Marker Of Heart Failure Research Articles

Metabolic status differentiates Trp53inp2 function in pressure-overload induced heart failure.

Cardiometabolic disorders encompass a broad range of cardiovascular complications associated with metabolic dysfunction. These conditions have an increasing share in the health burden worldwide due to worsening endemic of hypertension, obesity, and diabetes. Previous studies have identified Tumor Protein p53-inducible Nuclear Protein 2 (Trp53inp2) as a molecular link between hyperglycemia and cardiac hypertrophy. However, its role in cardiac pathology has never been determined in vivo. In this study, we generated a cardiac specific knockout model of Trp53inp2 (Trp53inp2-cKO) and investigated the impact of Trp53inp2 inactivation on the pathogenesis of heart failure under mechanic or/and metabolic stresses. Based on echocardiography assessment, inactivation of Trp53inp2 in heart led to accelerated onset of HFrEF in response to pressure-overload, with significantly reduced ejection fraction and elevated heart failure marker genes comparing to the control mice. In contrast, inactivation of Trp53inp2 ameliorated cardiac dysfunction induced by combined stresses of high fat diet and moderate pressure overload (Cardiometabolic Disorder Model). Moreover, Trp53inp2 inactivation led to reduced expression of glucose metabolism genes in lean, pressure-overloaded hearts. However, the same set of genes were significantly induced in the Trp53inp2-cKO hearts under both mechanical and metabolic stresses. In summary, we have demonstrated for the first time that cardiomyocyte Trp53inp2 has diametrically differential roles in the pathogenesis of heart failure and glucose regulation under mechanical vs. mechanical plus metabolic stresses. This insight suggests that Trp53inp2 may exacerbate the cardiac dysfunction during pressure overload injury but have a protective effect in cardiac diastolic function in cardiometabolic disease.

Coronary Microvascular Dysfunction and Hypertension: A Bond More Important than We Think.

Coronary microvascular dysfunction (CMD) is a clinical entity linked with various risk factors that significantly affect cardiac morbidity and mortality. Hypertension, one of the most important, causes both functional and structural alterations in the microvasculature, promoting the occurrence and progression of microvascular angina. Endothelial dysfunction and capillary rarefaction play the most significant role in the development of CMD among patients with hypertension. CMD is also related to several hypertension-induced morphological and functional changes in the myocardium in the subclinical and early clinical stages, including left ventricular hypertrophy, interstitial myocardial fibrosis, and diastolic dysfunction. This indicates the fact that CMD, especially if associated with hypertension, is a subclinical marker of end-organ damage and heart failure, particularly that with preserved ejection fraction. This is why it is important to search for microvascular angina in every patient with hypertension and chest pain not associated with obstructive coronary artery disease. Several highly sensitive and specific non-invasive and invasive diagnostic modalities have been developed to evaluate the presence and severity of CMD and also to investigate and guide the treatment of additional complications that can affect further prognosis. This comprehensive review provides insight into the main pathophysiological mechanisms of CMD in hypertensive patients, offering an integrated diagnostic approach as well as an overview of currently available therapeutical modalities.

The Relationship of Inflammatory Chemokine, CXCL12, with NT-proBNP: A Marker of Congestive Heart Failure in Rheumatoid Arthritis Patients

Background: Cardiovascular disease (CVD) is the most considerable long-term outcome of rheumatoid arthritis (RA) and the leading cause of premature death in RA patients. The pathogenesis of CVD in RA is largely determined by persistent systemic inflammation and its underlying factors, including chemokines. In this regard, C-X-C motif chemokine ligand 12 (CXCL12) has a crucial role in the CVD and RA pathogenesis. For the first time, plasma CXCL12 was related to conventional CV risk and well-established cardiac biomarkers in RA patients. Methods: This study was conducted on 30 RA patients who have been newly diagnosed, 30 under-treatment RA patients, and 30 healthy subjects. The plasma levels of CXCL12 and N-terminal pro-B-type natriuretic peptide (NT-ProBNP) were measured using the enzyme-linked immunosorbent assay (ELISA) technique. The high sensitivity C-reactive protein (HS-CRP) concentration was evaluated in plasma samples using the ADVIA 1800 Clinical Chemistry System based on the latex-enhanced immunoturbidimetric assay. The CVD risk was measured by calculating the Framingham risk score (FRS) and systematic coronary risk evaluation (SCORE). Results: The mean FRS and plasma concentration of high-density lipid (HDL), NT-proBNP, and HS-CRP were significantly different between the three groups (P = 0.029, P < 0.001, P = 0.016, P < 0.001, respectively). A significant positive correlation was found between CXCL12 with disease activity score-28 (DAS-28) (P = 0.024, r = 0.293) and NT-proBNP (P < 0.0001, r = 0.570) in the patients’ group. Conclusions: Based on the results, there was a significant relationship between the inflammatory mediator CXCL12 and a well-known cardiac biomarker, NT-proBNP.

HACE1 expression in heart failure patients might promote mitochondrial oxidative stress and ferroptosis by targeting NRF2.

