Postinfarction Left Ventricular Remodeling Research Articles

TLR7 deficiency alleviated myocardial ischemia reperfusion injury via regulating macrophage-neutrophil interaction

Abstract Background Toll-like receptor 7 (TLR7) is an intracellular innate immune receptor activated by single-stranded RNA. We previously reported that TLR7 could recognize RNA from dying cardiac cells and thereby deteriorating post myocardial infarction left ventricular remodeling. However, its effect on myocardial ischemia reperfusion (IR) injury is still unknown. Purpose In this study, we aimed to investigate the role of TLR7 in myocardial IR injury and the underlying mechanisms. Methods C57BL/6J wild type (WT) and TLR7 deficient (TLR7-/-) mice underwent left anterior descending artery occlusion for 30min followed by reperfusion. Myocardial infarct size was measured by Evan’s blue and TTC staining. mRNA expression levels of cytokines and phagocytosis-related receptors were detected by qPCR. TUNEL assay was conducted to determine apoptosis in the heart. Influx of neutrophils and macrophages in ischemic myocardium was analyzed by flow cytometry and Histone Cit3 was imaged to examine formation of neutrophils extracellular traps (NETs), cardiac function was evaluated by echocardiography during post-IR injury follow-up. Results TLR7 expression was up-regulated after IR injury in ischemic myocardium of WT mice. Compared to WT mice, fewer apoptotic cells and smaller infarct size (34±2% vs. 23±3% of area at risk, p<0.01) were observed in TLR7-/- mice at 24 hours post-IR, which was accompanied by reduced inflammatory cytokines (IL-1β: 110.5±14.1 vs. 54.8±13.7, p<0.05; TNF-α: 4.6±1.0 vs. 2.0±0.4, p<0.05) and increased anti-inflammatory factors (TNF-β: 2.9±0.3 vs. 8.6±2.6, p<0.05; IL-10: 14.2±2.1 vs. 32.3±8.8, p<0.05). Surprisingly, although the influx of neutrophils and macrophages increased to a similar extent in WT and TLR7-/- mice, the latter exhibited remarkably less NETs formation and enhanced macrophage phagocytosis in the infarct region. Moreover, TLR7 deficiency improved cardiac function, as indicated by increased left ventricular ejection fraction (LVEF) and fraction shortening (FS) at 56d post-IR. Conclusions TLR7 deficiency alleviates myocardial IR injury and improves cardiac function probably via enhancing macrophage clearance of NETs in the injured myocardium.TLR7 deficiency in cardiac functionTLR7 deficiency decreased NETs formation

LIM kinase 2 activates cardiac fibroblasts and exacerbates postinfarction left ventricular remodeling via crosstalk between the canonical and non-canonical Wnt pathways

Ischemic heart failure rates rise despite decreased acute myocardial infarction (MI) mortality. Excessive myofibroblast activation post-MI leads to adverse remodeling. LIM kinases (LIMK1 and LIMK2) regulate cytoskeleton homeostasis and are pro-fibrotic markers in atrial fibrillation. However, their roles and mechanisms in postinfarction fibrosis and ventricular remodeling remain unclear. This study found that the expression of LIMKs elevated in the border zone (BZ) in mice MI models. LIMK1/2 double knockout (DKO) restrained pathological remodeling and reduced mortality by suppressing myofibroblast activation. By using adeno-associated virus (AAV) with a periostin promoter to overexpress LIMK1 or LIMK2, this study found that myofibroblast-specific LIMK2 overexpression diminished these effects in DKO mice, while LIMK1 did not. LIMK2 kinase activity was critical for myofibroblast proliferation by using AAV overexpressing mutant LIMK2 lack of kinase activity. According to phosphoproteome analysis, functional rescue experiments, co-immunoprecipitation, and protein-protein docking, LIMK2 led to the phosphorylation of β-catenin at Ser 552. LIMK2 nuclear translocation also played a role in myofibroblast proliferation after MI with the help of AAV overexpressing mutant LIMK2 without nuclear location signal. Chromatin immunoprecipitation sequencing identified that LIMK2 bound to Lrp6 promoter region in TGF-β treated cardiac fibroblasts, positively regulating Wnt signaling via Wnt receptor internalization. This study demonstrated that LIMK2 promoted myofibroblast proliferation and adverse cardiac remodeling after MI, by enhancing phospho-β-catenin (Ser552) and Lrp6 signaling. This suggested that LIMK2 could be a target for the treatment of postinfarction injury.

