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Background Inflammation has emerged as a new treatment target in patients with coronary artery disease, and inflammation seems to play an important role in the ischemia/reperfusion injury in ST-elevation myocardial infarction (STEMI). The pro-inflammatory cytokine interleukin-6 (IL-6) has been shown to be associated with myocardial injury and poor prognosis in patients with STEMI. Purpose The aim of the study was to further elucidate possible associations between the IL-6 trans-signalling system and final infarct size, myocardial function, adverse remodelling, and future cardiovascular events in patients with STEMI. Methods A total of 272 patients with first-time STEMI included in the POSTEMI study on ischaemic postconditioning, with symptom duration Results There was a significant increase in IL-6 levels from admission to day 1 with a subsequent decline from day 1 to 4 months (Figure 1A). No significant change in IL-6R levels were found from admission to day 1 (Figure 1B). There was no difference between patients treated by postconditioning compared to routine PCI. High levels of IL-6 (> median) at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF) measured by CMR. Additionally, high levels of IL-6 (> median) at day 1 were associated with lower myocardial salvage, more presence of microvascular obstruction and larger increase in indexed LV end diastolic volume (LVEDVi). IL-6R measured during hospitalisation was significantly associated with change in LVEDVi, but did not associate with infarct size, LVEF or myocardial salvage. High levels of IL-6 (>75th percentile) at all sampling points were associated with an increased risk of having an adverse clinical event during the first year and with long-term all-cause mortality (Figure 2), whereas there was no association between IL-6R and adverse clinical events. Conclusion Patients with high IL-6 levels during the acute phase of STEMI had larger infarct size, reduced myocardial salvage, reduced LV function and worse clinical outcome than patients with lower levels of IL-6. High levels of IL-6 measured after 4 months were associated with larger infarct size, reduced LVEF and increased all-cause mortality. IL-6R was significantly associated with increase in LVEDVi. The results add important information to the role of IL-6 in myocardial injury in acute STEMI and the IL-6 pathway as a potential treatment target. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Stein Erik Hagen Foundation for Clinical Heart Research, Oslo, Norway. Figure 1Figure 2

The wound healing that follows myocardial infarction is a complex process involving multiple mechanisms, such as inflammation, angiogenesis and fibrosis. In the last two decades, the involvement of WNT signaling has been extensively studied and effects on virtually all aspects of this wound healing have been reported. However, as often is the case in a newly emerging field, inconsistent and sometimes even contradictory findings have been reported. The aim of this systematic review is to provide a comprehensive overview of studies in which the effect of interventions in WNT signaling were investigated in in vivo models of cardiac injury. To this end, we used different search engines to perform a systematic search of the literature using the key words "WNT and myocardial and infarction". We categorized the interventions according to their place in the WNT signaling pathway (ligand, receptor, destruction complex or nuclear level). The most consistent improvements of the wound healing response were observed in studies in which the acylation of WNT proteins was inhibited by administering porcupine inhibitors, by inhibiting of the downstream glycogen synthase kinase-3 beta (GSK3 beta) and by intervening in the beta-catenin-mediated gene transcription. Interestingly, in several of these studies, evidence was presented for activation of cardiomyocyte proliferation around the infarct area. These findings indicate that inhibition of WNT signaling can play a valuable role in the repair of cardiac injury, thereby improving cardiac function and preventing the development of heart failure.

The wound healing that follows myocardial infarction is a complex process involving multiple mechanisms, such as inflammation, angiogenesis and fibrosis. In the last two decades, the involvement of WNT signaling has been extensively studied and effects on virtually all aspects of this wound healing have been reported. However, as often is the case in a newly emerging field, inconsistent and sometimes even contradictory findings have been reported. The aim of this systematic review is to provide a comprehensive overview of studies in which the effect of interventions in WNT signaling were investigated in in vivo models of cardiac injury. To this end, we used different search engines to perform a systematic search of the literature using the key words “WNT and myocardial and infarction”. We categorized the interventions according to their place in the WNT signaling pathway (ligand, receptor, destruction complex or nuclear level). The most consistent improvements of the wound healing response were observed in studies in which the acylation of WNT proteins was inhibited by administering porcupine inhibitors, by inhibiting of the downstream glycogen synthase kinase-3β (GSK3β) and by intervening in the β-catenin-mediated gene transcription. Interestingly, in several of these studies, evidence was presented for activation of cardiomyocyte proliferation around the infarct area. These findings indicate that inhibition of WNT signaling can play a valuable role in the repair of cardiac injury, thereby improving cardiac function and preventing the development of heart failure.