Heart failure is a prevalent and life-threatening medical condition characterized by abnormal atrial electrical activity, contributing to a higher risk of ischemic stroke. Atrial remodelling, driven by oxidative stress and structural changes, plays a central role in heart failure progression. Recent studies suggest that HACE1, a regulatory gene, may be involved in cardiac protection against heart failure. Clinical data analysis involved heart failure patients, while an animal model utilized C57BL/6J mice. RT-PCR, microarray analysis, histological examination, ELISA, and Western blot assays were employed to assess gene and protein expression, oxidative stress, and cardiac function. Cell transfection and culture of mouse atrial fibroblasts were performed for in-vitro experiments. HACE1 expression was reduced in heart failure patients and correlated negatively with collagen levels. In mouse models, HACE1 up-regulation reduced oxidative stress, mitigated fibrosis, and improved cardiac function. Conversely, HACE1 knockdown exacerbated oxidative stress, fibrosis, and cardiac dysfunction. HACE1 also protected against ferroptosis and mitochondrial damage. NRF2, a transcription factor implicated in oxidative stress, was identified as a target of HACE1, with HACE1 promoting NRF2 activity through ubiquitination. HACE1 emerges as a potential therapeutic target and diagnostic marker for heart failure. It regulates oxidative stress, mitigates cardiac fibrosis, and protects against ferroptosis and mitochondrial damage. The study reveals that HACE1 achieves these effects, at least in part, through NRF2 activation via ubiquitination, offering insights into novel mechanisms for heart failure pathogenesis and potential interventions.

Associations between NTproBNP and 10‐year cognitive decline in The Irish Longitudinal Study on Ageing (TILDA)

AbstractBackgroundNT‐proB‐type Natriuretic Peptide (NTproBNP) is a hormone released in response to changes in pressure inside the heart often related to heart failure and other cardiac problems. Early evidence shows significant correlations between brain structure and markers of heart failure including ejection fraction and NTproBNP. We sought to investigate if levels of this biomarker are related to cognitive decline over 10 years in older adults participating in the Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of adults aged 50 years and older residing across Ireland.MethodLevels of NTproBNP were measured in 4,105 participants, mean age 61.5 years and 53.8% women, from blood drawn at baseline (Wave 1: 2009‐2011). Verbal memory (10‐word immediate and delayed recall) and verbal fluency/ executive function (animal naming) were measured every two‐years over a 10‐year follow‐up (Wave 1 – 6) and were used to create a composite score at each wave which served as a measure of global cognitive function. Linear mixed effect models with adjustment for covariates were performed. Model 1 included age, age^2, sex, education; Model 2 included Model 1 + cardiovascular diseases (heart failure, heart attack, stroke, tia, hypertension, diabetes), lifestyle factors (smoking, alcohol, physical activity, waist‐hip ratio) and depression.ResultNTproBNP was significantly and negatively associated with cognitive function at Wave 3 (B = ‐0.13, 95%CI = ‐0.20, ‐0.05), Wave 4 (B = ‐0.24, 95%CI = ‐0.31, ‐0.16), Wave 5 (B = ‐0.25, 95%CI = ‐0.32, ‐0.17) and Wave 6 (B = ‐0.26, 95%CI = ‐0.34, ‐0.17) (p<.001) (Figure 1). After further adjustment, the associations remained significant.ConclusionThese results suggest that NTproBNP may be useful as an early indicator of cognitive decline in older adults for those with and without current cardiovascular diseases.

Markers of heart failure with preserved ejection fraction in patients with unexplained dyspnea

Aim. To evaluate the prevalence of clinical, history, laboratory and ultrasound markers of heart failure with preserved ejection fraction (HFpEF) in patients with unexplained dyspnea, as well as to identify markers of structural myocardial remodeling in this group of patients.Material and methods. This retrospective study included 504 patients aged 18 to 84 years who were hospitalized from July 1, 2022 to March 31, 2023. Patients were divided into two groups depending on the presence of dyspnea. A comparative analysis of ultrasound parameters was carried out in order to identify myocardial structural remodeling.Results. A number of associated conditions and metabolic disorders, which are known to be risk factors for HFpEF, were detected more often in patients with unexplained dyspnea and myocardial remodeling. A model to determine the probability of structural remodeling was developed. Two most significant indicators were dyspnea and diabetes.Conclusion. This study demonstrated the relationship between unexplained dyspnea and structural myocardial remodeling. Identification of certain clinical and morphological signs of HFpEF in such patients requires apprehensive attitude and in-depth examination in order to rule out it.

