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Background: Acute myocardial infarction (AMI) is a leading cause of death and morbidity worldwide. Ferroptosis, a form of regulated cell death, plays a critical role in modulating immune functions during AMI. This study aimed to identify ferroptosis-related hub genes that could serve as potential therapeutic targets in the progression of AMI., Methods: Bioinformatics was used to identify overlapping genes associated with ferroptosis and the infiltration of 22 immune cells by Cell-type Identification by Estimating Relative Subsets of RNA Transcript (CIBERSORT) analysis. The expression of ferroptosis-related genes in AMI was validated across independent datasets, clinical samples, and in vitro cellular experiments. The predictive value for heart failure was evaluated in the first dimension of principal component analysis (PCA) using receiver operating characteristic (ROC) analysis., Results: The study identified 11 key ferroptosis-related genes significantly correlated with immune cell abundance. CIBERSORT analysis highlighted immune dysregulation in AMI. JDP2, DUSP1, TLR4, NFS1, and SLC1A5 were identified as potential biomarkers for AMI progression. Additionally, JDP2, DUSP1, and DDIT4 demonstrated strong predictive value for long-term heart failure., Conclusion: This study highlights the potential association of ferroptosis-related genes with the pathogenesis of AMI, suggesting a role in the molecular mechanisms that may underlie acute coronary events., Competing Interests: Declarations Ethics approval and consent to participate All experimental protocols were approved by the Ethics Committee of the Medical Ethics Committee of Xiangya Hospital of Central South University (IRB No. 2017121009). Informed consent was obtained from all participants and/or their legal guardians. All procedures were performed following the relevant guidelines and regulations, following the recommendations of the Declaration of Helsinki. All experiments were conducted according to relevant guidelines and regulations. Competing interest The authors declare no competing interests., (© 2024. The Author(s).)

Background: Although genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM), there are no studies available describing this entity. We sought to describe clinical features, analyze variant location, and explore predictors of bad prognosis in pediatric MYH7 -related DCM., Methods and Results: We evaluated clinical records from 44 patients (24 men; median age at diagnosis, 0.54 [interquartile range, 0.01-10.8] years) with pathogenic/likely pathogenic variants in MYH7 diagnosed with DCM at pediatric age (<18 years) followed at 13 international centers. We also explored risk factors associated with a composite end point of end-stage heart failure defined as heart transplantation or heart failure-related death. Twenty-two patients (50%) were diagnosed at age <6 months, including 7 (16%) at birth. Left ventricular (LV) hypertrabeculation features were present in 15 (38%), particularly among patients with genetic variants in the head domain. After a median follow-up of 6.1 years (interquartile range, 1.9-13.4), 15 patients (36%) required a heart transplant (n=14) or died due to end-stage heart failure (n=1), 15 patients (36%) persisted with systolic dysfunction despite treatment, 12 (29%) had a significant increase in LV ejection fraction, and 2 were lost to follow-up. Overall, end-stage heart failure event rate was 25% at 5 years. New York Heart Association class III to IV (hazard ratio [HR], 7.67 [95% CI, 2.16-27.2]; P =0.002) and LV ejection fraction ≤35% (HR, 4.00 [95% CI, 1.11-14.4]; P =0.03) were the best predictors of bad prognosis., Conclusions: Pediatric MYH7 -related DCM is characterized by early onset, frequent LV hypertrabeculation, and poor prognosis. Advanced New York Heart Association class and low LV ejection fraction emerged as predictors of end-stage heart failure.

The pathological activation of cardiac fibroblasts (CFs) plays a crucial role in the development of pressure overload-induced cardiac remodelling and subsequent heart failure (HF). Growing evidence demonstrates that multiple microRNAs (miRNAs) are abnormally expressed in the pathophysiologic process of cardiovascular diseases, with miR-425 recently reported to be potentially involved in HF. In this study, we aimed to investigate the effects of fibroblast-derived miR-425-5p in pressure overload-induced HF and explore the underlying mechanisms. C57BL/6 mice were injected with a recombinant adeno-associated virus specifically designed to overexpress miR-425-5p in CFs, followed by transverse aortic constriction (TAC) surgery. Neonatal mouse CFs (NMCFs) were transfected with miR-425-5p mimics and subsequently stimulated with angiotensin II (Ang II). We found that miR-425-5p levels were significantly downregulated in HF mice and Ang II-treated NMCFs. Notably, fibroblast-specific overexpression of miR-425-5p markedly inhibited the proliferation and differentiation of CFs, thereby alleviating myocardial fibrosis, cardiac hypertrophy and systolic dysfunction. Mechanistically, the cardioprotective actions of miR-425-5p may be achieved by targeting the TGF-β1/Smad signalling. Interestingly, miR-425-5p mimics-treated CFs could also indirectly affect cardiomyocyte hypertrophy in this course. Together, our findings suggest that fibroblast-derived miR-425-5p mitigates TAC-induced HF, highlighting miR-425-5p as a potential diagnostic and therapeutic target for treating HF patients., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Krüppel-like factor 9 (Klf9) is dysregulated in human and rodent cardiomyopathy. Both global and cardiac-specific Klf9-deficient mice displayed hypertrophic cardiomyopathy. Klf9 knockout led to mitochondrial disarray and fragmentation, impairing mitochondrial respiratory function in cardiomyocytes. Furthermore, cardiac Klf9 deficiency inhibited mitophagy, thereby causing accumulation of dysfunctional mitochondria and acceleration of heart failure in response to angiotensin II treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function. Mechanistically, Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2, thereby regulating mitochondrial dynamics and mitophagy. Finally, adeno-associated virus-mediated Mfn2 rescue in Klf9-CKO hearts improved cardiac mitochondrial and systolic function. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure., Competing Interests: Competing interests All authors declare no competing interests. There are no conflicts of interest in the submission of this manuscript, which was approved by all authors for publication. We also confirm that this work is original. It has not been published elsewhere and is not currently under consideration for publication elsewhere., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their cross-talk are poorly understood. In diseased organs, stress-induced gene expression changes fuel maladaptive cell state transitions 1 and pathological interaction between cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lungs, liver, kidneys and heart, and exacerbates many cancers 2 , the stress-sensing mechanisms initiating transcriptional activation of fibroblasts are poorly understood. Here we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1 + macrophages ameliorates heart failure in mice and significantly reduces fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1 + cells identified a large enhancer proximal to interleukin-1β (IL-1β, encoded by Il1b), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1β activated a fibroblast RELA-dependent (also known as p65) enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL-1β neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1β inhibition or targeted Il1b deletion in Cx3cr1 + cells prevented stress-induced Meox1 expression and fibroblast activation. The elucidation of BRD4-dependent cross-talk between a specific immune cell subset and fibroblasts through IL-1β reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodelling., Competing Interests: Competing interests D.S. is scientific co-founder, shareholder and director of Tenaya Therapeutics. S.M.H. is an executive, officer and shareholder of Amgen and is a scientific co-founder and shareholder of Tenaya Therapeutics. T.A.M. received funding from Italfarmaco for an unrelated project. K.S.P. is a shareholder of Tenaya Therapeutics., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Left ventricular hypertrophy (LVH) caused by chronic pressure overload with subsequent pathological remodeling is a major cardiovascular risk factor for heart failure and mortality. The role of deubiquitinases in LVH has not been well characterized. To define whether the deubiquitinase ubiquitin-specific peptidase 20 (USP20) regulates LVH, we subjected USP20 knockout (KO) and cognate wild-type (WT) mice to chronic pressure overload by transverse aortic constriction (TAC) and measured changes in cardiac function by serial echocardiography followed by histological and biochemical evaluations. USP20-KO mice showed severe deterioration of systolic function within 4 wk of TAC compared with WT cohorts. Both USP20-KO TAC and WT-TAC cohorts presented cardiac hypertrophy following pressure overload. However, USP20-KO-TAC mice showed an increase in cardiomyocyte length and developed maladaptive eccentric hypertrophy, a phenotype generally observed with volume overload states and decompensated heart failure. In contrast, WT-TAC mice displayed an increase in cardiomyocyte width, producing concentric remodeling that is characteristic of pressure overload. In addition, cardiomyocyte apoptosis, interstitial fibrosis, and mouse mortality were augmented in USP20-KO-TAC compared with WT-TAC mice. Quantitative mass spectrometry of LV tissue revealed that the expression of sarcomeric myosin heavy chain 7 (MYH7), a fetal gene normally upregulated during cardiac remodeling, was significantly reduced in USP20-KO after TAC. Mechanistically, we identified increased degradative lysine-48 polyubiquitination of MYH7 in USP20-KO hearts, indicating that USP20-mediated deubiquitination likely prevents protein degradation of MYH7 during pressure overload. Our findings suggest that USP20-dependent signaling pathways regulate the layering pattern of sarcomeres to suppress maladaptive remodeling during chronic pressure overload and prevent cardiac failure. NEW & NOTEWORTHY We identify ubiquitin-specific peptidase 20 (USP20) as an important enzyme that is required for cardiac homeostasis and function, particularly during myocardial pressure overload. USP20 regulates protein stability of cardiac MYH7, an essential molecular motor protein expressed in sarcomeres; loss-of-function mutations of MYH7 are associated with human hypertrophic cardiomyopathy, cardiac failure, and sudden death. Enhancing USP20 activity could be a potential therapeutic approach to prevent the development of maladaptive state of eccentric hypertrophy and heart failure.

