Noninfarct Zone Research Articles

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.

Trans-Valvular Unloading Reduces Anaerobic Glycolysis Before Reperfusion and Preserves Energy Substrate Utilization After Reperfusion in Models of Acute Myocardial Infarction

<h3>Purpose</h3> The impact of mechanical left ventricular (LV) unloading before reperfusion on myocardial energetics in acute myocardial infarction (AMI) is unknown. We hypothesized that LV unloading reduces anaerobic glycolysis in models of ischemia reperfusion injury (IRI). <h3>Methods</h3> Myocardial ischemia was induced by percutaneous occlusion of the left anterior descending (LAD) artery for 90 minutes in adult swine. In Groups A and B, an additional 120 minutes of LAD occlusion was performed in the presence or absence of a trans-valvular pump (TVP). In Group C and D, post ischemia or LV unloading was followed by 120 minutes of reperfusion (Fig. 1A). Tissue from the infarct and non-infarct zones was analyzed using Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy. <h3>Results</h3> In Groups A/B, LV unloading without reperfusion reduced lactate by 30±4% (p<0.006), glucose by 25±5% (p<0.02), and intermediates of glucose metabolism and ATP production consistent with decreased anaerobic glycolysis and reduced myocardial oxygen demand (Fig. 1B-C). In Groups C/D, LV unloading before reperfusion increased lactate and glucose levels by 30±5% and 75±30%, respectively (p<0.05), and increased intermediates of glucose oxidation and the tricarboxylic acid cycle. <h3>Conclusion</h3> We report for the first time that LV unloading during coronary occlusion reduces anaerobic glycolysis, energy substrate utilization and ATP production. These data support the need for further studies exploring the utility of LV unloading in AMI.

Evaluation of Variable Parameter Active Demons Algorithm-Based Diffusion Tensor Imaging on Ventricular Remodeling after Myocardial Infarction and Nursing

This study aimed to explore the effect of diffusion tensor imaging (DTI) image registration algorithm in the evaluation of ventricular remodeling in patients with myocardial infarction and the therapeutic effect of cross-theoretical model rehabilitation exercise care. The dynamic balance coefficient k was introduced to construct the DTI image registration algorithm k-AD based on the variable parameter AD algorithm. Then, it was compared with demons algorithm and AD algorithm and was applied in 110 patients with acute myocardial infarction. All patients were divided into the 55 cases of experimental group (cross-theoretical model rehabilitation exercise nursing) and 55 cases of control group (routine nursing). The myocardial tissue was labelled as infarction zone (IZ), infarction border zone (IBZ), and noninfarcted zone (NIZ). Finally, the fractional anisotropy (FA) and mean diffusivity (MD) were calculated. The results showed that the mean square error (MSE) of k-AD algorithm reduced to 0 after 35 iterations. The descent speed was obviously faster than AD and demons algorithms. The overlap of eigenvalue-eigenvector pairs (OVL-EEP) value of k-AD algorithm (0.25) was smaller than demons (0.81) and AD algorithms (0.56) (P&lt;0.05). The FA value in IZ was notably smaller than IBZ and NIZ, while the MD value was greater than those (P&lt;0.05). After nursing intervention, the FA value of myocardial infarction area in the experimental group was notably higher in contrast to control group, but the MD value was notably lower in contrast to it (P&lt;0.05). In short, the DTI image registration algorithm k-AD based on the variable parameter AD algorithm was remarkably better than the demons and AD algorithms in convergence and DTI image registration. FA and MD values obtained by DTI registration image based on k-AD algorithm could clearly indicate the ventricular remodeling after myocardial infarction and the rehabilitation effect of cross-theoretical model rehabilitation exercise nursing intervention.