Abstract Mo106: Inhibition of microRNA-200c promotes regeneration of the ischemic injured myocardium through activation of developmental pathways

Ischemic injury and adverse post-infarction myocardial remodeling are major causes of heart failure worldwide. Strategies designed to offset cell death with cardiomyocyte regeneration have, to date, not translated to routine clinical practice. Mir-200c modulates the transcripts of cardiogenic transcription factors (TFs) Tbx5 , Gata4 , Mef2c to promote myocyte maturation. We hypothesized that inhibition of mir-200c activity would result in postnatal myocyte de-differentiation and replication sufficient to ameliorate post-infarction decompensation after ischemic injury. To test this hypothesis, we preformed left coronary ligation on Wild-Type (WT) and transgenic mice expressing an RNA inhibitor against miR-200c ( PMIS-C ). Echocardiographic left ventricular (LV) ejection fraction (EF) fell from 88.41 ± 1.08% (WT) and 90% ± 1.42% ( PMIS-C ) (p=NS) to 28% ± 11.55% (WT) and 36% ± 9.35% at 1 day post injury (DPI) (p =NS). At 21DPI, LVEF was 27% ± 4.31% (WT) and 64% ± 4.25% ( PMIS-C ) [p ≤ 0.0001]. Post-infarction LV chamber dilation was reversed in PMIS-C mice (1.136 ± 0.19 v 0.67 ± 0.06 p ≤ 0.004 LV Vol/mass). By 9 WPI, PMIS-C heart function within non-significantly levels of sham and function prior to injury. These results indicated that inhibiting miR-200c following ischemic injury can recover cardiac function and prevent LV dilation. Moreover, trichrome stain showed a decrease in fibrosis 3 WPI (WT: 57% ± 17.46 v PMIS-C : 12% ± 3.01 p ≤ 0.001) and 9 WPI. To understand the mechanism causing this phenomenon, we analyzed expression of cardiac progenitor markers. Fold change in expression of TFs Tbx5, Gata4, Mef2c, and Isl1 were increased at 1 and 3 DPI in PMIS-C . At 1 WPI, PMIS-C border zone CMs express markers of a “progenitor-like” cell state seen during cardiogenesis. Conclusions: Inhibiting miR-200c abrogates post-infarction LV remodeling and significantly restores LV systolic function. Ongoing studies are investigating the therapeutic use of PMIS-C through delivery via AAV and nanoparticles.

Long-Term Protective Effects of Succinate Dehydrogenase Inhibition during Reperfusion with Malonate on Post-Infarction Left Ventricular Scar and Remodeling in Mice.

Succinate dehydrogenase inhibition with malonate during initial reperfusion reduces myocardial infarct size in both isolated mouse hearts subjected to global ischemia and in in situ pig hearts subjected to transient coronary ligature. However, the long-term effects of acute malonate treatment are unknown. Here, we investigated whether the protective effects of succinate dehydrogenase inhibition extend to a reduction in scar size and adverse left ventricular remodeling 28 days after myocardial infarction. Initially, ten wild-type mice were subjected to 45 min of left anterior descending coronary artery (LAD) occlusion, followed by 24 h of reperfusion, and were infused during the first 15 min of reperfusion with saline with or without disodium malonate (10 mg/kg/min, 120 μL/kg/min). Malonate-treated mice depicted a significant reduction in infarct size (15.47 ± 3.40% of area at risk vs. 29.34 ± 4.44% in control animals, p < 0.05), assessed using triphenyltetrazolium chloride. Additional animals were then subjected to a 45 min LAD ligature, followed by 28 days of reperfusion. Treatment with a single dose of malonate during the first 15 min of reperfusion induced a significant reduction in scar area, measured using Picrosirius Red staining (11.94 ± 1.70% of left ventricular area (n = 5) vs. 23.25 ± 2.67% (n = 9), p < 0.05), an effect associated with improved ejection fraction 28 days after infarction, as determined using echocardiography, and an attenuated enhancement in expression of the pro-inflammatory and fibrotic markers NF-κB and Smad2/3 in remote myocardium. In conclusion, a reversible inhibition of succinate dehydrogenase with a single dose of malonate at the onset of reperfusion has long-term protective effects in mice subjected to transient coronary occlusion.

