Osteoarthritis (OA) is the most prevalent form of arthritis and a major cause of pain and disability. The pathology of OA involves the whole joint in an inflammatory and degenerative process, especially in articular cartilage. OA may be divided into distinguishable phenotypes including one associated with the metabolic syndrome (MetS) of which dyslipidemia and hyperglycemia have been individually linked to OA. Since their combined role in OA pathogenesis remains to be elucidated, we investigated the chondrocyte response to these metabolic stresses, and determined whether a n-3 polyunsaturated fatty acid (PUFA), i.e., eicosapentaenoic acid (EPA), may preserve chondrocyte functions. Rat chondrocytes were cultured with palmitic acid (PA) and/or EPA in normal or high glucose conditions. The expression of genes encoding proteins found in cartilage matrix (type 2 collagen and aggrecan) or involved in degenerative (metalloproteinases, MMPs) or in inflammatory (cyclooxygenase-2, COX-2 and microsomal prostaglandin E synthase, mPGES) processes was analyzed by qPCR. Prostaglandin E2 (PGE2) release was also evaluated by an enzyme-linked immunosorbent assay. Our data indicated that PA dose-dependently up-regulated the mRNA expression of MMP-3 and -13. PA also induced the expression of COX-2 and mPGES and promoted the synthesis of PGE2. Glucose at high concentrations further increased the chondrocyte response to PA. Interestingly, EPA suppressed the inflammatory effects of PA and glucose, and strongly reduced MMP-13 expression. Among the free fatty acid receptors (FFARs), FFAR4 partly mediated the EPA effects and the activation of FFAR1 markedly reduced the inflammatory effects of PA in high glucose conditions. Our findings demonstrate that dyslipidemia associated with hyperglycemia may contribute to OA pathogenesis and explains why an excess of saturated fatty acids and a low level in n-3 PUFAs may disrupt cartilage homeostasis.

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 <0.001), each of which was a larger increase than that for NT-proBNP on top of clinical risk factors. Complex network analysis revealed a number of overrepresented pathways related to inflammation (eg, tumor necrosis factor and interleukin) and remodeling (eg, extracellular matrix and apoptosis). Conclusions: A multiprotein biomarker approach improves prediction of incident HF when added to natriuretic peptides and clinical risk factors.

This chapter addresses interstitium and collagen in heart failure. By definition, the interstitium represents the space between the specialized cells of a tissue. It is a complex compartment in which interstitial fluid and many different types of insoluble molecules (forming the extracellular matrix) undergo constant alterations to fulfil physiological needs. In the heart, the cardiac interstitium plays an instrumental role in dynamic myocyte activity and the plasticity, elasticity, and turgor of the interstitium are vital to allow the cardiac chambers to reach their optimal contractile and relaxation states. The chapter then explores the structure of the interstitium before looking at its pathological expansion, considering myocardial fibrosis in particular. The ability of treatment to reduce myocardial fibrosis in patients with heart failure may be monitored by the measurement of various serum peptides arising from the metabolism of collagen types.

Background: Adipose tissue influences the expression and degradation of circulating biomarkers. We aimed to identify the biomarker profile and biological meaning of biomarkers associated with obesity to assess the effect of spironolactone on the circulating biomarkers and to explore whether obesity might modify the effect of spironolactone. Methods and Results: Protein biomarkers (n = 276) from the Olink Proseek Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline, 1 month and 9 months from the HOMAGE randomized controlled trial participants. Of the 510 participants, 299 had obesity defined as an increased waist circumference (>= 102 cm in men and >= 88 cm in women). Biomarkers at baseline reflected adipogenesis, increased vascularization, decreased fibrinolysis, and glucose intolerance in patients with obesity at baseline. Treatment with spironolactone had only minor effects on this proteomic profile. Obesity modified the effect of spironolactone on systolic blood pressure (P-interaction = 0.001), showing a stronger decrease of blood pressure in obese patients (-14.8 mm Hg 95% confidence interval -18.45 to -11.12) compared with nonobese patients (-3.6 mm Hg 95% confidence interval -7.82 to 0.66). Conclusions: Among patients at risk for heart failure, those with obesity have a characteristic proteomic profile reflecting adipogenesis and glucose intolerance. Spironolactone had only minor effects on this obesity-related proteomic profile, but obesity significantly modified the effect of spironolactone on systolic blood pressure.

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.