Born in Salzwedel, East Germany, Matthias Nahrendorf entered adulthood just as the Iron Curtain was lifting in Eastern Europe. He earned his medical degree and PhD in cardiovascular biology at Heidelberg University, and completed his residency plus fellowships in internal medicine and cardiovascular imaging at University of Wuerzburg. In 2004, a postdoctoral position at Massachusetts General Hospital’s Center for Molecular Imaging Research brought Nahrendorf to Boston. He is now a principal investigator at MGH’s Center for Systems Biology and director of the hospital’s Mouse Imaging Program. Nahrendorf, 45, is pursuing a deeper understanding of the consequences of ischemic injury, especially regarding how monocytes/macrophages impact acute healing and scar development,1–3 and how an imbalance in the process fuels prolonged inflammation and then heart failure. An associate professor of radiology at Harvard Medical School, Nahrendorf and his collaborators are also developing molecular imaging tools to noninvasively study regulators of heart failure biology and infarct healing processes.4–6 A long-term goal of the work is to devise new therapies for ischemic injury that reduce the action of inflammatory cells to what is necessary only to promote healthy healing, Nahrendorf says. If that could be achieved, “Ideally we wouldn’t have heart failure anymore.” I have one brother, he’s younger, and my parents. It was a pretty sheltered childhood. I grew up in Magdeburg, and the (Berlin) Wall came down when I was 18. Army service was compulsory in East Germany. So I spent one year in the army and then Germany reunited, so I was free to go wherever I wanted. My parents are both doctors. My dad is a cardiologist, my mom a pediatrician. I had a happy childhood. They were never telling me what to do. But I was obviously influenced by their jobs. They talked about …

Magnetic resonance imaging (MRI) has been proven to reliably assess regional perfusion and left ventricular (LV) function of microembolized myocardium. The visibility of microinfarct on delayed enhancement MRI (DE-MRI) is limited and dependent on technical and biological issues. Furthermore, MRI underestimates total microinfarct size compared with microscopy. MRI studies revealed that the presence of microemboli in pre-existing acute infarct delays infarct healing and magnifies LV remodeling. Discrimination of acute from chronic microinfarct is based on presence of inflammatory cells, edema and scar tissue, respectively. These noninvasive findings highlight the importance of prognostic utility of MRI and warrant larger clinical studies or registries to evaluate the significance of presence of focal microinfarct. Serial microscopic studies revealed that intravascular microemboli migrate into the extravascular space and this migration process is a function of time. This phenomenon may limit the use of microemboli therapy in occluding hemorrhagic blood vessels or treating tumors. Despite current standard of care, existing methods and therapies do not prevent coronary embolization nor reverse their deleterious effects.

Cardiac Magnetic Resonance (CMR), thanks to high spatial resolution and absence of ionizing radiation, has been widely used in myocardial infarction (MI) assessment to evaluate cardiac structure, function, perfusion and viability. Nevertheless, it suffers from limitations in tissue and assessment of myocardial pathophysiological changes subsequent to MI. In this issue, nanoparticle-based contrast agents offer the possibility to track biological processes at cellular and molecular level underlying the various phases of MI, infarct healing and tissue repair. In this paper, first we examine the conventional CMR protocol and its findings in MI patients. Next, we looked at how nanoparticles can help in the imaging of MI and give an overview of the major approaches currently explored. Based on the presentation of successful nanoparticle applications as contrast agents (CAs) in preclinical and clinical models, we discuss promises and outstanding challenges facing the field of CMR in MI, their translational potential and clinical application.

Myocardial infarct expansion has been associated with an increased risk of infarct rupture and progression to heart failure, motivating therapies such as infarct restraint and polymer injection that aim to limit infarct expansion. However, an exhaustive review of quantitative studies of infarct remodeling reveals that only half found chronic in-plane expansion, and many reported in-plane compaction. Using a finite-element model, we demonstrate that the balance between scar stiffening due to collagen accumulation and increased wall stresses due to infarct thinning can produce either expansion or compaction in the pressurized heart – potentially explaining variability in the literature – and that loaded dimensions are much more sensitive to changes in thickness than in stiffness. Our analysis challenges the concept that in-plane expansion is a central feature of post-infarction remodeling; rather, available data suggest that radial thinning is the dominant process during infarct healing and may be an attractive therapeutic target.

Effects of white wine (WW) consumption on the expression of inflammatory markers/mediators (MMP-2, MMP-9, NF-ĸB p65 and TGF-β1) in myocardial tissue after experimentally induced permanent myocardial ischemia was investigated. Male Sprague-Dawley rats were given either a combination of WW and water or only water, for 28 days. After coronary ligation, animals were left to survive for 24 hours. Three representative areas: infarct/ischemic, peri-infarct/border zone, and control/non-ischemic zones were analyzed for expression of immunoreactivity by measuring the threshold area % of signal density. For MMP-9, significantly smaller expression was found in all 3 zones of wine drinking animals (P < 0.001). There was no difference in MMP-2 immunoreactivity between the 2 groups, except in peri-infarct zones, where the signal was significantly decreased (P < 0.001). The same pattern of expression was found for the NF-κB p65 signal, although no differences between experimental groups were observed for TGF-β1. White wine consumption decreases the expression of the 3 investigated inflammatory markers/mediators in the peri-infarct zone, suggesting its significant modulatory effect. For MMP-9 and MMP-2, expression was similar to the effect of postischemic reperfusion. No effect on TGF-β1 was observed, highlighting its role in being the master-switch, changing from the inflammatory to the proliferative stage of infarct healing.