ST-elevation myocardial infarction in patients with type 2 diabetes mellitus. Influence of the SGLT2 inhibitor dapagliflozin

Background. Patients with type 2 diabetes mellitus (T2DM) have a 2-fold higher risk of deve­loping coronary heart disease and mortality than those without carbohydrate metabolism disturbances. The reason for such negative trends is the occurrence of metabolic stress due to hyperglycemia and insulin resistance, which causes disturbance in energy metabolism and ischemic damage to cardiomyocytes. The purpose of the study is to improve the effectiveness of rehabilitation treatment and assess the dynamics of quality of life in patients with ST-elevation myocardial infarction (STEMI) and T2DM who are at high risk of develo­ping cardiac complications during the inpatient treatment by including the sodium-glucose transport protein 2 (SGLT2) inhibitor dapagliflozin in the comprehensive therapy. Materials and methods. The study group consisted of 38 patients with STEMI and T2DM who received dapagliflozin in addition to percutaneous coronary intervention (PCI). The control group included 37 patients with STEMI and T2DM who received only standard protocol treatment after PCI. In addition to general clinical examinations and assessment of quality of life using the EuroQol Group EQ-5D-5L questionnaire (1990), echocardiography was performed to determine general and local myocardial contractility by the Simpson method; plasma levels of glucose, insulin were evaluated, and insulin resistance was determined by the HOMA-IR. Results. Patients with STEMI and T2DM after PCI most often developed reperfusion syndrome with left ventricular failure and rhythm disturbances. Under the influence of standard medical treatment, a significant clinical and functional improvement was observed, but postinfarction remodeling progressed with impaired systolic and diastolic function and the development of heart failure syndrome, as well as treatment-resistant atrial and ventricular fibrillation paroxysms, supraventricular and ventricular extrasystoles, and bundle branch block. In patients of the study group with STEMI and T2DM on the comprehensive treatment with the SGLT2 inhibitor dapagliflozin, a significant decrease in the frequency of rhythm and conduction disturbances was noted on the se­cond day of observation, as well as a decrease in postinfarction left ventricular remodeling, which ultimately manifested in a statistically significant improvement of myocardial contractility (ejection fraction increased by 6.7 %) and a decrease in diastolic dysfunction. There was also a significant decrease in the frequency and severity of reperfusion arrhythmias, which was achieved due to the cardiometabolic effect of the SGLT2 inhibitor dapagliflozin. Conclusions. The inclusion of the SGLT2 inhibitor dapagliflozin in the comprehensive treatment led to a significant improvement in central cardiac hemodynamic parameters and a decrease in the frequency and severity of reperfusion arrhythmias and acute left ventricular failure, which contributed to the improvement in quality of life.

Impact of thrombus aspiration on left ventricular remodeling and function in patients with ST-segment elevation myocardial infarction: A meta-analysis of randomized controlled trials

BackgroundRoutine thrombus aspiration (TA) does not improve clinical outcomes in patients with ST-segment-elevation myocardial infarction (STEMI), although data from meta-analyses suggest that patients with high thrombus burden may benefit from it. The impact of TA on left ventricular (LV) functional recovery and remodeling after STEMI remains controversial. We aimed to pool data from randomized controlled trials (RCTs) on the impact of TA on LV function and remodeling after primary percutaneous coronary intervention (pPCI). MethodsPubMed and CENTRAL databases were scanned for eligible studies. Primary outcome measures were: LV ejection fraction (LVEF), LV end diastolic volume (LVEDV), LV end systolic volume (LVESV) and wall motion score index (WMSI). A primary pre-specified subgroup analysis was performed comparing manual TA with mechanical TA. ResultsA total of 28 studies enrolling 4990 patients were included. WMSI was lower in TA group than in control (mean difference [MD] -0.11, 95% confidence interval [CI] -0.19 to −0.03). A greater LVEF (MD 1.91, 95% CI 0.76 to 3) and a smaller LVESV (MD -6.19, 95% CI -8.7 to −3.6) were observed in manual TA group compared to control. Meta regressions including patients with left anterior descending artery (LAD) involvement showed an association between TA use and the reduction of both LVEDV and LVESV (z = −2.13, p = 0.03; z = −3.7, p < 0.01) and the improvement in myocardial salvage index (z = 2.04, p = 0.04). ConclusionTA is associated with improved LV function. TA technique, total ischemic time and LAD involvement appears to influence TA benefit on post-infarction LV remodeling.