Non-invasive myocardial work: an echocardiographic measure of post-infarct scar on contrast-enhanced cardiac magnetic resonance imaging

Abstract Background Late gadolinium contrast enhanced cardiac magnetic resonance (LGE CMR) imaging accurately quantifies the extent of fibrosis and transmurality in chronically infarcted left ventricular (LV) segments, and identifies viability. Moreover, CMR characterizes the remote, non-infarcted zone, which is an emerging region of interest following ST-segment elevation myocardial infarction (STEMI). Non-invasive myocardial work is a novel LV function parameter - calculated from speckle-tracking strain echocardiography and sphygmomanometrically-determined blood pressure, which has shown excellent correlation with invasively measured myocardial work. Purpose To explore the relation of non-invasively estimated parameters of LV myocardial work to post-infarct scar on LGE CMR, and to compare myocardial work indices between the infarct core and remote zone in STEMI patients who were treated with primary percutaneous coronary intervention (PCI). Methods Patients with a STEMI who underwent primary PCI and LGE CMR, in addition to echocardiographic studies where non-invasive myocardial work analysis was feasible, were included. The LV was subdivided into non-infarcted, non-transmural and transmurally infarcted segments. The remote zone was defined as the non-infarcted myocardial segment diametrically opposed to the infarct core, without any evidence of LGE. Myocardial work indices were compared with linear mixed models, ANOVA and Wilcoxon signed rank tests. Results 53 patients (89% male, age 58±9 years) and 689 segments were analysed. The mean scar burden comprised 14±7% of the total LV mass and 76 (11%) segments showed transmural LGE. The following non-invasive myocardial work indices: myocardial work index (MWI), constructive work (CW) and myocardial work efficiency (MWE) showed a significant inverse relationship with infarct transmurality (p&amp;lt;0.05 for all comparisons) while a positive trend was observed for wasted work (WW) (p=0.086) (Figure 1). The core zone demonstrated lesser MWI (1237±568 vs. 1514±518 mmHg%; p=0.010), CW (1331±627 vs. 1827±537 mmHg%; p&amp;lt;0.001) and MWE (92 (84–98) vs. 98 (95–99) %; p&amp;lt;0.001) as well as greater WW when compared to the remote zone (107 (26–196) vs. 26 (10–90) mmHg%; p=0.001). Conclusions In STEMI patients who underwent primary PCI, MWI, CW and MWE were significantly related to the extent of transmural infarction, while WW demonstrated a trend. MWI, CW and MWE were significantly lower, and WW higher, in the core zone compared to the remote zone. Non-invasive myocardial work indices may provide an echocardiographic method for determining post-infarct viability, as well as characterization of the remote zone. MW and scar transmurality on LGE CMR Funding Acknowledgement Type of funding source: None

Pharmacodynamic Evaluation of Shenfu Injection in Rats With Ischemic Heart Failure and Its Effect on Small Molecules Using Matrix-Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging.

Objectives: We aimed to evaluate the effect of Shenfu injection in a rat model of ischemic heart failure and explore its mechanism. Methods: A rat model of ischemic heart failure after myocardial infarction was established by ligating the left anterior descending coronary artery. Forty-eight hours after surgery, the rats were intraperitoneally administered Shenfu injection for 7 weeks. Then, left ventricular fractional shortening and left ventricular ejection fraction were measured using transthoracic echocardiography, whereas heart rate and left ventricular end-diastolic pressure were measured using a MD3000 biosignal acquisition and processing system. The hearts and lungs of the rats were excised and weighed to measure the heart and lung weight indexes. In addition, cardiac histopathological changes were observed via hematoxylin–eosin and Masson’s trichrome staining, and serum cardiac troponin content was detected using a cardiac troponin ELISA kit. Furthermore, matrix-assisted laser desorption/ionization–mass spectrometry imaging was used to detect the levels and distribution of small molecules in the hearts of rats with ischemic heart failure. Results: We found that Shenfu injection can significantly increase left ventricular fractional shortening and left ventricular ejection fraction in rats with ischemic heart failure and significantly reduce the left ventricular end-diastolic pressure, heart and lung weight indexes, and cardiac troponin content; improve cardiac tissue morphology; and reduce infarct size. In addition, the matrix-assisted laser desorption/ionization–mass spectrometry imaging results demonstrated that 22:6 phospholipids were predominately distributed in the non-infarct zone, whereas 20:4 phospholipids tended to concentrate in the infarct zone. Shenfu injection significantly reduced taurine, glutathione, and phospholipids levels in the hearts of rats with ischemic heart failure and primarily changed the distribution of these molecules in the non-infarct zone. Conclusion: Shenfu injection induced obvious myocardial protective effects in rats with ischemic heart failure by stimulating antioxidation and changing the phospholipid levels and distribution.