Value of inferior vena cava collapsibility index as marker of heart failure in chronic obstructive pulmonary disease exacerbation

IntroductionInferior vena cava (IVC) diameter variability with respiration measured by ultrasound was found to be useful for the diagnosis of heart failure (HF) in ED patients with acute dyspnea. Its value in identifying HF in acute exacerbation of chronic obstructive pulmonary disease exacerbation (AECOPD) was not specifically demonstrated.ObjectiveTo determine the value of ΔIVC in the diagnosis of HF patients with AECOPD.MethodsThis is a prospective study conducted in the ED of three Tunisian university hospitals including patients with AECOPD. During this period, 401 patients met the inclusion criteria. The final diagnosis of HF is based on the opinion of two emergency experts after consulting the data from clinical examination, cardiac echocardiography, and BNP level. The ΔIVC was calculated by two experienced emergency physicians who were blinded from the patient’s clinical and laboratory data. A cut off of 15% was used to define the presence (< 15%) or absence of HF (≥ 15%). Left ventricular ejection fraction (LVEF) was also measured. The area under the ROC curve, sensitivity, specificity, and positive and negative predictive values were calculated to determine the diagnostic and predictive accuracy of the ΔIVC in predicting HF.ResultsThe study population included 401 patients with AECOPD, mean age 67.2 years with male (68.9%) predominance. HF was diagnosed in 165 (41.1%) patients (HF group) and in 236 patients (58.9%) HF was excluded (non HF group). The assessment of the performance of the ΔIVC in the diagnosis of HF showed a sensitivity of 37.4% and a specificity of 89.7% using the threshold of 15%. The positive predictive value was 70.9% and the negative predictive value was 66.7%. The area under the ROC curve was 0.71(95%, CI 0.65–0.76). ΔIVC values were not different between HF patients with reduced LVEF and those with preserved LVEF.ConclusionOur results showed that ΔIVC has a good value for ruling out HF in ED patients consulting for AECOPD.

Guideline-directed medical therapy in severe heart failure with reduced ejection fraction: An analysis from the HELP-HF registry.

Persistent symptoms despite guideline-directed medical therapy (GDMT) and poor tolerance of GDMT are hallmarks of patients with advanced heart failure (HF) with reduced ejection fraction (HFrEF). However, real-world data on GDMT use, dose, and prognostic implications are lacking. We included 699 consecutive patients with HFrEF and at least one 'I NEED HELP' marker for advanced HF enrolled in a multicentre registry. Beta-blockers (BB) were administered to 574 (82%) patients, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor-neprilysin inhibitors (ACEi/ARB/ARNI) were administered to 381 (55%) patients and 416 (60%) received mineralocorticoid receptor antagonists (MRA). Overall, ≥50% of target doses were reached in 41%, 22%, and 56% of the patients on BB, ACEi/ARB/ARNI and MRA, respectively. Hypotension, bradycardia, kidney dysfunction and hyperkalaemia were the main causes of underprescription and/or underdosing, but up to a half of the patients did not receive target doses for unknown causes (51%, 41%, and 55% for BB, ACEi/ARB/ARNI and MRA, respectively). The proportions of patients receiving BB and ACEi/ARB/ARNI were lower among those fulfilling the 2018 HFA-ESC criteria for advanced HF. Treatment with BB and ACEi/ARB/ARNI were associated with a lower risk of death or HF hospitalizations (adjusted hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.48-0.84, and HR 0.74, 95% CI 0.58-0.95, respectively). In a large, real-world, contemporary cohort of patients with severe HFrEF, with at least one marker for advanced HF, prescription and uptitration of GDMT remained limited. A significant proportion of patients were undertreated due to unknown reasons suggesting a potential role of clinical inertia either by the prescribing healthcare professional or by the patient. Treatment with BB and ACEi/ARB/ARNI was associated with lower mortality/morbidity.

Radiomics of pericardial fat: a new frontier in heart failure discrimination and prediction

ObjectivesTo use pericardial adipose tissue (PAT) radiomics phenotyping to differentiate existing and predict future heart failure (HF) cases in the UK Biobank.MethodsPAT segmentations were derived from cardiovascular magnetic resonance (CMR) studies using an automated quality-controlled model to define the region-of-interest for radiomics analysis. Prevalent (present at time of imaging) and incident (first occurrence after imaging) HF were ascertained using health record linkage. We created balanced cohorts of non-HF individuals for comparison. PyRadiomics was utilised to extract 104 radiomics features, of which 28 were chosen after excluding highly correlated ones (0.8). These features, plus sex and age, served as predictors in binary classification models trained separately to detect (1) prevalent and (2) incident HF. We tested seven modeling methods using tenfold nested cross-validation and examined feature importance with explainability methods.ResultsWe studied 1204 participants in total, 297 participants with prevalent (60 ± 7 years, 21% female) and 305 with incident (61 ± 6 years, 32% female) HF, and an equal number of non-HF comparators. We achieved good discriminative performance for both prevalent (voting classifier; AUC: 0.76; F1 score: 0.70) and incident (light gradient boosting machine: AUC: 0.74; F1 score: 0.68) HF. Our radiomics models showed marginally better performance compared to PAT area alone.Increased PAT size (maximum 2D diameter in a given column or slice) and texture heterogeneity (sum entropy) were important features for prevalent and incident HF classification models.ConclusionsThe amount and character of PAT discriminate individuals with prevalent HF and predict incidence of future HF.Clinical relevance statementThis study presents an innovative application of pericardial adipose tissue (PAT) radiomics phenotyping as a predictive tool for heart failure (HF), a major public health concern. By leveraging advanced machine learning methods, the research uncovers that the quantity and characteristics of PAT can be used to identify existing cases of HF and predict future occurrences. The enhanced performance of these radiomics models over PAT area alone supports the potential for better personalised care through earlier detection and prevention of HF.Key Points•PAT radiomics applied to CMR was used for the first time to derive binary machine learning classifiers to develop models for discrimination of prevalence and prediction of incident heart failure.•Models using PAT area provided acceptable discrimination between cases of prevalent or incident heart failure and comparator groups.•An increased PAT volume (increased diameter using shape features) and greater texture heterogeneity captured by radiomics texture features (increased sum entropy) can be used as an additional classifier marker for heart failure.