Abstract P1081: Inhibition Of Mir-200c Abrogates Post-infarction LV Remodeling Following A Myocardial Infarct.

Ischemic injury and adverse post-infarction myocardial remodeling are major causes of heart failure worldwide. Strategies designed to offset cell death with cardiomyocyte regeneration have, to date, not translated to routine clinical practice. m ir-200c modulates the transcripts of cardiogenic transcription factors (TFs) Tbx5 and Gata4 to promote myocyte maturation. We hypothesized that inhibition of mir-200c activity would result in postnatal myocyte de-differentiation and replication sufficient to ameliorate post-infarction decompensation after ischemic injury. To test this hypothesis, we preformed left coronary ligation on Wild-Type (WT) and transgenic mice expressing an RNA inhibitor against miR-200c (I-200c). Echocardiographic left ventricular (LV) ejection fraction (EF) fell from 88.41 ± 1.08% (WT) and 90% ± 1.42% (I-200c) (p=NS) to 28% ± 11.55% (WT) and 36% ± 9.35% at 1 day post injury (DPI) (p =NS). At 21DPI, LVEF was 27% ± 4.31% (WT) and 64% ± 4.25% (I-200c) [p ≤ 0.0001]. Post-infarction LV chamber dilation was inhibited in I-200c mice (1.136 ± 0.19 v 0.67 ± 0.06 p ≤ 0.004 LV Vol/mass). These results indicated that inhibiting miR-200c following ischemic injury can recover cardiac function and prevent LV dilation. Moreover, trichrome stain showed a decrease in fibrosis 21 DPI (WT: 57% ± 17.46 v I-200c: 12% ± 3.01 p ≤ 0.001). To understand the mechanism causing this phenomenon, we analyzed expression of cardiac progenitor markers Tbx5 and Gata4 . Fold change in expression of both TFs were increased at 21 DPI (WT: 1.02 ± 0.09 v I-200c: 2.86 ± 0.76 p ≤ 0.05; WT: 1.00 ± 0.02 v I-200c: 3.08 ± 0.64 p ≤ 0.05). Additionally, I-200c mice have increased fold change of the cardiac progenitor factor Nkx2.5 (1.01 ± 0.07 v 4.16 ± 1.08 p ≤ 0.05). Tbx5, Gata4, Nkx2.5, in the context of ischemic injury, are thought to perturb post-infarct remodeling and promote CM survival. Conclusions: I-200c treatment abrogates post-infarction LV remodeling and significantly restores LV systolic function, which are associated with increased myocyte expression of cardiogenic progenitor markers. Future studies will determine the importance of myocyte proliferation vs. humoral modulation of surviving myocyte phenotype, toward protection of post-infarction LVs.

Deformational biomechanics and vagosympatic balance in adverse postinfarction left ventricular remodeling during high-dose atorvastatin therapy

Deformational biomechanics and vagosympatic balance in adverse postinfarction left ventricular remodeling during high-dose atorvastatin therapy

Pre-emptive iron supplementation prevents myocardial iron deficiency and attenuates adverse remodelling after myocardial infarction.

Heart failure (HF) after myocardial infarction (MI) is a major cause of morbidity and mortality. We sought to investigate the functional importance of cardiac iron status after MI and the potential of pre-emptive iron supplementation in preventing cardiac iron deficiency (ID) and attenuating left ventricular (LV) remodelling. MI was induced in C57BL/6J male mice by left anterior descending coronary artery ligation. Cardiac iron status in the non-infarcted LV myocardium was dynamically regulated after MI: non-haem iron and ferritin increased at 4 weeks but decreased at 24 weeks after MI. Cardiac ID at 24 weeks was associated with reduced expression of iron-dependent electron transport chain (ETC) Complex I compared with sham-operated mice. Hepcidin expression in the non-infarcted LV myocardium was elevated at 4 weeks and suppressed at 24 weeks. Hepcidin suppression at 24 weeks was accompanied by more abundant expression of membrane-localized ferroportin, the iron exporter, in the non-infarcted LV myocardium. Notably, similarly dysregulated iron homeostasis was observed in LV myocardium from failing human hearts, which displayed lower iron content, reduced hepcidin expression, and increased membrane-bound ferroportin. Injecting ferric carboxymaltose (15 µg/g body weight) intravenously at 12, 16, and 20 weeks after MI preserved cardiac iron content and attenuated LV remodelling and dysfunction at 24 weeks compared with saline-injected mice. We demonstrate, for the first time, that dynamic changes in cardiac iron status after MI are associated with local hepcidin suppression, leading to cardiac ID long term after MI. Pre-emptive iron supplementation maintained cardiac iron content and attenuated adverse remodelling after MI. Our results identify the spontaneous development of cardiac ID as a novel disease mechanism and therapeutic target in post-infarction LV remodelling and HF.

