint was observed in 1015 patients, with 563 deaths and 737 HF hospitalizations. Multivariate analysis in a Cox proportional hazards model showed that renal dysfunction alone (HR: 1.39, 95%CI:1.06-1.81, p=0.02) and combination of renal dysfunction and anemia (HR 1.72, 95%CI:1.34-2.21, p<0.01) were independent prognostic factors in all patients.

In patients with LVEF <49%, renal dysfunction alone (HR: 1.50, 95%CI:1.04-2.16, p=0.03) and combination of renal dysfunction and anemia (HR: 1.90, 95%CI:1.34-2.68, p<0.01) were predictive factors.

On the other hand, in patients with LVEF >50%, only the combination of renal dysfunction and anemia were independent predictors (HR: 1.46, 95%CI:1.01-2.10, p=0.04).

Conclusion

We identified differences in the prognostic impact of anemia and renal dysfunction by LVEF.
Incident heart failure: comparing management and outcome in primary care and hospital settings in Western Sweden 2008-2017
Authors: Chen X , Pivodic A , Schaufelberger M , Fu M
Published: October 2024

Background

Heart failure (HF) is a major problem in primary care (PC) and hospital care (HC). HF patients managed in these two settings may differ in their demography, comorbidities, treatment and outcomes.

Aim

We aimed to compare the patient management in PC and HC in the Västra Götaland Region (VGR) in Sweden.

Methods

The VEGA database is an administrative database includes all patients living in VGR. Patients with a first principal or contributory diagnosis of HF (I50) ≥18 years old between 2008 and 2017 were included. One-year mortality was used as the outcome.

Results

In total, 62,229 new-onset HF cases were included, with 18,722 identified only in PC and 16,651 in HC. HF patients in PC were older (80.7±10.9 vs 76.1±13.6), more women (57.1% vs 44.9%), with more hypertension, musculoskeletal and mental disorders, but less myocardial infarction. Guideline directed medical therapy was more frequently used in HC despite similar medication before HF diagnosis. Patients in HC had almost 4 times higher all-cause 1-year mortality [3.92 (3.77 - 4.08), p<0.0001] compared with PC after adjustment for age and sex. Over 10-year period, despite decreasing mortality in both settings, hazard ratios for HC vs. PC were significantly increased for all patients (p for interaction 0.0004), which was more marked in female and for 70-80 years old patients.

Conclusion

Over a 10-year period, not withstanding decreasing mortality in HF patients in both PC and HC settings, differences remain between these two HF populations not only demographic profile and medications but also outcomes.
ICARUS registry: findings from the first 1595 cases of acute decompensated heart failure in a single center in a latin american country
Authors: Echeverria L E , Gomez-Ochoa S A , Rodriguez J A , Garcia-Rueda K A , Torres-Bustamante A M , Serrano-Garcia A Y , Botero D R , Cantillo-Reines M , Jurado A M , Castro K J , Pinilla K , Mendoza-Quinonez A C , Rojas M , Ortega-Solano D M , Rojas L Z
Published: October 2024

Introduction

Institutional aCute decompensAted HeaRt FailUre RegiStry (ICARUS) will provide information on clinical characteristics, medical practice, patterns of treatment, and outcomes of patients hospitalized with Acute Decompensated Heart Failure (ADHF) in a hospital in a middle-income country.

Objective

Describe the methodological aspects, sociodemographic, and clinical characteristics of patients hospitalized with ADHF and their short-term outcomes.

Method

Prospective cohort of patients with ADHF from the emergency service of a cardiovascular center. Descriptive statistics were used to synthesize sociodemographic characteristics, clinical characteristics during hospitalization, and outcomes.

Results

1595 patients with ADHF. The median age was 68 years (Q1=58; Q3=76), and 69.28% were men. The median hospital stay was six days (Q1=4; Q3=11), with an accumulative incidence (AI) for rehospitalization at 30 days of 8.70 % (95% CI 7.18 to 10.40%), in-hospital mortality AI of 4.33% (95% CI 3.38 to 5.44%), and a median change in the quality-of-life score like Minnesota Living with Heart Failure Questionnaire (MLHFQ) at 30 days of -20 points (Q1=-37; Q3=-5). At discharge, all patients had a percentage greater than 70% of the use of quadruple neurohormonal blockade therapy.

