Cardiac fibrosis is a major contributor to the development and progression of heart failure. It involves an aberrant deposition of extracellular matrix components, leading to impaired mechanical and electrical function of the heart. Despite its clinical importance, effective anti-fibrotic treatments remain elusive, in part due to limited insight into the molecular and cellular processes that distinguish transient from sustained fibrotic responses. Central to these processes are fibroblasts, structurally supportive yet functionally diverse stromal cells that regulate tissue architecture, cell signalling, and immune responses. Recent technological advances, including lineage tracing models and single-cell omics, have begun to unravel the complexity of fibroblast populations within the heart. These approaches have identified distinct fibroblast states and highlighted their dynamic roles in both maintaining homeostasis and driving pathological remodelling. This review examines the evolving understanding of fibroblast biology in the context of myocardial fibrosis, emphasizing their contributions to inflammation and extracellular matrix dysregulation and their interactions with cardiomyocytes and endothelial cells. Finally, emerging therapeutic avenues aimed at selectively altering fibroblast activity and mechanosensitive therapies are highlighted.

Chronic low-grade inflammation underlies the heterogenous pathophysiology of heart failure with preserved ejection fraction (HFpEF) influenced by patient comorbidities. This review summarizes circulating inflammatory mediators in HFpEF, explores how comorbidities shape distinct immune signatures, and discusses current and emerging treatment strategies. Comorbidities, including hypertension, obesity, type 2 diabetes, and chronic kidney disease, drive distinct immune profiles in HFpEF through dysregulated cytokine signaling. Circulating mediators, including IL-6, IL-1β, TNF-α, soluble ST2, and CRP, reflect this comorbidity-driven immune activation and predict adverse outcomes. Current therapies, e.g. SGLT2 inhibitors, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors, display anti-inflammatory effects but benefit only specific subgroups. Emerging inflammation-targeted strategies, including anti-IL-6 or anti-IL-1β, NLRP3 inflammasome modulation and myeloperoxidase inhibition, are under clinical investigation. Linking immune profiles to HFpEF phenogroups may enable precision medicine by refining risk stratification and tailoring therapies, moving beyond the current one-size-fits-all approach.

There is strong evidence that hypertension is a major risk factor for heart failure (HF). Hypertension contributes to incident HF through direct and indirect effects. Indirect effects are consequences of ischaemic heart disease because hypertension facilitates atherosclerotic obstructive coronary artery disease. The direct effects are straightly related to hypertensive heart disease (HHD). Hypertensive heart disease poses a significant challenge with substantial medical and public health implications. Efforts should be made to recognize and manage HHD in a timely manner and optimize hypertension treatment. Reducing blood pressure (BP) and/or reassessing antihypertensive therapy using traditional or novel approaches can halt or delay progression to HF in patients with HHD and possibly prevent it. However, HHD's importance as a risk factor for overt HF is often overlooked in clinical practice. This document aims to summarize the current understanding of the burden of HHD and its risk for incident HF, discuss the mechanisms underlying HHD-related HF onset and progression, consider how diagnostic tools contribute to individualized phenotyping and HF risk stratification of HHD, address how therapeutic measures ameliorating or even preventing structural and functional alterations of HHD, along with BP control influence HHD-associated HF risk.

Background Plasma concentrations of procollagen type-I C-terminal pro-peptide (PICP) and collagen type-I C-terminal telopeptide (CITP) may reflect collagen turnover and systemic fibrosis. We investigated the effect of pirfenidone, an anti-fibrotic agent, on PICP and CITP, and their association with myocardial fibrosis, using cardiovascular magnetic resonance to measure extracellular volume (ECV).Methods In the trial (Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction), PICP, CITP and PICP:CITP ratio were measured at baseline and follow-up in patients with ECV≥27% randomised (n=94) to pirfenidone or placebo, and at baseline only in patients who were not randomised because of ECV<27% (n=13).Results There was no association between baseline myocardial ECV and baseline log PICP, log CITP and log PICP:CITP ratio (p=0.19, p=0.13, p=0.60, respectively). Treatment with pirfenidone did not alter PICP, but reduced CITP and increased PICP:CITP ratio at 13 and 26 weeks (all p<0.05) but not at 52 weeks. After multivariable adjustment, there was a weak relationship between change in myocardial ECV and change in log PICP (R2 0.16, p=0.01) and log CITP (R2 0.12, p=0.04), but not log PICP:CITP ratio (p=0.56).Conclusions In patients with stable heart failure with preserved ejection fraction, pirfenidone treatment had no sustained effect on plasma levels of PICP and CITP at 52 weeks. Changes in ECV during treatment with pirfenidone are associated with changes in plasma PICP and CITP, suggesting a weak association between changes in collagen volume/mass and plasma markers of collagen turnover.