Abstract Aims  To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure. Methods and results  Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): −0.15; 95% confidence interval (CI) −0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: −8.1; 95% CI −11.9 to −4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: −2.9; 95% CI −4.3 to −1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: −10; 95% CI −13 to −7 mmHg; P < 0.0001), left atrial volume (mdiff: −1; 95% CI −2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: −57; 95% CI −81 to −33 ng/L; P < 0.0001) were reduced in those assigned spironolactone. Conclusions  Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

Hypertension, obesity and diabetes are major and potentially modifiable “risk factors” for cardiovascular diseases. Identification of biomarkers specific to these risk factors may help understanding the underlying pathophysiological pathways, and developing individual treatment. The FIBRO-TARGETS (targeting cardiac fibrosis for heart failure treatment) consortium has merged data from 12 patient cohorts in 1 common database of > 12,000 patients. Three mutually exclusive main phenotypic groups were identified (“cases”): (1) “hypertensive”; (2) “obese”; and (3) “diabetic”; age–sex matched in a 1:2 proportion with “healthy controls” without any of these phenotypes. Proteomic associations were studied using a biostatistical method based on LASSO and confronted with machine-learning and complex network approaches. The case:control distribution by each cardiovascular phenotype was hypertension (50:100), obesity (50:98), and diabetes (36:72). Of the 86 studied proteins, 4 were found to be independently associated with hypertension: GDF-15, LEP, SORT-1 and FABP-2; 3 with obesity: CEACAM-8, LEP and PRELP; and 4 with diabetes: GDF-15, REN, CXCL-1 and SCF. GDF-15 (hypertension + diabetes) and LEP (hypertension + obesity) are shared by 2 different phenotypes. A machine-learning approach confirmed GDF-15, LEP and SORT-1 as discriminant biomarkers for the hypertension group, and LEP plus PRELP for the obesity group. Complex network analyses provided insight on the mechanisms underlying these disease phenotypes where fibrosis may play a central role. Patients with “mutually exclusive” phenotypes display distinct bioprofiles that might underpin different biological pathways, potentially leading to fibrosis. Plasma protein biomarkers and their association with mutually exclusive cardiovascular phenotypes: the FIBRO-TARGETS case–control analyses. Patients with “mutually exclusive” phenotypes (blue: obesity, hypertension and diabetes) display distinct protein bioprofiles (green: decreased expression; red: increased expression) that might underpin different biological pathways (orange arrow), potentially leading to fibrosis.

Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

The potential roles of metabolic syndrome (MetS) in the onset and progression of osteoarthritis (OA) have been a hot topic in the field since it may potentially open up to new non-surgical treatment regimens. To better study the relationship between MetS and OA, a suitable animal model would be a vital tool in understanding the pathomechanism and also for screening and testing various potential drug candidates. We have recently read Deng and colleagues’ letter entitled ‘Eplerenone treatment alleviates the development of joint lesions in a new rat model of spontaneous metabolic-associated osteoarthritis’ published online this May, which mentioned the use of ‘obese spontaneously hypertensive heart failure’ (SHHFcp/cp) rat model to study MetS-associated OA and chronic administration of eplerenone, a mineralocorticoid receptor antagonist, as a treatment.1 While we appreciate the authors’ dedicated effort, we believe there are several …

BackgroundAn increase in myocardial collagen content may contribute to the development of heart failure; this might be inhibited or reversed by mineralocorticoid receptor antagonists (MRAs). We investigated changes in serum concentrations of the collagen synthesis biomarkers N-terminal propeptide of procollagen type III (PIIINP) (primary outcome) and C-terminal propeptide of procollagen type I (PICP) (secondary outcome) after non-randomised initiation of spironolactone as add-on therapy among patients with resistant hypertension enrolled in the ‘Anglo-Scandinavian Cardiac Outcomes’ trial (ASCOT).MethodsAn age/sex matching plus propensity-scored logistic regression model incorporating variables related to the outcome and spironolactone treatment was created to compare patients treated with spironolactone for a 9-month period versus matched controls. A within-person analysis comparing changes in serum biomarker concentrations in the 9 months before versus after spironolactone treatment was also performed.ResultsPatients included in the between-person analysis (n=146) were well matched: the mean age was 63±7 years and 11% were woman. Serum concentrations of PIIINP and PICP rose in ‘controls’ and fell during spironolactone treatment (adjusted means +0.52 (−0.05 to 1.09) vs −0.41 (−0.97 to 0.16) ng/mL, p=0.031 for PIIINP and +4.54(−1.77 to 10.9) vs −6.36 (−12.5 to −0.21) ng/mL, p=0.023 for PICP). For the within-person analysis (n=173), spironolactone treatment was also associated with a reduction in PICP (beta estimate=−11.82(−17.53 to −6.10) ng/mL, p<0.001) but not in PIIINP levels.ConclusionsTreatment with spironolactone was associated with a reduction in serum biomarkers of collagen synthesis independently of blood pressure in patients with hypertension, suggesting that spironolactone might exert favourable effects on myocardial collagen synthesis and fibrosis. Whether this effect might contribute to slowing the progression to heart failure is worth investigating.