Giant postinfarction posterolateral left ventricular aneurysm, complicated by mitral insufficiency

Ischemic heart disease holds the leading position in the structure of cardiovascular diseases. Early reperfusion therapy for acute myocardial infarction led to a decrease in mortality and severe complications of coronary artery disease. Despite advances in the treatment of coronary artery disease, dilatation and remodeling of the left ventricle develop in 20% of patients who have had a heart attack, leading to mitral insufficiency and systolic dysfunction of the left ventricle. Aneurysm of the left ventricle is a delayed severe complication of myocardial infarction, which significantly worsens the prognosis. Large aneurysms of the left ventricle cause progressive dilatation of the left ventricle, its volumetric overload with an increase in wall tension in the non-infarction zone, decreased functional characteristics of the left ventricle, thrombosis in the aneurysm cavity, life-threatening arrhythmias, and sudden death. Postinfarction left ventricular remodeling can lead to secondary mitral regurgitation, which is an independent predictor of mortality in the longterm period. Surgical treatment of coronary heart disease and its complications is one of the main problems of modern cardiovascular surgery.

Myocardial strain parameters and autonomic balance in various variants of the postinfarction course in patients receiving high-dose atorvastatin therapy

Aim. To study parameters of left ventricular (LV) strain and heart rate variability (HRV) in patients with ST-segment elevation myocardial infarction (STEMI) in various variants of postinfarction receiving high-dose atorvastatin therapy.Material and methods. The study included 96 patients with STEMI. All patients underwent two-dimensional speckle tracking echocardiography and 24-hour electrocardiographic monitoring with HRV analysis. The included individuals were divided into groups without pathological LV remodeling (R (-), n=57) and with pathological post-infarction LV remodeling (R (+), n=39), the criterion for which was an increase in end-diastolic and/or end-systolic volume &gt;20% and &gt;15%, respectively. Further, depending on the achievement of target low-density lipoprotein cholesterol (LDL-C) (1,5 mmol/l and/or a decrease of more than 50%), the following subgroups were identified: 17 (43,6%) people, who reached target LDL-C levels (group 1), 22 (56,4%) patients, who did not reach target LDL-C levels (group 2). Similar subgroups were identified in the R (-) group as follows: 28 (49,1%) people, who reached target LDL-C levels (group 3) and 29 (50,9%) people, who did not reach target LDL-C levels (group 4).Results. Starting from the 12th week of follow-up, worsening of global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain (p&lt;0,01) was registered in group 2. In group 1, worsening of these parameters was registered only by the 48th week (p&lt;0,01). In group 3, an increase in GLS was revealed by the 48th week (p=0,001), GCS and GRS — by the 12th week (p&lt;0,05). In group 4, favorable changes were observed only in GLS and GCS by the 48th week (p&lt;0,01). A significant change in HRV parameters was observed in group 3. By the 48th week, there was an increase in temporal indicators (SDNN, SDNNi, SDANN, RMSSD, pNN50) (p&lt;0,0001) and total spectrum power (p=0,0001) due to an increase in all frequency indicators (p&lt;0,001), while the index of autonomic balance L/H decreased by 33% (p=0,002). In group 4, only SDNN, SDANN and pNN50 (p&lt;0,05), as well as the total spectrum power (p=0,001) increased, but no change in frequencies. According to intergroup analysis in the acute period of STEMI, group 4 patients had higher HRV than in group 3 (p&lt;0,05).Conclusion. High-dose atorvastatin therapy improves LV strain characteristics and autonomic balance during the rehabilitation period after STEMI.

Severe Impairment of Left Ventricular Regional Strain in STEMI Patients Is Associated with Post-Infarct Remodeling.