The change in the quantity of macrophages and their stabilin-1 + M2 subpopulation in the myocardium in patients during early postinfarction period

Investigation of the role of macrophages and their functional plasticity in reparative process accompanying myocardial infarction (MI) and postinfarction cardiac remodeling is the relevant issue of current medical science. The purpose of the study: to investigate CD68+ and stabilin-1 +-macrophage infiltration and its dynamics in patients with MI in comparison with intact myocardium. The study included patients with fatal MI type 1 (n=41). All patients were divided into 4 groups depending on the onset of death (group 1, n=13, patients who died during the first 24 hours of MI; group 2, n=11, patients who died within 24-72 hours of MI; group 3, n=9, patients who died on days 4-10; and group 4, n=8, patients who died 11-28 days after MI). The control group included patients (n=9) who died due to fatal trauma and who did not suffer from cardiovascular pathology. For evaluation of functional immunopheno-type of macrophages we used immunohistochemistry. We counted cells expressing on their surface a common macrophages marker - CD68 and specific marker of regulatory M2 macrophages that demonstrates an anti-inflammatory activity - stabilin-1 in the infarct area, peri-infarct area, and non-infarct area. In comparison with the intact myocardium (control group) the number of CD68+-macrophages in the infarct area, periinfarct area, and non-infarct area increased from the first day of disease and peaked on day 4-10. The quantity of stabilin-1 + macrophages in all zones investigated during the acute phase of MI was lower than in the intact myocardium and increased on day 4-10 in the infarct area. Furthermore, in the non-infarct zone the quantity of stabilin-1 +-macrophages was lower than its quantity in the control group both during the acute phase and the regenerative phase of MI. The data obtained indicate the participation of stabilin-1 + macrophages in process of postinfarction myocardial healing and the development of the inflammatory immune response in the myocardium during the acute phase of MI and its maintaining at late stages of the disease.

Liraglutide improves myocardial fibrosis after myocardial infarction through inhibition of CTGF by activating cAMP in mice.

To study the role and mechanism of liraglutide in myocardial fibrosis after myocardial infarction (MI). A total of 72 C57/BL male mice were randomly divided into sham operation group (Sham group), myocardial infarction group (MI group), and liraglutide intervention group (Lira group). The left anterior descending coronary artery (LAD) of the mice in MI group and Lira group was ligated to establish the MI model. One week after the operation, the mice in Lira group were intraperitoneally injected with 100 μg/kg of liraglutide once a day for 4 weeks. The mice in Sham group and MI group were injected with the equal volume of normal saline. At the 5th week after the operation, the cardiac morphologic indexes and cardiac function indexes were measured by echocardiography. After an ultrasound, the heart specimens of the mice were immediately harvested by thoracotomy, and histomorphological hematoxylin-eosin (HE) staining, collagen fiber Masson staining, and immunohistochemical staining were performed. The infarction zone and the non-infarction zone were isolated from another heart specimen; the cyclic adenosine monophosphate (cAMP) and hydroxyproline content were determined; and the expression levels of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) were detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting. Liraglutide improved the cardiac function of mice after myocardial infarction. Liraglutide improved the myocardial fibrosis in mice after myocardial infarction. Liraglutide increased cAMP in myocardial cells of mice after myocardial infarction. Liraglutide did not change the TGF-β1 expressions while reduced the CTGF expressions in infarct and non-infarct area of mice after myocardial infarction. Liraglutide, through increasing the level of cAMP, could decrease the deposition of collagen fibers in myocardial tissues of mice after MI, reduce the degree of infiltration of collagen fibers in the infarction zone into the myocardium in the non-infarction zone and inhibit the adverse ventricular remodeling in the non-infarction zone, thus improving the cardiac function after MI.

Relationships between selective neuronal loss and microglial activation after ischaemic stroke in man.