Despite early revascularization, remodeling and dysfunction of the left ventricle (LV) after acute myocardial infarction (AMI) remain important therapeutic targets. Intermittent pacing therapy (IPT) of the LV can limit infarct size, when applied during early reperfusion. However, the effects of IPT on post-AMI LV remodeling and infarct healing are unknown. We therefore investigated the effects of IPT on global LV remodeling and infarct geometry in swine with a 3-day old AMI. For this purpose, fifteen pigs underwent 2 h ligation of the left circumflex coronary artery followed by reperfusion. An epicardial pacing lead was implanted in the peri-infarct zone. After three days, global LV remodeling and infarct geometry were assessed using magnetic resonance imaging (MRI). Animals were stratified into MI control and IPT groups. Thirty-five days post-AMI, follow-up MRI was obtained and myofibroblast content, markers of extracellular matrix (ECM) turnover and Wnt/frizzled signaling in infarct and non-infarct control tissue were studied. Results showed that IPT had no significant effect on global LV remodeling, function or infarct mass, but modulated infarct healing. In MI control pigs, infarct mass reduction was principally due to a 26.2 ± 4.4% reduction in infarct thickness (P ≤ 0.05), whereas in IPT pigs it was mainly due to a 35.7 ± 4.5% decrease in the number of infarct segments (P ≤ 0.05), with no significant change in infarct thickness. Myofibroblast content of the infarct zone was higher in IPT (10.9 ± 2.1%) compared to MI control (5.4 ± 1.6%; P ≤ 0.05). Higher myofibroblast presence did not coincide with alterations in expression of genes involved in ECM turnover or Wnt/frizzled signaling at 5 weeks follow-up. Taken together, IPT limited infarct expansion and altered infarct composition, showing that IPT influences remodeling of the infarct zone, likely by increasing regional myofibroblast content. Electronic supplementary material The online version of this article (doi:10.1007/s00395-017-0616-3) contains supplementary material, which is available to authorized users.

Rationale:Macrophages are involved in wound healing after myocardial infarction (MI). The role of Dectin-2, a pattern recognition receptor mainly expressed on myeloid cells, in the infarct healing remains unknown.Objective:The aim of this study is to determine whether Dectin-2 signaling is involved in the healing process and cardiac remodeling after MI and to elucidate the underlying molecular mechanisms.Methods and Results:In a mouse model of permanent coronary ligation, Dectin-2, mainly expressed in macrophages, was shown to be increased in the early phase after MI. Dectin-2 knockout mice showed an improvement in the infarct healing and cardiac remodeling, compared with wild-type mice, which was demonstrated by significantly lower mortality because of cardiac rupture, increased wall thickness, and better cardiac function. Increased expression of α-smooth muscle actin and collagen I/III was observed, whereas the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 were decreased in the hearts of Dectin-2 knockout mice after MI. Dectin-2 deficiency inhibited the rate of apoptotic and necrotic cell death. However, Dectin-2 did not affect immune cell infiltration and macrophage polarization, but it led to a stronger activation of the Th1/interferon-γ immune reaction, through the enhancement of interleukin-12 production in the heart. Interferon-γ was shown to downregulate transforming growth factor-β–induced expression of α-smooth muscle actin and collagen I/III in isolated cardiac fibroblasts, leading to a decrease in migration and myofibroblast differentiation. Finally, Dectin-2 knockout improved myocardial ischemia–reperfusion injury and infarct healing.Conclusions:Dectin-2 leads to an increase in cardiac rupture, impairs wound healing, and aggravates cardiac remodeling after MI through the modulation of Th1 differentiation.

Introduction: Cardiac remodeling post myocardial infarction (MI) can be a critical determinant of outcome for patients with MI. Well-contained inflammation results in successful infarct healing while excessive inflammation cause adverse remodeling which leads to heart failure. Macrophages are important participants in inflammation, helping resolve pro-inflammatory reactions and performing reparative processes. Reprogramming macrophages towards a resolving and reparative phenotype is a potential therapeutic approach. We hypothesized that IL4/IL13-induced, alternatively activated macrophages (M2) have an important role in cardiac remodeling post-MI, and we tested this hypothesis in a mouse model of MI using myeloid-specific IL4 receptor α knockout mice (MyIL4RaKO). Methods: MyIL4RaKO mice were generated using IL4Ra flox/flox ;LysM-Cre. MI was induced by ligating the left anterior descending coronary artery. Hearts were cut into 1mm sections, and then stained by tetrazolium chloride for infarct size measurement. Evenly spaced radians were taken through the infarct with the center of left ventricle in 5μm heart sections, and the average infarct thickness was calculated. qPCR was used to determine gene expression. Echocardiography was performed at baseline and 3 weeks post MI. Results: Initial infarct size was not affected by IL4Ra knockout but at 1-week post MI, infarct size of MyIL4RaKO mice (16.54 ± 2.433, n=11) was shown significantly smaller than that of FC mice (24.96 ± 2.005, n=15) showing changes in remodeling (p= 0.0129). Changes in remodeling continued and at 3-week post MI, infarct thickness of MyIL4RaKO mice (0.2171 ± 0.01053, n=6) was significantly increased, compared with that of FC mice (0.3508 ± 0.03629, n=8, p= 0.0094). These changes were accompanied by MyIL4RaKO mice also showed lower level of fibrosis markers: Col1A1 and Plod2. A significantly lower ejection fraction was observed in MyIL4RaKO mice (25.46 ± 3.749, n=5) compared with FC mice (37.90 ± 2.309, n=5) at 3 weeks (p= 0.0223). Conclusions: Myeloid-specific IL4Ra knockout results in alteration of remodeling, altered fibrosis and decreased cardiac function post MI, although the cardiac hypertrophy did not show significant change.