Conclusions

ICARUS is one of the first registries in Latin America since the indication of the use of SGLT2 inhibitors, evaluating the clinical and sociodemographic characteristics, treatment patterns, and outcomes of a preliminary cohort of 1595 patients hospitalized for ADHF. The results indicate that, at discharge, up to 82.79% of patients were receiving quadruple neurohormonal blockade therapy, which is considerably challenging to achieve in Latin America. Considering the results of the Safety, tolerability and efficacy of up-titration of Guideline-Directed Medical therapies for acute heart failure (STRONG-HF study), our study reinforces the benefit of discharge with Guideline-Directed Medical Therapy (GDMT) for heart failure from hospitalization. The use of GDMT for heart failure may have influenced our positive outcomes in terms of in-hospital mortality, improvement in quality of life, and the percentage of short-term rehospitalizations compared to similar cohorts.Proportion of HF drug group
LVEF trajectory in HFimpEF and its association with prognosis
Authors: Huang L , Zhang J , Zhang Y
Published: October 2024

Background

The 2021 revised Universal Definition of Heart Failure (HF) introduced the subgroup known as HF with improved ejection fraction (HFimpEF), aiming to establish a standardized definition for left ventricular ejection fraction (LVEF) improvement and emphasize the importance of longitudinally assessment of LVEF. However, there remains an insufficient characterization of the association between serial LVEF trajectory before and after impEF, and outcomes in HFimpEF.

Purpose

We aim to delineate the LVEF trajectory in patients with impEF and to discern specific LVEF trajectory pattern that portends an unfavorable prognosis.

Methods

We conducted a retrospective analysis by including hospitalized HF patients with baseline LVEF ≤ 40% and satisfactory serial echocardiographic follow-ups. ImpEF was defined as a follow-up LVEF measurement of > 40% with a ≥10-point increase from baseline. Longitudinal LVEF trajectories for patients with impEF (before and after LVEF improvement) were plotted according to the clinical outcome of all-cause death using Loess curves. LVEF changes over time were analyzed by unconditional non-linear mixed-effects modeling, and compared between the groups of patients who died and those who survived using conditional non-linear mixed-effects modeling.

Results

Among the initial 923 patients with reduced LVEF, 517 had impEF. According to Loess curves and non-linear mixed-effects analysis, LVEF trajectory of impEF differed according to the clinical outcome of death. For patients who suffered all-cause death, there was a comparatively limited improvement in LVEF followed by a more rapid plateauing and decline, exhibiting an inverted U-shaped pattern with lower LVEF values towards both ends of the distribution.

Conclusions

In HFimpEF, an inverted U-shaped trajectory of LVEF, characterized by limited initial improvement followed by subsequent decline, is associated with poorer prognosis. Serial LVEF monitoring in patients with HFimpEF could help with early identification of at-risk patients.Graphical Abstract
Protein signatures associated with methylation patterns of heart failure phenotypes
Authors: Krolevets M , Ten Cate V , Buch G , Rapp S , Niehrs C , Wild P
Published: October 2024

Introduction

The heart failure (HF) syndrome is highly susceptible to the exposome. The interplay between DNA methylation (DNAm), surrogate for exposomal influences, and the plasma proteome in the progression and development of phenotypes of heart failure is unclear. We investigated the relation between methylation patterns of HF phenotypes and proteins signatures.

Methods

Individuals with symptomatic HF (stage C/D with HFpEF, HFmrEF and HFrEF) of the MyoVasc cohort (N=3,289) were investigated. EDTA-Plasma and DNA were extracted from peripheral blood and stored in -80°C. DNAm was measured using the Infinium MethylationEPIC v2.0 methylation array. Concentrations for 538 proteins were measured using an immuno-qPCR assay in EDTA plasma. Multivariable regression models adjusted for age and sex were used to assess the relationship between DNAm signatures and individual proteins in each phenotype. Ridge-regularized linear regression was used to generate a phenotype-specific protein-signature in relation to each methylation signature, linear regression to estimate links between protein signatures and cardiovascular traits and Cox regression relate protein signatures to clinical outcome.