This article refers to ‘Adiposity, body composition and ventricular-arterial stiffness in the elderly: the Atherosclerosis Risk in Communities Study’ by M.M. Fernandes-Silva et al., published in this issue on pages 1191–1201. As the world population gets older, clinicians can no longer deal only with children, adults and elderly since a fourth category of patients emerged: the very old adults represented by individuals over 80 years of age. Those very old adults have survived and adapted to all risk factors and adverse events they encountered during their lifespan. While this new category of patients is largely uncharacterized—mostly lacking reference data for any considered studied phenotypes—clinicians have to adapt their practice to them. Aging is a risk factor for cardiovascular diseases and clinicians have to prevent its premature onset. In order to phenotype this group of patients, clinical efforts like the one described in the study of Fernandes-Silva et al.1 in the current issue of the Journal are required to unravel the specificity of aged populations. Focusing on the characterization of the heart and large arterial stiffness—known consequences of aging—Fernandes-Silva et al. hypothesized that increased adiposity would be associated with higher left ventricular (LV) and arterial stiffness in the individuals examined during the fifth visit of the Atherosclerosis Risk in Communities (ARIC) study (aged 66–99 years). At the fifth visit, the ARIC population presented hypertension in over 73% of the participants, excessive adiposity (overweight to obese) in 73% of the individuals which was associated with higher prevalence of hypertension, diabetes mellitus and heart failure. Among markers of coronary artery disease, arterial stiffness has proven to be an important parameter for the assessment of cardiovascular risk. The carotid to femoral pulse wave velocity (PWV) used by the authors is the gold standard method2 and remains a prognostic marker in heart failure patients.3 If reference and normal values for PWV have been previously described based on a large (n = 16 867) European population,2 no stratification for adiposity was specifically analysed. The study from Scuteri et al.,4 however, has extensively investigated the relationship between total and abdominal adiposity in another large cohort of community dwelling volunteers. They demonstrated a non-linear relationship between obesity and arterial stiffness in 6148 participants aged 14 to 102 years. In this study, while age was strongly associated with PWV, the effects of body mass index (BMI) on PWV did not differ across age groups, although the association appeared weaker in subjects >65 years (not discriminating over 80 years old individuals). Interestingly, Fernandes-Silva et al.1 demonstrated that body fat percentage—another parameter assessing adiposity—showed as well non-linear relationships with PWV in the ARIC population. This non-linear relationship implies that smaller reduction in adiposity (by lifestyle intervention) will result in a dramatically greater impact on PWV and, thus, on individual cardiovascular risk profile in the elderly group of studied individuals. This comes in reinforcement of the observation made in the systematic review and meta-analysis performed by Petersen et al.5 and offers a clinical alternative to try reducing arterial stiffness in elderly patients. The protocol of the fifth visit allowed also a cardiac function evaluation of the ARIC participants. Of interest, this investigation showed that the association between obesity and high LV stiffness still holds among the elderly and that this was independent of other potentially confounding variables. This comes in line with the conclusion of Russo et al.6 who observed that in a population-based elderly cohort (mean age 71 ± 9 years) abdominal adiposity was independently associated with subclinical LV dysfunction in all BMI categories, suggesting that increased abdominal obesity might be a risk factor for LV dysfunction regardless of the presence of general obesity. Fernandes-Silva et al. have elegantly used three different morphometric parameters to evaluate fat deposition: BMI, waist circumference (WC) and body fat percentage, but yet none of them clearly locate fat deposits. Furthermore they reported stronger or weaker associations with ventricular and arterial stiffness depending on the used morphometric parameter. Thus, morphometric parameters used to clinically evaluate adiposity are not alike and this is probably because adipose tissue is a very complex organ and does not display the same characteristics depending on its location.7 In healthy individuals, white (WAT) and brown (BAT) adipose tissue deposits serve as storages and buffers for fatty acids. They serve also as attenuators of glycaemia and dyslipidaemia, and as controllers of vascular tension and inflammation. However, under abnormal or excessive fat accumulation, both types of deposits become dysfunctional. WAT hypertrophies and has a high lipolytic activity releasing free fatty acids, which are detrimental for the heart structure and function.8 It is also infiltrated by macrophages, which are interacting with the adipocytes, and contributes to trigger a low-grade inflammatory process by releasing pro-inflammatory factors (cytokines, chemokines, renin–angiotensin–aldosterone system compounds) into the circulation. In contrast, when becoming dysfunctional, BAT atrophies and becomes