Follistatin‐like 1 (Fstl1) is a secreted protein that is acutely induced in heart following myocardial infarction (MI). In this study, we investigated cell type‐specific regulation of Fstl1 and its function in a murine model of MI. Fstl1 was robustly expressed in fibroblasts and myofibroblasts in the infarcted area compared to cardiac myocytes. The conditional ablation of Fstl1 in S100a4‐expressing fibroblast lineage cells (Fstl1‐cfKO mice) led to a reduction in injury‐induced Fstl1 expression and increased mortality due to cardiac rupture during the acute phase. Cardiac rupture was associated with a diminished number of myofibroblasts and decreased expression of extracellular matrix proteins. The infarcts of Fstl1‐cfKO mice displayed weaker birefringence, indicative of thin and loosely packed collagen. Mechanistically, the migratory and proliferative capabilities of cardiac fibroblasts were attenuated by endogenous Fstl1 ablation. The activation of cardiac fibroblasts by Fstl1 was mediated by ERK1/2 but not Smad2/3 signaling. This study reveals that Fstl1 is essential for the acute repair of the infarcted myocardium and that stimulation of early fibroblast activation is a novel function of Fstl1.

Effective management of healing and remodelling after myocardial infarction is an important problem in modern cardiology practice. We have recently shown that the level of infarct anisotropy is a critical determinant of heart function following a large anterior infarction, which suggests that therapeutic gains may be realized by controlling infarct anisotropy. However, factors regulating infarct anisotropy are not well understood. Mechanical, structural and chemical guidance cues have all been shown to regulate alignment of fibroblasts and collagen in vitro, and prior studies have proposed that each of these cues could regulate anisotropy of infarct scar tissue, but understanding of fibroblast behaviour in the complex environment of a healing infarct is lacking. We developed an agent-based model of infarct healing that accounted for the combined influence of these cues on fibroblast alignment, collagen deposition and collagen remodelling. We pooled published experimental data from several sources in order to determine parameter values, then used the model to test the importance of each cue for predicting collagen alignment measurements from a set of recent cryoinfarction experiments. We found that although chemokine gradients and pre-existing matrix structures had important effects on collagen organization, a response of fibroblasts to mechanical cues was critical for correctly predicting collagen alignment in infarct scar. Many proposed therapies for myocardial infarction, such as injection of cells or polymers, alter the mechanics of the infarct region. Our modelling results suggest that such therapies could change the anisotropy of the healing infarct, which could have important functional consequences. This model is therefore a potentially important tool for predicting how such interventions change healing outcomes.

Today, cardiovascular MRI (CMR) is widely used for diagnosis and therapeutic decision making in the setting of different cardiac diseases. CMR allows to analyse anatomical and functional parameters, and enables a non-invasive, accurate and repeatable assessment of changes in myocardial tissue. For example, contrast-enhanced CMR techniques such as late gadolinium enhancement (LGE) imaging enable an accurate, however, unspecific detection of myocardial damage, caused by myocardial infarction (MI). In addition, T2 and T2*-weighted CMR techniques allow to detect myocardial oedema as well as myocardial haemorrhage (in case of acute MI) and thereby provide additional information on infarct pathology and prediction of adverse outcome—at least in some cases. Regarding the initiation of timely and adequate therapy, diagnosis of myocardial inflammation in the early phase of heart disease—before the occurrence of structural changes in the myocardium—is crucial. Unfortunately, T2-weighted CMR techniques that promise to depict myocardial oedema as the first morphological change in the sequence of events have a limited sensitivity, and are questioned with regard to their diagnostic value by some groups.1 Also novel T2-mapping techniques promise an improved diagnostic yield, neither LGE-based imaging nor T2- and T2*-weighted imaging do allow a direct visualisation of infiltrating macrophages in the infarcted myocardium, but rather depict myocardial tissue changes that are ‘associated’ with or the consequence of ongoing myocardial inflammation and healing. Hence, new and more specific CMR tools are needed to improve both early diagnosis and specificity of diagnosis. From a clinical point of view, the opportunity to directly image infiltrating macrophages in the infarcted myocardium will be of broad diagnostic as well as therapeutic value since the extent and degree of myocardial disease might be monitored more accurately and the therapeutic success be assessed more appropriately.2 In this context, two distinct phases in the process of infarct healing were described recently3: …