Results

Data from 1,317 individuals with symptomatic HF were analyzed. After FDR adjustment, 310 proteins were significantly related to HFpEF methylation signature, 314 to HFmrEF and 266 to HFrEF. Of associated proteins, 49.9% (198) were found in all phenotypes, 8.82% (35) only in HFpEF, 12.1% (48) in HFmrEF and 4.79% (19) in HFrEF. Tumor necrosis, arterial hypertension and T-cell regulation pathways were enriched in all three phenotypes. NT-proBNP had the strongest association with HFrEF (β=0.95 [0.82-1.08], p<0.0001) followed by presence of plaques in carotid artery and C-reactive protein, while left ventricular mass (LVM) had stronger association with HFpEF (β=0.22 [0.11-0.33], p=0.0001). All three signatures were associated with worsening of HF (HFpEF: HR=1.93 [1.61-2.30], p<0.0001; HFmrEF: HR=1.63 [1.29-2.04], p<0.0001; HFrEF: HR=1.64 [1.38-1.95], p<0.0001) and all-cause death in HF (HFpEF: HR=1.93 [1.65-2.26], p<0.0001; HFmrEF: HR=1.95 [1.58-2.42], p<0.0001; HFrEF: HR=2.24 [1.86-2.69], p<0.0001). Methylation-associated protein signatures had stronger associations with clinical outcome than the methylation signatures themselves (p < 0.01).

Conclusion

This study revealed protein signatures associated with methylation patterns of HF phenotypes that shared common and unique features for HF phenotypes. Important common pathways were enriched in tumour necrosis, arterial hypertension and regulation of T cells. However, important differences between phenotypes were also revealed, e.g. NT-proBNP was strongly associated with the HFrEF protein signature and LVM with the HFpEF signature. The methylation-associated protein signatures emphasise the possible exposomal influence on HF syndrome.
A streamlined protocol for exercise right heart catheterisation for the diagnosis of heart failure with preserved ejection fraction
Authors: Selvadurai M V , Dagan M , Mariani J , Vizi D , Dewar E M , Kaye D M , Nanayakkara S
Published: October 2024

Background

Heart failure with preserved ejection fraction (HFpEF) can be a challenging diagnosis. The gold standard diagnostic test is exercise right heart catheterisation (eRHC), with HFpEF confirmed if pulmonary capillary wedge pressure (PCWP) >15mmHg at rest or ≥25mmHg with exercise. However, many centres do not perform eRHC and the current, well-established, nine-minute eRHC protocol can be time consuming and costly.

Purpose

We sought to determine whether an abbreviated 3-minute eRHC protocol is sufficient for accurate diagnosis of HFpEF, thus allowing simplification, reduced patient risk and costs, and broader uptake of eRHC across centres.

Methods

Patients undergoing eRHC between 09/09/2008 and 18/07/2023 at a tertiary hospital in Australia were retrospectively analysed. Haemodynamic measurements at three minutes of exercise were correlated with peak measurements.

Results

Overall cohort of n=532, with a mean age of 64 ± 12 years, and 60% female. Compared to PCWP ≥25mmHg at peak exercise, measurement of PCWP at 3 minutes yielded an area under the receiver-operating characteristic curve of 0.92±0.01, P<0.0001. PCWP ≥25mmHg at 3 minutes has a high specificity (97%) but moderate sensitivity (65%) for diagnosis of HFpEF; PCWP ≥21 mmHg at 3 minutes has good specificity (83%) and sensitivity (85%) for predicting peak PCWP ≥25mmHg. Using the 3-minute protocol with PCWP cut-off of 21mmHg, 86% of participants were correctly diagnosed (Figure 1). There were strong positive correlations in PCWP (R2=0.6922), cardiac output (R2=0.5543) and pulmonary vascular resistance (R2=0.6516) between 3 minutes and peak exercise (Figure 2).

Conclusions

Abbreviated 3-minute eRHC protocol has good diagnostic potential in HFpEF, with strong correlations in haemodynamics, when compared to peak exercise. This suggests that simplification of the current HFpEF protocol to 3 minutes exercise could be a valid strategy to enable improved uptake and maximise resource utilisation while maintaining diagnostic accuracy.Figure 1.Sankey plot of PCWP valuesFigure 2.Haemodynamics during eRHC
The role of angiotensin II and endothelin receptor antibodies in COVID19 patients with HFpEF
Authors: Cherneva Z H , Marchev S , Jelev L , Markova P , Girchev R , Cherneva R
Published: October 2024

Background

The infection caused by the coronavirus SARS-COV-2, is associated with an unusual pattern of organ damage in comparison to other viral-induced pathologies. A theory of autoimmunity induced by ACE-2/SARS-COV-2 spike protein complex or its degradation products, was proposed as a possible explanation for the versatile and multiorgan damage in COVID-19.

Aim

The aim of the study is to determine whether antibodies against angiotensin II receptor type 1 (AT1R) or endothelin-1 receptor type A (ETAR) do exist in plasma of COVID -19 patients with heart failure with preserved ejection fraction and whether they correlate to the severity of the disease.