In the HOMAGE (Heart Omics in AGEing) trial, spironolactone reduced serum concentrations of procollagen Type I C-terminal propeptide (PICP), a fibrosis biomarker, in patients at risk of heart failure. To elucidate the underlying mechanisms, multidimensional analyses including proteomics were conducted. Olink cardiovascular and inflammation panels (n = 276 proteins) were measured in plasma from 488 HOMAGE participants at baseline, 1 month, and 9 months after randomization. Proteins associated with PICP changes were identified using machine learning algorithms (MLAs). Selected candidates were further analyzed in patients with heart failure and preserved ejection fraction (Aldo-DHF trial). Linear regression and mediation analyses assessed which MLA-selected proteins mediated spironolactone's effects on PICP. MLAs consistently linked PICP reduction to changes in biomarkers of collagen (e.g., decreased COL1A1), fatty acid metabolism (e.g., increased FABP4), immune function (e.g., increased CCL24 and IL6RA, and decreased FLT3L), neurological function (e.g., increased DNER), cell-matrix interactions (e.g., increased galectin-9 [GAL9] and decreased thrombospondin-2 [THBS2]), and reduced NT-proBNP. Mediation analysis suggested that changes in GAL9 and THBS2 were associated with spironolactone-induced PICP reduction, which was confirmed in Aldo-DHF patients. This study raises the hypothesis that spironolactone inhibits collagen synthesis via inflammatory, metabolic, and extracellular matrix pathways, and particularly through modulation of GAL9 and THBS2.

Importance:Patients undergoing aortic valve replacement (AVR) for chronic severe aortic regurgitation (AR) based on current guideline-based thresholds may have irreversible myocardial scarring. Objective:To quantify reverse remodeling, functional recovery, and symptomatic change after AVR and assess whether myocardial fibrosis is associated with incomplete recovery. Design, Setting, and Participants:In this prospective longitudinal observational study, patients with chronic severe AR referred for AVR by a cardiology team were included. Key exclusion criteria were previous valve surgery, moderate or greater valve disease, and other primary cardiomyopathies. Included patients underwent paired biomarkers, echocardiography, cardiopulmonary exercise testing, and cardiovascular magnetic resonance (CMR) at baseline and at a median of 7 months after AVR. The study took place at 2 tertiary cardiothoracic centers in London, United Kingdom, with enrollment from August 2021 to October 2023. Data were analyzed from January to April 2026. Exposure:AVR. Main Outcomes and Measures:Left ventricular (LV) reverse remodeling (change in LV end-diastolic volume [LVEDV] and LV mass) post-AVR and preoperative correlates of incomplete recovery, with prespecified focus on CMR fibrosis markers (late gadolinium enhancement [LGE] and extracellular volume [ECV]). Results:Seventy-two patients (median [IQR] age, 60 [6-70] years; 59 [82%] male, 35 [49%] with bicuspid aortic valve) completed paired studies. Median (IQR) regurgitant volume fell from 61 (38-83) mL to 5 (3-8) mL; median (IQR) LVEDV fell 44% from 273 (211-307) mL to 153 (130-177) mL; and median (IQR) LV mass fell 21% from 200 (159-226) g to 158 (137-184) g (all P < .001). Indexed intracellular volume declined 21% and indexed extracellular volume 15% (26 mL/m2 to 22 mL/m2; P < .001), raising extracellular volume fraction (ECV%) from 27.4% to 29.1% (P < .001). LGE as a percentage of LV mass was unchanged (2.3% to 2.4%; P = .36); baseline LGE burden was associated with less regression of LV mass (χ22 = 29.4; P < .001) and LVEDV at 7 months (χ21 = 7.9; P = .007). New York Heart Association class and quality of life improved (median [IQR] EQ-5D index improved from 0.89 [0.78-1.00] to 0.94 [0.81-1.00]; P < .001), but maximum oxygen consumption was unchanged (22.6 mL/kg/min to 21 mL/kg/min; P = .08). N-terminal pro-B-type natriuretic peptide decreased slightly (228 pg/mL to 198 pg/mL; P = .27), with a larger fall in patients with evidence of decompensation (n = 31; 469 pg/mL to 279 pg/mL; P = .02). Conclusions and Relevance:In this study, AVR was associated with substantial reverse remodeling at 7 months, including regression of hypertrophy and a fall in indexed extracellular (matrix) volume; the extracellular volume fraction rose, as cellular regression outpaced matrix regression. Focal scar, as a proportion of myocardium, was unchanged. Preoperative focal scar was independently associated with less recovery and may mark incomplete remodeling. Objective functional recovery did not improve at this time point.