Background: The inflammatory response and myocardial remodeling play critical roles in the progression of heart failure (HF) following myocardial infarction (MI). Isoliquiritigenin (ISL) possesses anti-inflammatory properties and has been investigated in cardiovascular diseases such as atherosclerosis. However, the effects and mechanism of ISL on MI-induced HF remain unclear. This research aimed to explore the effects and mechanism of ISL in the treatment of HF on the basis of network pharmacology, transcriptomics, and experimental verification., Methods and Results: We established an MI-induced HF mouse model in which ISL was administered via gavage for 28 days. Ultrasonic cardiogram data were collected from the mice, and pathological staining was conducted. Then, network pharmacology and molecular docking were performed. Transcriptomic analysis was also conducted on mouse myocardial tissue. Ultimately, we integrated transcriptomic data and network pharmacology to reveal the underlying mechanism, with the results verified through in vivo experiments. Our experiments indicated that ISL improved cardiac function, preserved myocardial structure, inhibited collagen fiber accumulation, reduced inflammatory factor secretion, and mitigated myocardial cell apoptosis in mice with MI-induced HF. A combination of transcriptomics and network pharmacology analysis revealed that core targets of ISL related to HF were significantly enriched in the Tumor Necrosis Factor (TNF) signaling pathway. Molecular docking validation demonstrated that ISL shows strong binding to these core targets. Additionally, in vivo experiments verified that ISL protects against HF post-MI by inhibiting the TNF signaling pathway., Conclusion: We clarified the anti-inflammatory and antimyocardial remodeling mechanisms of ISL in the treatment of HF post-MI, which involves the TNF signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Heart failure (HF) is highly prevalent. Mechanisms underlying HF remain incompletely understood. Splicing factors (SF), which control pre-mRNA alternative splicing, regulate cardiac structure and function. This study investigated regulation of the splicing factor heterogeneous nuclear ribonucleoprotein-L (hnRNPL) in the failing heart. hnRNPL protein increased in left ventricular tissue from mice with transaortic constriction-induced HF and from HF patients. In left ventricular tissue, hnRNPL was detected predominantly in nuclei. Knockdown of the hnRNPL homolog Smooth in Drosophila induced cardiomyopathy. Computational analysis of predicted mouse and human hnRNPL binding sites suggested hnRNPL-mediated alternative splicing of tropomyosin, which was confirmed in C2C12 myoblasts. These findings identify hnRNPL as a sensor of cardiac dysfunction and suggest that disturbances of hnRNPL affect alternative splicing in HF., (© 2024 Federation of European Biochemical Societies.)

microRNAs (miRNAs) are small regulatory RNAs implicated in various cardiac disorders. In this review, the role of miRNAs is discussed in relation to acute myocardial infarction and chronic heart failure. In both settings, miRNAs are altered, contributing to injury and adverse remodeling. Notably, miRNA profiles differ between acute ischemic injury and progressive heart failure. Owing to miRNA variabilities between disease stages and delivery difficulties, translation of animal studies to the clinic remains challenging. The identification of distinct miRNA signatures could lead to the development of miRNA therapies tailored to different disease stages. Here, we summarize the current understanding of miRNAs in acute and chronic cardiac diseases, identify knowledge gaps and discuss progress in developing miRNA-based treatment strategies., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: This study investigated changes in methylation concentrations within the glutathione peroxidase 3 (GPX3) promoter region among patients diagnosed with chronic heart failure (CHF). Peripheral blood samples were collected from 20 CHF patients and 20 healthy individuals for analysis., Methods: Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, methylation concentrations of 11 CpG sites within the GPX3 promoter region were quantified., Results: Results showed a significant increase in methylation at the GPX3&#95;FA10&#95;CpG&#95;24 site in patients with CHF compared with the control group (P < 0.05). Furthermore, a nonlinear dose-response relationship was observed between methylation concentrations at this site and key clinical parameters including serum apolipoprotein A-1, D-dimer, chlorine, potassium, and sodium (Na) (P < 0.05)., Conclusions: These findings suggest that aberrant methylation of the GPX3 promoter may impact disease progression by influencing physiological functions such as blood lipids, coagulation, and electrolytes. Further investigations are warranted to elucidate the role of GPX3 promoter methylation in CHF pathogenesis, potentially contributing valuable insights for its prevention, diagnosis, and treatment., Competing Interests: Conflict of interest RZ reports financial support was provided by by Special R&D Program Project of Chinese Academy of Se-enriched Industry (2020FXZX05-01). All other authors report no conflicts of interest., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Improving energy provision in the failing heart by augmenting the creatine kinase (CK) system is a desirable therapeutic target. However, over-expression of the creatine transporter (CrT-OE) has shown that very high creatine levels result in cardiac hypertrophy and dysfunction. We hypothesise this is due to insufficient endogenous CK activity to maintain thermodynamically favourable metabolite ratios. If correct, then double transgenic mice (dTg) overexpressing both CrT and the muscle isoform of CK (CKM-OE) would rescue the adverse phenotype. In Study 1, overexpressing lines were crossed and cardiac function assessed by invasive haemodynamics and echocardiography. This demonstrated that CKM-OE was safe, but too few hearts had creatine in the toxic range. In Study 2, a novel CrT-OE line was generated with higher, homogeneous, creatine levels and phenotyped as before. Myocardial creatine was 4-fold higher in CrT-OE and dTg hearts compared to wildtype and was associated with hypertrophy and contractile dysfunction. The inability of dTg hearts to rescue this phenotype was attributed to downregulation of CK activity, as occurs in the failing heart. Nevertheless, combining both studies in a linear regression analysis suggests a modest positive effect of CKM over a range of creatine concentrations. In conclusion, we confirm that moderate elevation of creatine is well tolerated, but very high levels are detrimental. Correlation analysis lends support to the theory that this may be a consequence of limited CK activity. Future studies should focus on preventing CKM downregulation to unlock the potential synergy of augmenting both creatine and CK in the heart., (Copyright © 2024. Published by Elsevier Ltd.)

MicroRNAs (miRNAs) play an important role in the process of heart failure (HF) and are emerging biomarkers that can be used for the auxiliary diagnosis of HF. However, it is very challenging to accurately analyze the expression levels of trace miRNAs in complex clinical samples. Here, we developed an enzyme-free colorimetric sensor for the ultrasensitive detection of miRNA-423-5p (HF-associated miRNA) based on three-dimensional DNA walkers constructed from functional nucleic acids and gold nanoparticles (AuNPs). DNAzyme with cleavage activity was specifically activated by miRNA-423-5p to sustainably cleave the substrate, thereby releasing the trigger sequence to initiate the subsequent mismatched catalytic hairpin assembly (MCHA) cycle. Then, as the MCHA cycle proceeded to continuously expose the G-quadruplex (GQ) sequence, the sequence bound with hemin to form a large amount of GQ/hemin DNAzyme on the surface of the AuNPs, which rapidly catalyzed the chromogenic oxidation of 3,3',5,5'-tetramethylbenzidine to yield an amplified colorimetric signal readout. The colorimetric sensor exhibited an ultralow detection limit (32 fM), showed excellent specificity and performed well in serum samples. The sensor was applied to detect miRNA-423-5p in clinical plasma samples from healthy individuals and HF patients, and the results revealed its good clinical application in HF diagnosis. Thus, the developed colorimetric sensor provides a convenient detection tool for early screening and diagnosis of HF, as well as for pathophysiological studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Heart Failure (HF) poses a challenge for our health systems, and early detection of Worsening HF (WHF), defined as a deterioration in symptoms and clinical and instrumental signs of HF, is vital to improving prognosis. Predicting WHF in a phase that is currently undiagnosable by physicians would enable prompt treatment of such events in patients at a higher risk of WHF. Although the role of Artificial Intelligence in cardiovascular diseases is becoming part of clinical practice, especially for diagnostic and prognostic purposes, its usage is often considered not completely reliable due to the incapacity of these models to provide a valid explanation about their output results. Physicians are often reluctant to make decisions based on unjustified results and see these models as black boxes. This study aims to develop a novel diagnostic model capable of predicting WHF while also providing an easy interpretation of the outcomes. We propose a threshold-based binary classifier built on a mathematical model derived from the Genetic Programming approach. This model clearly indicates that WHF is closely linked to creatinine, sPAP, and CAD, even though the relationship of these variables and WHF is almost complex. However, the proposed mathematical model allows for providing a 3D graphical representation, which medical staff can use to better understand the clinical situation of patients. Experiments conducted using retrospectively collected data from 519 patients treated at the HF Clinic of the University Hospital of Salerno have demonstrated the effectiveness of our model, surpassing the most commonly used machine learning algorithms. Indeed, the proposed GP-based classifier achieved a 96% average score for all considered evaluation metrics and fully supported the controls of medical staff. Our solution has the potential to impact clinical practice for HF by identifying patients at high risk of WHF and facilitating more rapid diagnosis, targeted treatment, and a reduction in hospitalizations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV K c ) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs ( n = 9) by sequential ascending aortic cuff and age- and weight-matched pigs ( n = 6) served as controls. LV function was measured by echocardiography and LV K c by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed ( n = 10, n = 9, respectively). LV samples from LVPO and controls ( n = 6, respectively) were subjected to RNA sequencing. LV mass and K c increased by over 40% with LVPO ( P < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV K c ( P < 0.05) that mapped to functional domains relevant to K c such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold ( P < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets. NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is an ever-growing cause for the HF burden. HFpEF is particularly difficult to treat as the mechanisms responsible for this specific form of HF are poorly understood. Using a relevant large animal model, this study uncovered a unique molecular signature with the development of HFpEF that regulates specific biological pathways relevant to the progression of this ever-growing cause of HF.

