post-MI Left Ventricular Remodeling Research Articles

99mTc-HFAPi SPECT imaging predicts left ventricular remodeling after acute myocardial infarction

BackgroundDespite improved treatments for acute myocardial infarction (AMI), myocardial fibrosis remains a key driver of adverse left ventricular (LV) remodeling and increased mortality. Fibroblast activation and proliferation significantly contribute to this process by enhancing cardiac fibrosis, which can lead to detrimental changes in LV structure. This study evaluates the effectiveness of 99mTc-labeled fibroblast activation protein inhibitor (99mTc-HFAPi) SPECT imaging in predicting LV remodeling over 12 months in post-AMI patients. MethodsA cohort of 58 AMI patients (46 males, median age 61 [53, 67] years) underwent baseline 99mTc-HFAPi imaging (5 ± 2 days post-MI), perfusion imaging (6 ± 2 days post-MI), and echocardiography (2 ± 2 days post-MI). Additionally, 15 patients had follow-up 99mTc-HFAPi and perfusion imaging, while 30 patients had follow-up echocardiography. Myocardial 99mTc-HFAPi activity was assessed at the patient level. LV remodeling was defined as a ≥10% increase in LV end-diastolic diameter (LVEDD) or LV end-systolic diameter (LVESD) from baseline to follow-up echocardiography. ResultsAMI patients displayed localized but non-uniform 99mTc-HFAPi uptake, exceeding perfusion defects. Baseline 99mTc-HFAPi activity exhibited significant correlations with BNPmax, LDHmax, cTNImax, and WBCmax, inversely correlating with LVEF. After 12 months, 11 patients (36.66%) experienced LV remodeling. Univariate regression analysis demonstrated an association between baseline 99mTc-HFAPi uptake extent and LV remodeling (OR = 2.14, 95%CI, 1.04, 4.39, P = 0.038). Conclusions99mTc-HFAPi SPECT imaging holds promise in predicting LV remodeling post-MI, providing valuable insights for patient management and prognosis.

Simulated Effects of Acute Left Ventricular Myocardial Infarction on Mitral Regurgitation in an Ovine Model.

Ischemic mitral regurgitation (IMR) occurs from incomplete coaptation of the mitral valve (MV) after myocardial infarction (MI), typically worsened by continued remodeling of the left ventricular (LV). The importance of LV remodeling is clear as IMR is induced by the post-MI dual mechanisms of mitral annular dilation and leaflet tethering from papillary muscle (PM) distension via the MV chordae tendineae (MVCT). However, the detailed etiology of IMR remains poorly understood, in large part due to the complex interactions of the MV and the post-MI LV remodeling processes. Given the patient-specific anatomical complexities of the IMR disease processes, simulation-based approaches represent an ideal approach to improve our understanding of this deadly disease. However, development of patient-specific models of left ventricle-mitral valve (LV-MV) interactions in IMR are complicated by the substantial variability and complexity of the MR etiology itself, making it difficult to extract underlying mechanisms from clinical data alone. To address these shortcomings, we developed a detailed ovine LV-MV finite element (FE) model based on extant comprehensive ovine experimental data. First, an extant ovine LV FE model (Sci. Rep. 2021 Jun 29;11(1):13466) was extended to incorporate the MV using a high fidelity ovine in vivo derived MV leaflet geometry. As it is not currently possible to image the MVCT in vivo, a functionally equivalent MVCT network was developed to create the final LV-MV model. Interestingly, in pilot studies, the MV leaflet strains did not agree well with known in vivo MV leaflet strain fields. We then incorporated previously reported MV leaflet prestrains (J. Biomech. Eng. 2023 Nov 1;145(11):111002) in the simulations. The resulting LV-MV model produced excellent agreement with the known in vivo ovine MV leaflet strains and deformed shapes in the normal state. We then simulated the effects of regional acute infarctions of varying sizes and anatomical locations by shutting down the local myocardial contractility. The remaining healthy (noninfarcted) myocardium mechanical behaviors were maintained, but allowed to adjust their active contractile patterns to maintain the prescribed pressure-volume loop behaviors in the acute post-MI state. For all cases studied, the LV-MV simulation demonstrated excellent agreement with known LV and MV in vivo strains and MV regurgitation orifice areas. Infarct location was shown to play a critical role in resultant MV leaflet strain fields. Specifically, extensional deformations of the posterior leaflets occurred in the posterobasal and laterobasal infarcts, while compressive deformations of the anterior leaflet were observed in the anterobasal infarct. Moreover, the simulated posterobasal infarct induced the largest MV regurgitation orifice area, consistent with experimental observations. The present study is the first detailed LV-MV simulation that reveals the important role of MV leaflet prestrain and functionally equivalent MVCT for accurate predictions of LV-MV interactions. Importantly, the current study further underscored simulation-based methods in understanding MV function as an integral part of the LV.

