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Myocardial fibrosis may increase vulnerability to poor prognosis in patients with heart failure (HF), even in those patients exhibiting left ventricular reverse remodeling (LVRR) after guideline-based therapies.This study sought to characterize fibrosis at baseline in patients with HF with left ventricular ejection fraction (LVEF)50% by determining serum collagen type I-derived peptides (procollagen type I C-terminal propeptide [PICP] and ratio of collagen type I C-terminal telopeptide to matrix metalloproteinase-1) and to evaluate their association with LVRR and prognosis.Peptides were determined in 1,034 patients with HF at baseline. One-year echocardiography was available in 665 patients. Associations of peptides with 1-year changes in echocardiographic variables were analyzed by multivariable linear mixed models. LVEF was considered improved if it increased by ≥15% or to ≥50% or if it increased by ≥10% to40% in patients with LVEF ≤40%. Cardiovascular death and HF-related outcomes were analyzed in all patients randomized to derivation (n = 648) and validation (n = 386) cohorts.Continuous associations with echocardiographic changes were observed only for PICP. Compared with high-PICP (≥108.1 ng/mL) patients, low-PICP (108.1 ng/mL) patients exhibited enhanced LVRR and a lower risk of HF-related outcomes (P ≤ 0.018), with women and nonischemic patients with HF showing a stronger LVEF increase (interaction P ≤ 0.010). LVEF increase was associated with a better prognosis, particularly in low-PICP patients (interaction P ≤ 0.029). Only patients with both low PICP and improved LVEF exhibited a better clinical evolution than patients with nonimproved LVEF (P 0.001).Phenotyping with PICP, a peptide associated with myocardial fibrosis, may be useful to differentiate patients with HF who are more likely to experience clinical myocardial recovery from those with partial myocardial improvement.

Congestion is a cardinal sign of heart failure (HF). In the past, it was seen as a homogeneous epiphenomenon that identified patients with advanced HF. However, current evidence shows that congestion in HF varies in quantity and distribution. This updated view advocates for a congestive-driven classification of HF according to onset (acute vs. chronic), regional distribution (systemic vs. pulmonary), compartment of distribution (intravascular vs. extravascular), and clinical vs. subclinical. Thus, this review will focus on the utility of circulating biomarkers for assessing and managing the different fluid overload phenotypes. This discussion focused on the clinical utility of the natriuretic peptides, carbohydrate antigen 125 (also called mucin 16), bio-adrenomedullin and mid-regional pro-adrenomedullin, ST2 (also known as interleukin-1 receptor-like 1), cluster of differentiation 146, troponin, C-terminal pro-endothelin-1, and parameters of haemoconcentration. The utility of circulation biomarkers on top of clinical evaluation, haemodynamics, and imaging needs to be better determined by dedicated studies. Some multiparametric frameworks in which these tools contribute to management are proposed.

In patients with heart failure, the beneficial effects of drug and device therapies counteract to some extent ongoing cardiac damage. According to the net balance between these two factors, cardiac geometry and function may improve (reverse remodelling, RR) and even completely normalize (remission), or vice versa progressively deteriorate (adverse remodelling, AR). RR or remission predict a better prognosis, while AR has been associated with worsening clinical status and outcomes. The remodelling process ultimately involves all cardiac chambers, but has been traditionally evaluated in terms of left ventricular volumes and ejection fraction. This is the second part of a review paper by the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology dedicated to ventricular remodelling. This document examines the proposed criteria to diagnose RR and AR, their prevalence and prognostic value, and the variables predicting remodelling in patients managed according to current guidelines. Much attention will be devoted to RR in patients with heart failure with reduced ejection fraction because most studies on cardiac remodelling focused on this setting. © 2022 European Society of Cardiology.

Background: We sought to identify protein biomarkers of new-onset heart failure (HF) in 3 independent cohorts (HOMAGE cohort [Heart Omics and Ageing], ARIC study [Atherosclerosis Risk in Communities], and FHS [Framingham Heart Study]) and assess if and to what extent they improve HF risk prediction compared to clinical risk factors alone. Methods: A nested case-control design was used with cases (incident HF) and controls (without HF) matched on age and sex within each cohort. Plasma concentrations of 276 proteins were measured at baseline in ARIC (250 cases/250 controls), FHS (191/191), and HOMAGE cohort (562/871). Results: In single protein analysis, after adjusting for matching variables and clinical risk factors (and correcting for multiple testing), 62 proteins were associated with incident HF in ARIC, 16 in FHS, and 116 in HOMAGE cohort. Proteins associated with incident HF in all cohorts were BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), eukaryotic translation initiation factor 4E-BP1 (4E-binding protein 1), hepatocyte growth factor (HGF), Gal-9 (galectin-9), TGF-alpha (transforming growth factor alpha), THBS2 (thrombospondin-2), and U-PAR (urokinase plasminogen activator surface receptor). The increment in C -index for incident HF based on a multiprotein biomarker approach, in addition to clinical risk factors and NT-proBNP, was 11.1% (7.5%–14.7%) in ARIC, 5.9% (2.6%–9.2%) in FHS, and 7.5% (5.4%–9.5%) in HOMAGE cohort, all P Conclusions: A multiprotein biomarker approach improves prediction of incident HF when added to natriuretic peptides and clinical risk factors.

