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Aims: We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI)., Methods and Results: HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow-up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between-group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase-7 (MMP-7), galectin-4 (GAL4), plasminogen activator inhibitor 1 (PAI-1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP-7, neurotrophin-3 (NT3), pulmonary surfactant-associated protein D (PSPD), and lower plasma tumour necrosis factor-related activation-induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months., Conclusions: In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Myocardial infarction (MI) is among the commonest attributable risk factors for heart failure (HF). We compared clinical characteristics associated with the progression to HF in patients with or without a history of MI in the HOMAGE cohort and validated our results in UK Biobank., Methods and Results: During a follow-up of 5.2 (3.5-5.9) years, 177 (2.4%) patients with prior MI and 370 (1.92%) patients without prior MI experienced HF onset in the HOMAGE cohort (n = 26 478, history of MI: n = 7241). Older age, male sex and higher heart rate were significant risk factors of HF onset in patients with and without prior MI. Lower renal function was more strongly associated with HF onset in patients with prior MI. Higher body mass index (BMI), systolic blood pressure and blood glucose were significantly associated with HF onset only in patients without prior MI (all p for interactions <0.05). In the UK Biobank (n = 500 001, history of MI: n = 4555), higher BMI, glycated haemoglobin, diabetes and hypertension had a stronger association with HF onset in participants without prior MI compared to participants with MI (all p for interactions <0.05)., Conclusion: The importance of clinical risk factors associated with HF onset is dependent on whether the patient has had a prior MI. Diabetes and hypertension are associated with new-onset HF only in the absence of MI history. Patients may benefit from targeted risk management based on MI history., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.

Optimal healing after myocardial infarction requires not only the induction of inflammation, but also its timely resolution. In patients, 30 days post myocardial infarction, circulating monocytes have increased expression of Semaphorin3A (Sema3A) as compared to directly after admission. This increased expression coincides with increased expression of Cx3CR1-a marker of non-classical monocytes that are important for immune resolution hence proper wound healing. In mice, the expression of Sema3A also increases in response to myocardial ischemia being expressed by infiltrating leukocytes. Comparing Sema3A heterozygote (HZ) and wild type (WT) mice post myocardial infarction, revealed increased presence of leukocytes in the cardiac tissues of HZ mice as compared to WT, with no differences in capillary density, collagen deposition, cardiomyocyte surface area, chemokine-or adhesion molecules expression. Whilst infarct sizes were similar 14 days after myocardial infarction in both genotypes, Sema3A HZ mice had thinner infarcts and reduced cardiac function as compared to their WT littermates. In vitro experiments were conducted to study the role of Sema3A in inflammation and resolution of inflammation as a potential explanation for the differences in leukocyte recruitment and cardiac function observed in our in vivo experiments. Here, recombinant Sema3A protein was able to affect the pro-inflammatory state of cultured bone marrow derived macrophages. First, the pro-inflammatory state was altered by the induced apoptosis of classical macrophages in the presence of Sema3A. Second, Sema3A promoted the polarization of classical macrophages to resolution-phase macrophages and enhanced their efferocytotic ability, findings that were reflected in the infarcted cardiac tissue of the Sema3A HZ mice. Finally, we demonstrated that besides promoting resolution of inflammation, Sema3A was also able to retard the migration of monocytes to the myocardium. Collectively our data demonstrate that Sema3A reduces cardiac inflammation and improves cardiac function after myocardial infarction by promoting the resolution of inflammation.