Methods

A total of 61 patients with COVID-19 and heart failure with preserved ejection fraction and 48 controls (free of COVID19) with heart failure with preserved ejection fraction were included. Patients were divided into two groups: patients with severe disease (admitted at the intensive care (n=30)), patients with milder clinical presentation that remained in the general therapeutical department (n=31). The plasma levels of IL-6 and auto-antibodies against AT1R or ETAR in peripheral blood were measured and compared between COVID19 patients with severe and milder disease and age matched controls. Clinical and standard laboratory parameters were also collected and their association with the research biomarkers was analysed.

Results

Auto-antibodies against AT1R were significantly increased in severe disease course (median 19.60 U/mL, IQR 4.8-34.75) compared to milder disease (median 10.95 U/mL, IQR 7.69 – 17.67, p=0.017) and the control group (median 6.79 U/mL, IQR 5.10 – 14.05, p< 0.001). ETAR antibody titers were also significantly increased in severe disease (median 14.52, IQR 6.76-32.94), compared to milder disease course (median 8.73 U/mL, IQR 6.59 –13.45, p=0.023) and to the control group (median 6.64, IQR 6.79 – 17.92, p <0.001). The same was the trend regarding IL-6 antibodies. Severe disease (median 12.11 U/mL, IQR 5.59–19.38); milder disease disease (median 8.64U/mL, IQR 1.84 – 14.13, p=0.039); control group (median 4.28U/mL, IQR 0.11–1.43, p<0.001).Both AT1R and ETAR correlated to IL-6 plasma levels. The results did not show association with the concomitant therapy.

Conclusion

In conclusion, we establishеd the presence of AT1R and ETAR autoantibodies in COVID-19 patients with heart failure with preserved ejection fraction. They correlated to IL-6 plasma levels (systemic inflammation) and are associated with severe form of the disease.
Construction of an inflammatory, nutritional, and metabolic prognostic risk score in patients with heart failure with preserved ejection fraction: a machine learning-based approach
Authors: Feng J , Huang L , Li X , Xin A , Wang C , Zhang J , Zhang Y
Published: October 2024

Background

Chronic inflammation, malnutrition, and metabolic syndrome contribute to the underlying mechanisms of heart failure with preserved ejection fraction (HFpEF). Inflammatory, nutritional, and metabolic biomarkers often interact with each other and affect the prognosis of patients.

Purpose

We aimed to identify the most predictive indicators from a pool of 21 biomarkers encompassing inflammation, nutritional status, as well as lipid, glucose, thyroid, and uric acid metabolism. Subsequently, predictive biomarkers were used to develop a risk score to enhance risk prediction for patients with HFpEF.

Methods

We included patients diagnosed with HFpEF and without infective or systemic disease. The primary outcome was all-cause mortality. We employed the Least Absolute Shrinkage and Selection Operator (LASSO) regression to screen the biomarkers. A machine learning-based approach was utilized to fine-tune the optimal model parameters. Additionally, we generated 1000 bootstrapping datasets to identify biomarkers recurring above a 95% frequency in repetitions, which were then employed to formulate the biomarker risk score. The discrimination of incorporating the risk score into the basic model was evaluated using 100 iterations of 5-fold cross-validation to assess the predictive efficacy.

Results

Among the 1311 included patients (with a median age of 64 years and 42.6% female), 363 patients (27.7%) experienced mortality over a median follow-up period of 2.7 years. The final risk score model was derived from 5 biomarkers—albumin (ALB), red blood cell distribution width-standard deviation (RDW-SD), lymphocytes, triiodothyronine (T3), and uric acid—each selected in over 95% of 1000 bootstrapping iterations. Integration of this risk score into the basic model notably enhanced discrimination (∆C-index=0.015, 95% CI 0.005-0.023) and reclassification (IDI: 3.3%, 95% CI 1.7%-5.8%; NRI: 15.2%, 95% CI 6.5%-22.5%) for risk stratification. In time-dependent receiver operating characteristic (ROC) analysis, the mean area under the curve (AUC) of the risk score was 0.688, 0.710, and 0.738 at 1, 3, and 5 years post-discharge, respectively, in the cross-validation sets. Incorporating the risk score into the basic model significantly improved the AUC at 1, 3, and 5 years (DeLong test P-value<0.05). Furthermore, in multivariable Cox regression, the risk score demonstrated an independent association with all-cause mortality (HR: 1.81, 95% CI 1.51-2.16, P<0.001 per 1 score increase).