Modern ischaemic stroke management involves intravenous thrombolysis followed by mechanical thrombectomy, which allows markedly higher rates of recanalization and penumbral salvage than thrombolysis alone. However, <50% of treated patients eventually enjoy independent life. It is therefore important to identify complementary therapeutic targets. In rodent models, the salvaged penumbra is consistently affected by selective neuronal loss, which may hinder recovery by interfering with plastic processes, as well as by microglial activation, which may exacerbate neuronal death. However, whether the salvaged penumbra in man is similarly affected is still unclear. Here we determined whether these two processes affect the non-infarcted penumbra in man and, if so, whether they are inter-related. We prospectively recruited patients with (i) acute middle-cerebral artery stroke; (ii) penumbra present on CT perfusion obtained <4.5 h of stroke onset; and (iii) early neurological recovery as a marker of penumbral salvage. PET with 11C-flumazenil and 11C-PK11195, as well as MRI to map the final infarct, were obtained at predefined follow-up times. The presence of selective neuronal loss and microglial activation was determined voxel-wise within the MRI normal-appearing ipsilateral non-infarcted zone and surviving penumbra masks, and their inter-relationship was assessed both across and within patients. Dilated infarct contours were consistently excluded to control for partial volume effects. Across the 16 recruited patients, there was reduced 11C-flumazenil and increased 11C-PK11195 binding in the whole ipsilateral non-infarcted zone (P = 0.04 and 0.02, respectively). Within the non-infarcted penumbra, 11C-flumazenil was also reduced (P = 0.001), but without clear increase in 11C-PK11195 (P = 0.18). There was no significant correlation between 11C-flumazenil and 11C-PK11195 in either compartment. This mechanistic study provides direct evidence for the presence of both neuronal loss and microglial activation in the ipsilateral non-infarcted zone. Further, we demonstrate the presence of neuronal loss affecting the surviving penumbra, with no or only mild microglial activation, and no significant relationship between these two processes. Thus, microglial activation may not contribute to penumbral neuronal loss in man, and its presence in the ipsilateral hemisphere may merely reflect secondary remote degeneration. Selective neuronal loss in the surviving penumbra may represent a novel therapeutic target as an adjunct to penumbral salvage to further improve functional outcome. However, microglial activation may not stand as the primary therapeutic approach. Protecting the penumbra by acutely improving perfusion and oxygenation in conjunction with thrombectomy for example, may be a better approach. 11C-flumazenil PET would be useful to monitor the effects of such therapies.

Myeloid peroxisome proliferator-activated receptor gamma deficiency aggravates myocardial infarction in mice

Background and aimsAgonists of peroxisome proliferator-activated receptor gamma (Pparγ) have been demonstrated to reduce the risk of myocardial infarction (MI) in clinical trials and animal experiments. However, the cellular and molecular mechanisms are not completely understood. We aimed to reveal the functions of myeloid Pparγ in MI and explore the potential mechanisms in this study. MethodsMyeloid Pparγ knockout (MPGKO) mice (n = 12) and control mice (n = 8) underwent coronary artery ligation to induce MI. Another cohort of MPGKO mice and control mice underwent coronary artery ligation and were then treated with IgG or neutralizing antibodies against interleukin (IL)-1β. Infarct size was determined by TTC staining and cardiac function was measured using echocardiography. Conditioned media from GW9662- or vehicle-treated macrophages were used to treat H9C2 cardiomyocyte cell line. Gene expression was analyzed using quantitative PCR. Reactive oxygen species were measured using flow cytometry. ResultsMyeloid Pparγ deficiency significantly increased myocardial infarct size. Cardiac hypertrophy was also exacerbated in MPGKO mice, with upregulation of β-myosin heavy chain (Mhc) and brain natriuretic peptide (Bnp) and downregulation of α-Mhc in the non-infarcted zone. Conditioned media from GW9662-treated macrophages increased expression of β-Mhc and Bnp in H9C2 cells. Echocardiographic measurements showed that MPGKO mice had worsen cardiac dysfunction after MI. Myeloid Pparγ deficiency increased gene expression of NADPH oxidase subunits (Nox2 and Nox4) in the non-infarcted zone after MI. Conditioned media from GW9662-treated macrophages increased reactive oxygen species in H9C2 cells. Expression of inflammatory genes such as IL-1β and IL-6 was upregulated in the non-infarcted zone of MPGKO mice after MI. With the injection of neutralizing antibodies against IL-1β, control mice and MPGKO mice had comparable cardiac function and expression of inflammatory genes after MI. ConclusionsMyeloid Pparγ deficiency exacerbates MI, likely through increased oxidative stress and cardiac inflammation.