Endotrophin is a matrikine released from the C-terminus of the alpha-3 chain of type VI collagen, gaining increasing attention both as a biomarker and as a therapeutic target in the cardiometabolic space. So far, it has been quantified in circulation by the PRO-C6 assay, which detects different-sized proteolytic fragments of the C-terminus, including endotrophin. Here, we developed and evaluated a novel immunoassay targeting the full-length endotrophin, explored its biological relevance in two clinical cohorts of HFpEF, and investigated its potential as a prognostic biomarker. Increased circulating Endotrophin levels were associated with cardiovascular and all-cause mortality in both cohorts. When adjusting for relevant confounders, Endotrophin remained independently associated with both endpoints only in cohort 1. This work emphasizes the importance of the extracellular matrix in disease, confirms the prognostic value of endotrophin, and provides a novel tool for further exploration of its biological role.

To delve deeper into the molecular mechanisms underlying pulmonary hypertension secondary to left heart disease (PH-LHD), an essential step toward developing a comprehensive classification, reliable biomarkers and targeted therapies. In this study, we analyzed the whole transcriptome (mRNA and microRNA) of a unique cohort of patients with persistent PH due to valvular heart disease (PH-VHD) to identify biological pathways associated with disease prognosis. The analysis was performed using the well-characterized SIOVAC (Sildenafil for Improving Outcomes after Valvular Correction) clinical trial cohort. We included 116 patients with demonstrated PH-LHD after valvular correction, and 30 VHD patients with no or mild PH (Control). The comparison between PH-LHD patients and controls of the whole blood transcriptome identified 3,217 differentially expressed genes. Unsupervised clustering in PH-VHD patients revealed three clusters (K1–K3), with K1 showing significantly worse 84-month survival (p = 0.017) despite no clinical or hemodynamic differences among clusters. Enrichment analysis identified 173 significantly altered canonical pathways, involved in inflammatory and stress-related networks (e.g., Granzyme A, IL-15, JAK/STAT, HIF1α) and inhibition of metabolic and translational processes (e.g., oxidative phosphorylation, EIF2). Circulating microRNA analysis identified 97 differentially expressed microRNAs; notably, BMPR2 was regulated by 22 of these and demonstrated significant downregulation of its functional isoform A in K1 patients. In conclusion PH-VHD transcriptomic signature identifies a cluster of patients associated with higher risk of mortality characterized by immune overactivation and a mitochondrial metabolic shift, with BMPR2 emerging as a key metabolic target.

BACKGROUND:Diffuse fibrosis is central to the pathophysiology of aortic stenosis (AS), can be assessed using cardiovascular magnetic resonance (CMR) with extracellular volume fraction (ECV%), and is associated with mortality. The relevance of this signal to long-term prognosis remains unclear. We aim to assess predictors of long-term mortality with focus on diffuse fibrosis. METHODS:Single-center prospective observational cohort study of patients with severe, symptomatic AS undergoing aortic valve replacement (AVR). Patients were assessed using echocardiography, high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and CMR, including T1 mapping for ECV% quantification. All-cause mortality was identified using the NHS National Spine Database. Univariable and multivariable Cox regression models were fitted to assess all-cause mortality associations. RESULT:One hundred and sixty-eight patients (age 72 [65-77] years, 55% [92/168] male) underwent CMR. Over a follow-up period of 9.7 (6.8-10.9) years, 76 deaths occurred. Patients who died had higher ECV% (29.9% vs 27.6%, p = 0.014) and greater late gadolinium enhancement (3.9% vs 2.0%, p = 0.013). Univariable predictors of mortality were age, atrial fibrillation (AF), left atrial area, left atrial volume, total cholesterol, triglycerides, HDL:LDL ratio, non-bicuspid aortic valve, hs-cTnT, NT-proBNP, EuroSCORE II and ECV%. On multivariable regression, age, AF and ECV% remained significant predictors of mortality, independently of sex. AIC indicated that the model with four covariates was preferable to the one also including EuroSCORE II and coronary artery disease, and this result was confirmed by a likelihood ratio test (p=0.387). CONCLUSIONS:In the longest follow-up cohort of T1 mapping in severe AS, we demonstrate diffuse fibrosis remains an independent predictor of long-term mortality. Integration of ECV% in baseline risk stratification should be explored further in patients with AS undergoing AVR.