Background: Measures of global left ventricular (LV) systolic function have limitations for the prediction of post-infarct LV remodeling (LVR). Therefore, we tested the association between a new measure of regional LV systolic function—the percentage of severely altered strain (%SAS)- and LVR after acute ST-elevation myocardial infarction (STEMI). As a secondary objective, we also evaluated the association between %SAS and clinical events during follow-up. Methods: Of 177 patients undergoing echocardiography within 24 h from primary percutaneous coronary angioplasty, 172 were studied for 3 months, 167 for 12 months, and 10 died. The %SAS was calculated by dividing the number of LV myocardial segments with ≥−5% peak systolic longitudinal strain by the total number of segments. LVR was defined as the increase in end-diastolic volume >20% at its first occurrence compared to baseline. Results: LVR percentage was 10.2% and 15.8% at 3 and 12 months, respectively. Based on univariable analysis, a number of clinical, laboratory, electrocardiographic and echocardiographic variables were associated with LVR. Based on multivariable analysis, %SAS and TnI peak remained associated with LVR (for %SAS 5% increase, OR 1.226, 95% CI 1.098–1.369, p < 0.0005; for TnI peak, OR 1.025, 95% CI 1.004–1.047, p = 0.022). %SAS and LVR were also associated with occurrence of clinical events at a median follow-up of 43 months (HR 1.02, 95% CI 1.0–1.04, p = 0.0165). Conclusions: In patients treated for acute STEMI, acute %SAS is associated with post-infarct LVR. Therefore, we suggest performing such evaluations on a routine basis to identify, as early as possible, STEMI patients at higher risk.

Insight into the Role of the PI3K/Akt Pathway in Ischemic Injury and Post-Infarct Left Ventricular Remodeling in Normal and Diabetic Heart.

Despite the significant decline in mortality, cardiovascular diseases are still the leading cause of death worldwide. Among them, myocardial infarction (MI) seems to be the most important. A further decline in the death rate may be achieved by the introduction of molecularly targeted drugs. It seems that the components of the PI3K/Akt signaling pathway are good candidates for this. The PI3K/Akt pathway plays a key role in the regulation of the growth and survival of cells, such as cardiomyocytes. In addition, it has been shown that the activation of the PI3K/Akt pathway results in the alleviation of the negative post-infarct changes in the myocardium and is impaired in the state of diabetes. In this article, the role of this pathway was described in each step of ischemia and subsequent left ventricular remodeling. In addition, we point out the most promising substances which need more investigation before introduction into clinical practice. Moreover, we present the impact of diabetes and widely used cardiac and antidiabetic drugs on the PI3K/Akt pathway and discuss the molecular mechanism of its effects on myocardial ischemia and left ventricular remodeling.

Early predictors of the development of pathological postinfarction left ventricular remodeling

Abstract Funding Acknowledgements Type of funding sources: None. Objective to assess the ability of standard echocardiography parameters and parameters of myocardial deformation on the 7th-9th day of the STEMI to predict the risk of pathological remodeling in the postinfarction period. Methods the study included 114 patients with ST-segment elevation myocardial infarction (STEMI) mean age was 52.3 ± 8.4 years, men prevailed 100 (88%). On the 7th-9th day, echocardiography has been performed using the MyLab device (Italy) with the determination of end-diastolic and systolic volume indices (EDVi, ESVi), left ventricular myocardial mass index (LVMI). Global longitudinal (GLS), circumferential (GCS) and radial (GRS) strain (-%) have been determined using X-Strain ™ software. The development of pathological left ventricular remodeling (an increase in EDVi of more than 20% and / or ESVi of more than 15% at any visit within 48 weeks) has been considered as the end point. Multivariate Cox regression analysis was performed by including significant variables from a one-dimensional model (p &amp;lt;0.05), taking into account the absence of correlations between them. Results within 48 weeks, 45 (39%) patients developed pathological postinfarction remodeling. The following strong and independent predictors of the pathological postinfarction remodeling were included in the multivariate predictive model: GLS - RR 0.799 (95% CI 0.735-0.868) (p = 0.001), GRS - 1.047 (95% CI 1.013-1.083) (p = 0.001), EDVi - RR 1.041 (95% CI 1.015-1.07) (p = 0.026). Chi-square model 30.02, p ˂ 0.0001. Maximum likelihood ratio 385. Conclusions a multivariate model including GLS, GRS, and EDVi parameters on the 7th-9th day of STEMI is able to predict the development of pathological remodeling in patients within 48 weeks of the postinfarction period.