Predicting left ventricular remodeling post-MI through coronary physiological measurements based on computational fluid dynamics

Early detection of left ventricular remodeling (LVR) is crucial. While cardiac magnetic resonance (CMR) provides valuable information, it has limitations. Coronary angiography-derived fractional flow reserve (caFFR) and index of microcirculatory resistance (caIMR) offer viable alternatives. 157 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention were prospectively included. 23.6% of patients showed LVR. Machine learning algorithms constructed three LVR prediction models: Model 1 incorporated clinical and procedural parameters, Model 2 added CMR parameters, and Model 3 included echocardiographic and functional parameters (caFFR and caIMR) with Model 1. The random forest algorithm showed robust performance, achieving AUC of 0.77, 0.84, and 0.85 for Models 1, 2, and 3. SHAP analysis identified top features in Model 2 (infarct size, microvascular obstruction, admission hemoglobin) and Model 3 (current smoking, caFFR, admission hemoglobin). Findings indicate coronary physiology and echocardiographic parameters effectively predict LVR in patients with STEMI, suggesting their potential to replace CMR.

Systemic immune- inflammation index predicts post-MI left ventricular remodeling.

Previous studies demonstrated that remodeling after successful percutaneous coronary intervention (PCI) depends on the inflammatory response triggered by myocardial infarction (MI). The systemic immune-inflammation index (SII) is a novel inflammation index strongly associated with coronary artery disease. In our study, we sought to determine whether SII could predict Post-MI LV remodeling. The study population included 528 patients (mean age 62.5 ± 10.2, 73% male) diagnosed with STEMI. Based on the increase in LVEDV within the first 12 months after STEMI, patients were divided into two groups. We categorized the ≥ 20% increase in LVEDV among remodelers (257 patients, 49%), and the other 271 patients (51%), as non-remodelers. To determine the relationship between laboratory parameters and LV remodeling, univariate and multivariate logistic regression models were used. In a univariate model, higher hs-CRP and SII values were associated with increased LVEDV. In a multivariate analysis, SII independently correlated with LV remodeling A cut-off value of 613.3 or higher for SII was significantly correlated with LV remodeling based on ROC analysis. SII provides an easy-to-calculate and affordable biomarker for cardiovascular diseases. It may be used as a new biomarker to predict LV remodeling in patients with STEMI.

Macrophage neogenin deficiency exacerbates myocardial remodeling and inflammation after acute myocardial infarction through JAK1-STAT1 signaling.