BACKGROUNDMineralocorticoid receptor (MR) activation induces fibrosis. Urinary proteomic profiling (UPP) detects thousands of sequenced peptides, mainly derived from collagen. No previous study applied UPP to generate insights in the antifibrotic actions of MR antagonism.METHODSBased on urine sample availability, subsets of the open HOMAGE trial (n=290; 23.8% women; median age: 73 years) and the double-blind PRIORITY trial (n=110; 21.8% women; 64 years) were analyzed as discovery and replication data sources. In the open HOMAGE trial, patients at risk of heart failure were randomized to usual therapy or usual therapy combined with spironolactone 25-50 mg/d. In the double-blind PRIORITY trial, type-2 diabetic patients with normal renal function were randomized to placebo or spironolactone 25 mg/d, both given on top of usual therapy. UPP relied on capillary electrophoresis coupled with mass spectrometry. In HOMAGE, the PICP/CITP ratio was calculated from serum PICP and serum CITP, which are markers of type-1 collagen synthesis and degradation, respectively. After rank-normalization of the biomarker distributions, between-group differences in the biomarker changes were analyzed by multivariable models. Correlations between the changes in urinary peptides and in serum CITP, derived from mature type-1 collagen, were compared between groups, using Fisher Z transform.RESULTSIn the HOMAGE and PRIORITY analytical subsets, patients had detectable signals of 1498 urinary peptides. Follow-up totaled 9 months in HOMAGE and was 30 months (median) in PRIORITY. All changes in urinary peptides that remained significantly different (PP≤0.0129). Correlations between changes from baseline to follow-up in urinary type-1 collagen fragments and CITP were positive often reaching significance if fragments increased during follow-up, but were nonsignificant if fragments decreased during follow-up. There were no between-group differences in these correlations.CONCLUSIONSMR antagonism predominantly reduces collagen-derived urinary peptides. Inhibition of collagen synthesis by lowering the amount available for breakdown may be a contributing mechanism.Clinical PerspectiveWhat Is New?Few studies addressed the association between urinary and serum markers of fibrosis and how MR antagonism influences urinary peptides derived from collagen.MR antagonism reduces collagen-derived urinary peptides. Inhibition of type-1 collagen synthesis by lowering the amount available for breakdown may be a contributing mechanism.Correlations between changes from baseline to follow-up in type-1 collagen and in CITP were positive if fragments increased during follow-up and nonsignificant if fragments decreased.What Are the Clinical Implications?Spironolactone inhibits fibrosis, supporting the use of MRAs in patients at risk of heart failure or chronic kidney disease.UPP profiling opens new research perspectives in documenting the antifibrotic properties of novel drug classes, such as nonsteroidal MR antagonists or sodium-glucose cotransporter-2 inhibitors.The development of novel medicines that would promote collagen degradation in addition to MRAs would strengthen the therapeutic armamentarium to modify fibrosis.GRAPHICAL ABSTRACT

BACKGROUND: This study investigates the effects of exercise training on exerkines in patients with type 2 diabetes mellitus to determine the optimal exercise prescription. METHODS: A systematic search for relevant studies was performed in 3 databases. Randomized controlled trials investigating the effects of exercise training on at least one of the following exerkines were included: adiponectin, apelin, brain-derived neurotrophic factor, fetuin-A, fibroblast growth factor-21, follistatin, ghrelin, interleukin (IL)-6, IL-8, IL-10, IL-15, IL-18, leptin, myostatin, omentin, resistin, retinol-binding protein 4, tumor necrosis factor-α, and visfatin. RESULTS: Forty randomized controlled trials were selected for data extraction (n = 2160). Exercise training induces changes in adiponectin, fetuin-A, fibroblast growth factor-21, IL-6, IL-10, leptin, resistin, and tumor necrosis factor-α levels but has no significant effects on apelin, IL-18, and ghrelin compared to controls. Physical exercise training favored large and positive changes in pooled exerkines (i.e., an overall effect size calculated from several exerkines) (Hedge's g = 1.02, 95% confidence interval (95%CI): 0.76−1.28), which in turn were related to changes in glycated hemoglobin (mean difference (MD) = −0.81%, 95%CI: −0.95% to −0.67%), fasting glucose (MD = −23.43 mg/dL, 95%CI: −30.07 mg/dL to −16.80 mg/dL), waist circumference (MD = −3.04 cm, 95%CI: −4.02 cm to −2.07 cm), and body mass (MD = −1.93 kg, 95%CI: −2.00 kg to −1.86 kg). Slightly stronger effects were observed with aerobic, resistance, or high-intensity interval protocols at moderate- to vigorous-intensity and with programs longer than 24 weeks that comprise at least 3 sessions per week and more than 60 min per session. CONCLUSION: Exercise training represents an anti-inflammatory therapy and metabolism-improving strategy with minimal side effects for patients with type 2 diabetes mellitus.