BMPR2 A-isoform expression is involved in PH with left heart disease and has potential as a novel prognosis biomarker, supporting the development of new therapeutic approaches targeting the BMPR2-activin type IIA receptor pathway https://bit.ly/45tywJI.

A better understanding of additional mechanisms of heart failure (HF) progression may allow a different and more complete phenotyping of the disease and identification of novel therapeutic targets. Persistent latent myocardial inflammation/immune activation in HF may represent an attempt to restore tissue homeostasis in the failing heart, where cardiomyocytes and immune cells undergo metabolic reprogramming, which allows them to deal with decreased availability of nutrients and oxygen. This status can trigger a metabolic crosstalk between immune cells and cardiomyocytes which, depending on the outcome, can either perpetuate the maladaptive remodelling of the heart, or determine an adaptive response. Therefore, the interplay between immune activation and metabolism is gaining recognition as a potential therapeutic framework. On these premises, future studies addressing novel HF treatments should attempt to evaluate the potential therapeutic role of direct metabolic and immunological crosstalk modulation. The aim of the present scientific statement from the Heart Failure Association of the ESC is to summarize the current evidence for the connection between inflammatory and immune activation and metabolic adaptation in the onset and progression of HF, in order to promote future strategies for the development of targeted-disease preventive and therapeutic measures.

Collagen type I (COL1) is the most abundant protein in the human body and is a main component in the extracellular matrix. The COL1 structure vastly influences normal tissue homeostasis, and changes in the matrix drive progression in multiple diseases. Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity in many Western countries; alterations in the extracellular matrix turnover processes, including COL1, are known to influence the pathophysiological processes leading to CVD outcome. Peptides reflecting COL1 formation and degradation have been established and explored for over two decades in CVD. This review aims to combine and assess the evidence for using COL1-derived circulating peptides as biomarkers in CVD. Secondly, the review identifies existing pitfalls, and evaluates future opportunities for improving the technical characteristics and performance of the biomarkers for implementation in the clinical setting.

A rift has opened and is widening between basic research (bench) and clinical research and patients (bed) who need their new treatments, diagnostics and preventive strategies. This problem involving the 'translation' of basic scientific findings into clinical applications and potential treatments or biomarkers for a condition like heart failure is widely recognized both in academia and industry. Despite the attempts that have been made by both sides to improve this situation, the high attrition rates of drug development and the problem with reproducibility and translatability of preclinical findings to human applications still persist. As a result, the return on investment of basic research has been limited in terms of clinical impact. In this scientific statement we describe and discuss various issues with relevance to this theme and try to dissect how to move our field towards the development of more effective heart failure drugs. We zoom in on facilitating the process of heart failure drug development, the unnecessary gaps ('valley of death') between the critical steps in heart failure drug development, validation and de-validation of new concepts as early as possible ('rigorous translation'). We describe forums on how to stimulate cross-talk and interaction between clinician-scientists, basic heart failure researchers, biotech and industry, and how to enable them to speak the same language, and lessons learned from successes outside the heart failure field.

BMPR2 is widely known to be key in the pathobiology of pulmonary arterial hypertension. Recently, data regarding pulmonary hypertension (PH) secondary to left-heart disease (LHD) have focused on inflammatory and proliferative pathways rather than classic hemodynamic scope but BMPR2 role is yet to be determined. In the current study, we assessed BMPR2 and its regulatory factor, SRSF2, in patients with PH due to valvular heart disease (VHD). Blood samples from patients included in the Sildenafil for Improving Outcomes after Valvular Correction (SIOVAC) clinical trial were analysed. The study involved PH-VHD patients with combined pre-and postcapillary PH, isolated postcapillary PH, control patients without PH and healthy subjects. We sequenced the BMPR2 exons, measured BMPR2 A-isoform expression and analysed SRSF2 gene expression levels in blood samples. Our results demonstrate that BMPR2 A-isoform levels are reduced in patients with PH-VHD compared to controls and, even more, healthy subjects. Furthermore, BMPR2 A-isoform expression showed meaningful prognostic value among PH-VHD patients. Notably, whereas pathogenic gene variants were ruled out, SRSF2 was indeed associated with BMPR2 A-isoform differential expression. To the best of our knowledge, this is the first study demonstrating the involvement of BMPR2 gene expression in PH-LHD patients, supports BMPR2 A-isoform as a potential prognosis biomarker and this pathway as a therapeutic target. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Instituto de Salud Carlos III (SIOVAC-MOL project: PI19/00649). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study received approval of Spanish Agency for Drugs and Medical Products, Spanish Ministry of Health (EC07-90772). All patients signed the informed consent for the study. A second approval by the ethics committees was obtained for the purpose of extending follow‐up, which waived the need for signing a new informed consent (Comite de Etica de la Investigacion con Medicamentos del Hospital General Universitario Gregorio Maranon, Madrid, Spain (CEIm 13/19). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