Using parameters of myocardial deformation as markers of pathological postinfarction remodeling

Abstract Funding Acknowledgements Type of funding sources: None. Objective to predict pathological left ventricular (LV) remodeling using global parameters of strain and twisting. Methods the study included 114 people with primary ST-segment elevation myocardial infarction (STEMI): 14 women and 100 males aged 32 to 67 years (52.3 ± 8.4). STEMI has been confirmed by ECG data, cardiospecific biomarkers (troponin T, CPK-MB) and coronary angiography - the presence of one infarct-related coronary artery in the absence of hemodynamically significant stenosis of other arteries. Echocardiography has been performed using a MyLab ultrasound scanner (Italy) on the 7th-9th day, 3rd, 6th and 12th months after the disease onset with the evaluation of standard parameters. On the 7th-9th days the parameters of global longitudinal (GLS,%), circumferential (GCS,%) strain, and LV twisting (Twist, °) have been analyzed using the X-Strain ™ software. The criterion for pathological LV remodeling has been considered to be an increase in EDVi ≥ 20% compared with the initial value. Prediction of pathological remodeling has been performed using ROC analysis by 3 criteria. To assess the quality of the model, the area under the curve (AUR –Area under ROC) has been determined with the calculation of 95% confidence intervals and the statistical significance of the point estimate of the area. Results Within 48 weeks pathological remodeling was developed in 45 (39.5%) patients. Three months after the index event, LV remodeling was detected in 24 (53.3%) patients of these 45; after 6 months - in another 15 (33.3%); after 12 months - in another 6 (13.4%). GLS - 11.7% with 96% sensitivity and 80% specificity, AUR 0.750 (95% CI 0.659 - 0.841), GCS - 12.4% with test sensitivity and specificity - 90% and 82%, respectively ((AUR 0.641 ( 95% CI 0.534 - 0.749)), Twist - 7.8 ° with a sensitivity of 93% and a specificity of 78%, AUR 0.657 (95% CI 0.558 - 0.757) predict the development of pathological postinfarction LV remodeling on the 7th-9th day. For all models the value of p ≤ 0.001. Conclusion Previously, LV remodeling has developed within 3 months after STEMI in 45 (39.5%) patients. The longitudinal strain, measured in the acute period of STEMI, has the greatest predictive ability in relation to the development of pathological postinfarction LV remodeling.

Functional classification of left ventricular remodelling: prognostic relevance in myocardial infarction.

AimsThe current definition of post ST‐segment elevation myocardial infarction (STEMI) left ventricular (LV) remodelling is purely structural (LV dilatation) and does not consider LV function (ejection fraction, EF), even though it is known to be a predictor of long‐term post‐STEMI outcome. This study aimed to reclassify LV remodelling after STEMI by integrating LV dilatation and function (LVEF) and to investigate the prognostic implications.Methods and resultsData from an ongoing registry of STEMI patients who were treated with primary percutaneous coronary intervention (PCI) were retrospectively evaluated. Four distinct remodelling subgroups were identified: (i) no LV dilatation, no LVEF impairment,(ii) no LV dilatation but LVEF impairment, (iii) LV dilatation but no LVEF impairment, and (iv) LV dilatation and LVEF impairment. The impact of functional LV remodelling on outcomes was analysed. A total of 2346 patients were studied (mean age 60 ± 11 years, 76% men). During a median follow‐up of 76 (interquartile range 52 to 107) months, 282 (12%) died, while the composite of death and heart failure hospitalization occurred in 305 (13%) patients. Those with LV remodelling and LVEF impairment had a significantly lower survival rate (P < 0.001) and event‐free survival rate (P < 0.001) compared with other functional LV remodelling groups.ConclusionsEmploying a functional LV post‐infarct remodelling classification has the potential to improve risk stratification beyond structural LV remodelling alone. Identification of patients with the worst prognosis by using a functional LV remodelling approach may allow institution of early preventative therapies.