The approval of new heart failure (HF) therapies has slowed over the past two decades in part due to the high costs of conducting large randomized clinical trials that are needed to adequately power major clinical endpoint studies. Several biomarkers have been identified reflecting different elements of HF pathophysiology, with possible applications in diagnosis, risk stratification, treatment monitoring, and even in the design of clinical trials. Biomarkers could potentially be used to refine study inclusion criteria to enable enrolment of patients who are more likely to respond to a therapeutic intervention, despite being at sufficient risk to meet pre-determined study endpoint rates. When there is a close relationship between biomarker levels and clinical endpoints, changes in biomarker levels after a given treatment can act as a surrogate endpoint, potentially reducing the duration and cost of a clinical trial. Natriuretic peptides have been widely used in clinical trials with a variable amount of added value, which such variation being probably due to the absence of a close pathophysiological connection to the study drug. Notable exceptions to this include sacubitril/valsartan and vericiguat. Future studies should seek to adopt unbiased approaches for discovery of true companion diagnostics; with -omics-based tools, biomarkers might be more precisely selected for use in clinical trials to identify responses that closely reflect the biological effects of the drug under investigation. Finally, biomarkers associated with cardiac damage and remodelling, such as cardiac troponin, could be employed as safety endpoints provided that standardization between different assays is achieved. © 2022 European Society of Cardiology.

OBJECTIVES This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.BACKGROUND In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.METHODS Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledgebased network analysis. RESULTS A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).CONCLUSIONS Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450) (C) 2021 by the American College of Cardiology Foundation.

Preliminary results suggest that high circulating insulin-like growth factor binding protein 2 (IGFBP2) levels are associated with mortality risk in heart failure (HF) patients. As IGFBP2 levels are increased in patients with chronic kidney disease (CKD), which is associated with a higher mortality risk in HF patients, we examined whether IGFBP2 is associated with CKD in HF patients, and whether CKD modifies the prognostic value of this protein in HF patients.HF patients (n=686, mean age 66.6 years, 32.7% women) were enrolled and followed up for a median of 3.5 (min-max range: 0.1-6) years. Patients were classified as having CKD with decreased estimated glomerular filtration rate (eGFR60mL/min/1.73 mIGFBP2 was increased (P.001) in CKD patients with decreased eGFR (n=290, 42.3%) compared with patients with nondecreased eGFR. IGFBP2 was directly associated with NT-proBNP (P.001) and inversely associated with eGFR (P.001), with both associations being independent of confounding factors. IGFBP2 was directly and independently associated with cardiovascular and all-cause death (P.001) in the whole group of patients, but showed a stronger association with cardiovascular death in CKD patients with decreased eGFR (P for interaction.05), improving risk prediction in these patients over clinically relevant risk factors.Serum IGFBP2 is associated with impaired renal function and prognosticates cardiovascular death in patients with HF and CKD with decreased eGFR. Thus, there is an effect modification of CKD on circulating IGFBP2 and on its association with cardiovascular mortality in HF patients.

Noninvasive imaging of myocardial function has limitations as a readout of myocardial biology and therefore as the basis for cardiomyopathy treatments. Measuring scar by using cardiovascular magnetic resonance (CMR) adds value but does not inform about non-scarred myocardium, the key therapeutic

Resumen Introduccion y objetivos Los niveles circulantes de la proteina de union del factor de crecimiento de tipo insulina 2 (IGFBP2) aumentan en la insuficiencia renal cronica (IRC), y se asocian con un mayor riesgo de mortalidad en la miocardiopatia dilatada. Dado que la IRC se asocia con una mayor mortalidad en la insuficiencia cardiaca (IC), hemos investigado si, en pacientes con IC de distinta etiologia, IGFBP2 se asocia con la IRC, y si la IRC modifica el valor pronostico de esta proteina. Metodos Se estudiaron pacientes con IC (n = 686, edad media 66,6 anos, 32,7% mujeres) durante 3,5 anos (min-max: 0,1-6 anos). Los pacientes se clasificaron como IRC con una tasa de filtrado glomerular estimada disminuida (TFGe Resultados La IGFBP2 serica estaba aumentada (p Conclusiones Los niveles sericos de IGFBP2 se asocian con un empeoramiento de la funcion renal en pacientes con IC y con un mayor riesgo de muerte cardiovascular, principalmente en los pacientes con IC y IRC con una TFGe disminuida.