Dilated cardiomyopathy (DCM) is defined as left ventricular enlargement accompanied by systolic dysfunction not explained by abnormal loading conditions or coronary heart disease. The DCM clinical spectrum is broad, ranging from subclinical to severe presentation with progression to end stage heart failure. To date, different genetic loci have been found to have moderate/definitive evidence for causality in DCM and pathogenic variants in the TTN gene represent the main genetic determinant. Here, we describe a family in which the co-occurrence of two genetic hits, one in the TTN and one in the BAG3 gene, was associated with heterogeneous clinical presentation ranging from subclinical phenotypes to acute cardiogenic shock mimicking fulminant myocarditis. We hypothesize that at least some specific BAG3 genotypes could be related to DCM presenting with acute heart failure and suggest that patients and relatives carrying BAG3 pathogenic variants should be addressed to a tertiary-level heart care center., Competing Interests: Declaration of competing interest All authors disclose any actual or potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: The population prevalence of cardiac transthyretin amyloidosis (ATTR) caused by pathogenic variation in the TTR gene (vATTR) is unknown., Objective: To estimate the population prevalence of disease-causing TTR variants and evaluate associated phenotypes and outcomes., Design, Setting, and Participants: This population-based cohort study analyzed UK Biobank (UKB) participants with whole-exome sequencing, electrocardiogram, and cardiovascular magnetic resonance data. Participants were enrolled from 2006 to 2010, with a median follow-up of 12 (IQR, 11-13) years (cutoff date for the analysis, March 12, 2024). Sixty-two candidate TTR variants were extracted based on rarity (minor allele frequency ≤0.0001) and/or previously described associations with amyloidosis if more frequent., Exposure: Carrier status for TTR variants., Main Outcomes and Measures: Associations of TTR carrier status with vATTR prevalence and cardiovascular imaging and electrocardiogram traits were explored using descriptive statistics. Associations between TTR carrier status and atrial fibrillation, conduction disease, heart failure, and all-cause mortality were evaluated using adjusted Cox proportional hazards models. Genotypic and diagnostic concordance was examined using International Statistical Classification of Diseases, Tenth Revision codes from the hospital record., Results: The overall cohort included 469 789 UKB participants (mean [SD] age, 56.5 [8.1] years; 54.2% female and 45.8% male). A likely pathogenic/pathogenic (LP/P) TTR variant was detected in 473 (0.1%) participants, with Val142Ile being the most prevalent (367 [77.6%]); 91 individuals (0.02%) were carriers of a variant of unknown significance . The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry. The LP/P variants were associated with higher left ventricular mass indexed to body surface area (β = 4.66; 95% CI, 1.87-7.44), and Val142Ile was associated with a longer PR interval (β = 18.34; 95% CI, 5.41-31.27). The LP/P carrier status was associated with a higher risk of heart failure (hazard ratio [HR], 2.68; 95% CI, 1.75-4.12) and conduction disease (HR, 1.88; 95% CI, 1.25-2.83). Higher all-cause mortality risk was observed for non-Val142Ile LP/P variants (HR, 1.98; 95% CI, 1.06-3.67). Thirteen participants (2.8%) with LP/P variants had diagnostic codes compatible with cardiac or neurologic amyloidosis. Variants of unknown significance were not associated with outcomes., Conclusions and Relevance: This study found that approximately 1 in 1000 UKB participants were LP/P TTR variant carriers, exceeding previously reported prevalence. The findings emphasize the need for clinical vigilance in identifying individuals at risk of developing vATTR and associated poor outcomes.

Background: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear., Methods: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N 6 -methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF., Results: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury., Conclusions: Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions., Competing Interests: None.

Background: Breast cancer and heart failure are major public health issues globally, characterized by significant genetic heterogeneity and complex molecular mechanisms. This study aims to explore potential genetic targets in heart failure and breast cancer through combining genetic inference and single-cell expression analysis, and to assess the causal relationships of these targets using Mendelian randomization methods., Methods: We first identified genetic variants associated with heart failure and breast cancer using genome-wide association study (GWAS) data. Subsequently, we analyzed the expression patterns of these genetic variants in different cell types through single-cell RNA sequencing technology. Furthermore, we utilized in vitro experiment to assess the effects of ITM2B on MCF7 using immunofluorescence., Results: Our study identified multiple genetic variants associated with heart failure and breast cancer, showing specific expression patterns in heart and breast cells. The ITM2B gene is highly expressed in breast cancer. ITM2B shows the highest expression in T cells and the lowest expression in proliferating cells. Silencing the ITM2B gene can promote apoptosis and inhibit proliferation and migration of MCF7 breast cancer cells., Conclusion: By integrating genetic inference and single-cell expression analysis, this study revealed potential genetic targets in heart failure and breast cancer, and validated the causal effects of these targets using Mendelian randomization methods., (© 2024. The Author(s).)

Recent advances in genomics and proteomics have helped in understanding the molecular mechanisms and pathways of comorbidities and heart failure. In this narrative review, we reviewed molecular alterations in common comorbidities associated with heart failure such as obesity, diabetes mellitus, systemic hypertension, pulmonary hypertension, coronary artery disease, hypercholesteremia and lipoprotein abnormalities, chronic kidney disease, and atrial fibrillation. We searched the electronic databases, PubMed, Ovid, EMBASE, Google Scholar, CINAHL, and PhysioNet for articles without time restriction. Although the association between comorbidities and heart failure is already well established, recent studies have explored the molecular pathways in much detail. These molecular pathways demonstrate how novels drugs for heart failure works with respect to the pathways associated with comorbidities. Understanding the altered molecular milieu in heart failure and associated comorbidities could help to develop newer medications and targeted therapies that incorporate these molecular alterations as well as key molecular variations across individuals to improve therapeutic outcomes. The molecular alterations described in this study could be targeted for novel and personalized therapeutic approaches in the future. This knowledge is also critical for developing precision medicine strategies to improve the outcomes for patients living with these conditions., (© 2024. The Author(s).)

This study analyzed transcriptomic and proteomic data to identify molecular changes during heart failure (HF). Additionally,we embarked on an exploration of the prospect of therapeutic intervention through the manipulation of proteins implicated in ferroptosis. Three publicly available microarray datasets (GSE135055, GSE147236, GSE161472) profiling left ventricular samples from HF patients and healthy controls were obtained. Differentially expressed genes were identified in each dataset and cross-analyzed to determine shared gene signatures. Enrichment analysis of Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and gene set enrichment analysis were performed. Differentially expressed proteins were obtained from published proteomic studies and integrated with the transcriptomic results. To validate findings, a HF mouse model was generated and ferroptosis-related proteins were evaluated. Additionally, the effect of suppression of ferroptosis on hypoxia-induced ischemia model in HL-1 cardiomyocytes was assessed by knocking down Acyl-CoA synthetase long-chain family member 4 (ACSL4) using small interfering RNA (siRNA).Cross-analysis of differentially expressed genes (DEGs) in the GSE135055, GSE147236 and GSE161472 datasets revealed 224 up-regulated and 187 down-regulated potential genes which showed high enrichment in immune, inflammatory and metabolic pathways. Notably, four proteins, among them ACSL4, displayed consistent alterations at both the transcriptional and protein levels. In the HF mouse model, ACSL4 exhibited an elevation, whereas negative regulators of ferroptosis witnessed a decrement. Subsequently, knockdown of ACSL4 in a hypoxia-induced ischemic HL-1 cardiomyocyte cell model upregulated the expression of ferroptosis inhibitory protein and decreased the levels of reactive oxygen species (ROS), malondialdehyde (MDA)., and free iron and increased cell viability. Comprehensive multi-omics analysis revealed that the expression of the molecular target ACSL4 was increased in HF. Targeting ACSL4 to inhibit ferroptosis may represent a novel therapeutic strategy for HF treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chronic heart failure (CHF) is closely associated with inflammation and mitochondrial dysfunction in cardiomyocytes. This study attempts to investigate the effects of microRNA-21-3p (miR-21-3p) on macrophage polarization and mitophagy in CHF. Here we found miR-21-3p was upregulated in CHF and negatively correlated with carnitine palmitoyl transferase 1A (CPT1A). L-palmitoyl carnitine (L-PC) exacerbated isoproterenol (ISO)-induced myocardial structural disruption and fibrosis in rats, which was exacerbated by miR-21-3p. Mechanistically, miR-21-3p accelerated M1 macrophage polarization. Both miR-21-3p inhibitor and CPT1A overexpression suppressed mitophagy. The inhibition of CPT1A on mitophagy was reversed by miR-21-3p. MiR-21-3p targeted CPT1A mRNA and co-localized with CPT1A protein in cardiomyocytes. In the co-culture system of M1 macrophages and H9c2 cells, miR-21-3p mimics in H9c2 cells promoted M1 polarization, whereas miR-21-3p inhibitor reduced M1 phenotype. M1 macrophages exacerbated H9c2 cell damage. These findings support the potential therapeutic targeting of miR-21-3p to regulate inflammation and mitophagy by inducing CPT1A in CHF., (© 2024. The Author(s).)