Objective: Although lymphocytic myocarditis (LM) clinically can mimic myocardial infarction (MI), they are regarded as distinct clinical entities. However, we observed a high prevalence (32%) of recent MI in patients diagnosed post-mortem with LM. To investigate if LM changes coronary atherosclerotic plaque, we analyzed in autopsied hearts the inflammatory infiltrate and stability in coronary atherosclerotic lesions in patients with LM and/or MI., Methods: The three main coronary arteries were isolated at autopsy of patients with LM, with MI of 3-6h old, with LM and MI of 3-6h old (LM+MI) and controls. In tissue sections of atherosclerotic plaque-containing coronary segments inflammatory infiltration, plaque stability, intraplaque hemorrhage and thrombi were determined via (immuno)histological criteria., Results: In tissue sections of those coronary segments the inflammatory infiltrate was found to be significantly increased in patients with LM, LM+MI and MI compared with controls. This inflammatory infiltrate consisted predominantly of macrophages and neutrophils in patients with only LM or MI, of lymphocytes in LM+MI and MI patients and of mast cells in LM+MI patients. Moreover, in LM+MI and MI patients this coincided with an increase of unstable plaques and thrombi. Finally, LM and especially MI and LM+MI patients showed significantly increased intraplaque hemorrhage., Conclusions: This study demonstrates prevalent co-occurrence of LM with a very recent MI at autopsy. Moreover, LM was associated with remodeling and inflammation of atherosclerotic plaques indicative of plaque destabilization pointing to coronary spasm, suggesting that preexistent LM, or its causes, may facilitate the development of MI., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Renal impairment is a major risk factor for mortality in various populations. Three formulas are frequently used to assess both glomerular filtration rate (eGFR) or creatinine clearance (CrCl) and mortality prediction: body surface area adjusted-Cockcroft-Gault (CG-BSA), Modification of Diet in Renal Disease Study (MDRD4), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The CKD-EPI is the most accurate eGFR estimator as compared to a "gold-standard"; however, which of the latter is the best formula to assess prognosis remains to be clarified. This study aimed to compare the prognostic value of these formulas in predicting the risk of cardiovascular mortality (CVM) in population-based, cardiovascular risk, heart failure (HF) and post-myocardial infarction (MI) cohorts., Methods: Two previously published cohorts of pooled patient data derived from the partners involved in the HOMAGE-consortium and from four clinical trials - CAPRICORN, EPHESUS, OPTIMAAL and VALIANT - the high risk MI initiative, were used. A total of 54,111 patients were included in the present analysis: 2644 from population-based cohorts; 20,895 from cardiovascular risk cohorts; 1801 from heart failure cohorts; and 28,771 from post-myocardial infarction cohorts. Participants were patients enrolled in the respective cohorts and trials. The primary outcome was CVM., Results: All formulas were strongly and independently associated with CVM. Lower eGFR/CrCl was associated with increasing CVM rates for values below 60 mL/min/m 2 . Categorical renal function stages diverged in a more pronounced manner with the CG-BSA formula in all populations (higher χ 2 values), with lower stages showing stronger associations. The discriminative improvement driven by the CG-BSA formula was superior to that of MDRD4 and CKD-EPI, but remained low overall (increase in C-index ranging from 0.5 to 2 %) while not statistically significant in population-based cohorts. The integrated discrimination improvement and net reclassification improvement were higher (P < 0.05) for the CG-BSA formula compared to MDRD4 and CKD-EPI in CV risk, HF and post-MI cohorts, but not in population-based cohorts. The CKD-EPI formula was superior overall to MDRD4., Conclusions: The CG-BSA formula was slightly more accurate in predicting CVM in CV risk, HF, and post-MI cohorts (but not in population-based cohorts). However, the CG-BSA discriminative improvement was globally low compared to MDRD4 and especially CKD-EPI, the latter offering the best compromise between renal function estimation and CVM prediction.