International audience; AIMS:Asymptomatic patients with coronary artery disease (CAD), hypertension and/or type 2 diabetes mellitus (T2DM) are at greater risk of developing heart failure (HF). Fibrosis, leading to myocardial and vascular dysfunction, might be an important pathway of progression. The Heart OMics in AGing (HOMAGE) trial aims to investigate the effects of spironolactone on serum markers of collagen metabolism and on cardiovascular structure and function in people at risk of developing HF and potential interactions with a marker of fibrogenic activity, galectin-3.METHODS AND RESULTS:The HOMAGE trial is a prospective, randomised, open-label, blinded endpoint (PROBE) study comparing spironolactone (up to 50 mg/day) and standard care over 9 months in people with clinical risk factors for developing HF, including hypertension, CAD and T2DM, and elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP, 125 to 1000 ng/L) or B-type natriuretic peptide (BNP, 35 to 280 ng/L). Exclusion criteria included left ventricular ejection fraction

Patients with the dual burden of chronic kidney disease (CKD) and chronic congestive heart failure (HF) experience unacceptably high rates of symptom load, hospitalization, and mortality. Currently, concerted efforts to identify, prevent and treat HF in CKD patients are lacking at the institutional level, with emphasis still being placed on individual specialty views on this topic. The authors of this review paper endorse the need for a dedicated cardiorenal interdisciplinary team that includes nephrologists and renal nurses and jointly manages appropriate clinical interventions across the inpatient and outpatient settings. There is a critical need for guidelines and best clinical practice models from major cardiology and nephrology professional societies, as well as for research funding in both specialties to focus on the needs of future therapies for HF in CKD patients. The implementation of cross-specialty educational programs across all levels in cardiology and nephrology will help train future specialists and nurses who have the ability to diagnose, treat, and prevent HF in CKD patients in a precise, clinically effective, and cost-favorable manner. Resumen: Los pacientes con enfermedad renal crónica (ERC) que desarrollan insuficiencia cardíaca (IC) congestiva crónica presentan cifras inaceptablemente altas de síntomas, hospitalización y mortalidad. Actualmente, se echan en falta iniciativas institucionales dirigidas a identificar, prevenir y tratar la IC en los pacientes con ERC de manera multidisciplinar, prevaleciendo las actuaciones de las especialidades individuales. Los autores de este artículo de revisión respaldan la necesidad de crear equipos multidisciplinares cardiorrenales, en los que participen nefrólogos y enfermeras renales, que gestionen colaborativamente las intervenciones clínicas apropiadas en los entornos de pacientes con ERC e IC hospitalizados y ambulatorios. Es necesario y urgente que se elaboren guías y modelos de práctica clínica sobre la ERC con IC por parte de las sociedades profesionales de cardiología y nefrología, así como financiación para la investigación concertada entre ambas especialidades sobre la necesidad de futuros tratamientos para la IC en pacientes con ERC. La implementación de programas educativos cardiorrenales a todos los niveles en cardiología y nefrología ayudará a formar a los futuros especialistas y enfermeras para que tengan la capacidad de diagnosticar, tratar y prevenir la IC en pacientes con ERC de manera precisa, clínicamente efectiva y económicamente favorable.

Resumen La fibrosis intersticial miocardica es un hallazgo constante en las cardiopatias estructurales que desarrollan insuficiencia cardiaca. Aunque la fibrosis facilita la progresion de la insuficiencia cardiaca, aun no se dispone de una estrategia terapeutica que la revierta. Probablemente, ello se deba al error de considerar la fibrosis intersticial miocardica como una lesion homogenea y no como una lesion heterogenea en la que coexisten diferentes fenotipos. Hay que tener presente tambien que la heterogeneidad de la fibrosis intersticial miocardica puede variar entre distintas cardiopatias. Por ello, el diagnostico y el tratamiento de la fibrosis intersticial miocardica suponen un verdadero desafio para la transicion de un manejo convencional de la insuficiencia cardiaca a un manejo basado en los principios de la medicina de precision. Como prueba de concepto, en este articulo revisamos como el fenotipado de pacientes con insuficiencia cardiaca atribuible a cardiopatia hipertensiva basado en las alteraciones histomoleculares principales de la fibrosis intersticial miocardica permite identificar subgrupos de pacientes con caracteristicas fisiopatologicas, clinicas y pronosticas diferentes. Ademas, discutimos la informacion disponible sobre el empleo de determinados biomarcadores circulantes y ciertos farmacos utiles para el diagnostico no invasivo y el tratamiento personalizado, respectivamente, de dichos subgrupos de pacientes.

Aims: \ud Left ventricular ejection fraction (LVEF) can provide haemodynamic information and may influence the response to spironolactone and other heart failure (HF) therapies. We aimed to study patient characteristics and circulating protein associations with LVEF, and whether LVEF influenced the response to spironolactone.\ud \ud Methods and results: \ud HOMAGE enrolled patients aged >60 years at high risk of developing HF with a LVEF ≥45%. Overall, 527 patients were randomized to either spironolactone or standard of care for ≈9 months, and 276 circulating proteins were measured using Olink® technology. A total of 364 patients had available LVEF determined by the Simpson's biplane method. The respective LVEF tertiles were: tertile 1: 65% (n = 121). Patients with a LVEF >65% had smaller left ventricular chamber size and volumes, and lower natriuretic peptide levels. Compared to patients with a LVEF 65% had higher levels of circulating c-c motif chemokine ligand-23 and interleukin-8, and lower levels of tissue plasminogen activator, brain natriuretic peptide (BNP), S100 calcium binding protein A12, and collagen type I alpha 1 chain (COL1A1). Spironolactone significantly reduced the circulating levels of BNP and COL1A1 without significant treatment-by-LVEF heterogeneity: BNP change β = −0.36 log2 and COL1A1 change β = −0.16 log2 (p 0.1 for both). Spironolactone increased LVEF from baseline to month 9 by 1.1% (p = 0.007).\ud \ud Conclusion: \ud Patients with higher LVEF had higher circulating levels of chemokines and inflammatory markers and lower levels of stretch, injury, and fibrosis markers. Spironolactone reduced the circulating levels of natriuretic peptides and type 1 collagen, and increased LVEF.