Chronic heart failure (CHF) can induce chronic kidney disease (CKD), called type 2 cardio-renal syndrome (CRS2). The mechanism is not completely clear, and there is a lack of early warning biomarkers of CKD in the context of CHF. Two CKD, one CHF-PBMC and four CHF-cardiac tissue expression profile datasets were obtained from GEO database. Differential expression analysis and WGCNA were used to detect CKD key genes and CHF-related secreted proteins. Protein-protein interaction (PPI), functional enrichment, and cMAP analysis reveal potential mechanisms and drugs of CHF-related CKD. Five machine learning algorithms were used to screen candidate biomarkers, construct a diagnostic nomogram for CKD and validate it in two external cohorts. Clinical serum samples were collected in our hospital to evaluate the correlation and diagnostic value of biomarkers and CKD. 225 CKD key genes and 316 CHF-related secreted proteins were identified. Four key subgroups, including 204 genes, were identified as CRS2-related pathogenic genes by PPI analysis. Enrichment analysis revealed that the identified subgroups exhibited significant enrichment in cytokine action, immune responses, and inflammatory processes. The cMAP analysis highlighted metiradone as a drug with greater potential for therapeutic intervention for CRS2. Utilizing five machine learning algorithms, three hub genes (CD48, COL3A1, LOXL1) were pinpointed as potential biomarkers for CKD, and a nomogram model was constructed. Receiver operating characteristic analysis demonstrated that the nomogram's area under the curve (AUC) exceeded 0.80 in both the CKD combined dataset and two external cohorts. In addition, the three biomarkers were significantly correlated with the glomerular filtration rate, and the AUC of the model predicting disease progression was 0.944. Furthermore, analysis of immune cell infiltration indicated a correlation between the three biomarkers and the infiltration fraction of macrophages, neutrophils, and other immune cells in CKD. Our clinical cohort validated the expression patterns of three biomarkers in serum, and the diagnostic model achieved an AUC of 0.876. CHF has the potential to facilitate the progression of CKD via the release of cardiac and PBMC secreted proteins. Furthermore, CD48, COL3A1, and LOXL1 have been identified as potential biomarkers for the detection of CKD., (© 2024. The Author(s).)

Growing evidence suggests that heart failure (HF) is associated with an increased risk of depressive disorders and anxiety. However, the existing studies were observational and may have confounded and not reflected true causal relationships. This study collected genetic instruments about HF, depression, and anxiety from publicly available genetic summary data. Two-sample Mendelian randomization (MR) analysis was performed, with inverse-variance weighted designated as the primary approach for determining causal effects. Secondary analyses included MR-Egger regression and the weighted media method. Additionally, we conducted MR pleiotropy residual sum and outlier to address horizontal pleiotropy. Cochran Q test, MR-Egger intercept test, and leave-one-out analysis were used to assess the robustness of the findings. The significance is determined by a P-value below .05. Gene prediction result revealed that HF did not exhibit a significant association with elevated incidence of depression by inverse-variance weighted method no matter HF from the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 0.93-1.18, P = .424 for major depressive disorder, MDD; OR = 1.01, 95% CI = 0.94-1.09, P = .782 for major depression) or the FinnGen Consortium (OR = 1.03, 95% CI = 0.92-1.15, P = .644 for MDD; OR = 1.00, 95% CI = 0.94-1.07, P = .962 for major depression). In contrast, the results of HF on anxiety exhibited inconsistency (OR = 1.60, 95% CI = 1.10-2.31, P = .013 for Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium; OR = 1.42, 95% CI = 0.91-2.21, P = .123 for FinnGen Consortium); however, a combined effect analysis indicated support causal relationship between HF and the risk of anxiety (OR = 1.52, 95% CI = 1.07-2.00, P < .001). Our findings did not reveal evidence to confirm a causal association between HF and depression. However, our results provide support for a causal effect of HF on the risk of anxiety., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study aims to identify m6A methylation-related and immune cell-related key genes with diagnostic potential for heart failure (HF) by leveraging various bioinformatics techniques., Methods: The GSE116250 and GSE141910 datasets were sourced from the Gene Expression Omnibus (GEO) database. Correlation analysis was conducted between differentially expressed genes (DEGs) in HF and control groups, alongside differential m6A regulatory factors, to identify m6A-related DEGs (m6A-DEGs). Subsequently, candidate genes were narrowed down by intersecting key module genes derived from weighted gene co-expression network analysis (WGCNA) with m6A-DEGs. Key genes were then identified through the Least Absolute Shrinkage and Selection Operator (LASSO) analysis. Correlation analyses between key genes and differentially expressed immune cells were performed, followed by the validation of key gene expression levels in public datasets. To ensure clinical applicability, five pairs of blood samples were collected for quantitative real-time fluorescence PCR (qRT-PCR) validation., Results: A total of 93 m6A-DEGs were identified (|COR| > 0.6, P < 0.05), and five key genes (LACTB2, NAMPT, SCAMP5, HBA1, and PRKAR2A) were selected for further analysis. Correlation analysis revealed that differential immune cells were negatively associated with the expression of LACTB2, NAMPT, and PRKAR2A (P < 0.05), while positively correlated with SCAMP5 and HBA1 (P < 0.05). Subsequent expression validation confirmed significant differences in key gene expression between the HF and control groups, with consistent expression trends observed across both training and validation sets. The expression trends of LACTB2, PRKAR2A, and HBA1 in blood samples from the qRT-PCR assay aligned with the results derived from public databases., Conclusion: This study successfully identified five m6A methylation-related key genes with diagnostic significance, providing a theoretical foundation for further exploration of m6A methylation's molecular mechanisms in HF., (© 2024. The Author(s).)

Background: In the past decade, the biological functions of various RNA modifications in mammals have been uncovered. N4-acetylcytidine (ac4C), a highly conserved RNA modification, has been implicated in human diseases. Despite this, the involvement of RNA ac4C modification in cardiac physiology and pathology remains incompletely understood. NAT10 (N-acetyltransferase 10) stands as the sole acetyltransferase known to catalyze RNA ac4C modification. This study aims to explore the role of NAT10 and ac4C modification in cardiac physiology and pathology., Methods and Results: Cardiac-specific knockout of NAT10, leading to reduced RNA ac4C modification, during both neonatal and adult stages resulted in severe heart failure. NAT10 deficiency induced cardiomyocyte apoptosis, a crucial step in heart failure pathogenesis, supported by in vitro data. Activation of the p53 signaling pathway was closely associated with enhanced apoptosis in NAT10-deficient cardiomyocytes. As ac4C modification on mRNA influences translational efficiency, we employed ribosome footprints coupled with RNA sequencing to explore genome-wide translational efficiency changes caused by NAT10 deficiency. We identified and validated that the translational efficiency of Kmt5a was suppressed in NAT10 knockout hearts due to reduced ac4C modification on its mRNA. This finding was consistent with the observation that Kmt5a protein levels were reduced in heart failure despite unchanged mRNA expression. Knockdown of Kmt5a in cardiomyocytes recapitulated the phenotype of NAT10 deficiency, including increased cardiomyocyte apoptosis and activated p53 signaling. Finally, overexpression of Kmt5a rescued cardiomyocyte apoptosis and p53 activation induced by NAT10 inhibition., Conclusions: Our study highlights the significance of NAT10 in cardiomyocyte physiology, demonstrating that NAT10 loss is sufficient to induce cardiomyocyte apoptosis and heart failure. NAT10 regulates the translational efficiency of Kmt5a , a key mediator, through mRNA ac4C modification during heart failure.