Immune response plays a crucial role in post-myocardial infarction (MI) myocardial remodeling. Neogenin (Neo1), a multifunctional transmembrane receptor, plays a critical role in the immune response; however, whether Neo1 participates in pathological myocardial remodeling after MI is unclear. Our study found that Neo1 expression changed significantly after MI in vivo and after LPS + IFN-γ stimulation in bone marrow-derived macrophages (BMDMs) in vitro. Neo1 functional deficiency (using a neutralizing antibody) and macrophage-specific Neo1 deficiency (induced by Neo1flox/flox;Cx3cr1cre mice) increased infarction size, enhanced cardiac fibrosis and cardiomyocyte apoptosis, and exacerbated left ventricular dysfunction post-MI in mice. Mechanistically, Neo1 deficiency promoted macrophage infiltration into the ischemic myocardium and transformation to a proinflammatory phenotype, subsequently exacerbating the inflammatory response and impairing inflammation resolution post-MI. Neo1 deficiency regulated macrophage phenotype and function, possibly through the JAK1-STAT1 pathway, as confirmed in BMDMs in vitro. Blocking the JAK1-STAT1 pathway with fludarabine phosphate abolished the impact of Neo1 on macrophage phenotype and function, inflammatory response, inflammation resolution, cardiomyocyte apoptosis, cardiac fibrosis, infarction size and cardiac function. In conclusion, Neo1 deficiency aggravates inflammation and left ventricular remodeling post-MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway. These findings highlight the anti-inflammatory potential of Neo1, offering new perspectives for therapeutic targets in MI treatment. Neo1 deficiency aggravated inflammation and left ventricular remodeling after MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway.

Subtle Changes in Myocardial Work Indices Assessed by 2D-Speckle Tracking Echocardiography Are Linked with Pathological LV Remodeling and MACEs Following an Acute Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention.

The goal of this study was to assess whether subtle changes in myocardial work indices may predict left ventricular (LV) remodeling and major cardiac events (MACEs) in patients with a first ST-elevation acute myocardial infarction (STEMI) and preserved LVEF after successful myocardial revascularization with PCI. Methods. Consecutive STEMI patients in sinus rhythm and with an LV ejection fraction ≥ 50% following a successful PCI were recruited. Conventional and two-dimensional speckle tracking echocardiography (2D-STE) was conducted within 36 h of the PCI and 3 months later. Patients having an increase of more than 20% in LV diastolic volume were included in the LV remodeling group. MACEs were noted throughout a four-year period of follow-up. Results: The study comprised 246 STEMI patients with a mean age of 66; 72% of whom were men. In 24% (58) of the patients, LV remodeling developed. These patients were older, more frequently hypertensive, and had a smoking history. They also exhibited significantly lower baseline and 3-month values for the myocardial global index (GWI), global constructive work (GCW), and global myocardial efficiency (GWE). The cut-off values of 1670 mmHg% for GWI and 83% for GWE were predictive of LV remodeling (p < 0.0001). During the four-year follow-up period, 19% of STEMI patients experienced a MACE, involving 15% from non-LV remodelers and 34% from LV remodelers (p = 0.01). The cut-off values for baseline GWI of 1680 mmHg% and baseline GWE of 84% had the best accuracy in predicting MACEs. In conclusion, non-invasive myocardial work indices offered a reproducible and accurate method to predict post-MI LV remodeling and MACEs.

Collagen matricryptin promotes cardiac function by mediating scar formation

AimsA peptide mimetic of a collagen-derived matricryptin (p1159) was shown to reduce left ventricular (LV) dilation and fibrosis after 7 days delivery in a mouse model of myocardial infarction (MI). This suggested p1159 long-term treatment post-MI could have beneficial effects and reduce/prevent adverse LV remodeling. This study aimed to test the potential of p1159 to reduce adverse cardiac remodeling in a chronic MI model and to elucidate p1159 mode-of-action. Materials and methodsUsing a permanent occlusion MI rodent model, animals received p1159 or vehicle solution up to 28 days. We assessed peptide treatment effects on scar composition and structure and on systolic function. To assess peptide effects on scar vascularization, a cohort of mice were injected with Griffonia simplicifolia isolectin-B4. To investigate p1159 mode-of-action, LV fibroblasts from naïve animals were treated with increasing doses of p1159. Key findingsMatricryptin p1159 significantly improved systolic function post-MI (2-fold greater EF compared to controls) by reducing left ventricular dilation and inducing the formation of a compliant and organized infarct scar, which promoted LV contractility and preserved the structural integrity of the heart. Specifically, infarcted scars from p1159-treated animals displayed collagen fibers aligned parallel to the epicardium, to resist circumferential stretching, with reduced levels of cross-linking, and improved tissue perfusion. In addition, we found that p1159 increases cardiac fibroblast migration by activating RhoA pathways via the membrane receptor integrin α4. SignificanceOur data indicate p1159 treatment reduced adverse LV remodeling post-MI by modulating the deposition, arrangement, and perfusion of the fibrotic scar.