International audience; Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling.

Aims The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial.Methods and results Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean difference(sspiro/control): -1.77 (95% confidence interval, CI -2.94 to -0.59) and -2.52 (95% CI -4.46 to -0.58) mL/m(2); interaction p(across-tertiles) = 0.005; interaction p(third tertile) = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differences(spiro/control): -0.47 (95% CI -0.66 to -0.28) and -0.31 (95% CI -0.59 to -0.04) ng/L; interaction p(across-tertiles) = 0.09; interaction p(third tertile) < 0.001].Conclusions These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1).[GRAPHICS]Patients at risk of heart failure from the HOMAGE clinical trial were classified according to the baseline degree of myocardial collagen cross-linking, non-invasively assessed by the serum collagen type I C-terminal telopeptide (CITP) to matrix metalloproteinase-1 (MMP-1) ratio (CITP:MMP-1). As highly cross-linked collagen fibres are more resistant to degradation and CITP is a cross-linked peptide, for a given MMP-1 quantity less CITP will be released and, subsequently, serum CITP:MMP-1 will be lower. Whereas patients with low collagen cross-linking (high CITP:MMP-1) benefit from the cardioprotective effects of treatment with spironolactone on left atrial remodelling [i.e. a decrease in left atrial volume index (LAVI)] and on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, these beneficial effects are not found in patients with higher collagen cross-linking (low CITP:MMP-1).

Simple Summary Left ventricular dysfunction (LVD) induced by anthracycline-based cancer chemotherapy (ACC) is becoming an urgent healthcare concern. Myocardial fibrosis (MF) may contribute to LVD after ACC. We show that elevated circulating levels of procollagen type I C-terminal propeptide (PICP, biomarker of MF) are associated with early subclinical LVD and predict later development of cardiotoxicity in patients treated with ACC. In addition, an association between PICP and LVD in patients with ACC-induced heart failure is observed. These results provide novel insights into MF as a mechanism underlying LVD after ACC, with PICP emerging as a promising tool to monitor cardiotoxicity in patients treated with ACC. Anthracycline-based cancer chemotherapy (ACC) causes myocardial fibrosis, a lesion contributing to left ventricular dysfunction (LVD). We investigated whether the procollagen-derived type-I C-terminal-propeptide (PICP): (1) associates with subclinical LVD (sLVD) at 3-months after ACC (3m-post-ACC); (2) predicts cardiotoxicity 1-year after ACC (12m-post-ACC) in breast cancer patients (BC-patients); and (3) associates with LVD in ACC-induced heart failure patients (ACC-HF-patients). Echocardiography, serum PICP and biomarkers of cardiomyocyte damage were assessed in two independent cohorts of BC-patients: CUN (n = 87) at baseline, post-ACC, and 3m and 12m (n = 65)-post-ACC; and HULAFE (n = 70) at baseline, 3m and 12m-post-ACC. Thirty-seven ACC-HF-patients were also studied. Global longitudinal strain (GLS)-based sLVD (3m-post-ACC) and LV ejection fraction (LVEF)-based cardiotoxicity (12m-post-ACC) were defined according to guidelines. BC-patients: all biomarkers increased at 3m-post-ACC versus baseline. PICP was particularly increased in patients with sLVD (interaction-p < 0.001) and was associated with GLS (p < 0.001). PICP increase at 3m-post-ACC predicted cardiotoxicity at 12m-post-ACC (odds-ratio >= 2.95 per doubling PICP, p

Exercise intolerance remains a major unmet medical need in patients with heart failure (HF). Skeletal myopathy is currently considered as the major limiting factor for exercise capacity in HF patients. On the other hand, emerging evidence suggest that physical exercise can decrease morbidity and mortality in HF patients. Therefore, mechanistic insights into skeletal myopathy may uncover critical aspects for therapeutic interventions to improve exercise performance in HF. Emerging data reviewed in this article suggest that the assessment of circulating myokines (molecules synthesized and secreted by skeletal muscle in response to contraction that display autocrine, paracrine and endocrine actions) may provide new insights into the pathophysiology, phenotyping and prognostic stratification of HF-related skeletal myopathy. Further studies are required to determine whether myokines may also serve as biomarkers to personalize the modality and dose of physical training prescribed for patients with HF and exercise intolerance. In addition, the production and secretion of myokines in patients with HF may interact with systemic alterations (e.g., inflammation and metabolic disturbances), frequently present in patients with HF. Furthermore, myokines may exert beneficial or detrimental effects on cardiac structure and function, which may influence adverse cardiac remodelling and clinical outcomes in HF patients. Collectively, these data suggest that a deeper knowledge on myokines regulation and actions may lead to the identification of novel physical exercise-based therapeutic approaches for HF patients. Instituto de Salud Carlos III (Spain) (CB16/11/00483 to JD, PI18/01469 co-financed by “Fondos Europeos de Desarrollo Regional to AG, CP18/0150 Miguel Servet Fellow to AG-H); Ministerio de Ciencia e Innovación (Spain) (PID2020-113098RB-I00 to MI); European Commission CRUCIAL project (grant agreement 848109 to AG). Open access funding provided by Universidad Pública de Navarra.