Background: Heart failure (HF) presents a massive burden to health care with a complex pathophysiology that results in HF with reduced left ventricle ejection fraction (EF) or HF with preserved EF. It has been shown that relatively modest changes in protein glycosylation, an essential posttranslational modification, are associated with clinical presentations of HF. We and others previously showed that such aberrant protein glycosylation in animal models can lead to HF., Methods and Results: We develop and characterize a novel, tamoxifen-inducible, cardiomyocyte Mgat1 knockout mouse strain, achieved through deletion of Mgat1 , alpha-1,3-mannosyl-glycoproten 2-beta-N-acetlyglucosaminyltransferase, which encodes N-acetylglucosaminyltransferase I. We investigate the role of hybrid/complex N-glycosylation in adult HFrEF pathogenesis at the ion channel, cardiomyocyte, tissue, and gross cardiac level. The data demonstrate successful reduction of N-acetylglucosaminyltransferase I activity and confirm that hybrid/complex N-glycans modulate gating of cardiomyocyte voltage-gated calcium channels. A longitudinal study shows that the tamoxifen-inducible, cardiomyocyte Mgat1 knockout mice present with significantly reduced systolic function by 28 days post induction that progresses into HFrEF by 8 weeks post induction, without significant ventricular dilation or hypertrophy. Further, there was minimal, if any, physiologic or pathophysiologic cardiomyocyte electromechanical remodeling or fibrosis observed before (10-21 days post induction) or after (90-130 days post induction) HFrEF development., Conclusions: The tamoxifen-inducible, cardiomyocyte Mgat1 knockout mouse strain created and characterized here provides a model to describe novel mechanisms and causes responsible for HFrEF onset in the adult, likely occurring primarily through tissue-level reductions in electromechanical activity in the absence of (or at least before) cardiomyocyte remodeling and fibrosis.

Background: Prescription opioid use (POU) has been shown to lead to cardiovascular disease (CVD), but its association with heart failure has not been well studied. We investigated the potential causal association between POU and HF using cohort studies and Mendelian Randomization (MR) analysis., Methods: Initially, we examined the longitudinal association between POU and HF using the data from the Health and Retirement Study (HRS) and the UK biobank. Next, we employed a two-sample MR analysis using summary statistics from genome-wide association studies (GWAS) to assess the potential causal associations between POU and HF., Results: During a median of 3.8 and 13.8 years of follow-up, there were 441(8.04 per 1000 person-year) and 16,170 (3.96 per 1000 person-year) HF cases in the HRS and the UK biobank, respectively. After adjusting for covariates, participants who used prescription opioids had a 32% increased risk of developing HF, compared with non-users (HR = 1.32, 95%CI: 1.26-1.38, P < 0.001). In the MR analysis, summary statistics for POU were obtained from 78,808 UK Biobank study participants, and summary data for HF were obtained from 218,792 participants of a European population. A causal effect of genetic liability for POU on an increased risk of HF (OR = 1.16, 95% CI = 1.06, 1.27, P = 0.001) was suggested. The results were generally consistent in the sensitivity analysis, and no pleiotropy or heterogeneity were observed., Conclusions: POU is associated with a high risk of HF. Our findings provide new insight into prescription opioid use among populations at risk of heart failure. More studies are needed to validate our results and further investigate the underlying mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Epicardial adipose tissue (EAT) surrounds the heart and is hypothesised to play a role in the development of heart failure (HF). In this study, we first investigated the differences in gene expression between epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) in patients undergoing elective coronary artery bypass graft (CABG) surgery (n = 21; 95% male). Secondly, we examined the association between EAT and SAT in patients at risk for HF stage A (n = 12) and in pre-HF patients, who show signs but not symptoms of HF, stage B (n = 9)., Results: The study confirmed a distinct separation between EAT and SAT. In EAT 17 clusters of genes were present, of which several novel gene modules are associated with characteristics of HF. Notably, seven gene modules showed significant correlation to measures of HF, such as end diastolic left ventricular posterior wall thickness, e' mean , deceleration time and BMI. One module was particularly distinct in EAT when compared to SAT, featuring key genes such as FLT4, SEMA3A, and PTX3, which are implicated in angiogenesis, inflammation regulation, and tissue repair, suggesting a unique role in EAT linked to left ventricular dysfunction. Genetic expression was compared in EAT across all pre-HF and normal phenotypes, revealing small genetic changes in the form of 18 differentially expressed genes in ACC/AHA Stage A vs. Stage B., Conclusions: The roles of subcutaneous and epicardial fat are clearly different. We highlight the gene expression difference in search of potential modifiers of HF progress. The true implications of our findings should be corroborated in other studies since HF ACC/AHA stage B patients are common and carry a considerable risk for progression to symptomatic HF., (© 2024. The Author(s).)

BACKGROUND X-PROLYL AMINOPEPTIDASE 3: (XPNPEP3) mutations are known to cause nephronophthisis-like nephropathy-1 (NPHPL1), a rare autosomal-recessive kidney disease characterized by progressive kidney failure and cystic kidney disease in childhood. The full phenotypic spectrum associated with mutations in XPNPEP3 is not fully elucidated. CASE PRESENTATION: A 13-year-old Chinese female patient with intellectual disability presented with a 2-year history of convulsions and fatigue, with a recent episode of swelling, breathlessness, and nocturnal dyspnea lasting 10 days. The patient was diagnosed with heart failure and kidney failure. Whole exome sequencing revealed a homozygous c.970-2 A > G mutation in XPNPEP3 associated with severe cardiac dysfunction and neurological symptoms, including epilepsy and intellectual disability. Notably, kidney ultrasound did not reveal the typical changes of NPHPL1, and kidney failure was hypothesized to be secondary to cardiac dysfunction rather than primary kidney pathology. CONCLUSIONS: This case suggests the possible association of additional phenotypic features associated with XPNPEP3 mutations, emphasizing the need for further investigation into the heterogeneous clinical presentations associated with XPNPEP3 mutations. The findings highlight the importance of considering alternative phenotypes in patients with genetic mutations traditionally associated with specific diseases. Segregation and functional analyses are necessary to determine causality between the c.970-2 A > G XPNPEP3 mutation and disease., (© 2024. The Author(s).)

Background: Women with heart failure and reduced ejection fraction (HFrEF) have greater symptoms and a lower quality of life compared with men; however, the role of noncardiac mechanisms remains poorly resolved. We hypothesized that differences in skeletal muscle pathology between men and women with HFrEF may explain clinical heterogeneity., Methods: Muscle biopsies from both men (n=22) and women (n=16) with moderate HFrEF (New York Heart Association classes I-III) and age- and sex-matched controls (n=18 and n=16, respectively) underwent transcriptomics (RNA-sequencing), myofiber structural imaging (histology), and molecular signaling analysis (gene/protein expression), with serum inflammatory profiles analyzed (enzyme-linked immunosorbent assay). Two-way ANOVA was conducted (interaction sex and condition)., Results: RNA-sequencing identified 5629 differentially expressed genes between men and women with HFrEF, with upregulated terms for catabolism and downregulated terms for mitochondria in men. mRNA expression confirmed an effect of sex ( P <0.05) on proatrophic genes related to ubiquitin proteasome, autophagy, and myostatin systems (higher in all men versus all women), whereas proanabolic IGF1 expression was higher ( P <0.05) in women with HFrEF only. Structurally, women compared with men with HFrEF showed a pro-oxidative phenotype, with smaller but higher numbers of type I fibers, alongside higher muscle capillarity ( P interaction <0.05) and higher type I fiber areal density ( P interaction <0.05). Differences in gene/protein expression of regulators of muscle phenotype were detected between sexes, including HIF1α , ESR1 , VEGF (vascular endothelial growth factor), and PGC1α expression ( P <0.05), and for upstream circulating factors, including VEGF, IL (interleukin)-6, and IL-8 ( P <0.05)., Conclusions: Sex differences in muscle pathology in HFrEF exist, with men showing greater abnormalities compared with women related to the transcriptome, fiber phenotype, capillarity, and circulating factors. These preliminary data question whether muscle pathology is a primary mechanism contributing to greater symptoms in women with HFrEF and highlight the need for further investigation., Competing Interests: None.

Several large-scale studies have measured plasma levels of the proteome in individuals with cardiovascular diseases (CVDs) 1-7 . However, since the majority of such proteins are interrelated 2 , it is difficult for observational studies to distinguish which proteins are likely to be of etiological relevance. Here we evaluate whether plasma levels of 2,919 proteins measured in 52,164 UK Biobank participants are associated with incident myocardial infarction, ischemic stroke or heart failure. Of those proteins, 126 were associated with all three CVD outcomes and 118 were associated with at least one CVD in the China Kadoorie Biobank. Mendelian randomization and colocalization analyses indicated that genetically determined levels of 47 and 18 proteins, respectively, were associated with CVDs, including FGF5, PROCR and FURIN. While the majority of protein-CVD observational associations were noncausal, these three proteins showed evidence to support potential causality and are therefore promising targets for drug treatment for CVD outcomes., (© 2024. The Author(s).)