Exogenous BMP-7 Facilitates the Recovery of Cardiac Function after Acute Myocardial Infarction through Counteracting TGF-β1 Signaling Pathway.

Myocardial fibrosis after acute myocardial infarction (AMI) is one of the main causes of myocardial remodeling and heart function abnormalities. Bone morphogenetic protein-7 (BMP-7) has been reported to play essential roles in anti-fibrosis. In this study, we demonstrated the role of exogenous BMP-7 on myocardial fibrosis and heart function recovery after AMI. A rat model of AMI was established via ligation of the left anterior descending coronary artery (LAD). Twenty rats were grouped into sham group which underwent chest open operation, but did not receive LAD ligation. Another 40 rats underwent LAD ligation were randomly grouped into saline-treated group (n = 20) and BMP-7-treated group (n = 20) which received saline treatment or exogenous BMP-7 treatment for 14 days, respectively. Two weeks after LAD ligation, the survival rate of BMP-7-treated AMI group was significantly improved compared to the saline group. Moreover, the cardiac function was preserved as shown by echocardiography examination, and the infarcted size was limited upon BMP-7 treatment. In addition, we investigated the role of TGF-β1 signaling pathway in BMP-7-mediated cardioprotective effects by analyzing the expression levels of TGF-β1, Smad 2 and Smad 3 in the infarct zone, border zone, and non-infarct zone. Western blot and quantitative PCR results suggested that BMP-7 attenuated myocardial fibrosis through counteracting TGF-β1 signaling pathway, thereby exerting cardioprotective effects. In conclusion, our data provide a potential therapeutic direction for preserving cardiac function and improving prognosis of AMI patients.

Therapeutic Benefit and Gene Network Regulation by Combined Gene Transfer of Apelin, FGF2, and SERCA2a into Ischemic Heart.

Despite considerable advances in cardiovascular disease treatment, heart failure remains a public health challenge. In this context, gene therapy appears as an attractive approach, but clinical trials using single therapeutic molecules result in moderate benefit. With the objective of improving ischemic heart failure therapy, we designed a combined treatment, aimed to simultaneously stimulate angiogenesis, prevent cardiac remodeling, and restore contractile function. We have previously validated IRES-based vectors as powerful tools to co-express genes of interest. Mono- and multicistronic lentivectors expressing fibroblast growth factor 2 (angiogenesis), apelin (cardioprotection), and/or SERCA2a (contractile function) were produced and administrated by intramyocardial injection into a mouse model of myocardial infarction. Data reveal that combined treatment simultaneously improves vessel number, heart function parameters, and fibrosis prevention, due to FGF2, SERCA2a, and apelin, respectively. Furthermore, addition of SERCA2a in the combination decreases cardiomyocyte hypertrophy. Large-scale transcriptome analysis reveals that the triple treatment is the most efficient in restoring angiogenic balance as well as expression of genes involved in cardiac function and remodeling. Our study validates the concept of combined treatment of ischemic heart disease with apelin, FGF2, and SERCA2a and shows that such therapeutic benefit is mediated by a more effective recovery of gene network regulation.

Xinfuli Granule improves post-myocardial infarction ventricular remodeling and myocardial fibrosis in rats by regulating TGF-β/Smads signaling pathway.