Introduction The global burden of heart failure (HF), with either reduced (HFrEF) or preserved (HFpEF) ejection fraction, has increased dramatically over the past years, and HFpEF is projected to become the dominant type of HF. Fibrogenesis, promoted by fibroblast activity, plays an important role in the pathology of HF regardless of subtype, causing impaired cardiac function. Endotrophin is a bioactive molecule released from collagen type VI during its maturation, and it is a marker of fibroblast activity. The aim of this post-hoc analysis was to confirm the previously observed prognostic potential of endotrophin (measured by PRO-C6) for adverse outcome in HFpEF and to test its prognostic abilities in HFrEF. Methods 234 patients with hypertension and either HFrEF (30.3%) or HFpEF (69.7%) were included for analysis. 43.2% were NYHA Class II, 52.5% NYHA Class III and 2.5% NYHA Class IV. 53.4% of patients had a previous history of atrial fibrillation. The cohort did not include diabetic patients. Cardiac function was assessed by echocardiography and standard clinical measures, including left ventricle ejection fraction (EF), blood pressure (BP) and measurement of N-terminal natriuretic brain-peptide (NT-proBNP). Circulating endotrophin was quantified at baseline in serum by means of an enzyme-linked immunosorbent assay, PRO-C6. Results PRO-C6 levels increased significantly with disease severity in HFpEF patients (NYHA Class III vs II, p=0.0003), but not in HFrEF patients (NYHA Class III vs II, p=0.33). In HFpEF patients, PRO-C6 was able to discriminate between patients that were hospitalized for HF (AUC=0.69, p Conclusion In this population of hypertensive HF patients, circulating endotrophin, measured by PRO-C6, was increased with increasing disease severity, and associated with a higher risk of adverse outcome in HFpEF, but not in HFrEF patients. The data presented here suggest a potential role of endotrophin in HFpEF pathophysiology and further underline the differences between HFpEF and HFrEF. These data confirm previous observations, and strengthen the usefulness of endotrophin, measured by the PRO-C6 biomarker, as a prognostic tool aiding in assessment of HFpEF patients. Funding Acknowledgement Type of funding sources: None.

Background A combination of circulating biomarkers associated with excessive myocardial collagen type-I cross-linking or CCL+ (i.e., decreased carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 ratio) and with excessive myocardial collagen type-I deposition or CD+ (i.e., increased carboxy-terminal propeptide of procollagen type-I) has been described in heart failure (HF) patients and associates with poor outcomes. Objectives The purpose of this study was to investigate whether the CCL+CD+ combination of biomarkers associates with atrial fibrillation (AF). Methods Biomarkers were analyzed in serum samples from 242 HF patients (study 1) and 150 patients referred for AF ablation (study 2). Patients were classified into 3 groups (CCL−CD−, CCL+CD− or CCL−CD+, and CCL+CD+) in accordance to biomarker threshold values. Left atrial electroanatomic high-density mapping was performed in 71 patients from study 2. Results In study 1, 53.7% patients had AF at baseline and 19.6% developed AF (median follow-up 5.5 years). Adjusted odds and hazard ratios associated with baseline and new-onset AF, respectively, were both ≥3.3 (p ≤ 0.050) in CCL+CD+ patients compared with CCL−CD− patients, with nonsignificant changes in the other group. In study 2, 29.3% patients had AF recurrence during 1-year post-ablation. The adjusted hazard ratio for AF recurrence was 3.4 (p = 0.008) in CCL+CD+ patients compared with CCL−CD− patients, with nonsignificant changes in the other group. The CCL+CD+ combination added incremental predictive value over relevant covariables. CCL+CD+ patients exhibited lower left atrial voltage than the remaining patients (p = 0.005). Conclusions A combination of circulating biomarkers reflecting excessive myocardial collagen type-I cross-linking and deposition is associated with higher AF prevalence, incidence, and recurrence after ablation.

(2019). Analysis of the pilot survey INKLUGI about aging and disabilities to promote Inclusive Design in industry. The Design Journal: Vol. 22, Running with Scissors: 13th International Conference of the European Academy of Design, Dundee, 10-12th April, 2019, edited by Louise Valentine, Joanna Bletcher and Leon Cruickshank, pp. 417-427.