Background: Activation of the immune system contributes to cardiovascular diseases. The role of human-specific long noncoding RNAs in cardioimmunology is poorly understood., Methods: Single-cell sequencing in peripheral blood mononuclear cells revealed a novel human-specific long noncoding RNA called HEAT4 (heart failure-associated transcript 4). HEAT4 expression was assessed in several in vitro and ex vivo models of immune cell activation, as well as in the blood of patients with heart failure (HF), acute myocardial infarction, or cardiogenic shock. The transcriptional regulation of HEAT4 was verified through cytokine treatment and single-cell sequencing. Loss-of-function and gain-of-function studies and multiple RNA-protein interaction assays uncovered a mechanistic role of HEAT4 in the monocyte anti-inflammatory gene program. HEAT4 expression and function was characterized in a vascular injury model in NOD.CB17-Prkdc scid/Rj mice., Results: HEAT4 expression was increased in the blood of patients with HF, acute myocardial infarction, or cardiogenic shock. HEAT4 levels distinguished patients with HF from people without HF and predicted all-cause mortality in a cohort of patients with HF over 7 years of follow-up. Monocytes, particularly anti-inflammatory CD16 + monocytes, which are increased in patients with HF, are the primary source of HEAT4 expression in the blood. HEAT4 is transcriptionally activated by treatment with anti-inflammatory interleukin-10. HEAT4 activates anti-inflammatory and inhibits proinflammatory gene expression. Increased HEAT4 levels result in a shift toward more CD16 + monocytes. HEAT4 binds to S100A9, causing a monocyte subtype switch, thereby reducing inflammation. As a result, HEAT4 improves endothelial barrier integrity during inflammation and promotes vascular healing after injury in mice., Conclusions: These results characterize a novel endogenous anti-inflammatory pathway that involves the conversion of monocyte subtypes into anti-inflammatory CD16 + monocytes. The data identify a novel function for the class of long noncoding RNAs by preventing protein secretion and suggest long noncoding RNAs as potential targets for interventions in the field of cardioimmunology., Competing Interests: None.

Aims: The molecular signatures in epicardial adipose tissue (EAT) that contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF) are poorly characterized. In this study, we sought to elucidate molecular signatures including genetic transcripts and long non-coding RNAs (lncRNAs) in EAT that might modulate HFpEF development., Methods: RNA sequencing (RNA-seq) was performed to identify differentially expressed lncRNAs and mRNAs in EAT samples from patients with HFpEF (n = 5) and without HF (control, n = 5) who underwent coronary artery bypass grafting. The sequencing results were validated using quantitative real-time PCR (qRT-PCR). Bioinformatics analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of differentially expressed RNAs was performed to predict enriched functions., Results: HFpEF patients had higher EAT thickness and NT-proBNP levels than the control group. A total of 64 471 transcripts were detected including 35 395 protein-coding sequences, corresponding to 16 854 genes in EAT. RNA-seq identified a total of 741 dysregulated mRNA transcripts (394 up-regulated and 347 down-regulated) and 334 differentially expressed lncRNA transcripts (222 up-regulated and 112 down-regulated) in the HFpEF group compared with the control group (P < 0.05). qRT-PCR analysis confirmed that two lncRNAs ENST00000561775 (P = 0.0194) and ENST00000519093 (P = 0.027) and an mRNA POSTN (P = 0.003) were differentially expressed. Functional enrichment analysis of the differentially expressed mRNAs suggested their potential roles in immune response involving cytokine interaction and chemokine signalling., Conclusions: We are the first group to report on the lncRNA and mRNA landscape in EAT in HFpEF patients. Our study suggests the possible role of lncRNAs in EAT., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Heart failure (HF) is a prevalent cardiovascular disease with significant morbidity and mortality rates worldwide. Due to the intricate structure of the heart, diverse cell types, and the complex pathogenesis of HF, further in-depth investigation into the underlying mechanisms  is required. The elucidation of the heterogeneity of cardiomyocytes and the intercellular communication network is particularly important. Traditional high-throughput sequencing methods provide an average measure of gene expression, failing to capture the "heterogeneity" between cells and impacting the accuracy of gene function knowledge. In contrast, single-cell sequencing techniques allow for the amplification of the entire genome or transcriptome at the individual cell level, facilitating the examination of gene structure and expression with unparalleled precision. This approach offers valuable insights into disease mechanisms, enabling the identification of changes in cellular components and gene expressions during hypertrophy associated with HF. Moreover, it reveals distinct cell populations and their unique roles in the HF microenvironment, providing a comprehensive understanding of the cellular landscape that underpins HF pathogenesis. This review focuses on the insights provided by single-cell sequencing techniques into the mechanisms underlying HF and discusses the challenges encountered in current cardiovascular research., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease; DDX5 (dead-box helicase 5) is a master regulator of many RNA processes, although its function in heart physiology remains unclear., Methods: We assessed DDX5 expression in human failing hearts and a mouse HF model. To study the function of DDX5 in heart, we engineered cardiomyocyte-specific Ddx5 knockout mice. We overexpressed DDX5 in cardiomyocytes using adeno-associated virus serotype 9 and performed transverse aortic constriction to establish the murine HF model. The mechanisms underlined were subsequently investigated using immunoprecipitation-mass spectrometry, RNA-sequencing, alternative splicing analysis, and RNA immunoprecipitation sequencing., Results: We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of Ddx5 resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. DDX5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. We found that DDX5 regulated the aberrant splicing of Ca 2+ /calmodulin-dependent protein kinase IIδ ( CamkIIδ ), thus preventing the production of CaMKIIδA, which phosphorylates L-type calcium channel by serine residues of Cacna1c, leading to impaired Ca 2+ homeostasis. In line with this, we found increased intracellular Ca 2+ transients and increased sarcoplasmic reticulum Ca 2+ content in DDX5-depleted cardiomyocytes. Using adeno-associated virus serotype 9 knockdown of CaMKIIδA partially rescued the cardiac dysfunction and HF in Ddx5 knockout mice., Conclusions: These findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes, identifying the DDX5 as a potential target for therapeutic intervention in HF., Competing Interests: None.

We explored N 6 -methyladenosine (m6A) RNA methylation as one of the gene regulatory mechanisms in heart failure (HF) biology. Understanding the different physiological mechanisms will facilitate the prevention and individualized treatment of HF. The Gene Expression Omnibus (GEO) database served as the source of the data. In GSE116250, differential analysis between ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM) and controls yielded differentially expressed m6A regulators. Differential analysis between HF and controls in GSE131296 identifies m6A-modified genes and then performs enrichment analysis. Protein-protein interaction (PPI) network analysis was performed for the differentially expressed ICM- or DCM-associated genes in GSE116250 and GSE55296, respectively. Finally, the diagnostic genes for ICM and DCM were predicted using receiver operating characteristic (ROC) curve. YTHDC1, HNRNPC and HNRNPA2B1 were significantly downregulated in GSE116250 in DCM and ICM compared with controls. A total of 195 genes were identified in GSE131296 as subject to m6A alteration. These genes may play a role in HF through the MAPK signaling pathway and p53 signaling pathway. PPI network analysis identified CCL5 , CXCR4 and CCL2 as key genes for ICM and IL-6 as a key gene for DCM. Through ROC curves, we identified m6A-modified APLP1 , KLF2 as potential diagnostic genes for ICM, and m6A-modified FGF7 , FREM1 and C14orf132 as potential diagnostic genes for DCM. Our findings support m6A modifying mechanisms in HF etiology that contribute to the treatment of HF. Thus, our data suggest that m6A methylation may be an interesting target for therapeutic intervention.

Heart failure (HF) remains a major cause of mortality and morbidity worldwide. Understanding the genetic basis of HF allows for the development of disease-modifying therapies, more appropriate risk stratification, and personalised management of patients. The advent of next-generation sequencing has enabled genome-wide association studies; moving beyond rare variants identified in a Mendelian fashion and detecting common DNA variants associated with disease. We summarise the latest GWAS and rare variant data on mixed and refined HF aetiologies, and cardiomyopathies. We describe the recent understanding of the functional impact of titin variants and highlight FHOD3 as a novel cardiomyopathy-associated gene. We describe future directions of research in this field and how genetic data can be leveraged to improve the care of patients with HF., (© 2024. The Author(s).)