To analyze the remodeling processes of the infarct territory in the time course of infarct healing.Serial late enhancement (LE) studies were performed in 30 patients following reperfused myocardial infarction (MI) in the first and second week post-MI and after 3 months. To characterize infarct remodeling over time, the following variables were derived and analyzed in a blinded fashion: Infarct size (IS, in mm(3)), maximum infarct thickness (IT(max), mm), mean infarct thickness (IT(mean), mm) and the variability of infarct thickness (VIT=IT(max)/IT(mean)). Further, a new parameter for the assessment of infarct remodeling, the infarct extent (IE, mm(2)) was computed. IE quantifies IS in two dimensions along the heart's circumferential and longitudinal directions. IS was divided by the IE to obtain IT(mean).Overall infarct thickness was highly variable. Infarct shrinkage due to infarct thinning and IE reduction was found in the first months of healing. IS, IT(mean) and IT(max) significantly decreased during follow-up. There was a less consistent change of the IE: IE decreased in 75% of all infarcts from the first week up to 3 months post-MI, whereas 25% of infarcts expanded. Infarct thinning was found in almost all patients (92%), hence occurring in patients with infarct expansion and in patients without infarct expansion.Infarct thinning and-to a lesser extent-IE reduction, contribute to infarct shrinkage in the time course of infarct healing. Infarct thinning may occur without infarct expansion.

To describe the time course of myocardial infarct (MI) healing and left ventricular (LV) remodelling and to assess factors predicting LV remodelling using cardiac MRI.In 58 successfully reperfused MI patients, MRI was performed at baseline, 4 months (4M), and 1 year (1Y) post MI RESULTS: Infarct size decreased between baseline and 4M (p0.001), but not at 1Y; i.e. 18 ± 11%, 12 ± 8%, 11 ± 6% of LV mass respectively; this was associated with LV mass reduction. Infarct and adjacent wall thinning was found at 4M, whereas significant remote wall thinning was measured at 1Y. LV end-diastolic and end-systolic volumes significantly increased at 1Y, p0.05 at 1Y vs. baseline and vs. 4M; this was associated with increased LV sphericity index. No regional or global LV functional improvement was found at follow-up. Baseline infarct size was the strongest predictor of adverse LV remodelling.Infarct healing, with shrinkage of infarcted myocardium and wall thinning, occurs early post-MI as reflected by loss in LV mass and adjacent myocardial remodelling. Longer follow-up demonstrates ongoing remote myocardial and ventricular remodelling. Infarct size at baseline predicts long-term LV remodelling and represents an important parameter for tailoring future post-MI pharmacological therapies designed to prevent heart failure.

Infarct healing is sought to be a dynamic process occurring in the subacute and chronic phase after ST-elevation myocardial infarction (STEMI) and is preferentially investigated by means of cardiac magnetic resonance (CMR) imaging. Previous studies indicate a reduction of infarct size (IS) during

After acute myocardial infarction (AMI), the recovery of perfusion in infarct area may lead to significant spontaneous infarct size (IS) reduction during the subsequent period. The natural course of infarct-healing process after reperfusion therapy has not been fully elucidated. In this study, we investigated the time course of the spontaneous infarct-healing process in patients with reperfused AMI.Fifty-two patients with AMI who underwent primary percutaneous intervention were included. IS was measured with single-photon emission tomography using Bull's eye method at 4th day, at 5th, and at 10th months. IS was expressed as a percentage of the total myocardium. IS decreased by 33.6% at 5th month when compared with 4th day IS (from 26.3% +/- 18.8% to 17.5% +/- 12.9%, P0.001, n = 44). At 10th month, mean IS decreased by 21% when compared with 5th month IS (from 15.89% +/- 12.65% to 12.53% +/- 9.35%, P = 0.007, n = 31) and 49% when compared with 4th day IS (24.02% +/- 17.67% to 12.53% +/- 9.35%, P0.001).Significant endogenous recovery of perfusion in the infarct area occurs at the long term in patients with reperfused AMI. Infarct healing is a dynamic and ongoing process and decrease in IS continues long term after reperfused AMI.

de Waard MC, Duncker DJ. Prior exercise improves survival, infarct healing, and left ventricular function after myocardial infarction. J Appl Physiol 107: 928-936, 2009; doi:10.1152/japplphysiol.91281.2008.-We investigated the effects of voluntary wheel running before an acute myocardial infarction (MI) on survival, left ventricular (LV) remodeling and dysfunction and whether exercise before and after MI provides superior protection compared with either exercise intervention alone. After 2 wk of voluntary wheel running or sedentary housing, MI was induced in C57B1/6 mice, after which exercise was stopped (EX-MI-SED and SED-MI-SED groups, where EX is exercise and SED is sedentary) or continued (EX-MI-EX and SED-MI-EX groups) for a period of 8 wk. Exercise after MI in SED-MI-EX mice had no effect on survival, the area of infarction, and global LV remodeling, but attenuated fibrosis and apoptosis in the remote myocardium and blunted LV dysfunction and pulmonary congestion compared with SED-MI-SED mice. Exercise before MI in both EX-MI-SED and EX-MI-EX mice decreased post-MI mortality compared with both SED-MI-SED and SED-MI-EX mice. Furthermore, in both pre-MI exercise groups, the infarct area was thicker, whereas interstitial fibrosis and apoptosis in the remote LV myocardium were blunted. In contrast, the ameliorating effects of either pre-MI or post-MI exercise alone on LV dysfunction were lost in EX-MI-EX mice, which may in part be related to the increased daily exercise distance in the first week post-MI in EX-MI-EX versus SED-MI-EX mice. In conclusion, exercise before or after MI blunted LV dysfunction, whereas only exercise before MI improved survival. These findings suggest that even when regular physical activity fails to prevent an acute MI, it can still act to improve cardiac function and survival after MI.