Background: Von Willebrand A domain Related Protein (WARP), is a recently identified extracellular matrix protein. Based upon its involvement in matrix biology and its expression in the heart, we hypothesized that WARP regulates cardiac remodeling processes in the post-infarct healing process., Methods and Results: In the mouse model of myocardial infarction (MI), WARP expression increased in the infarcted area 3-days post-MI. In the healthy myocardium WARP localized with perlecan in the basement membrane, which was disrupted upon injury. In vitro studies showed high expression of WARP by cardiac fibroblasts, which further increases upon TGFβ stimulation. Furthermore, WARP expression correlated with aSMA and COL1 expression, markers of fibroblast to myofibroblast transition, in vivo and in vitro. Finally, WARP knockdown in vitro affected extra- and intracellular basic fibroblast growth factor production in myofibroblasts. To investigate the function for WARP in infarction healing, we performed an MI study in WARP knockout (KO) mice backcrossed more than 10 times on an Australian C57Bl/6-J background and bred in-house, and compared to wild type (WT) mice of the same C57Bl/6-J strain but of commercial European origin. WARP KO mice showed no mortality after MI, whereas 40% of the WT mice died due to cardiac rupture. However, when WARP KO mice were backcrossed on the European C57Bl/6-J background and bred heterozygous in-house, the previously seen protective effect in the WARP KO mice after MI was lost. Importantly, comparison of the cardiac response post-MI in WT mice bred heterozygous in-house versus commercially purchased WT mice revealed differences in cardiac rupture., Conclusion: These data demonstrate a redundant role for WARP in the wound healing process after MI but demonstrate that the continental/breeding/housing origin of mice of the same C57Bl6-J strain is critical in determining the susceptibility to cardiac rupture and stress the importance of using the correct littermate controls.

Aim: Heart disease is recognized as a consequence of dysregulation of cardiac gene regulatory networks. Previously, unappreciated components of such networks are the long non-coding RNAs (lncRNAs). Their roles in the heart remain to be elucidated. Thus, this study aimed to systematically characterize the cardiac long non-coding transcriptome post-myocardial infarction and to elucidate their potential roles in cardiac homoeostasis., Methods and Results: We annotated the mouse transcriptome after myocardial infarction via RNA sequencing and ab initio transcript reconstruction, and integrated genome-wide approaches to associate specific lncRNAs with developmental processes and physiological parameters. Expression of specific lncRNAs strongly correlated with defined parameters of cardiac dimensions and function. Using chromatin maps to infer lncRNA function, we identified many with potential roles in cardiogenesis and pathological remodelling. The vast majority was associated with active cardiac-specific enhancers. Importantly, oligonucleotide-mediated knockdown implicated novel lncRNAs in controlling expression of key regulatory proteins involved in cardiogenesis. Finally, we identified hundreds of human orthologues and demonstrate that particular candidates were differentially modulated in human heart disease., Conclusion: These findings reveal hundreds of novel heart-specific lncRNAs with unique regulatory and functional characteristics relevant to maladaptive remodelling, cardiac function and possibly cardiac regeneration. This new class of molecules represents potential therapeutic targets for cardiac disease. Furthermore, their exquisite correlation with cardiac physiology renders them attractive candidate biomarkers to be used in the clinic., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Rationale: To maintain cardiac mechanical and structural integrity after an ischemic insult, profound alterations occur within the extracellular matrix. Osteoglycin is a small leucine-rich proteoglycan previously described as a marker of cardiac hypertrophy., Objective: To establish whether osteoglycin may play a role in cardiac integrity and function after myocardial infarction (MI)., Methods and Results: Osteoglycin expression is associated with collagen deposition and scar formation in mouse and human MI. Absence of osteoglycin in mice resulted in significantly increased rupture-related mortality with tissue disruption, intramyocardial bleeding, and increased cardiac dysfunction, despite equal infarct sizes. Surviving osteoglycin null mice had greater infarct expansion in comparison with wild-type mice because of impaired collagen fibrillogenesis and maturation in the infarcts as revealed by electron microscopy and collagen polarization. Absence of osteoglycin did not affect cardiomyocyte hypertrophy in the remodeling remote myocardium. In cultured fibroblasts, osteoglycin knockdown or supplementation did not alter transforming growth factor-β signaling. Adenoviral overexpression of osteoglycin in wild-type mice significantly improved collagen quality, thereby blunting cardiac dilatation and dysfunction after MI. In osteoglycin null mice, adenoviral overexpression of osteoglycin was unable to prevent rupture-related mortality because of insufficiently restoring osteoglycin protein levels in the heart. Finally, circulating osteoglycin levels in patients with heart failure were significantly increased in the patients with a previous history of MI compared with those with nonischemic heart failure and correlated with survival, left ventricular volumes, and other markers of fibrosis., Conclusions: Increased osteoglycin expression in the infarct scar promotes proper collagen maturation and protects against cardiac disruption and adverse remodeling after MI. In human heart failure, osteoglycin is a promising biomarker for ischemic heart failure., (© 2014 American Heart Association, Inc.)