BackgroundRecent clinical and experimental studies have confirmed the effects of Xinfuli Granule (XG), a compound Chinese medicine in the prevention and treatment of heart failure (HF). This study aimed to investigate the effects and the mechanisms of XG on ventricular reconstruction in rats with acute myocardial infarction (AMI).MethodsSprague-Dawley rats were subjected to left anterior descending branch ligation. The rats that survived 24 h were randomly assigned to five groups: medium-dose of XG group (MI+XGM), high-dose of XG group (MI+XGH), carvedilol group (MI+C), medium-dose of XG + carvedilol group (MI+C+XGM). Fourteen rats underwent identical surgical procedures without artery ligation, serving as sham controls. At 28 days, left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW) were calculated; left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS), left ventricular internal diameter at systole (LVIDS) were measured by ultrasound; HE staining, Masson staining, and Sirius red staining were used to assess the myocardial pathological and physiological changes as well as myocardial fibrosis area and non-infarct zone I/III collagen ratio. Expression of Smad3 were detected and analyzed by Western blot, immunohistochemistry and immunofluorescence. P-Smad3, Smad2 and Smad7 in the TGF-β/Smads signaling pathway were also analyzed by Western blot.ResultsThe LVIDS (P < 0.01), HW/BW (P < 0.05), type I/III collagen ratio (P < 0.01) and myocardial collagen (P < 0.01) decreased significantly while the LVW/BW, LVFS (P < 0.05) increased significantly in MI+XGM group as compared with those in other groups. The expression of key signal molecules of the TGF-β/Smads signaling pathway, including Smad3, P-Smad3 and Smad2 protein were decreased, while the expression of Smad7 increased in both XG and carvedilol treatment groups as compared to those of the MI group (all P < 0.01). Immunohistochemistry and immunofluorescence further confirmed the down-regulated Smad3 expression.ConclusionXG can improve ventricular reconstruction and inhibit myocardial fibrosis in rats with AMI by regulating TGF-β/Smads signaling pathway.

Evaluation of ventricular remodeling after myocardial infarction using diffusion tensor imaging combined with serum angiotensin-II and transforming growth factor-.BETA.1

Objective To gain insight into myocardial microstructure remodeling in the core-infarction zone (CIZ), peri-infarction zone(PIZ) and non-infarction zone (NIZ) using diffusion tensor imaging(DTI), and combined with angiotensin-Ⅱ(Ang-Ⅱ) and transforming growth factor-β1(TGF-β1) in the serum, so as to explore the ventricular remodeling(VR) mechanism at both the microstructural level and molecular level and correlations between both. Methods From August to December 2015, we chose 34 adult male rabbits which were divided into normal group(n=5), sham-operation group(n=5), and MI group with 8 rabbits at 1, 2 and 4 w respectively. Thirty-one survived and 3 died, with one at the 1, 2 and 4 w respectively. The MI model was established by ligating the left ventricular branch of the coronary artery. Aserum sample was collected from the ear vein of each rabbit prior to execution. Ang-Ⅱ and TGF-β1 of each sample were measured using the ELISA method. Each rabbit was executed to obtain the whole heart for ex-vivo 3.0 T DTI. Fractional anisotropy(FA) and mean diffusion(MD) coefficient values were measured in the CIZ, PIZ and NIZ. Comparison of DTI indicators (FA and MD values) and serum biomarkers (Ang-Ⅱand TGF-β1) between the normal group and the sham-operation group were made with independent sample t-test, while comparison among MI subgroups at the different time points and two control groups were analyzed using one-way ANOVA. The Pearson correlation analysis was done between DTI indicators and serum biomarkers. Results Both the FA values of the CIZ and PIZ significantly decreased in the 1st week, 0.185±0.012 and 0.221±0.005 respectively, then decreased slowly, both reached the lowest values at the 4th week, 0.138±0.012 and 0.201±0.014 respectively. The FA values at 1, 2 and 4 w in the CIZ and PIZ were statistically significant compared with the normal group (F=229.130, 38.321, P<0.01) , respectively. The MD values in the CIZ increased rapidly and dramatically in four weeks after operation, (0.869±0.085)×10-3, (0.955±0.109)×10-3, (1.113±0.100)×10-3mm2/s respectively. While those in the PIZ increased slowly and gradually, (0.809±0.111)×10-3, (0.830±0.043)×10-3, (0.912±0.100)×10-3mm2/s respectively. Both were reaching the peak at the 4th week synchronously. The MD values at 1, 2 and 4 w in the CIZ and PIZ were statistically significant compared with the normal group (F=20.756、6.448, P<0.01) . The Ang-II and TGF-β1 changed similarly, both increased rapidly and significantly during the 1st week, which appeared a small reduction at the 2nd week. Then, they stayed stable. In the CIZ and PIZ, the FA had negative correlations with Ang-Ⅱ and TGF-β1, with rCIZ=-0.681 and rPIZ=-0.729 (FA vs. Ang-Ⅱ) and rCIZ=-0.555 and rPIZ=-0.608 (FA vs. TGF-β1). Conclusions The ventricular remodeling after MI was a complex and dynamic process, especially in the 1st week, the CIZ and PIZ remodeled very quickly and obviously, and the Ang-Ⅱ and TGF-β1 reached the peak meanwhile, validating they mediated in regulating VR. Key words: Ventricular remodeling; Myocardial infarction; Magnetic resonance imaging; AngiotensinⅡ