Background—Postinfarction cardiac repair is regulated through timely activation and repression of inflammatory pathways, followed by transition to fibrous tissue deposition and formation of a scar. The transforming growth factor-β/Smad3 pathway is activated in healing infarcts and may regulate cellular events critical for the inflammatory and the fibrotic responses.Methods and Results—We examined the effects of Smad3 gene disruption on infarct healing and the pathogenesis of cardiac remodeling. In the absence of injury, Smad3-null hearts had comparable function to and similar morphology as wild-type hearts. Smad3-null animals had suppressed peak chemokine expression and decreased neutrophil recruitment in the infarcted myocardium but showed timely repression of inflammatory gene synthesis and resolution of the inflammatory infiltrate. Although myofibroblast density was higher in Smad3-null infarcts, interstitial deposition of collagen and tenascin-C in the remodeling myocardium was markedly reduced. Compared with wild-type animals, Smad3−/−mice exhibited decreased dilative remodeling and attenuated diastolic dysfunction; however, infarct size was comparable between groups. Transforming growth factor-β–mediated induction of procollagen type III and tenascin-C in isolated cardiac fibroblasts was dependent on Smad3, which suggests that decreased fibrotic remodeling in infarcted Smad3-null hearts may be due to abrogation of the profibrotic transforming growth factor-β responses.Conclusions—Smad3 loss does not alter the time course of resolution of inflammation in healing infarcts, but it prevents interstitial fibrosis in the noninfarcted myocardium and attenuates cardiac remodeling. Thus, the Smad3 cascade may be a promising therapeutic target for the treatment of myocardial infarction.

Although large collagen fibers in myocardial infarct scar are highly organized, little is known about mechanisms controlling this organization. The preexisting extracellular matrix may act as a scaffold along which fibroblasts migrate. Conversely, deformation within the ischemic area could guide fibroblasts so new collagen is oriented to counteract the stretch. To investigate these potential mechanisms, we infarcted three groups of pigs. Group 1 served as infarct controls. Group 2 had the endocardium slit longitudinally to alter local systolic deformation. Group 3had a plug sectioned from ischemic tissue and rotated 90°. The slit altered systolic deformation in the infarcted tissue, changing circumferential strain from expansion to compression and increasing radial strain and shears and the variability of collagen fiber angles but not the mean angle. In the plug pigs, when deformation, matrix orientation, and continuity are altered in the infarct area, the result is complete disarray in the organization of collagen within the infarct scar.

Wnt/frizzled signaling in the adult heart is quiescent under normal conditions; however it is reactivated after myocardial infarction (MI). Any intervention at the various levels of this pathway can modulate its signaling. Several studies have targeted Wnt/frizzled signaling after MI with the majority of them indicating that the inhibition of the pathway is beneficial since it improves infarct healing and prevents heart failure. This suggests that blocking the Wnt/frizzled signaling pathway could be a potential novel therapeutic target to prevent the adverse cardiac remodeling after MI.

Summary To test the hypothesis that fibrotic burden in remote myocardium quantified by CMR during early period of infarct healing is a strong determinant of the cardiac remodeling outcome. Background After acute myocardial infarction (AMI), co-existing myocardial stunning, ischemia, and architectural alteration may yield variable patterns of ventricular remodeling with potential long-term prognostic implications. We hypothesize that CMR quantification of fibrotic content, based on R1 (1/T1) assessment, in non-infarct myocardium early after infarction and during the infarct healing phases may provide novel prediction of the final infarct size and alteration of ventricular functions during infarct healing. Methods

Background Fat suppressed T2-weighted black blood turbo spin echo (BBTSE) imaging can detect myocardial edema developed after acute myocardial infarction (MI) and characterize the extent of myocardium at risk in comparison to late gadolinium enhancement (LGE) imaging. Purpose We hypothesized that T2-extent at baseline and changes during follow-up are associated with dynamic changes of infarct heterogeneity during the convalescence phase of infarct healing. We further explored the strength of association in quantifying T2-based myocardial edema, using a semi-automated method and manual tracing. Methods Fifty-one patients (40 men) underwent 3T cardiac MRI both at 18±10 days and 7.7±1.1 months after an acute MI, including: 3 short-axis slices of T2-weighted fat-suppressed BBTSE, LV function assessment by SSFP and LGE imaging. Area of hyperintensity on T2 images was assessed by a semi-automated method using a threshold of mean signal intensity in the remote ROI ± 2 SD and by manual tracing. In further analyses, correlations of T2 extent, expressed as the percentage of total myocardium, and other MRI results were assessed by Spearman correlation. Results Correlations between the T2 extent, LV parameters, infarct heterogeneity and their respective changes are displayed in the table. At baseline, hyperintense T2 myocardium was demonstrated in 50 patients (98%) and represented 20.5±14.0% of total myocardium. Baseline T2 size was inversely correlated with LVEF and was directly correlated with total MI size. Hyperintense T2 areas persisted in 12 patients (24%) at follow-up. Manual-tracing was correlated well with the semi-automated method (Spearman’s rho 0.84; P