Post-myocardial infarction late diastolic left ventricular blood flow energetics are independently associated with left ventricular remodeling

Abstract Background Post-myocardial infarction (MI) left ventricular (LV) remodeling emerges as a compensatory mechanism and leads to complex pathophysiological changes in LV blood flow hemodynamics. The interplay, if any, between LV blood flow energetics and remodeling remains unknown. We hypothesized that LV blood flow energetics early after MI are independently related to the temporal changes in LV end-diastolic volume (LVEDV). Methods In this prospective cohort study, 69 patients with acute re-perfused ST-segment elevation MI (STEMI) were included. The patients underwent cardiovascular magnetic resonance (CMR) examination within 2 days of the index event and at 3-month. CMR examination included cine, late gadolinium enhancement, and whole-heart 4D flow acquisitions. LV volume-function, infarct size (indexed to body surface area), microvascular obstruction (MVO), mitral inflow, and 4D blood flow kinetic energy (KE) characteristics were obtained. LV mean and peak KEi (indexed to LVEDV) were quantified for all time parameters (entire cardiac cycle, during systole/diastole, at E- and A-waves). Results In univariable linear regression analysis, peak KEi (R-R interval), mean systolic KEi, A-wave KEi, MVO presence were all associated with the relative change (%) of LVEDV (p=0.03, p=0.01, p&amp;lt;0.01, P=0.03, respectively). In multivariable linear regression analysis, A-wave KEi was identified as the only independent marker for association with the relative change of LVEDV (p=0.02). In another univariable linear regression analysis, A-wave KEi, infarct size, and MVO presence were all associated with the absolute change of LVEDV (p=0.03, p=0.04, p=0.04, respectively). In multivariable linear regression analysis, A-wave KEi was determined as the only independent marker for association with the absolute change of LVEDV (p=0.02). No significant association was observed between mitral inflow characteristics and relative and absolute change of LVEDV. Conclusion Late diastolic LV blood flow energetics early after acute MI are independently associated with both absolute and relative longitudinal changes in LVEDV and may provide incremental value over infarct and mitral inflow characteristics to be associated with post-MI LV remodeling. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Enhanced Thrombin Generation Is Associated with Worse Left Ventricular Scarring after ST-Segment Elevation Myocardial Infarction: A Cohort Study.

Acute myocardial infarction (AMI) is associated with heightened thrombin generation. There are limited data relating to thrombin generation and left ventricular (LV) scarring and LV dilatation in post-MI LV remodeling. We studied 113 patients with ST-segment elevation myocardial infarction (STEMI) who had undergone primary percutaneous coronary intervention (PPCI) (n = 76) or pharmaco-invasive management (thrombolysis followed by early PCI, n = 37). Endogenous thrombin potential (ETP) was measured at baseline, 1 month and 6 months. Cardiovascular magnetic resonance imaging was performed at baseline and 6 months post-MI. Outcomes studied were an increase in scar change, which was defined as an increase in left ventricular infarct size of any magnitude detected by late gadolinium enhancement, adverse LV remodeling, defined as dilatation (increase) of left ventricular end-diastolic volume (LVEDV) by more than 20% and an increase in left ventricular ejection fraction (LVEF). The mean age was 55.19 ± 8.25 years and 91.2% were men. The baseline ETP was similar in the PPCI and pharmaco-invasive groups (1400.3 nM.min vs. 1334.1 nM.min, p = 0.473). Each 10-unit increase in baseline ETP was associated with a larger scar size (adjusted OR 1.020, 95% CI 1.002–1.037, p = 0.027). Baseline ETP was not associated with adverse LV remodeling or an increase in LVEF. There was no difference in scar size or adverse LV remodeling among patients undergoing PPCI vs. pharmaco-invasive management or patients receiving ticagrelor vs. clopidogrel. Enhanced thrombin generation after STEMI is associated with a subsequent increase in myocardial scarring but not LV dilatation or an increase in LVEF at 6 months post-MI.