Infertility and Subclinical Antecedents of Heart Failure With Preserved Ejection Fraction in the Framingham Heart Study

BackgroundInfertility has been shown to be associated with a greater risk of incident heart failure with preserved ejection fraction. We studied the association of infertility with subclinical markers of heart failure with preserved ejection fraction, including echocardiographic signs of cardiac remodeling and cardiac biomarkers. Methods and ResultsA history of infertility was ascertained in 2002 women enrolled in the Framingham Heart Study. We examined the association of infertility with echocardiographic measures and cardiac biomarkers with multivariable-adjusted linear regression models. Among 2002 women (mean age 40.84 ± 9.71 years), 285 (14%) reported a history of infertility. Infertility was associated with a greater E/e′ ratio (β = 0.120, standard error 0.057, P = .04), even after adjustment for common confounders. Infertility was not associated with other echocardiographic measures or cardiac biomarkers. ConclusionsInfertility was associated with a greater E/e′ ratio, a marker of diastolic dysfunction that may signal earlier subclinical cardiac remodeling in women with infertility.

Identification CCL2,CXCR2,S100A9 of the immune-related gene markers and immune infiltration characteristics of inflammatory bowel disease and heart failure via bioinformatics analysis and machine learning.

Recently, heart failure (HF) and inflammatory bowel disease (IBD) have been considered to be related diseases with increasing incidence rates; both diseases are related to immunity. This study aims to analyze and identify immune-related gene (IRG) markers of HF and IBD through bioinformatics and machine learning (ML) methods and to explore their immune infiltration characteristics. This study used gene expressiondata (GSE120895, GSE21610, GSE4183) from the Gene Expression Omnibus (GEO) database to screen differentially expressed genes (DEGs) and compare them with IRGs from the ImmPort database to obtain differentially expressed immune-related genes (DIRGs). Functional enrichment analysis of IRGs was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, three machine models and protein-protein interactions (PPIs) were established to identify diagnostic biomarkers. The receiver operating characteristic (ROC) curves were applied to evaluate the diagnostic value of the candidate biomarkersin the validation set (GSE1145, GSE36807) and obtain their correlations with immune cells through the Spearman algorithm. Finally, the CIBERSORT algorithm was used to evaluate the immune cell infiltration of the two diseases. Thirty-four DIRGs were screened and GO and KEGG analysis results showed that these genes are mainly related to inflammatory and immune responses. CCL2, CXCR2 and S100A9 were identified as biomarkers.The immune correlation results indicated in both diseases that CCL2 is positively correlated with mast cell activation, CXCR2 is positively correlated with neutrophils and S100A9 is positively correlated with neutrophils and mast cell activation. Analysis of immune characteristics showed that macrophages M2, macrophages M0 and neutrophils were present in both diseases. CCL2, CXCR2 and S100A9 are promising biomarkers that will become potential immunogenetic biomarkers for diagnosing comorbidities of HF and IBD. macrophages M2, macrophages M0, neutrophil-mediated inflammation and immune regulation play important roles in the development of HF and IBD and may become diagnostic and therapeutic targets.

Integrating scRNA-seq to explore novel macrophage infiltration-associated biomarkers for diagnosis of heart failure

ObjectiveInflammation and immune cells are closely intertwined mechanisms that contribute to the progression of heart failure (HF). Nonetheless, there is a paucity of information regarding the distinct features of dysregulated immune cells and efficient diagnostic biomarkers linked with HF. This study aims to explore diagnostic biomarkers related to immune cells in HF to gain new insights into the underlying molecular mechanisms of HF and to provide novel perspectives for the detection and treatment of HF.MethodThe CIBERSORT method was employed to quantify 22 types of immune cells in HF and normal subjects from publicly available GEO databases (GSE3586, GSE42955, GSE57338, and GSE79962). Machine learning methods were utilized to screen for important cell types. Single-cell RNA sequencing (GSE145154) was further utilized to identify important cell types and hub genes. WGCNA was employed to screen for immune cell-related genes and ultimately diagnostic models were constructed and evaluated. To validate these predictive results, blood samples were collected from 40 normal controls and 40 HF patients for RT-qPCR analysis. Lastly, key cell clusters were divided into high and low biomarker expression groups to identify transcription factors that may affect biomarkers.ResultsThe study found a noticeable difference in immune environment between HF and normal subjects. Macrophages were identified as key immune cells by machine learning. Single-cell analysis further showed that macrophages differed dramatically between HF and normal subjects. This study revealed the existence of five subsets of macrophages that have different differentiation states. Based on module genes most relevant to macrophages, macrophage differentiation-related genes (MDRGs), and DEGs in HF and normal subjects from GEO datasets, four genes (CD163, RNASE2, LYVE1, and VSIG4) were identified as valid diagnostic markers for HF. Ultimately, a diagnostic model containing two hub genes was constructed and then validated with a validation dataset and clinical samples. In addition, key transcription factors driving or maintaining the biomarkers expression programs were identified.ConclusionThe analytical results and diagnostic model of this study can assist clinicians in identifying high-risk individuals, thereby aiding in guiding treatment decisions for patients with HF.