inactive by losing its protective anti-glycaemic/dyslipidaemic and anti-inflammatory properties. Experimental and clinical evidence have suggested that when dysfunctional adipocytes are located in close vicinity (visceral adipose tissue) with major organs, they become more harmful to the myocardium and the coronary arteries than the subcutaneous ones.9 Furthermore, there is a growing body of evidence that when compared to the subcutaneous adipocyte, visceral fat cells are shown to have a differential production of adipokines. Furthermore, epicardial adipose tissue has been described as a unique and multifaceted fat depot with local and systemic effects. This tissue shares with the heart an unobstructed microcirculation that facilitates the interaction between these two organs.10 The epicardial-fat-specific transcriptome has been shown to be down-regulated in the presence of severe and advanced coronary artery disease. If straightforward morphometric parameters could help identifying patients with increased risk of ventricular and arterial stiffness or patients who might gain greater benefit from a given treatment,11 those parameters do not inform on the altered biological functions and signalling. The clinical evidence of Fernandes-Silva et al.1 sustain the conclusion that increased adiposity is associated with increased ventricular–arterial stiffness among very old adults (i.e. >80 years), suggesting a potential mechanism by which obesity might contribute to the development of heart failure. The deleterious effects of the exocrine activity of the adipose tissue have probably harmed the ventricle and artery since several visits. This long-lasting dysregulation of many signalling pathways before the fifth visit resulting in organ stiffness could have been followed through bioprofiling at different follow-up times of the participant. Excess adiposity is associated with numerous alterations that could partly be evaluated through biomarker analysis: higher levels of inflammation, insulin resistance as evaluated by the authors, but also fibrosis and alteration of extracellular matrix protein expression.12-14 However, numerous other parameters could follow the alterations arising from excess adiposity.15 Stiffer arteries have been proposed to be associated with higher leptin and high-sensitivity C-reactive protein.16 An excessive production of aldosterone influences outcomes in obese patients, and excessive activity of the renin–angiotensin–aldosterone system has been associated with LV hypertrophy, arterial stiffness and fibrosis development, experimentally as well as clinically.17 As mentioned by the authors, a limitation of their study is the cross-sectional design of the approach. It precludes the determination of this stiffening onset—potential early vascular aging18—in the individuals presenting increased adiposity as compared to the leaner ones. As mentioned above, this limitation could have been partly compensated by the coupling of their clinical observations with molecular evidence. Indeed, information about alteration of pre-identified or novel signalling pathways would have offered additional hypothesis towards understanding of the patient's stiffness status and origin. Taking advantage of the development of high throughput technologies, assessment of hundreds of biomarkers of different kinds (proteomic, transcriptomic, metabolomic, genomic) can now be performed even in very small volumes of biosamples. Hence, avoiding the exhaustion of the precious clinical biosamples, those optimized approaches can help stratifying patients at the visit they have been fully phenotyped. Where cross-sectional design has been seen as a limitation in the current ARIC study, the use of bioprofiles could have helped identifying biomarkers within signalling pathways associated with stiffness phenotype. Even better, they could have helped following their dysregulation along aging based on retrospective bioprofiling of the individuals at earlier visits (determination of the onset of ventricular and arterial stiffness). Pushing forwards, as vascular and cardiac stiffening is not exclusively characteristic of older subjects and as it has been described in obese children cohorts, the expression of the identified biomarkers could also be evaluated in any cohort where premature aging is suspected. Of course dealing with several hundreds of supplemental measurements performed in addition to more classical phenotyping requires from clinicians to collaborate with computer scientists specialized in computational biology and larger budgets. Several huge ongoing scientific programmes are already bridging clinicians (to phenotype individual and suggest associations) together with mathematicians (to model diseases), computational biologists (to stratify patients according to signalling pathways) and basic scientists (to experimentally validate the suggested association) (HOMAGE: www.homage-hf.eu; HERMES: www.hermes-h2020.eu). Approaching disease using trans-disciplinary approaches will optimize the expected outcomes of huge investigations like the ARIC study. Joining efforts to cross validate hypothesis between consortia will also empower the data and their analysis and substantiate the conclusions. And because of this in-depth characterization of clinical phenotypes, one can expect that precision medicine is not just an utopia but will progressively be integrated in the daily practice. Conflict of interest: none declared.