Background Diffusion tensor MRI (DTI) has been used to investigate infarct healing and remodeling in several species. Tractography of the myocardium has also recently been reported. However, these prior studies were conducted ex-vivo on excised hearts. Here, we use in-vivo DTI of the mouse heart to follow microstructural changes in the myocardium in response to ischemia. Mean diffusivity (MD) and fractional anisotropy (FA) were measured 24 hours and 2-3 weeks after ischemia-reperfusion. In addition, 3D diffusion MRI tractography of the mice hearts was performed in-vivo.

To the Editor: We read with great interest the article by Westermann et al1 in which the authors showed that biglycan expression was strongly increased in the myocardium after permanent coronary occlusion in wild-type mice. In the hearts of bgn −/ 0 mice 21 days after coronary occlusion, however, collagen matrix organization was impaired, and several parameters of left ventricular function were deteriorated. Furthermore, these animals showed increased mortality rates after infarction. The authors conclude that the complete absence of biglycan is deleterious and prevents the establishment of a stable infarct scar and hemodynamic adaptation, suggesting that biglycan is required for proper infarct healing. Although the observations of the authors are most valuable, the major conclusion of the authors1 is …

The delaying effect of prednisolone on the healing process of myocardial infarction was quantitatively estimated and whether its effect is mediated via inhibition of prostaglandin synthesis was investigated using DP 1904 （a new thromboxane A2 synthetase inhibitor） and indomethacin. In addition, the effects of metoprolol and verapamil on the infarct healing process were also studied. A rabbit model was employed, and the coronary artery was occluded for 30 min and reperfused for 72 hr. The infarcted area and the central core of necrosis were delineated by hematoxylineosin and Mallory's staining modified by Heidenhein. The area of the occluded coronary artery （area at risk） was determined by fluorescent particles. As an index of infarct healing, the volume ratio of the central core of necrosis to the whole infarct （%N/I） was calculated. The thinning of the infarcted wall was evaluated by the thickness ratio of the infarcted wall to the normal wall adjacent to the infarcted area （thinning ratio）. The rabbits were divided into 7 groups: 1） prednisolone （5mg/kg）-treated group （PSL5）, 5mg/kg of prednisolone was i.m. injected every 24 hr; 2） prednisolone （10 mg/kg）-treated group （PSL10）, 10mg/kg of prednisolone was i.m. injected every 24 hr; 3） DP 1904-treated group （DP group）, 10mg/kg of DP 1904 was i.v. injected every 24 hr starting 2 hr prior to coronary occlusion; 4） indomethacin-treated group （IND group）, 5mg/kg of indomethacin was i.v. injected after 15 min ischemia, which was followed by 10mg/kg s.c. 5 min after reperfusion and then every 24 hr; 5） metoprolol-treated group （MET group）, 0.15mg/kg of metoprolol was injected i.v. bolus 25 min prior to coronary occlusion, and followed by constant infusion at 0.003mg/kg/min for 70 min from 15 min after bolus injection; 6） verapamil-treated group （VER group）, 0.2mg/kg of verapamil was injected i.v. bolus 15 min prior to ishemia, followed by constant infusion at 0.04mg/kg/min for 45 min, and 7） untreated control group. In IND group, serum indomethacin level at 30 min and 72 hr after reperfusion was assayed using HPLC. The following results were obtained. 1） The size of area at risk, absolute infarct size, and infarct size as the percentage of area at risk were comparable for all 7 groups. 2） In PSL5 and PSL10 groups, %N/I were 51.5±5.0%, and 73.2±2.5%, respectively, both of ?which were significantly higher than that in the control group （30.4±4.5%）. 3） In IND group, serum indomethacin level was 10532±2907ng/ml at 30 min and 367±140ng/ml at 72 hr after reperfusion. However, %N/I of IND group （46.6±4.7%） was not significantly different from that of the control group. The %N/I of DP group, 36.3±6.2%, was not different from that of the control group, even though the dose of DP 1904 used in this study is considered to be sufficient to completely inhibit thromboxane B2 formation after 2 hr and by about 60% even 24 hr after its administration. 4） MET group showed a higher value of %N/I （50.0±9.0%） compared with that of the control group （30.4±4.5%）, though it was not statistically significant. %N/I in VER group （27.8±5.9%） was similar to that of the control group. 5） There were no significant differences in the thinning ratio for the 7 experimental groups. These results suggest that prednisolone delayed infarct healing dose dependently. Since indomethacin and DP 1904 failed to modify %N/I, the effect of prednisolone on infarct healing is unlikely to be mediated by the reduction of thromboxane A2 formation. Metoprolol and verapamil may not have any delaying effects on the healing process of myocardial infarction.