Right ventricular-pulmonary artery coupling in the early stages of infarction could optimize patient risk stratification over five years

Abstract Background Right ventricular (RV) dysfunction is recognized as a cardinal prognostic marker in heart failure (HF) patients. Myocardial infarction (MI) is often followed by unrecognized RV dysfunction, which can be associated with worse outcome. It is recently shown that the ratio between TAPSE and PASP (RV/PA) may depict cardiopulmonary hemodynamics better than the two parameters alone. Aim To evaluate the interactions between left ventricular (LV) and RV function in early phase of MI and to assess the prognostic significance of RV/PA coupling in patients with first MI during 5 years follow up. Methods The prospective study included 144 patients with the first MI treated with the primary percutaneous coronary intervention (p PCI) who underwent Doppler echocardiography within 2±1 days of MI. LV function analysis included: LV ejection fraction (EF), ratio between early diastolic velocity and tissue annular velocity (E/e) and global longitudinal strain (GLS). RV function and RV-PA interaction was expressed as ratio between TAPSE and PASP. During the five-year follow-up, major cardiovascular events and especially hospitalization for HF were analyzed. Results Progressive RV/PA uncoupling was associated with higher degree of LV impairment and dysfunction (EF p&amp;lt;0.001, E/e p=0.002, GLS p&amp;lt;0.001) and severity of mitral regurgitation (p=0.013). Lower baseline RV/PA coupling significantly reflects the frequency of hospitalizations for HF in the population of patients with first MI during five-year follow-up (0.62 v.s.0.51, p=0.021). After multivariate adjustment RV/PA remained an independent predictor of all major cardiac events (MACE) after five years (OR 14.0 [1.5–130.8], p=0.019). Conclusion A lower baseline RV-PA coupling, reflecting a higher degree of LV-induced pulmonary hypertension and secondary RV-dysfunction, is associated with decline of LV function in early phase of MI, and is independently associated with worse prognosis after five years. The value of RV-PA ratio as an prognstic marker warrants further investigation.

Single-nucleus RNA sequencing of TMEM43 induced arrhythmogenic cardiomyopathy reveals altered cell compositions and transcriptional states in mice

Abstract Introduction and purpose TMEM43 induced Arrhythmogenic cardiomyopathy, also referred to as arrhythmogenic cardiomyopathy type 5 or ACM5, is caused by a point mutation in TMEM43 (p.S358L). The disease is characterised by chamber dilation and a progressive dystrophy of the ventricular myocardium causing life-threatening ventricular arrhythmias and sudden cardiac death. Loss of cardiomyocytes and fibrofatty replacement of the myocardium is clearly observed in our transgenic mouse model of ACM5 overexpressing TMEM43-S358L in postnatal cardiomyocytes. However, the mechanisms underlying cardiomyocyte death and fibroblast activation remain elusive, precluding the development of effective therapeutic options. Here we applied the state-of-the-art analysis on single-nucleus RNA sequencing (snRNA-seq) to characterise the cellular compositions and molecular states in ACM5 mouse hearts. Methods Left ventricular heart tissues of severely affected ACM5 mice and their corresponding transgenic controls overexpressing wild-type TMEM43 were used for snRNA-seq analysis. We identified 10 major cell types, which aggregated into 23 distinct clusters on the basis of transcriptional similarity. Results ACM5 nuclei showed significant depletion of cardiomyocytes and expanded populations of fibroblasts and myeloid cells. Fibroblasts from mutant mice acquired an activated phenotype related to remodelling of the extracellular matrix with a large number of genes like LOX, POSTN, NOX4 or COL1A1 significantly upregulated. In addition, the mutant cardiomyocytes showed altered transcriptional states characterized by cardiac stress and heart failure markers such as NPPB or MYH7. Interestingly, we were able to identify a cluster of mutant cardiomyocytes with a highly apoptotic profile. This cluster is also enriched in genes related to the unfolding protein response (UPR) stress sensors and the DNA damage response (DDR), elucidating a new potential mechanism of myocyte death in ACM5. Furthermore, heterogeneity of the myeloid populations is also observed. The number of tissue resident macrophages is increased in mutant samples and myeloid cells show additional disease-associated transcriptional states that are almost entirely absent in control samples. Conclusion Together these data illuminated shared and distinct cell and molecular architectures of ACM5 in mouse hearts. Further confirmation on diverse gene expression profiles like the UPR and DDR pathways related to cardiomyocyte death will establish a valuable resource to explore novel therapeutic targets and personalized therapies for ACM5.