Regional heterogeneity in determinants of atrial matrix remodeling and association with atrial fibrillation vulnerability postmyocardial infarction.

Left ventricular (LV) remodeling following a myocardial infarction (MI) is associated with new-onset atrial fibrillation (AF). LV remodeling post-MI is characterized by regional changes in matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), causing extracellular matrix (ECM) remodeling. The purpose of this study was to test the hypothesis that a shift in regional atrial MMP activity, MMP/TIMP expression, and ECM remodeling occurs post-MI, which cause increased vulnerability to AF. MI was induced in pigs (weight 25 kg; coronary ligation; n = 9). At approximately 14 days post-MI, an atrial electrical stimulation protocol was performed, after which an MMP radiotracer was infused, MMP/TIMP mRNA profiling performed, and ECM collagen assessed by histochemistry. An additional 7 non-MI pigs served as controls. AF could be induced in 89% (8/9) of the post-MI pigs but none of the controls. MMP activity (MMP radiotracer uptake) increased by approximately 2-fold in most atrial regions post-MI, whereas fibrillar collagen content was unchanged or actually reduced in right atrial regions and increased in left atrial regions. MMP/TIMP profiles revealed a heterogeneous pattern from the left atrial appendage to right atrial regions. AF vulnerability early post-MI was associated with a heterogeneous pattern of atrial ECM remodeling, detectable by noninvasive molecular imaging. Detection of early atrial MMP activation post-MI may help define the myocardial substrate underlying AF.

Cardiac protection by pirfenidone after myocardial infarction: a bioinformatic analysis

Left ventricular (LV) remodeling after myocardial infarction (MI) is promoted by an intense fibrotic response, which could be targeted by the anti-fibrotic drug pirfenidone. We explored the relationship between protein modulation by pirfenidone and post-MI remodeling, based on molecular information and transcriptomic data from a swine model of MI. We identified 6 causative motives of post-MI remodeling (cardiomyocyte cell death, impaired myocyte contractility, extracellular matrix remodeling and fibrosis, hypertrophy, renin–angiotensin–aldosterone system activation, and inflammation), 4 pirfenidone targets and 21 bioflags (indirect effectors). Pirfenidone had a more widespread action than gold-standard drugs, encompassing all 6 motives, with prominent effects on p38γ-MAPK12, the TGFβ1-SMAD2/3 pathway and other effector proteins such as matrix metalloproteases 2 and 14, PDGFA/B, and IGF1. A bioinformatic approach allowed to identify several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodeling, and suggests additional effects over guideline-recommended therapies.

Abstract 10948: Post-Infarct Cardiac Remodeling Predictions with Machine Learning

Introduction: We sought to improve the risk prediction of 3-month left ventricular remodeling (LVR) occurrence after myocardial infarction (MI), using a state-of-the-art machine learning approach. Methods: We retrieved 135 variables, ranging from clinical, biological and cardiac magnetic resonance data, from 379 patients with ST-elevated myocardial infarction and processed them with a machine learning pipeline using advanced feature selection and modelling algorithms such as gradient boosting, neural networks or recurrent neural networks. Results: A baseline logistic regression model using known variables such as infarct size, creatine kinase peak, no reflow and cardiovascular risk factors, achieved an AUC of 0.71 on the test, with 67% sensitivity and 64 % specificity. In comparison, our best predictive model was a neural network using seven variables (in order of importance): creatine kinase, mean corpuscular volume, baseline left atrial surface, history of diabetes, history of hypertension, red blood cell distribution width, and creatinine. This model achieved an AUC of 0.78 on the test set, reaching a sensitivity of 92% and a specificity of 67%, outperforming the baseline model. Conclusions: We were able to achieve state-of-the-art performance with a high level of sensitivity for the prediction of a 3-month post-MI LVR. Our unbiased data-driven machine learning approach highlights the role of classical parameters alongside unexpected variables such as left atrial dilation at baseline, mean corpuscular volume and red blood cell distribution width whose role in the pathophysiology of post-MI cardiac remodeling remain to be clarified. The relative simplicity and the good availability of these parameters make our new approach suitable for clinical testing.