Myocardial fibrosis is a main contributor to the development of heart failure (HF). CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) are increased in HF and associated with myocardial fibrosis. The aim of this study is to analyze whether CT-1 regulates Gal-3. Proteomic analysis revealed that Gal-3 was upregulated by CT-1 in human cardiac fibroblasts in parallel with other profibrotic and proinflammatory markers. CT-1 upregulation of Gal-3 was mediated by ERK (extracellular signal-regulated kinase) 1/2 and Stat-3 (signal transducer and activator of transcription 3) pathways. Male Wistar rats and B6CBAF1 mice treated with CT-1 (20 µg/kg per day) presented higher cardiac Gal-3 levels and myocardial fibrosis. In CT-1–treated rats, direct correlations were found between cardiac CT-1 and Gal-3 levels, as well as between Gal-3 and perivascular fibrosis. Gal-3 genetic disruption in human cardiac fibroblasts and pharmacological Gal-3 inhibition in mice prevented the profibrotic and proinflammatory effects of CT-1. Dahl salt-sensitive hypertensive rats with diastolic dysfunction showed increased cardiac CT-1 and Gal-3 expression together with cardiac fibrosis and inflammation. CT-1 and Gal-3 directly correlated with myocardial fibrosis. In HF patients, myocardial and plasma CT-1 and Gal-3 were increased and directly correlated. In addition, HF patients with high CT-1 and Gal-3 plasma levels presented an increased risk of cardiovascular death. Our data suggest that CT-1 upregulates Gal-3 which, in turn, mediates the proinflammatory and profibrotic myocardial effects of CT-1. The elevation of both molecules in HF patients identifies a subgroup of patients with a higher risk of cardiovascular mortality. The CT-1/Gal-3 axis emerges as a candidate therapeutic target and a potential prognostic biomarker in HF.

Background and Aims Right ventricular dysfunction (RVD) has been shown to predict mortality in patients with kidney failure. It has been proposed that RVD in these patients is mediated by inflammatory and fibrotic mechanisms, which may be enhanced by hemodialysis (HD). The present study aimed to investigate the potential associations between RVD and circulating biomarkers of myocardial inflammation and fibrosis with all-cause mortality in HD patients. Method We performed a retrospective single-centre cohort study of prevalent patients admitted in a chronic HD program for more than 3 months. Clinical characteristics and echocardiographic parameters were assessed in all patients. Pre-dialysis blood samples for measurement of inflammatory (e.g., C reactive protein, interleukin-1, interleukin-18) and fibrotic (e.g., soluble suppression of tumorigenesis-2 [sST2], galectin-3, C-terminal pro-peptide of procollagen type I and N-terminal pro-peptide of procollagen type III) biomarkers were collected. Right ventricular dysfunction (RVD) was defined using tricuspid annular plane systolic excursion (TAPSE) Results We enrolled 48 patients (mean age 74 [64–79] years, 62.5% males) followed over a period of 1.4 years. Mortality was higher 45.5% (log-rank, p=0.003) in patients with RVD as diagnosed by S' than in patients without RVD. No difference in mortality was observed for RVD defined by TAPSE. There were no differences in the morphology and function parameters of the left ventricle between patients with and without RVD. From all biomarkers measured only sST2 was associated with RVD. Indeed, an age- and sex-adjusted analyses showed that doubling of sST2 was inversely associated with a decreased in S´ (estimate=-2.03, 95% CI [-3.04 to -1.00] cm/s; P=0.002). Mortality was increased in patients with sST2 ≥40.45 ng/mL compared to patients with sST2 9.5 cm/s and sST2 Conclusion Albeit preliminary these findings suggest that an excess of sST2 may be involved in RVD and on its effect on mortality in HD patients. The myocardial pro-remodeling effect of sST2 among HD patients with RVD warrants further investigation.

Maturation of fibrillar collagen is known to play a crucial role in the pathophysiology of myocardial fibrosis. Procollagen C-proteinase enhancer 1 (PCPE1) has a key role in procollagen maturation and collagen fibril formation. The phenotype of both male and female PCPE1 knock-out mice was investigated under basal conditions to explore the potential of PCPE1 as a therapeutic target in heart failure. Global constitutive PCPE1-/- mice were generated. Serum procollagen I C-terminal propeptide, organ histology, and cutaneous wound healing were assessed in both wild type (WT) and PCPE1-/- mice. In addition, the cardiac expression of genes involved in collagen metabolism was investigated and the total and insoluble cardiac collagen contents determined. Cardiac function was evaluated by echocardiography. No differences in survival, clinical chemistry, or organ histology were observed in PCPE1-/- mice compared with WT. Serum procollagen I C-terminal propeptide was lower in PCPE1-/- mice. Cardiac mRNA expression of Bmp1, Col1a1, Col3a1, and Loxl2 was similar, whereas Tgfb and Loxl1 mRNA levels were decreased in PCPE1-/- mice compared with sex-matched WT. No modification of total or insoluble cardiac collagen content was observed between the 2 strains. Ejection fraction was slightly decreased in PCPE1-/- male mice, but not in females. Finally, wound healing was not altered in PCPE1-/- mice. PCPE1 deficiency does not trigger any major liabilities and does not affect cardiac collagen content nor its function under basal conditions. Further studies are required to evaluate its role under stressed conditions and determine its suitability as a therapeutic target for heart failure.