Conclusions

A risk score derived from 5 commonly used inflammatory, nutritional, thyroid and uric acid metabolic biomarkers can effectively identify high-risk patients with HFpEF. This approach supports the development of potential individualized management strategies for patients with HFpEF.Study population and model constructionPredictive performance of the risk score
Prognostic value of circulating glypican-4 in patients with chronic heart failure with reduced ejection fraction
Authors: Schwegel N , Santner V , Zach D K , Hoeller V , Wallner M , Muendlein A , Brandtner E M , Leiherer A , Drexel H , Mader A , Von Lewinski D , Ablasser K , Kolesnik E , Zirlik A , Verheyen N
Published: October 2024

Background

Chronic heart failure is one of the leading causes of hospitalization and mortality worldwide, with an ever-increasing prevalence. Glypican-4 (GPC4) is a cell surface protein part of the endothelial glycocalyx which is actively released into the circulation in the context of ischemia, inflammation, neurohumoral activity, and shear stress. The current literature on the association between circulating GPC4 and heart failure is limited and its prognostic value on top of established risk markers in chronic heart failure is unknown.

Purpose

In the present study, we aim to investigate the prognostic value of circulating GPC4 on clinical outcomes in a contemporary cohort of patients with stable chronic heart failure with reduced ejection fraction (HFrEF).

Methods

Symptomatic outpatients with stable chronic HFrEF were consecutively enrolled in a prospective cohort study. Circulating serum GPC4 levels were assessed using an enzyme-linked immunosorbent at baseline. Patient outcomes were retrieved from medical and health insurance records.

Results

We enrolled 205 patients with a median (interquartile range) age of 66 (59-74) years, with 22% females. Median left ventricular ejection fraction (LVEF) was 37 (30-43)%, median estimated glomerular filtration rate (eGFR) was 64 (48-80) ml/min/1,73 m2, median N-terminal pro-brain natriuretic peptide (NT-proBNP) was 964 (336-2173) pg/ml, median interleukin 6 (IL6) was 4.7 (3.2-7.9) pg/ml, and median GPC4 was 1553 (1034-1950) pg/ml.

During a median follow-up of 4.7 (4.0-5.3) years, 46 patients (22%) were hospitalized due to worsening heart failure (WHF), 18 patients (9%) died of cardiovascular (CV) cause, and 58 patients (28%) died of any cause. In univariate Cox-regression, serum GPC4 levels predicted WHF (HR 1.57, 95%CI 1.29-1.92, p<0.001), CV death (HR 2.07, 95%CI 1.56-2.74, p<0.001), and all-cause mortality (HR 1.93, 95%CI 1.59-2.34, p<0.001). The association between serum GPC4 levels and both, CV death (HR 1.69, 95%CI 1.04-2.86, p=0.048) and all-cause mortality (HR 1.56, 95%CI 1.14-2.14, p=0.006) remained significant in a multivariable Cox-regression model adjusted for age, sex, eGFR, IL6, NT-proBNP, and LVEF.

Conclusion

In patients with stable chronic HFrEF, circulating GPC4 is significantly associated with cardiovascular outcome and is an independent predictor of all-cause mortality. The potential prognostic value in clinical routine of GPC4 should be addressed in prospective studies.
Prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in patients admitted with acute heart failure
Authors: Kandiah A , Taraldsen I , El-Sheikh M , Olsen El Caidi N , Dencker Wisborg F , Dahlgaard Hove J , Grand J
Published: October 2024

Introduction

The inflammatory marker, soluble urokinase plasminogen activator receptor (suPAR), has emerged as a promising prognostic biomarker of heart failure (HF). Higher levels of suPAR in plasma are indicative of hospital readmissions and mortality. Currently little is known about suPAR-values upon admission in patients with acute heart failure (AHF).

Purpose

This study investigates the prevalence of elevated suPAR and prognostic value in patients hospitalized with AHF.

Methods

In this prospective cohort study, all patients ≥ 18 years old admitted at the Emergency Department at a large University Hospital in Denmark, were consecutively included from March 10, 2020, to March 31, 2022. The follow-up period was 365 days. The biomarker suPAR was measured in all patients upon admission (median time from admission to suPAR measurement was two hours (IQR 3: 3,9-6,9)). Patient data was extracted from the electronic patient record system, and a cardiologist adjudicated whether the patients had AHF. Patients were stratified according to validated cut-off values of suPAR above or below 6 ng/mL. Kaplan-Meier survival analysis and Cox Regression were used to assess the association between suPAR levels and one-year mortality outcomes.