Mechanisms of cardiac protection by pirfenidone in the post-myocardial infarction setting

Abstract Background A high proportion of patients with ST-segment elevation myocardial infarction (STEMI) experience adverse left ventricular (LV) remodelling despite guideline-recommended therapy. An excessive and dysregulated fibrotic response is involved in LV remodelling, and could be targeted by anti-fibrotic drugs such as pirfenidone, which is an approved treatment for idiopathic pulmonary fibrosis. Methods We evaluated the mechanisms of action of pirfenidone in the post-MI setting through sampling method-based mathematical models, enriched with transcriptomic data of swine experimental models of MI translated to the human proteome. Results The analysis of proteins modulated by pirfenidone shows that pirfenidone has a strong impact on several pathways involved in post-MI remodeling (Figure). The inhibition of p38γ-MAPK12 and furin displays the most prominent role on post-MI remodeling when compared to the other pirfenidone targets (PAI-1 and GLI2). p38γ-MAPK12 blockade inhibits cardiomyocyte apoptosis mediated by BCL2 and BAX. Myocardial hypertrophy and inflammation might be modulated by pirfenidone through the regulation of proteins downstream to p38γ-MAPK12, such as the NFATC1/NFATC2/NFATC3 pathway, and the transcription factors FOXO1, FOXO3 and NFκB, which are involved in TNFα regulation. The transcription factor AP-1 (homo-heterodimers of c-JUN/c-FOS), also downstream to p38γ-MAPK12, regulate the expression of genes involved in hypertrophy, fibrosis and inflammation (for example, IFNγ) By blocking both p38γ-MAPK12 and furin, pirfenidone can modulate extracellular matrix remodelling and cardiac fibrosis by targeting the TGFβ1-SMAD2/3 pathway, known to be highly involved in the progression of myocardial fibrosis, and other effector proteins such as MMP2 and MMP14 metalloproteases, PDGFA/B, and IGF1, many found to be involved also in myocardial fibrosis, impaired myocyte contractility and cell hypertrophic response. Conclusions We have identified several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodelling. These findings support future research regarding pirfenidone's clinical benefit in post-MI patients. Funding Acknowledgement Type of funding sources: None.

MicroRNAs-The Heart of Post-Myocardial Infarction Remodeling.

Myocardial infarction (MI) is one of the most frequent cardiac emergencies, with significant potential for mortality. One of the major challenges of the post-MI healing response is that replacement fibrosis could lead to left ventricular remodeling (LVR) and heart failure (HF). This process involves canonical and non-canonical transforming growth factor-beta (TGF-β) signaling pathways translating into an intricate activation of cardiac fibroblasts and disproportionate collagen synthesis. Accumulating evidence has indicated that microRNAs (miRNAs) significantly contribute to the modulation of these signaling pathways. This review summarizes the recent updates regarding the molecular mechanisms underlying the role of the over 30 miRNAs involved in post-MI LVR. In addition, we compare the contradictory roles of several multifunctional miRNAs and highlight their potential use in pressure overload and ischemia-induced fibrosis. Finally, we discuss their attractive role as prognostic biomarkers for HF, highlighting the most relevant human trials involving these miRNAs.

AMPK\u03b11 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism

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.

Biophysical and Lipidomic Biomarkers of Cardiac Remodeling Post-Myocardial Infarction in Humans.