At the start of the genomics era when the first human genome became available, it was thought that knowing our DNA code would provide sufficient biomarkers to get us a good way toward our precision medicine goal. Unfortunately, the underlying complexity of the genome (and epigenome) proved to be far more intractable than many researchers expected. It soon became clear that genomics was not the panacea we sought, but required complementation from other'omics, including (but not limited to) proteomics, metabolomics, and transcriptomics. We are now at the point where genomics discovery tools (mostly high-throughput, rapid-sequencing technologies) are reaching maturity, while proteomics and other technologies are on the upswing. The articles in this booklet describe recent advances in proteomics technologies and how they are enabling the identification of new biomarkers that researchers are optimistic will advance us well along the track to realizing our objective for precision medicine. Much work remains to be done, but there is little doubt that the wind is at our backs and the scientific discoveries coming out of this multi-omics era will benefit patients in measurable ways.

Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network that occur in response to cardiac ischaemic insults, systemic diseases, drugs, or any other harmful stimulus affecting the circulatory system or the heart itself. Myocardial fibrosis alters the architecture of the myocardium, facilitating the development of cardiac dysfunction, also inducing arrhythmias, influencing the clinical course and outcome of heart failure patients. Focusing on myocardial fibrosis may potentially improve patient care through the targeted diagnosis and treatment of emerging fibrotic pathways. The European Commission funded the FIBROTARGETS consortium as a multinational academic and industrial consortium with the primary aim of performing a systematic and collaborative search of targets of myocardial fibrosis, and then translating these mechanisms into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. This review focuses on those methodological and technological aspects considered and developed by the consortium to facilitate the transfer of the new mechanistic knowledge on myocardial fibrosis into potential biomedical applications.

The aim of personalized medicine is to offer a tailored approach to each patient in order to provide the most effective therapy, while reducing risks and side effects. The use of mineralocorticoid receptor antagonists (MRAs) has demonstrated major benefits in heart failure with reduced ejection fraction (HFrEF), results with challenging inconsistencies in heart failure with preserved ejection fraction (HFpEF), and ‘neutral’ preliminary results in acute heart failure. Data derived from landmark trials are generally applied in a ‘one size fits all’ manner and the development and implementation of more personalized MRA management would offer the potential to improve outcomes and reduce side effects. However, the personalization of pharmacotherapy regimens remains poorly defined in the cardiovascular field (in light of current knowledge) and until further trials targeting specific subpopulations have been conducted, MRAs should be provided to the great majority of HFrEF patients in the absence of contraindication. Spironolactone should be considered for symptomatic HFpEF patients with elevated natriuretic peptides. In the near future, trials should target HFrEF patients using exclusion criteria sourced from landmark trials (e.g. severe renal impairment), select more homogeneous HFpEF populations (e.g. with elevated BNP and structural abnormalities on echocardiography), and determine which patients are likely to benefit from MRAs (e.g. according to prespecified biomarkers).

AIMS:Myocardial fibrosis alters the cardiac architecture favouring the development of cardiac dysfunction, including arrhythmias and heart failure. Reducing myocardial fibrosis may improve outcomes through the targeted diagnosis and treatment of emerging fibrotic pathways. The European-Commission-funded 'FIBROTARGETS' is a multinational academic and industrial consortium with the main aims of (i) characterizing novel key mechanistic pathways involved in the metabolism of fibrillary collagen that may serve as biotargets, (ii) evaluating the potential anti-fibrotic properties of novel or repurposed molecules interfering with the newly identified biotargets, and (iii) characterizing bioprofiles based on distinct mechanistic phenotypes involving the aforementioned biotargets. These pathways will be explored by performing a systematic and collaborative search for mechanisms and targets of myocardial fibrosis. These mechanisms will then be translated into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure.METHODS AND RESULTS:The FIBROTARGETS consortium has merged data from 12 patient cohorts in a common database available to individual consortium partners. The database consists of >12 000 patients with a large spectrum of cardiovascular clinical phenotypes. It integrates community-based population cohorts, cardiovascular risk cohorts, and heart failure cohorts.CONCLUSIONS:The FIBROTARGETS biomarker programme is aimed at exploring fibrotic pathways allowing the bioprofiling of patients into specific 'fibrotic' phenotypes and identifying new therapeutic targets that will potentially enable the development of novel and tailored anti-fibrotic therapies for heart failure.

An excessive production of aldosterone influences outcome in patients with heart failure (HF) and in obese patients. Findings from laboratory studies suggest that chronic aldosterone blockade maybe more beneficial in abdominally obese HF‐prone rats. In the current study, we investigated if the clinical response to a mineralocorticoid receptor antagonist in mildly symptomatic HF patients varied by abdominal obesity.