Traditional cardiovascular risk factors, including hypertension, only explain part of major adverse cardiac events (MACEs). Understanding what other risk factors contribute to MACE is essential for prevention. Constipation shares common risk factors with hypertension and is associated with an increased risk of several cardiovascular diseases. We hypothesized that constipation is an underappreciated risk factor for MACE. We used the population healthcare and genomic data in the UK Biobank ( n = 408,354) to study the contribution of constipation (ICD10 K59.0) to the risk of MACE, defined by any episode of acute coronary syndrome (ACS), ischemic stroke, and heart failure (HF). Analyses were controlled for traditional cardiovascular risk factors. We also assessed genetic correlations ( r g ) between constipation and MACE. Constipation cases ( n = 23,814) exhibited a significantly higher risk of MACE compared with those with normal bowel habits [odds ratio (OR) = 2.15, P < 1.00 × 10 -300 ]. Constipation was also significantly associated with individual MACE subgroups, in order: HF (OR = 2.72, P < 1.00 × 10 -300 ), ischemic stroke (OR = 2.36, P = 2.02 × 10 -230 ), and ACS (OR = 1.62, P = 5.82 × 10 -113 ). In comparison with patients with constipation-free hypertension, patients with hypertension with constipation showed significantly higher odds of MACE (OR = 1.68, P = 1.05 × 10 -136 ) and a 34% increased risk of MACE occurrence ( P = 2.3 × 10 -50 ) after adjustment for medications that affect gut motility and other traditional cardiovascular risk factors. Finally, we detected positive genetic correlations between constipation and MACE subgroups ACS ( r g = 0.27, P = 2.12 × 10 -6 ), ischemic stroke ( r g = 0.23, P = 0.011), and HF ( r g = 0.21, P = 0.0062). We identified constipation as a potential risk factor independently associated with higher MACE prevalence. These findings warrant further studies on their causal relationship and identification of pathophysiological mechanisms. NEW & NOTEWORTHY Analyzing 408,354 participants of the UK Biobank, we show that constipation cases exhibited a significantly higher risk of major adverse cardiac events (MACEs) than those with regular bowel habits. In comparison with patients with constipation-free hypertension, patients with hypertension with constipation showed significantly higher odds of MACE and a 34% increased risk of subsequent MACE occurrence. Finally, we detected positive genetic correlations between constipation and MACE. This association holds potential for therapeutic exploitation and prevention based on individuals' risk assessment.

Pressure overload-induced cardiac hypertrophy is a common cause of heart failure (HF), and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes. However, the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown. Here, we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines (PEs) and Acsl4 expression are significantly increased in mice with transverse aortic constriction (TAC)-induced HF compared to sham-operated mice. In addition, we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload‒induced cardiac dysfunction via ferroptosis. Notably, both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF. Moreover, silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus‒induced cell growth. Mechanistically, we found that Acsl4-dependent ferroptosis activates the pyroptotic signaling pathway, which leads to increased production of the proinflammatory cytokine IL-1β, and neutralizing IL-1β improved cardiac function in Acsl4 transgenic mice following TAC. These results indicate that ACSL4 plays an essential role in the heart during pressure overload‒induced cardiac remodeling via ferroptosis-induced pyroptotic signaling. Together, these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure., (© 2024. The Author(s).)

Adhesion G-protein-coupled receptors (AGPCRs), containing large N-terminal ligand-binding domains for environmental mechano-sensing, have been increasingly recognized to play important roles in numerous physiologic and pathologic processes. However, their impact on the heart, which undergoes dynamic mechanical alterations in healthy and failing states, remains understudied. ADGRG1 (formerly known as GPR56) is widely expressed, including in skeletal muscle where it was previously shown to mediate mechanical overload-induced muscle hypertrophy; thus, we hypothesized that it could impact the development of cardiac dysfunction and remodeling in response to pressure overload. In this study, we generated a cardiomyocyte (CM)-specific ADGRG1 knockout mouse model, which, although not initially displaying features of cardiac dysfunction, does develop increased systolic and diastolic LV volumes and internal diameters over time. Notably, when challenged with chronic pressure overload, CM-specific ADGRG1 deletion accelerates cardiac dysfunction, concurrent with blunted CM hypertrophy, enhanced cardiac inflammation and increased mortality, suggesting that ADGRG1 plays an important role in the early adaptation to chronic cardiac stress. Altogether, the present study provides an important proof-of-concept that targeting CM-expressed AGPCRs may offer a new avenue for regulating the development of heart failure., (© 2024 The Author(s).)

Phenotypic associations have been reported between heart failure (HF) and blood lipids (BLs), blood pressure (BP), and blood glucose (BG). However, the shared genetic etiology underlying these associations remains incompletely understood. Conducting a large-scale multi-trait association study for HF with these traits, we discovered 143 previously unreported genomic risk loci for HF. Results showed that 46, 35, and 14 colocalized loci were shared by HF with BLs, BP, and BG, respectively. Notably, the loci shared by HF with these traits rarely overlapped, indicating distinct mechanisms. The combination of gene-mapping, gene-based, and transcriptome-wide association analyses prioritized noteworthy candidate genes (such as lipoprotein lipase [LPL], G protein-coupled receptor kinase 5 [GRK5], and troponin C1, slow skeletal and cardiac type [TNNC1]) for HF. Enrichment analysis revealed that HF exhibited comparable characteristics to cardiovascular traits and metabolic traits correlated to BLs, BP, and BG. Finally, we reported drug repurposing candidates and plasma protein targets for HF. These results provide biological insights into the pathogenesis of these comorbidities of HF., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: βII spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, the roles of βII spectrin in cardiac contractile function and pathological post-myocardial infarction remodelling remain unclear. Here, we investigated whether and how βII spectrin, the most common isoform of non-erythrocytic spectrin in cardiomyocytes, is involved in cardiac contractile function and ischaemia/reperfusion (I/R) injury., Methods and Results: We observed that the levels of serum βII spectrin breakdown products (βII SBDPs) were significantly increased in patients with acute myocardial infarction (AMI). Concordantly, βII spectrin was degraded into βII SBDPs by calpain in mouse hearts after I/R injury. Using tamoxifen-inducible cardiac-specific βII spectrin knockout mice, we found that deletion of βII spectrin in the adult heart resulted in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy, and fibrosis at 5 weeks after tamoxifen treatment. Moreover, at 1 week after tamoxifen treatment, although spontaneous cardiac dysfunction in cardiac-specific βII spectrin knockout mice had not developed, deletion of βII spectrin in the heart exacerbated I/R-induced cardiomyocyte death and heart failure. Furthermore, restoration of βII spectrin expression via adenoviral small activating RNA (saRNA) delivery into the heart reduced I/R injury. Immunoprecipitation coupled with mass spectrometry (IP-LC-MS/MS) analyses and functional studies revealed that βII spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, βII spectrin promotes translocation of NADH:ubiquinone oxidoreductase 75-kDa Fe-S protein 1 (NDUFS1) from the cytosol to mitochondria by crosslinking with actin filaments (F-actin) to maintain F-actin stability., Conclusion: βII spectrin is an essential cytoskeletal element for preserving mitochondrial homeostasis and cardiac function. Defects in βII spectrin exacerbate cardiac I/R injury., Competing Interests: Conflict of interest: The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Given expanding studies in epidemiology and disease-oriented human studies offering hundreds of associations between the human "ome" and disease, prioritizing molecules relevant to disease mechanisms among this growing breadth is important. Here, we link the circulating proteome to human heart failure (HF) propensity (via echocardiographic phenotyping and clinical outcomes) across the lifespan, demonstrating key pathways of fibrosis, inflammation, metabolism, and hypertrophy. We observe a broad array of genes encoding proteins linked to HF phenotypes and outcomes in clinical populations dynamically expressed at a transcriptional level in human myocardium during HF and cardiac recovery (several in a cell-specific fashion). Many identified targets do not have wide precedent in large-scale genomic discovery or human studies, highlighting the complementary roles for proteomic and tissue transcriptomic discovery to focus epidemiological targets to those relevant in human myocardium for further interrogation., Competing Interests: Declaration of interests S.G.D. is a consultant for Abbott, and S.G.D. and K.J.L. have industry research support from Novartis. R.V.S. has served as a consultant for Amgen, Cytokinetics, and Thryv Therapeutics (with options ownership in Thryv). R.V.S. is a co-inventor on a patent for ex-RNA signatures of cardiac remodeling and a pending patent on proteomic signatures of fitness and lung and liver diseases. R.V.S. also has stock options with Thryv Therapeutics. A.S.P. is a co-inventor on a pending patent for proteomic signatures of fitness, lung, and liver diseases. K.A. does ad hoc consulting for Tegus and Guidepoint and serves on a DSMB for Fortrea. M.N. has received speaking honoraria from Cytokinetics. K.J.L. serves as a consultant for Medtronic, Implicit Biosciences, Kiniksa Pharmaceuticals, and Cytokinetics. K.J.L. receives grant support from Amgen, Novartis, Kiniksa Pharmaceuticals, and Implicit Biosciences. S.D. is a co-founder and has equity in Thryv therapeutics and Switch Therapeutics. S.D. has received grant support from Abbot Laboratories and Bristol Myers Squib. S.D. is a co-inventor on a patent on tissue-specific EV-RNAs. R.K. has received personal fees from GSK, Astrazeneca, Boehringer Ingelheim, and CVS Caremark. S.J.S. has received consulting fees from 35Pharma, Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, BaroPace, Bayer, Boehringer-Ingelheim, Boston Scientific, BridgeBio, Bristol Myers Squibb, Corvia, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, eMyosound, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, SalubriusBio, Sardocor, Shifamed, Tectonic, Tenax, Tenaya, Ulink, and Ultromics. J.M.A. was employed by Amgen. J.W. reports consulting/scientific advisory board for Abiomed, Abbott, Astra Zeneca, Boehringer Ingelheim, and Cytokinetics within the last 24 months., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF., Methods: Fluorescence recovery after photobleaching assay, differential interference contrast analysis, pull-down assay, immunofluorescence, and immunohistochemical analysis were used to investigate the liquid-liquid phase separation capacity of HIP-55 and its dynamic regulation in vivo and in vitro. Mice with genetic deletion of HIP-55 and mice with cardiac-specific overexpression of HIP-55 were used to examine the role of HIP-55 on β-adrenergic receptor hyperactivation-induced HF. Mutation analysis and mice with specific phospho-resistant site mutagenesis were used to identify the role of phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 in HF., Results: Genetic deletion of HIP-55 aggravated HF, whereas cardiac-specific overexpression of HIP-55 significantly alleviated HF in vivo. HIP-55 possesses a strong capacity for phase separation. Phase separation of HIP-55 is dynamically regulated by AKT-mediated phosphorylation at S269 and T291 sites, failure of which leads to impairment of HIP-55 dynamic phase separation by formation of abnormal aggregation. Prolonged sympathetic hyperactivation stress induced decreased phosphorylation of HIP-55 S269 and T291, dysregulated phase separation, and subsequent aggregate formation of HIP55. Moreover, we demonstrated the important role of dynamic phase separation of HIP-55 in inhibiting hyperactivation of the β-adrenergic receptor-mediated P38/MAPK (mitogen-activated protein kinase) signaling pathway. A phosphorylation-deficient HIP-55 mutation, which undergoes massive phase separation and forms insoluble aggregates, loses the protective activity against HF., Conclusions: Our work reveals that the phosphorylation-regulated dynamic phase separation of HIP-55 protects against sympathetic/adrenergic system-mediated heart failure., Competing Interests: None.