Assessment of global and segmental strain in heterozygous APE1/Ref-1 transgenic mice using cardiac magnetic resonance imaging

Abstract Background Apurinic/apyrimidinic-endonuclease1(APE1/Ref-1) is a redox factor necessary for DNA binding and transcription regulator in ROS generation. The association between APE1/Ref-1 and heart failure(HF) has been observed in previous studies. Heterozygous APE1/Ref-1 transgenic mice displayed endothelial cell dysfunction with systemic hypertension. Global strain(GS) measures the myocardium's deformation along its axis and is known to be a sensitive marker of subclinical HF in hypertensive patients with preserved ejection fraction. Purpose This study aims to investigate the functional dynamics and GS of the heart in heterozygous APE1/Ref-1 mice to help identify the association between APE1/Ref-1 and early signs of HF and translate to clinical applications. Methods A study was conducted to assess the functional parameters of both the left ventricle(LV) and right ventricle (RV) and perform LV global and segmental strain analysis using cardiac magnetic resonance imaging(CMR) in heterozygous APE1/Ref-1 transgenic mice(n=4) and wild type mice (n=4) of age 10-12 weeks. A 7T CMR scanner and FSE T1 sequence were used to acquire short-axis views of mouse cardiac images. LV and RV functional parameters including ejection fraction(EF), stroke volume(SV), cardiac output, peak filling rate, peak emptying rate and strain indices including global circumferential strain, global radial strain, segmental circumferential strain, and segmental radial strain were calculated with a software dedicated to analyzing CMR images. Global LV and RV function was quantified both manually and using an AI-based algorithm of LV and RV segmentation. The strain analysis was performed using the strain medical image tracking toolbox module. Additionally, reproducibility testing was done to validate the accuracy of AI-driven calculations. Results We found that heterozygous APE1/Ref-1 mice displayed a decrease in SV(8.00±0.01ul vs 9.75±0.96ul, p=0.01) and LVEF(58.75±2.63% vs 66.50±2.89%, p=0.007) compared to controls while the functional parameters of RV were similar. Interestingly, the circumferential strain rate of LV was significantly reduced in APE1/Ref-1 mice compared to controls(p&amp;lt;0.001), particularly in the systolic phase. In addition, the study showed that manually-calculated and AI-derived indices were within an acceptable margin of error, rendering the AI system reproducible and reliable in calculating volumetric parameters and strain of the mice's hearts. Conclusions This study demonstrated that LV global circumferential strain rate, along with SV and LVEF decreased in heterozygous APE1/Ref-1 transgenic mice. These parameters could serve as markers for assessing early functional changes of mice hearts in a non-invasive manner. Volumetric and strain indices measured by AI-based analysis of mouse CMR images are reproducible parameters for cardiovascular research in small animals.LV strain analysis of mice CMRTable of volumetric parameters

Circulating SerpinA3 as a novel indicator of cardiovascular dysfunction after anthracycline chemotherapy

Abstract Background Close monitoring of development of cardiovascular toxicity during anthracycline (AC) chemotherapy is crucial for early diagnosis and guidance of therapy. SerpinA3, a serine protease inhibitor, was recently described as prognostic marker for heart failure and elevated plasma levels are associated with increased mortality. The effect of AC on SERPINA3 levels in a cancer population has not been studied yet Purpose To investigate whether SERPINA3 plasma levels could serve as a marker for cancer therapy-related cardiac dysfunction and whether its levels are influenced by AC chemotherapy Methods Adult cancer patients requiring AC chemotherapy were enrolled between January 2020 and June 2022. Patients with a history of heart failure or prior cardiotoxicity were excluded. Measurement of cTnI and NT-proBNP and echocardiography (LVEF and GLS) were performed at four timepoints: before the start of AC (V1), directly after completion of chemotherapy (V2), 3 months thereafter (V3) and 1 year after V2 (V4). CTRCD was diagnosed according to the recent ESC guidelines. Results Fifty-one patients fulfilled inclusion criteria and agreed to participate in the study. Patients were on average 54 years old and the majority were female (80.4%). After anthracyclines, 38 patients developed asymptomatic CTRCD, graded as mild in 29 patients and moderate (LVEF 40-49%) in patients. SerpinA3 plasma levels at V3 were significantly higher in patients with moderate CTRCD (247.7; [196.4-428.9]) compared to patients with no CTRCD (142.7; [126.5-170.2]; p=0.004). In patients developing moderate CTRCD, a significant increase in SerpinA3 from baseline to V2 ( 209.0 [162.025-2.7]; 313.3 [212.6- 387.1, p=0.028) and remained elevated till V3 (247.7 [196.4-428.9], p=0.038). In patients with no CTRCD SerpinA3 showed an opposite trend with no significant difference at V2 compared to V1 (190.1 [165.2-230.5] vs 196.3 [170.8-297.1]; p= 0.972), but a subsequent significant decline from V2 to V3 (142.7 [126.5-170.2]; p=0.003). In patients with mild CTRCD a similar, but non-significant trend as in no CTRCD patients was seen(211.4 [167.8-302.6] vs 218.3 [171.9-277.7]; p=0.346 vs 167.5 [140.5-286.8]; p=0.122). These findings were confirmed by the absolute change in SerpinA3 from baseline to V4 which differed significantly in moderate CTRCD (+51.3; [7.1-176.4]) compared to both patients with no CTRCD (-47.5;[ -78.0- -35.4]; p=0.019) and patients with mild CTRCD (-52.0;[ -78.6- 32.8]; p=0.043). In patients with moderate CTRCD SerpinA3 values at V4 remained significantly elevated in patients without full cardiac recovery 1 year after the end of chemotherapy (4/5 patients; p=0.050). Conclusion SerpinA3 is increased after anthracycline chemotherapy in patients with moderate CTRCD. A lasting increase of serpinA3 was observed in in patients who did not show a complete recovery of cardiac function, potentially indicative of a worse cardiac prognosis.Figure 1Figure 2