Background: Rapid and correct diagnosis of acute myocardial infarction (MI) has an important impact on patient treatment and prognosis. We compared the diagnostic performance of high-sensitivity cardiac troponin T (hs-cTnT) and cardiac enriched microRNAs (miRNAs) in patients with MI., Methods: Circulating concentrations of cardiac-enriched miR-208b and miR-499 were measured by quantitative PCR in a case-control study of 510 MI patients referred for primary mechanical reperfusion and 87 healthy controls., Results: miRNA-208b and miR-499 were highly increased in MI patients (>10(5)-fold, P < 0.001) and nearly undetectable in healthy controls. Patients with ST-elevation MI (n= 397) had higher miRNA concentrations than patients with non-ST-elevation MI (n = 113) (P < 0.001). Both miRNAs correlated with peak concentrations of creatine kinase and cTnT (P < 10(-9)). miRNAs and hs-cTnT were already detectable in the plasma 1 h after onset of chest pain. In patients who presented <3 h after onset of pain, miR-499 was positive in 93% of patients and hs-cTnT in 88% of patients (P= 0.78). Overall, miR-499 and hs-cTnT provided comparable diagnostic value with areas under the ROC curves of 0.97. The reclassification index of miR-499 to a clinical model including several risk factors and hs-cTnT was not significant (P = 0.15)., Conclusion: Circulating miRNAs are powerful markers of acute MI. Their usefulness in the establishment of a rapid and accurate diagnosis of acute MI remains to be determined in unselected populations of patients with acute chest pain.

Excessive activation of the β-adrenergic, angiotensin II (Ang II) and aldosterone signaling pathways promotes mortality after myocardial infarction, and antagonists targeting these pathways are core therapies for treating this condition. Catecholamines and Ang II activate the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), the inhibition of which prevents isoproterenol-mediated and Ang II-mediated cardiomyopathy. Here we show that aldosterone exerts direct toxic actions on myocardium by oxidative activation of CaMKII, causing cardiac rupture and increased mortality in mice after myocardial infarction. Aldosterone induces CaMKII oxidation by recruiting NADPH oxidase, and this oxidized and activated CaMKII promotes matrix metalloproteinase 9 (MMP9) expression in cardiomyocytes. Myocardial CaMKII inhibition, overexpression of methionine sulfoxide reductase A (an enzyme that reduces oxidized CaMKII) or NADPH oxidase deficiency prevented aldosterone-enhanced cardiac rupture after myocardial infarction. These findings show that oxidized myocardial CaMKII mediates the cardiotoxic effects of aldosterone on the cardiac matrix and establish CaMKII as a nodal signal for the neurohumoral pathways associated with poor outcomes after myocardial infarction.

The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell-matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC-null infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor beta (TGF)-mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-beta rescued cardiac rupture in SPARC-null mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.