AIMS: Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on the European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology. METHODS AND RESULTS: Analysable data from 5608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann-Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. A total of 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (P

Aims Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone’s effect. Methods and results HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25–50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25–75) age was 73 (69–79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by −10.3 (−13.0 to −7.5) mmHg and DBP by −3.2 (−4.8 to −1.7) mmHg (P Conclusion Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.

n/a Funding Agencies|Applied Therapeutics; Innolife; Novartis PharmaceuticalsNovartis; Abbott DiagnosticsAbbott Laboratories; AstraZenecaAstraZeneca; AbbottAbbott Laboratories; Boehringer IngelheimBoehringer Ingelheim; Cardior Pharmaceuticals Gmbh; Ionis Pharmaceuticals, Inc.; Novo NordiskNovo Nordisk; RocheRoche Holding; Swiss National Science FoundationSwiss National Science Foundation (SNSF)European Commission; Swiss Heart Foundation; KTI; European UnionEuropean Commission; University of Basel; University Hospital Basel; Beckman Coulter; BRAHMS; Idorsia; NovartisNovartis; Ortho Clinical Diagnostics; Quidel; SiemensSiemens AG; Singulex; Sphingotec; CardioRenal

Patients with heart failure (HF) who contract SARS-CoV-2 infection are at a higher risk of cardiovascular and non-cardiovascular morbidity and mortality. Regardless of therapeutic attempts in COVID-19, vaccination remains the most promising global approach at present for controlling this disease. There are several concerns and misconceptions regarding the clinical indications, optimal mode of delivery, safety and efficacy of COVID-19 vaccines for patients with HF. This document provides guidance to all healthcare professionals regarding the implementation of a COVID-19 vaccination scheme in patients with HF. COVID-19 vaccination is indicated in all patients with HF, including those who are immunocompromised (e.g. after heart transplantation receiving immunosuppressive therapy) and with frailty syndrome. It is preferable to vaccinate against COVID-19 patients with HF in an optimal clinical state, which would include clinical stability, adequate hydration and nutrition, optimized treatment of HF and other comorbidities (including iron deficiency), but corrective measures should not be allowed to delay vaccination. Patients with HF who have been vaccinated against COVID-19 need to continue precautionary measures, including the use of facemasks, hand hygiene and social distancing. Knowledge on strategies preventing SARS-CoV-2 infection (including the COVID-19 vaccination) should be included in the comprehensive educational programmes delivered to patients with HF. This article is protected by copyright. All rights reserved. [Abstract copyright: This article is protected by copyright. All rights reserved.]

Clinical and translational medicine 11(1), e267 (2021). doi:10.1002/ctm2.267, Published by Wiley, Hoboken, NJ

Aims To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients. Methods and results We quantified fibrosis in 209 DCM patients at three levels: (i) non‐invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers [amino‐terminal propeptide of procollagen type III (PIIINP) and carboxy‐terminal propeptide of procollagen type I (PICP)], (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life‐threatening arrhythmias, after adjusting for known clinical predictors [adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90–6.60; P, Multilevel assessment of myocardial fibrosis demonstrates significant correlations between histology, non‐invasive imaging, and blood markers. A combined multi‐parametric approach with carboxy‐terminal propeptide of procollagen type I (PICP) and late gadolinium enhancement (LGE) allows the best risk stratification of idiopathic dilated cardiomyopathy (DCM) patients, accompanied with a profile of high expression of combined pro‐inflammatory and pro‐fibrotic genes, indicating a potential marker for disease activity.

Diffuse myocardial fibrosis resulting from the excessive deposition of collagen fibres through the entire myocardium is encountered in a number of chronic cardiac diseases. This lesion results from alterations in the regulation of fibrillary collagen turnover by fibroblasts, facilitating the excessive deposition of type I and type III collagen fibres within the myocardial interstitium and around intramyocardial vessels. The available evidence suggests that, beyond the extent of fibrous deposits, collagen composition and the physicochemical properties of the fibres are also relevant in the detrimental effects of diffuse myocardial fibrosis on cardiac function and clinical outcomes in patients with heart failure. In this regard, findings from the past 20 years suggest that various clinicopathological phenotypes of diffuse myocardial fibrosis exist in patients with heart failure. In this Review, we summarize the current knowledge on the mechanisms and detrimental consequences of diffuse myocardial fibrosis in heart failure. Furthermore, we discuss the validity and usefulness of available imaging techniques and circulating biomarkers to assess the clinicopathological variation in this lesion and to track its clinical evolution. Finally, we highlight the currently available and potential future therapeutic strategies aimed at personalizing the prevention and reversal of diffuse myocardial fibrosis in patients with heart failure.