Results

A total of 408 (5%) AHF patients, from a total population of 6,715, were included in the study. 40 patients were excluded due to missing suPAR-values and the final analysis comprised of 368 AHF patients. Among AHF patients upon admission, the mean suPAR value was 6.2 ng/mL (standard deviation [SD] = 4.8 ng/mL), and non-AHF patients had a mean value of 4.5 ng/mL (SD = 3.1 ng/mL).

A suPAR level above 6 ng/mL was significantly associated with mortality (figure 1), log-rank test p-value < 0.0001. Furthermore, Cox regression analysis demonstrated that elevated suPAR levels were independently associated with increased risk of mortality with a hazard ratio (HR): 2.09 (95% CI: 1.59-2.90), p-value < 0.001 after adjusting for potential confounders: age, sex, atrial fibrillation, Chronic Obstructive Pulmonary Disease, and Creatinine levels.

Conclusion

The inflammatory biomarker suPAR measured upon hospital admission in AHF patients is significantly associated with one-year mortality in patients admitted with AHF. The potential of suPAR as a valuable prognostic marker in AHF is offering clinicians a tool to identify high-risk patients and tailor management strategies, accordingly, thereby improving patient outcomes.Figure 1 - 1 year mortality
Associations between biomarkers and P-wave indices in patients with heart failure
Authors: Nezami Z , Jujic A , Holm Isholth H , Magnusson M , Platonov P
Published: October 2024

Background

Atrial structural abnormalities linked to the risk of atrial fibrillation (AF), as indicated by P-wave indices on surface ECG, are associated with the fibrotic transformation of the atrial myocardium. To what extent incident AF can be predicted by ECG characteristics in patients with advanced atrial structural remodeling, such as patients with heart failure (HF), is less well studied.

Purpose

To evaluate the association between P-wave indices and biomarkers implicated in cardiac fibrosis, and incident AF in patients with HF.

Methods

Patients with new-onset or worsening of HF were prospectively recruited in a observational study (n=501) and followed-up for 5 years. Blood samples were collected for analysis using proximity extension assay that included a subset of biomarkers that were associated with fibrosis development (TIMP-2, MMP-2, MMP-3, MMP-9, ST-2, GDF-15, Gal-3). All ECGs ever recorded in the hospital catchment area were exported in digital format and processed using Glasgow algorithm for calculation of the P-wave indices (P-wave duration [PWD], P-wave terminal force in V1 [PTFV1] and P-wave axis [Paxis]) and rhythm identification. AF diagnosis was ascertained by manual ECG review. Only patients who did not have AF reported or ECG documented at enrolment were included in the analysis. Of those subjects, 121 patients also had biomarkers of fibrosis analyzed. Cox-regression analyses were used to assess biomarkers’ and p-wave indices’ associations with incident AF.

Results

After exclusion of patients with prevalent AF (n=317), 184 patients comprised the study group (mean age of 71 years, 33.2% women, 121 patients with biomarker data available). During follow-up, incident AF was observed in 39 patients. At enrolment, PWD>120 ms was observed in 38.7%, abnormal PTFV1>40 mm*ms in 24.5% and Paxis<0° in 5.4%. Among the seven biomarkers assessed, five demonstrated significant associations with incident AF in adjusted analyses: TIMP4 (HR 1.78; 95%CI 1.03-3.05; p=0.037); MMP2 (HR 1.97; 95%CI 1.03-3.80; p=0.042), MMP3 (HR 1.39; 95%CI 1.03-1.88; p=0.031); ST2 (HR 1.91; 95%CI 1.29-2.83; p=0.001) and GDF-15 (HR 2.56; 95%CI 1.50-4.35; p=0.001) (Figure 1). However, none of the tested P-wave variables (P-wave duration, P-wave terminal force, and P-wave axis) were associated to incident AF.

Conclusions

In this prospective long-term follow-up study of patients admitted for acute HF, biomarkers with proven associations to fibrosis were strongly associated with incident AF. P-wave indices used for prediction of AF in epidemiological cohorts appear to have limited value in patients with HF who have high prevalence of ECG atrial abnormalities at baseline.
Role of urea to creatinine ratio in the prediction of outcomes in chronic heart failure
Authors: Moreira G , Avila D X , Candia A M , Scaramussa V D , Villacorta H
Published: October 2024

Background

Renal function predicts events in chronic heart failure (HF). Urea to creatinine ratio (UCR) is a simple and cheap biomarker which correlates with neuroendocrine pathways.

Objectives

Evaluate the prognostic role of UCR in patients with chronic HF.