MUC-16, tumour and congestive heart failure marker, is expressed on epicardial mesothelial cells and is inversely associated with epicardial fat genesis

Abstract Background CA-125 or mucin-16 (MUC-16) is a protector protein on epithelial luminal surfaces against physical stress through hydration process. However, some evidence suggests a role in fibrogenesis. MUC-16 can be detected in plasma after proteolytic cleavage with a predictive value for heart failure progression. Our main objective was to study the expression levels of this glycoprotein on epicardial mesothelial cells, its association with epicardial fat genesis, and biochemical markers. Methods and results We have used epicardial and subcutaneous fat from patients(n = 29) undergoing open heart surgery under informed consent and after approval by Ethics Committee. MUC-16 expression levels were detected on formalin-fixed paraffin-embedded epicardial fat biopsies with CA-125 antibody or real-time PCR on stored biopsies (n = 18) at -80ºC. Epicardial cells scraped with a scalpel were cultured and their MUC-16 expression was confirmed with a specific antibody and secondary fluorescent antibody. Primary cultures from epicardial stromal cells of 8 patients were obtained with collagenase digestion. After 15 days, adipogenesis was induced for 15 days with an adipogenic cocktail. Adipogenesis (AdipoQ) and mesothelial (ITLN-1) markers were quantified by real-time PCR on cells with and without adipogenesis. CA-125 expression levels were analyzed by real time-PCR on epicardial fat from 18 patients, as well as inflammation, fibrosis, stretch and adiposity markers levels on plasma by multiplex assay. Our results showed that MUC-16 is localized on epicardial mesothelial cells but not on adipocytes. The MUC-16-stained cells can be cultured and isolated after scraping the epicardium. The isolated epicardial stromal cells with collagenase showed a positive relationship between mesothelial maker (ITLN-1) and CA125 (Figure below). The higher presence of MUC-16 levels was inversely associated with AdipoQ after adipogenesis induction. From 8 plasma studied proteins, thrombospondin-2 (TP-2), was the best associated protein with MUC-16 on epicardial fat (r = 0,472; p = 0,48). Conclusion Epicardial cells express MUC-16. These types of cells can be isolated and cultured for studying their cleavage regulation and modulation. Epicardial stromal cells with a higher percentage of MUC-16 reduce the epicardial fat genesis. Further studies are needed for finding the main circulating plasma levels associated with epicardial MUC-16.

Meteorin-like plasma levels as a novel biomarker for heart failure

Abstract Introduction Meteorin-like (metrnl), a new adipokine with insulin-sensitizing and anti-inflammatory action, has recently drawn much attention due to its protective effects in the cardiovascular system. Metrnl promotes heart repair after insults like ischemia/reperfusion, cardiotoxicity, or diabetic cardiomyopathy in mice, and its circulating levels in patients have been associated with the presence and severity of coronary artery disease and heart failure, although in the latter with contradictory results. Purpose Our aim was to study the correlation between plasma metrnl levels and biochemical and echocardiographic parameters in patients hospitalized with de novo heart failure (HF) to determine whether this adipokine could be a useful biomarker/therapeutic target for HF. Methods Blood samples of 400 patients hospitalized with de novo HF were collected in a multicenter clinical study. Plasma levels of metrnl were measured by enzyme-linked immunosorbent assay. Results In de novo HF patients, metrnl plasma levels were positively correlated with age (r = 0.322, P &amp;lt; 0.0001), NT-proBNP (r = 0.293, P &amp;lt; 0.0001), troponin (r = 0.192, P &amp;lt; 0.001), creatinine (r = 0.353, P &amp;lt; 0.0001) and urea (r = 0.322, P &amp;lt; 0.0001), while negatively correlated with albumin (r = -0.308, P &amp;lt; 0.0001) and alanine aminotransferase (r = -0.183, P &amp;lt; 0.0001). Metrnl plasma levels were also positively correlated with echocardiographic data of cardiac morphology as intraventricular septum thickness (r = 0.197, P &amp;lt; 0.0001) and left ventricular posterior wall thickness (r = 0.150, P &amp;lt; 0.004). On the other hand, Cox regression analysis suggested that higher plasma metrnl was associated with increased cardiovascular mortality (HR, 1.004, P &amp;lt; 0.004)) and rate of readmission for HF (HR, 1.002, P &amp;lt; 0.008). Regarding the different types of HF, we found that metrnl plasma levels were lower in HF with reduced ejection fraction (HFrEF) in comparison those with preserved ejection fraction (HFpEF) [408.06 (354.05 - 537.71) pg/mL vs. 486.06 (391.94 – 607.80), median (interquartile range), respectively; P &amp;lt; 0.0001]. Conclusion Metrnl plasma levels were associated with markers of cardiac (troponin), renal (creatinine and urea) and hepatic (alanine aminotransferase and albumin) damage. The HF marker NT-proBNP and the echocardiographic parameters intraventricular septum thickness and left ventricular posterior wall thickness are also linked to metrnl plasma levels. Moreover, metrnl levels were found to be independent predictors of cardiovascular mortality and readmission for heart failure. And finally, metrnl plasma levels in patients hospitalized with de novo HF were increased in patients with HFpEF vs. HFrEF. Our results reinforce the relevance of the adipokine metrnl in the pathophysiology and diagnosis of HF, and supports its possible use in the future as biomarker/therapeutic target for HF.