Few studies have analyzed the potential of biophysical parameters as markers of cardiac remodeling post-myocardial infarction (MI), particularly in human hearts. Fourier transform infrared spectroscopy (FTIR) illustrates the overall changes in proteins, nucleic acids and lipids in a single signature. The aim of this work was to define the FTIR and lipidomic pattern for human left ventricular remodeling post-MI. A total of nine explanted hearts from ischemic cardiomyopathy patients were collected. Samples from the right ventricle (RV), left ventricle (LV) and infarcted left ventricle (LV INF) were subjected to biophysical (FTIR and differential scanning calorimetry, DSC) and lipidomic (liquid chromatography–high-resolution mass spectrometry, LC–HRMS) studies. FTIR evidenced deep alterations in the myofibers, extracellular matrix proteins, and the hydric response of the LV INF compared to the RV or LV from the same subject. The lipid and esterified lipid FTIR bands were enhanced in LV INF, and both lipid indicators were tightly and positively correlated with remodeling markers such as collagen, lactate, polysaccharides, and glycogen in these samples. Lipidomic analysis revealed an increase in several species of sphingomyelin (SM), hexosylceramide (HexCer), and cholesteryl esters combined with a decrease in glycerophospholipids in the infarcted tissue. Our results validate FTIR indicators and several species of lipids as useful markers of left ventricular remodeling post-MI in humans.

Targeted Injection of a Truncated Form of Tissue Inhibitor of Metalloproteinase 3 Alters Post-Myocardial Infarction Remodeling.

Infarct expansion can occur after myocardial infarction (MI), which leads to adverse left ventricular (LV) remodeling and failure. An imbalance between matrix metalloproteinase (MMP) induction and tissue inhibitors of MMPs (TIMPs) can accelerate this process. Past studies have shown different biologic effects of TIMP-3, which may depend upon specific domains within the TIMP-3 molecule. This study tested the hypothesis that differential effects of direct myocardial injections of either a full-length recombinant TIMP-3 (F-TIMP-3) or a truncated form encompassing the N-terminal region (N-TIMP-3) could be identified post-MI. MI was induced in pigs that were randomized for MI injections (30 mg) and received targeted injections within the MI region of F-TIMP-3 (n = 8), N-TIMP-3 (n = 9), or saline injection (MI-only, n = 11). At 14 days post-MI, LV ejection fraction fell post-MI but remained higher in both TIMP-3 groups. Tumor necrosis factor and interleukin-10 mRNA increased by over 10-fold in the MI-only and N-TIMP-3 groups but were reduced with F-TIMP-3 at this post-MI time point. Direct MI injection of either a full-length or truncated form of TIMP-3 is sufficient to favorably alter the course of post-MI remodeling. The functional and differential relevance of TIMP-3 domains has been established in vivo since the TIMP-3 constructs demonstrated different MMP/cytokine expression profiles. These translational studies identify a unique and more specific therapeutic strategy to alter the course of LV remodeling and dysfunction after MI. SIGNIFICANCE STATEMENT: Using different formulations of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), when injected into the myocardial infarction (MI) region, slowed the progression of indices of left ventricular (LV) failure, suggesting that the N terminus of TIMP-3 is sufficient to attenuate early adverse functional events post-MI. Injections of full-length recombinant TIMP-3, but not of the N-terminal region of TIMP-3, reduced relative indices of inflammation at the mRNA level, suggesting that the C-terminal region affects other biological pathways. These unique proof-of-concept studies demonstrate the feasibility of using recombinant small molecules to selectively interrupt adverse LV remodeling post-MI.

The Apolipoprotein A-I Mimetic L-4F Attenuates Monocyte Activation and Adverse Cardiac Remodeling after Myocardial Infarction.