Introduction: Heart failure (HF) and kidney failure (KF) are closely related conditions that often coexist, posing a complex clinical challenge. Understanding the shared mechanisms between these two conditions is crucial for developing effective therapies., Methods: This study employed transcriptomic analysis to unveil molecular signatures and novel biomarkers for both HF and KF. A total of 2869 shared differentially expressed genes (DEGs) were identified in patients with HF and KF compared to healthy controls. Functional enrichment analysis was performed to explore the common mechanisms underlying these conditions. A protein-protein interaction (PPI) network was constructed, and machine learning algorithms, including Random Forest (RF), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Least Absolute Shrinkage and Selection Operator (LASSO), were used to identify key signature genes. These genes were further analyzed using Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA), with their diagnostic values validated in both training and validation sets. Molecular docking studies were conducted. Additionally, immune cell infiltration and correlation analyses were performed to assess the relationship between immune responses and the identified biomarkers., Results: The functional enrichment analysis indicated that the common mechanisms are associated with cellular homeostasis, cell communication, cellular replication, inflammation, and extracellular matrix (ECM) production, with the PI3K-Akt signaling pathway being notably enriched. The PPI network revealed two key protein clusters related to the cell cycle and inflammation. CDK2 and CCND1 were identified as signature genes for both HF and KF. Their diagnostic value was validated in both training and validation sets. Additionally, docking studies with CDK2 and CCND1 were performed to evaluate potential drug candidates. Immune cell infiltration and correlation analyses highlighted the immune microenvironment, and that CDK2 and CCND1 are associated with immune responses in HF and KF., Discussion: This study identifies CDK2 and CCND1 as novel biomarkers linking cell cycle regulation and inflammation in heart and kidney failure. These findings offer new insights into the molecular mechanisms of HF and KF and present potential targets for diagnosis and therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Long, Zhang, Ren, Wu and Wang.)

Background: Non-alcoholic fatty liver disease (NAFLD) and heart failure (HF) are related conditions with an increasing incidence. However, the mechanism underlying their association remains unclear. This study aimed to explore the shared pathogenic mechanisms and common biomarkers of NAFLD and HF through bioinformatics analyses and experimental validation., Methods: NAFLD and HF-related transcriptome data were extracted from the Gene Expression Omnibus (GEO) database (GSE126848 and GSE26887). Differential analysis was performed to identify common differentially expressed genes (co-DEGs) between NAFLD and HF. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were conducted to explore the functions and regulatory pathways of co-DEGs. Protein-protein interaction (PPI) network and support vector machine-recursive feature elimination (SVM-RFE) methods were used to screen common key DEGs. The diagnostic value of common key DEGs was assessed by receiver operating characteristic (ROC) curve and validated with external datasets (GSE89632 and GSE57345). Finally, the expression of biomarkers was validated in mouse models., Results: A total of 161 co-DEGs were screened out in NAFLD and HF patients. GO, KEGG, and GSEA analyses indicated that these co-DEGs were mainly enriched in immune-related pathways. PPI network revealed 14 key DEGs, and SVM-RFE model eventually identified two genes ( CD163 and CCR1 ) as common key DEGs for NAFLD and HF. Expression analysis revealed that the expression levels of CD163 and CCR1 were significantly down-regulated in HF and NAFLD patients. ROC curve analysis showed that CD163 and CCR1 had good diagnostic values for HF and NAFLD. Single-gene GSEA suggested that CD163 and CCR1 were mainly engaged in immune responses and inflammation. Experimental validation indicated unbalanced macrophage polarization in HF and NAFLD mouse models, and the expression of CD163 and CCR1 were significantly down-regulated., Conclusion: This study identified M2 polarization impairment characterized by decreased expression of CD163 and CCR1 as a common pathogenic pathway in NAFLD and HF. The downregulation of CD163 and CCR1 may reflect key pathological changes in the development and progression of NAFLD and HF, suggesting their potential as diagnostic and therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Lu and Chen.)

Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of the stabilizing subunit calstabin-2. This results in a diastolic sarcoplasmic reticulum Ca 2+ leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca 2+ leak, leading to arrhythmias and sudden cardiac death. Here, we solved the cryogenic electron microscopy structures of ryanodine receptor 2 variants linked either to heart failure or inherited sudden cardiac death. All are in the primed state, part way between closed and open. Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca 2+ leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders., (© 2024. The Author(s).)

Background: Heart failure (HF) and colorectal cancer are significant public health concerns with substantial morbidity and mortality. Previous studies have indicated a close association between HF and various tumors, including colorectal cancer. Further understanding the potential causal relationship between them could provide insights into their shared pathophysiological mechanisms and inform strategies for prevention and treatment., Methods: This study employed a bidirectional Mendelian randomization (MR) approach using genetic variants from large genome-wide association studies (GWAS) as instrumental variables (IVs). The inverse-variance weighted (IVW) method was employed for the MR analysis. Meta-analyses of IVW results from discovery and validation cohorts were performed to enhance the power of detecting causal effects. Sensitivity analyses, including heterogeneity analysis and tests for horizontal pleiotropy, were conducted to test the robustness of the conclusions., Results: Results from the discovery cohort suggest HF is associated with an approximately 30% increased risk of colorectal cancer (OR 1.32, 95% CI 1.03-1.69, P=0.025), although this finding did not reach statistical significance in the validation cohort (OR 1.19, 95% CI 0.97-1.46, P=0.090). However, meta-analysis supports HF as a potential risk factor for colorectal cancer (Pooled OR 1.24, 95% CI 1.06-1.25, P=0.007). Reverse MR analysis found no evidence of colorectal cancer increasing HF risk (Pooled OR 1.03, 95% CI 0.99-1.07, P=0.121). Sensitivity analyses (all P>0.05) indicate robustness against heterogeneity and horizontal pleiotropy., Conclusion: This comprehensive bidirectional MR study provides genetic evidence supporting a causal link between HF and colorectal cancer. The insights gained enhance understanding of their interconnectedness and may guide future research and clinical practices aimed at mitigating their risks through targeted interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Han, Cai and Liu.)

To investigate the causal relationship between sleep duration and heart failure (HF) in a European population. We focused on the continuous sleep duration of 460,099 European individuals as our primary exposure. Genome-wide significant single nucleotide polymorphisms (SNPs, n = 9851,867) linked to continuous sleep duration were adopted as instrumental variables. The outcome of interest was based on HF events in a European cohort (n = 977,323; with 930,014 controls and 47,309 cases). We employed a two-sample Mendelian randomization (MR) approach to infer causality between sleep duration and the incidence of HF. For validation purposes, an additional cohort of 336,965 European individuals diagnosed with insomnia was selected as a secondary exposure group. Using its SNPs, a subsequent two-sample MR analysis was conducted with the HF cohort to further corroborate our initial findings. Employing the MR methodology, we selected 57 SNPs that are associated with sleep duration, and 24 SNPs that are associated with insomnia as instrumental variables. We discerned a substantial association between genetically inferred sleep duration and HF risk (odds ratio: 0.61; 95% confidence interval: 0.47-0.78, P < .0001). Our subsequent analysis highlighted a pronounced increased HF risk associated with insomnia (odds ratio: 1.54; 95% confidence interval: 1.08-2.17, P < .02). These conclusions were further bolstered by consistent results from sensitivity analyses. Our study suggests a causal linkage between sleep duration and the onset risk of HF in the European population. Notably, shorter sleep durations were associated with a heightened risk of HF., Competing Interests: The authors declare no conflict of interest, financial or otherwise. We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work. There is no professional or other personal interest in any product, service, and/or company that could be construed as influencing the position presented in the manuscript entitled., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)