Background: The cell-associated proteoglycan syndecan-1 (Synd1) closely regulates inflammation and cell-matrix interactions during wound healing and tumorigenesis. The present study investigated whether Synd1 may also regulate cardiac inflammation, matrix remodeling, and function after myocardial infarction (MI)., Methods and Results: First, we showed increased protein and mRNA expression of Synd1 from 24 hours on, reaching its maximum at 7 days after MI and declining thereafter. Targeted deletion of Synd1 resulted in increased inflammation and accelerated, yet functionally adverse, infarct healing after MI. In concordance, adenoviral gene expression of Synd1 protected against exaggerated inflammation after MI, mainly by reducing transendothelial adhesion and migration of leukocytes, as shown in vitro. Increased inflammation in the absence of Synd1 resulted in increased monocyte chemoattractant protein-1 expression, increased activity of matrix metalloproteinase-2 and -9, and decreased activity of tissue transglutaminase, associated with increased collagen fragmentation and disorganization. Exaggerated inflammation and adverse matrix remodeling in the absence of Synd1 increased cardiac dilatation and impaired systolic function, whereas gene overexpression of Synd1 reduced inflammation and protected against cardiac dilatation and failure., Conclusions: Increased expression of Synd1 in the infarct protects against exaggerated inflammation and adverse infarct healing, thereby reducing cardiac dilatation and dysfunction after MI in mice.

The post-myocardial infarction wound repair process involves temporarily overlapping phases that include inflammation, formation of granulation tissue, scar formation, and overall left ventricle (LV) remodelling. The myocardial extracellular matrix (ECM) plays an important role in maintaining the structural and functional integrity of the heart and is centrally involved in wound repair post-myocardial infarction (MI). The main proteolytic system involved in the degradation of the ECM in the heart is the matrix metalloproteinase (MMPs) system. The present review will focus on the importance of the unique temporal and spatial window of MMPs and their inhibitors (TIMPs) within the different wound healing phases post-MI. It summarizes (1) the MMP/TIMP levels at different time points post-MI, (2) the alterations seen in post-MI healing in genetically modified mice, and (3) the effects and limitations of therapeutic MMP-inhibition post-MI.

Matricellular proteins are extracellular matrix proteins that modulate cell-matrix interactions and cell function, and do not seem to have a direct structural role. The family includes tenascin-C (TN-C), tenascin-X (TN-X), osteonectin, osteopontin, thrombospondin-1 (TSP1) and thrombospondin-2 (TSP2). Expression of matricellular proteins is high during embryogenesis, but almost absent during normal postnatal life. Interestingly, it re-appears in response to injury. Left ventricular remodeling is a complicated process that occurs in the stressed heart, and is still not completely understood. Several members of the matricellular protein family, like tenascin-C, osteopontin, and osteonectin are up-regulated after cardiac injury. Therefore, this group of proteins may have crucial functions in the heart coping with stress. This review will focus on the expression, regulation and function of these matricellular proteins, and will discuss the crucial functions that these proteins might exert during remodeling of the stressed heart.

The plasminogen system plays an important role in the proteolytic degradation of extracellular matrices during wound healing. In the present study we investigated the impact of the plasminogen system on cardiac wound healing and function after myocardial infarction. Myocardial infarction was induced in plasminogen-deficient mice (Plg-/-) and in wild-type controls (Plg+/+). Structural analysis 1, 2, and 5 weeks after infarction revealed that infarct healing was virtually abolished in Plg-/- mice, indicating that the plasminogen system is required for the repair process of the heart after infarction. In the absence of plasminogen, inflammatory cells did not migrate into the infarcted myocardium. Necrotic cardiomyocytes were not removed and the formation of granulation tissue and fibrous tissue did not occur. In these non-healing infarcted hearts, LV dilatation was not altered. In addition, gelatinolytic activity of MMP-2 and MMP-9 was depressed in the Plg-/- infarcted hearts, suggesting that the plasmin effect on infarct healing may be mediated by MMPs. Surprisingly, cardiac function was only attenuated to a rather small extent in the Plg-/- infarcted mice when compared to the wild-types. This study provides direct prove that plasmin-mediated proteolysis plays a central role in cardiac wound healing after myocardial infarction in mice.

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.

An abstract of the study "Increased Expression of Syndecan-1 Protects Against Cardiac Dilatation and Dysfunction After Myocardial Infarction," by D. Vanhoutte and colleagues is presented.