The healing process of myocardial infarction and its possible determinants were investigated by using rabbits. Under pentobarbital anesthesia and mechanical ventilation, a coronary branch was either ligated （non-reperfused infarct groups） or occluded for 30 or 60 min and then reperfused （reperfused infarct groups）. As an index of infarct healing, the volume ratio of the central core of coagulative necrosis to the whole infarct （%N/I） was determined histologically. The area at risk was measured by fluorescent particles. The thinning of the infarcted ventricular wall was estimated by the ratio of the minimal thickness of the infarcted region to the average thickness of the normal region adjacent to the infarcted area （thinning ratio）. The percentage of area at risk infarcted （%I/R） was similar in the non-reperfused groups and 60 min-ischemia-reperfused groups （83.4±3.0% vs 74.9±4.3% at 72 hr, 72.5±4.9% vs 64.7±4.7% at 7 days, respectively）, while massive intramyocardial hemorrhage occurred only in reperfused infarcts. The %I/R was significantly smaller in 30 min-ischemia-reperfused infarct than 60 min-ischemia-reperfused （48.6±3.2% vs 74.9±4.3% at 72 hr, p

Objective: The MRL mouse strain shows extraordinary wound healing capacities. Some years ago, Leferovich et al. (Proc Natl Acad Sci U. S. A. 2001;98:9830-35) have reported the absence of scar formation after cryogenically-induced right ventricular myocardial infarcts in adult MRL mice. An independent group (Oh et al., Cardiovasc Pathol 2004; 13:203-6) found that MRL mice repair left ventricular ischemic infarcts after coronary artery ligation with regular scar formation. Given the divergent outcomes in infarct healing in MRL mice reported by those two studies, we have investigated whether MRL mice heal myocardial infarcts, without scar both in the cryoinjury and in the coronary ligation model. Methods and Results: Four different protocols of cryogenically induced right and left ventricular injury, as well as permanent ligation of the left anterior descending coronary artery, were tested in adult MRL and control C57Bl/6 mice. At 60 days after experimental infarction, MRL mice showed pronounced scarring of the affected right and left ventricular areas, with no significant differences in infarct size and thickness between MRL and C57Bl/6 mice using any of the five experimental protocols. Analysis of cell proliferation by 5-bromo-2' -deoxyuridine (BrdU) incorporation into the DNA did not show any difference between the two strains of mice after infarction. Histological analysis of infarct areas using picrosirius red staining did not show differences in extent of collagen and distribution between the two mouse strains. Conclusions: NIRL mice heal myocardial infarcts with scar formation in response to ischemic as well as to cryogenic injuries. (c) 2008 Elsevier Inc. All rights reserved.

s S59 implantation attenuated the decline of fractional shortening after MI and the scar was significantly thicker in both BMMC groups compared to the media injected controls (p

Previous studies have suggested that the jaggedness of the healed or healing infarct edge influences cardiac electrical stability. However, these findings have been based on histological observations rather than quantitative measurements. The aim of this study was to assess infarct jaggedness by calculating its fractal dimension and to examine how this influences cardiac electrical stability during late infarct healing in the rabbit. Using programmed electrical stimulation, it was found that the fractal dimension did not differ significantly in 19 rabbits that had inducible ventricular tachycardia and 16 that did not. We conclude from these studies in the mature rabbit that infarct edge jaggedness does not influence the ease with which ventricular tachycardia is induced during late myocardial infarct healing.

The importance, implications, and potential value of pharmacologic interventions during healing of the wound of myocardial infarction have become apparent as a result of recent advances in pathophysiology of healing and ventricular remodeling post-infarction. Over the last three decades, therapeutic efforts after myocardial infarction have centered around minimizing the loss of myocardium and function. Therapy focused on acute reduction of myocardial infarct size in the mid-seventies and on restoration of perfusion in the infarct zone in the mid-eighties. Over the last decade, chronic therapies have been developed for prevention of ventricular remodeling, progressive ventricular dilation and ventricular dysfunction [1, 2]. It became evident during the last 30 years that some pharmacologic therapies aimed at salvaging ischemic myocardium also exerted other effects on infarct healing, and those with clearly adverse effects were best avoided [3–7]. Recognition that the substrate for ventricular remodeling changes during infarct healing led to the suggestion that timing and duration of specific antiremodeling interventions should be based on knowledge of the natural pathophysiologic stage of healing in order to maximize therapeutic benefits [2, 8, 9]. To date, therapies have not been primarily targeted at improving the healing process post-infarction. This chapter will review current and potential pharmacologic interventions in post-infarction wound healing.

Background Late gadolinium enhancement (LGE) with infarct tissue heterogeneity characterized by cardiac magnetic resonance imaging (CMR) has been shown to be associated with arrhythmogenic substrates and increased mortality. Preliminary data suggests that areas of heterogeneous signal intensity (SI) within an infarct may represent an admixture of myocardial fibrosis, ischemic cellular apoptosis and viable myocytes potentially capable of functional recovery.