Methodology

86 patients with chronic HF from an academic hospital were included (with reduced, mildly reduced or improved left ventricular ejection fraction). UCR was calculated at baseline, and patients were followed for a median of 360 (interquartile range 180-472) days. We plotted ROC curves for NT-proBNP and UCR and evaluated two scenarios using the Kaplan-Meier curve to determine the event-free survival. We grouped patients into four subgroups: a) UCR and NT-proBNP below the cut-off; b) UCR above and NT-proBNP below; c) UCR below and NT-proBNP above; and d) both above the cut-off. A second scenario was analysed, grouped as follows: a) UCR and NT-proBNP below; b) at least one of them above the cut-off; and c) both above the cutoff. The primary endpoint was cardiovascular death or HF hospitalisation. The level of significance was 5%.

Results

The mean age was 66.1±12.1y, and 60.5% were male. There were 28 events in the follow-up (32.5%). The ROC curve for UCR had an AUC of 0.75 (CI 0.64-0.86; p=0.0002) for a cut-off of 43.8 (sensitivity of 75% and specificity of 70.7%). The AUC for NT-proBNP was 0.64 (0.51-0.77; p=0.043) for a cut-off of 2010 pg/mL (sensitivity of 64.3% and specificity of 65.5%). In the Cox regression model, the UCR was the only independent predictor with HR of 1.06 per 1 unit increase (1.03-1.10; p=0.0002). UCR above cut-off (as a categorical variable) was the only independent predictor, with HR 5.34 (2.26-12.6; p=0.0001). Kaplan-Meier curves in Figures 1 and 2 show the UCR performance associated with NT-proBNP.

Conclusions

UCR is a simple and cheap biomarker that has been shown to have predictive power, probably due to persistent neuroendocrine activation in patients with low volume. In this population, elevated UCR added risk even in patients with low levels of NT-proBNP.
Blood urea monitoring in heart failure patients - an important predictor of mortality
Authors: Oswald A S , Hussain M S , Win M L , Liew Y J , Dihoun A , Nicholls J , Newey R , Baird E , Smith G , Garland C , Pigazzani F , Khan F , Choy A M , Mordi I R , Lang C C
Published: October 2024

Background

Recent ESC position statement regarding worsening renal failure recommends the use of blood urea monitoring of patients with heart failure with reduced ejection fraction (HFrEF). Although both serum creatinine and blood urea nitrogen are markers for renal dysfunction, blood urea nitrogen levels are also affected by reabsorption in the renal tubules, a process modulated by renin-angiotensin-aldosterone activity, sympathetic nervous activity and arginine-vasopressin activity. Thus, neurohormonal activity is reflected in the BUN/creatinine ratio (bUCR) which effectively ‘normalizes’ BUN for the degree of renal dysfunction, as measured by the creatinine level. Previous studies have demonstrated increased mortality at bUCR >100mmol/l. however, most of the prognostic data has come from patients admitted with acute heart failure. The use of bUCR in patients with chronic HFrHF receiving intensive titration of guideline directed medical therapy (GDMT) has not been studied.

Purpose

To identify the extent of blood urea monitoring in primary care in HFrEF and whether bUCR remains a significant prognostic indicator despite intensive GDMT.

Methods

We analysed the electronic health records of all patients referred to the Heart Failure Nurse Service (HFNS) in an NHS population approx. 400,000 in 2022. Inclusion criteria consists of patients with symptomatic heart failure NYHA II-IV with echocardiogram demonstrating HFrEF. Patients were segregated into two cohorts, with a urea/creatinine ratio greater or less than 100mmol/l and analysed.

Results

Data from 338 patients [mean age 72.3 ± 15.6 years; 218 (64.5%) males; 143 (42.3%) ischaemic cardiomyopathy; 141 (41.7%) AF; 49 (14.5%)] were analysed. Of these, 112 (33.1%) had chronic kidney disease (CKD) with eGFR <60 ml/min/1.73m2 at the time of HF diagnosis and 181 (53.6%) had CKD on discharge from the HFNS. During follow-up, 132 (39%) had further admission with HF and 76 (22.5%) died. Sixty-eight (20.1%) patients did not have blood urea checked despite the availability of serum creatinine. While an eGFR < 60 ml/min/1.73m2 at discharge was associated with a twofold increased risk of death (OR 2.4, 95% CI 1.1-5.3, p=0.029), a bUCR > 100mmol/l at discharge was associated with a four-times greater risk of death (OR 4.2, 95% CI 2.2-7.9, p <0.001).