Human Lysyl Oxidase Over-Expression Enhances Baseline Cardiac Oxidative Stress but Does Not Aggravate ROS Generation or Infarct Size Following Myocardial Ischemia-Reperfusion

Lysyl oxidase (LOX) is an enzyme critically involved in collagen maturation, whose activity releases H2O2 as a by-product. Previous studies demonstrated that LOX over-expression enhances reactive oxygen species (ROS) production and exacerbates cardiac remodeling induced by pressure overload. However, whether LOX influences acute myocardial infarction and post-infarct left ventricular remodeling and the contribution of LOX to myocardial oxidative stress following ischemia-reperfusion have not been analyzed. Isolated hearts from transgenic mice over-expressing human LOX in the heart (TgLOX) and wild-type (WT) littermates were subjected to global ischemia and reperfusion. Although under basal conditions LOX transgenesis is associated with higher cardiac superoxide levels than WT mice, no differences in ROS production were detected in ischemic hearts and a comparable acute ischemia-reperfusion injury was observed (infarct size: 56.24 ± 9.44 vs. 48.63 ± 2.99% of cardiac weight in WT and TgLOX, respectively). Further, similar changes in cardiac dimensions and function were observed in TgLOX and WT mice 28 days after myocardial infarction induced by transient left anterior descending (LAD) coronary artery occlusion, and no differences in scar area were detected (20.29 ± 3.10 vs. 21.83 ± 2.83% of left ventricle). Our data evidence that, although LOX transgenesis induces baseline myocardial oxidative stress, neither ROS production, infarct size, nor post-infarction cardiac remodeling were exacerbated following myocardial ischemia-reperfusion.

Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis

Abstract Introduction The coagulation protein tissue factor (TF) regulates inflammation and angiogenesis via its cytoplasmic domain in infection, cancer and diabetes. While TF is highly abundant in the heart and implicated in cardiac injuries and dysfunction, the contribution of its cytoplasmic domain in cardiac pathology remains unclear. Purpose We aimed to investigate the contribution of the cytoplasmic domain of TF to post-infarct myocardial injury and adverse left ventricular (LV) remodeling. Methods and results Myocardial infarction was induced by permanent occlusion of the left anterior descending coronary artery. Male mice with C57BL/Jax background were used for the study. Compared with wild-type mice, mice lacking the TF cytoplasmic domain (TFΔCT) had a higher survival rate (90.5% versus 70%, p=0.0298) during a 28-day follow-up after myocardial infarction. Among surviving mice, TFΔCT mice had better cardiac function and less LV remodeling (ESV: 114.5±13.1mL for WT, 67.06±10.8mL for TFΔCT, p&amp;lt;0.001; EDV: 146.6±12.4mL for WT, 99.97±11.71mL for TFΔCT, p&amp;lt;0.001) than wild-type mice. Bone marrow chimerism indicated that deletion of the TF cytoplasmic domain in either bone marrow-derived cells or cardiac resident cells could alleviate post-infarct cardiac dysfunction. Speckle-tracking strain analysis revealed that the overall improvement of post-infarct cardiac performance in TFΔCT mice was attributed to reduced myocardial deformation in the peri-infarct region (strain-%: 11.14±0.97 for WT, 15.34±1.10 for TFΔCT, p=0.007; strain rate-/s: 3.89±0.26 for WT, 5.18±0.21 for TFΔCT, p=0.0005). Histological analysis demonstrated that TFΔCT hearts had in the infarct area greater proliferation of endothelial cells and myofibroblasts accompanied with better scar formation. Compared with wild-type hearts, infarcted TFΔCT hearts showed less infiltration of proinflammatory cells with concomitant lower expression of protease-activated receptor-1 (PAR1)-Rac1 axis. Furthermore, infarcted TFΔCT hearts presented markedly higher peri-infarct vessel density associated with enhanced endothelial cell proliferation and higher expression of PAR2 and PAR2-associated pro-angiogenic pathway factors. Conclusions Our findings demonstrate that the TF cytoplasmic domain exacerbates post-infarct cardiac injury and adverse LV remodeling via differential regulation of inflammation and angiogenesis. Targeted inhibition of the TF cytoplasmic domain-mediated intracellular signaling may ameliorate post-infarct LV remodeling without perturbing coagulation. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National University Health System of Singapore

Proteomics of Mouse Heart Ventricles Reveals Mitochondria and Metabolism as Major Targets of a Post-Infarction Short-Acting GLP1Ra-Therapy.

Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein–protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.

Electrical instability of the myocardium during therapy with atorvastatin in patients with postinfarction remodeling

Background and Aims: To study the dynamics of heart rate turbulence (HRT) and late ventricular potentials (LVP) depending on the postinfarction left ventricular (LV) remodeling and the effectiveness of atorvastatin therapy in STEMI patients.