To assess the changes in circulating biomarkers concentrations after mitral valve transcatheter edge-to-edge repair (M-TEER) and their relationship with procedural success vs. failure in patients with severe mitral regurgitation (MR) and heart failure (HF). Pre-procedural, post-intervention, and 30 days post-intervention plasma samples were analyzed for 266 different proteins using the Olink Proseek® Multiplex cardiovascular (CVD) II, CVD III, and inflammation panels, in patients with MR undergoing M-TEER. Multiple biomarkers showed a differential expression 30 days after M-TEER in patients with procedural failure vs. those with a successful evolution. The proteins upregulated in patients with procedural failure were functionally enriched in pathways related to immune regulation, inflammation, extracellular matrix organization, and cellular structures. After adjustment for confounding variables, increases in IL2RA, RAGE, IGFBP2, and COL1A1 values at 30 days post-intervention were associated with procedural failure. Changes in IGFBP2 and IL2RA values were also independently associated with pulmonary artery systolic pressure (PASP) increases after M-TEER. In a cohort of patients with severe MR undergoing M-TEER, differences in circulating biomarkers concentrations related to inflammation and fibrosis were observed between patients with procedural success as compared to those with procedural failure. Biomarkers known to be associated with HF severity were over-expressed in patients with procedural failure, compared with those with procedural success, after M-TEER.

Aortic stenosis (AS) is common and can cause heart failure (HF) or contribute to the progression of pre-existing HF. The management of patients with concomitant AS and HF poses specific clinical challenges. Optimization of guideline-directed medical therapy for HF may be difficult in patients with AS, especially in case of reduced left ventricular ejection fraction. Transcatheter or surgical aortic valve replacement (AVR) is the evidence-based treatment of choice for patients with severe AS and HF. However, advanced cardiac damage, concomitant conditions that can cause HF in addition to AS, as well as some procedure-related factors, may contribute to persistence or worsening of HF after AVR. A multidisciplinary management involving an HF specialist is crucial in this setting and should include a dedicated pre-procedural HF and AS assessment, as well as a careful post-procedural follow-up, including monitoring of HF status. The aim of this clinical consensus statement is to summarize current knowledge on AS and HF, with a focus on pre-procedural and post-procedural management of patients with HF undergoing AVR.

Obesity and heart failure (HF) represent two growing pandemics. In the general population, obesity affects one in eight adults and is linked with an increased risk for HF. Obesity is even more common in patients with HF, where it complicates the diagnosis of HF and is linked with worse symptoms and impaired exercise capacity. Over the past few years, new evidence on the mechanisms linking obesity with HF has been reported, particularly in relation to HF with preserved ejection fraction. Novel therapies inducing weight loss appear to have favourable effects on health status and cardiovascular risk. Against the backdrop of this rapidly evolving evidence landscape, HF clinicians are increasingly required to tailor their preventive, diagnostic, and therapeutic approaches to HF in the presence of obesity. This scientific statement by the Heart Failure Association of the European Society of Cardiology provides an up-to-date summary on obesity in HF, covering key areas such as epidemiology, translational aspects, diagnostic challenges, therapeutic approaches, and trial design.

Coronary artery disease (CAD) and diabetes mellitus (DM) can induce changes in myocardial structure and function, thereby increasing the risk of heart failure (HF). We aimed to identify the alterations in echocardiographic variables and circulating biomarkers associated with DM, CAD, or both and to assess the effect of spironolactone on them. The “Heart OMics in AGEing” (HOMAGE) trial evaluated the effect of spironolactone on circulating markers of fibrosis over 9 months of follow-up in people at risk for HF. From the initial population (N = 527) of the HOMAGE trial, a total of 495 participants (mean age 74 years, 25