Conclusion

Blood urea/creatinine ratio is an important predictor of outcome and can be utilised to help identify at-risk patients with HFrEF despite intensive GDMT.Survival from diagnosis bUCR
SNORD3A: a new possible circulating biomarker of human heart failure
Authors: Polese P , Paolillo R , Schiattarella G G , D'apice S , Cattaneo F , Lee Holley C , Prevete N , Della Corte A , Bancone C , Ioele D , Carotenuto M , Watson M , Esposito G , Rockman H , Perrino C
Published: October 2024

Background

Heart failure (HF) is a complex clinical syndrome and the leading cause of mortality, morbidity and hospitalization in industrialized countries. Human cardiac biopsies are invaluable resources for identifying cardiac signaling pathways, however blood fractions and peripheral blood mononuclear cells (PBMCs) could be used as a source of surrogate biomarkers of signaling pathway activation in human heart failure.

Purpose

In the present study we aimed to identify novel circulating biomarkers mirroring human myocardial signaling in HF and to study the role played by SNORD3A in cardiomyocyte survival and death.

Methods

Cardiac left ventricle samples and PBLs from 8 HF patients undergoing heart transplantation and 2 control patients (CTRL) were analyzed by RNA sequencing (RNASeq) to identify transcripts that were regulated in both hearts and PBLs. Five identified transcripts, KCNQOT1, MIAT, SCRN1, MALAT1 and SNORD3A, were then validated by quantitative real-time PCR in PBMCs and in LVs. Next, we analyzed the expression of the Small Nucleolar RNA (snoRNA) SNORD3A in LVs and PBMCs from 8-week-old wild type C57BL/6 mice with pressure overload-induced HF by transverse aortic constriction (TAC). Sham-operated mice (sham) were used as controls. To further investigate the role of SNORD3A in cardiomyocyte function and survival, SNORD3A antisense oligonucleotides (SNOaso) and scramble control sequences (GFPaso) were synthesized and tested in cardiomyoblasts H9C2 cells under normoxic or hypoxic conditions to evaluate SNORD3A transcription levels, cell death and protein synthesis.

Results

SNORD3A expression was significantly increased in both LVs and PBMCs from HF patients compared to control subjects. Consistent with these results, SNORD3A levels were increased both in PBMCs and LVs from TAC mice compared to sham. In vitro hypoxia significantly increased SNORD3A expression levels in H9C2 cells, compared to normoxia. After SNOaso transfection, SNORD3A transcripts were downregulated, and they were further reduced following 3-hour-hypoxia. Depletion of SNORD3A levels increased cardiomyocyte death and reduced protein synthesis in H9C2 cells.

Conclusions

Our data suggest that SNORD3A might be involved in the regulation of cardiomyocyte survival in HF and could be useful for diagnostic and prognostic applications in HF.
Innovations in abortion care in France, Germany and the UK following the COVID-19 pandemic
Authors: Miani C , Niemann J
Published: October 2024

Background

Through an international comparison of health systems and policies, we aim at assessing the contextual and circumstantial characteristics of abortion care innovation in three European countries following the upheaval of the COVID-19 pandemic. The three contrasting care models pre-pandemic constitute an interesting baseline for observing different systems’ reaction to health crises.

Methods

We conducted a review of the recent (2020 onward) peer-reviewed and grey literature, including national policy documents and guidelines. We then carried a comparative analysis of innovations implemented during the pandemic and their sustainability post-crisis.

Results

In France and the UK, where abortion care was more accessible before the pandemic than in Germany, a series of innovations were officially introduced to facilitate access during the pandemic. They included teleconsultations and the mailing of abortion medication. Most changes have been sustained since then, contributing to addressing historic and systemic health inequities in terms of access (e.g. due to geography and the existence of “medical deserts”). In Germany, innovations during the pandemic have been crafted by the civil society through NGOs offering for the first time teleabortion services (e.g. Balance Berlin and Doctors for Choice). The legitimation of those practices by professional bodies is still in the making, highlighting the limitations of the catalyst role of crises in the face of cultural barriers and resistance of health systems to innovation.

Conclusions

The COVID-19 pandemic provoked or accelerated innovation in terms of abortion care in France, Germany and the UK. Yet, its sustainability, as well as its scaling up, remains fragile, especially in Germany, where the disruptive approach of civil society organisations has not yet found its way into mainstream health care services.

Key messages

• International comparison of health systems’ reaction to the COVID-19 pandemic in terms of abortion care shows different paths to innovation.

• The sustainability of innovation beyond the first pandemic years pertains to the wider debate on equity in access to abortion care.