Excessive inflammation after myocardial infarction (MI) can promote infarct expansion and adverse left ventricular (LV) remodeling. L-4F, a mimetic peptide of apolipoprotein A-I (apoA-I), exhibits anti-inflammatory and anti-atherogenic properties; however, whether L-4F imparts beneficial effects after myocardial infarction (MI) is unknown. Here we demonstrate that L-4F suppresses the expansion of blood, splenic, and myocardial pro-inflammatory monocytes and macrophages in a mouse model of reperfused MI. Changes in immune cell profiles were accompanied by alleviation of post-MI LV remodeling and dysfunction. In vitro, L-4F also inhibited pro-inflammatory and glycolytic gene expression in macrophages. In summary, L-4F treatment prevents prolonged and excessive inflammation after MI, in part through modulation of pro-inflammatory monocytes and macrophages, and improves post-MI LV remodeling. These data suggest that L-4F could be a used as a therapeutic adjunct in humans with MI to limit inflammation and alleviate the progression to heart failure.

Treatment of hypoxia-dependent cardiovascular diseases by myo-inositol trispyrophosphate (ITPP)-enhancement of oxygen delivery by red blood cells.

Heart failure is a consequence of progression hypoxia‐dependent tissue damages. Therapeutic approaches to restore and/or protect the healthy cardiac tissue have largely failed and remain a major challenge of regenerative medicine. The myo‐inositol trispyrophosphate (ITPP) is a modifier of haemoglobin which enters the red blood cells and modifies the haemoglobin properties, allowing for easier and better delivery of oxygen by the blood. Here, we show that this treatment approach in an in vivo model of myocardial infarction (MI) results in an efficient protection from heart failure, and we demonstrate the recovery effect on post‐MI left ventricular remodelling in the rat model. Cultured cardiomyocytes used to study the molecular mechanism of action of ITPP in vitro displayed the fast stimulation of HIF‐1 upon hypoxic conditions. HIF‐1 overexpression was prevented by ITPP when incorporated into red blood cells applied in a model of blood‐perfused cardiomyocytes coupling the dynamic shear stress effect to the enhanced O2 supply by modification of haemoglobin ability to release O2 in hypoxia. ITPP treatment appears a breakthrough strategy for the efficient and safe treatment of hypoxia‐ or ischaemia‐induced injury of cardiac tissue.

Plasma Indoleamine 2,3-dioxygenase is predictive of left ventricular remodeling after myocardial infarction

Acute myocardial infarction (MI) is associated with an inflammatory response that may lead and/or worsen adverse left ventricular (LV) remodeling. Among inflammation markers is Indoleamine 2,3-dioxygenase (IDO), which production is induced upon inflammation. IDO catalyzes the transformation of tryptophane into kynurenine. We tested plasma IDO activity as a predictor of LV remodeling post-MI. The PREGICA cohort recruited prospectively patients with first MI. Blood samples, echocardiography and cardiac MRI were obtained at day 4 and at 6 months. To be included, the number of akinetic LV wall segments had to be ≥ 3 at day 4. IDO activity was the ratio between kynurenine and tryptophane measured by high-pressure liquid chromatography coupled with fluorimetric detection. Remodelers were identified as patients with a variation of end-diastolic left ventricular volume (EDLVV) between day 4 and 6 months post-MI ≥ 20%. Among the 292 patients studied (mean age 57 y, mean necrosis size 26% on MRI), the median increase in EDLVV was 16.7% and 137 (47%) were classified as remodelers. At day 4, IDO activity was significantly higher in remodelers (8.2 ± 4.2% vs. 5.3 ± 2.5% and 8.7 ± 5.7% vs. 5.6 ± 4.4%, p < 0.001) and remained higher at 6 months post-MI. IDO activity at day 4 was highly predictive of LV remodeling (AUC = 87% [95% CI 83–91%]);IDO threshold of 5.8 resulted in specificity = 81%, sensitivity = 89%, negative predictive value = 89%, positive predictive value = 80%. In contrast, plasma levels of NT-proBNP, ST2, Galectin 3 or CRP at day 4 were poorly predictive. In multivariate analysis including other predictive variables at day 4 (primary angioplasty, EDLVV, LVEF, necrosis size), increase in IDO activity was significantly associated with LV remodeling (OR 1.21 [95%CI 1.11–1.33]). IDO activity appears as a promising biomarker for the prediction of LV remodeling after MI. Its specific role in post-MI remodeling pathways requires further investigation.