Relaxin as a biological marker and therapeutic target in heart failure

An important task of modern cardiology is the search and study of new cardiovascular biological markers that can help in the early diagnosis of heart diseases, serve as a tool to assess the effectiveness of treatment, and act as a prognostic marker and risk stratification criterion. This literature review aimed to consider relaxin (RLN) as a new diagnostic and prognostic cardiovascular biological marker. RLN is a natural peptide hormone with a molecular weight of approximately 6000 daltons. RLN2 is the main circulating form of RLN in the blood. Although human RLN2 was originally discovered as a hormone mainly secreted by the corpus luteum of the ovary, it is also synthesized in various tissues in non-pregnant women and men and is considered one of the most pleiotropic hormones of the human body, which perform various activities beyond reproduction.&#x0D; The availability of serelaxin (a recombinant molecule identical to human RLN2) has made it possible to study the effects of RLN2 on the cardiovascular system, kidneys, liver, and brain and to evaluate it in several randomized placebo-controlled clinical trials. RLN2 exerts many cardioprotective effects on the heart and vessels and has been proposed as a therapeutic target for cardiovascular diseases such as heart failure, atrial fibrillation, coronary heart disease, myocardial infarction, and arterial hypertension. Through the activation of its cognate receptor and subsequent flow of several molecular signaling pathways in the cardiovascular system, RLN2 can induce vasodilation and angiogenesis, increase arterial compliance and cardiac output, reduce vascular resistance, exert antifibrotic effects through regulation and remodeling of extracellular matrix turnover, reduce inflammation and apoptosis, inhibit oxidative stress, induce chronotropic and inotropic effects, and inhibit ventricular and atrial ectopic activity.&#x0D; Further studies are needed to demonstrate the potential use of RLN as an additional laboratory tool for diagnosis, risk stratification, and prediction of cardiovascular events in patients with heart failure. The effects of relaxin on morbidity and mortality in patients with heart failure have yet to be evaluated in more detail.

Abstract 15401: Artificial Intelligence-Enabled Exercise-CMR for Evaluation of Cardiac Functional Reserve in Heart Failure

Introduction: Exercise unmasks pathophysiological markers in heart failure (HF), not evident at rest. Exercise CMR (Ex-CMR) has the potential to offer an accurate and reproducible assessment of cardiac functional reserve in HF. Objective: To study the cardiac functional reserve in HF using an artificial intelligence (AI) enabled exercise CMR imaging protocol. Method: We prospectively recruited patients with an established clinical diagnosis of HF and healthy adults. Subjects were imaged at rest and immediately post-exercise using a supine ergometer positioned on the CMR scan. The imaging protocol included free-breathing, real-time, highly accelerated cine short-axis images covering the entire LV. Cine images were collected with a spatial resolution of 1.9 х 1.9 mm 2 and temporal resolution of 38.8 ms using a 14.8-fold acceleration using an in-house inline deep learning reconstruction. Pre- and post-exercise biventricular volumetric and functional parameters and their corresponding percentage changes were calculated. Results: The study included 77 subjects, consisting of 37 HF patients (24 males; 60 ± 12 years) [HFpEF, n=13; HFmrEF, n=5; HFimpEF, n=13; and HFrEF, n=6], and 40 healthy adult (20 males; 45 ± 16 years). Changes in LV end-diastolic and end-systolic volume among subgroups revealed distinct clusters (Fig 1). These findings corresponded to a blunted to a modest rise in stroke volume (SV) observed in HFpEF and HFmrEF patients, respectively, while HFimpEF and HFrEF patients exhibited a mildly to excessively higher SV rise compared to other subgroups (Fig 1). HFpEF and HFmrEF showed no improvement in SV index beyond 10 ml/m 2 . Patients with known post capillary pulmonary hypertension demonstrated an inadequate right ventricle response in preload recruitment, contributing to a blunted increase in RV SV (Fig 1). Conclusion: Our AI-enabled, high-accelerated Ex-CMR imaging protocol reveals a distinctive biventricular functional reserve response in HF.