Quantitative proteomic changes during post myocardial infarction remodeling reveals altered cardiac metabolism and Desmin aggregation in the infarct region

Myocardial infarction is one of the leading causes of cardiac dysfunction, failure and sudden death. Post infarction cardiac remodeling presents a poor prognosis, with 30%–45% of patients developing heart failure, in a period of 5–25years. Oxidative stress has been labelled as the primary causative factor for cardiac damage during infarction, however, the impact it may have during the process of post infarction remodeling has not been well probed. In this study, we have implemented iTRAQ proteomics to catalogue proteins and functional processes, participating both temporally (early and late phases) and spatially (infarct and remote zones), during post myocardial infarction remodeling of the heart as functions of the differential oxidative stress manifest during the remodeling process. Cardiac metabolism was the dominant network to be affected during infarction and the remodeling time points considered in this study. A distinctive expression pattern of cytoskeletal proteins was also observed with increased remodeling time points. Further, it was found that the cytoskeletal protein Desmin, aggregated in the infarct zone during the remodeling process, mediated by the protease Calpain1. Taken together, all of these data in conjunction may lay the foundation to understand the effects of oxidative stress on the remodeling process and elaborate the mechanism behind the compromised cardiac function observed during post myocardial infarction remodeling. SignificanceOxidative stress is the major driving force for cardiac damage during myocardial infarction. However, the impact of oxidative stress on the process of post MI remodeling in conducting the heart towards functional failure has not been well explored. In this study, a spatial and temporal approach was taken to elaborate the major proteins and cellular processes involved in post MI remodeling. Based on level/ intensity of ROS, spatially, infarct and noninfarct zones were chosen for analysis while on the temporal scale, early (30days) and late time points (120days) post MI were included in the study. This design enabled us to delineate the differential protein expression on a spectrum of maximum oxidative stress at infarct zone during MI to minimum oxidative stress at noninfarct zone during late time point post MI. The proteome profiles for each of the study groups when comparatively analysed gave a holistic idea about the dominant cellular processes involved in post MI remodeling such as cardiac metabolism, both for short term and long term remodeling as well as unique processes such as Desmin mediated cytoskeletal remodeling of the infarcted myocardium that are involved in the compromise of cardiac function.

Abstract 216: Intra-myocardial Injection of a Novel Thermosensitive Hydrogel Inhibits Post-infarct Heart Failure in Rats

Intra-myocardial injection of hydrogel after myocardial infarction (MI) has been confirmed for preventing post-infarct ventricular remodeling (VR) in numerous studies. Meanwhile, VR or existed heart failure (HF) symptoms of patients with MI was improved after intra-myocardial injection of hydrogels in recent clinical trials. However, whether the injection of hydrogel immediately after MI can prevent post-infarct HF in a long follow-up period is unclear. In present study, MI was induced by permanent coronary artery ligation in SD rats. Immediately, 100μl Dex-PCL-HEMA/ PNIPAAm (DPHP) hydrogel solution was injected into the infarct border myocardium of experimental rats, while phosphate-buffered saline (PBS) was employed in control group. Twelve weeks later, compared with PBS group (n=11), echocardiography and hemodynamics showed left ventricle dilatation was attenuated (end-diastolic diameter 9.30±0.73 mm vs 10.74±0.57 mm, p &lt;0.01) and cardiac function was improved (+dp/dt 12351±1158 mmHg/s vs 9488±695 mmHg/s, p &lt;0.01) in hydrogel group (n=11). Serum brain natriuretic peptide (107.74±18.21 pg/ml vs 132.17±20.62 pg/ml, p &lt;0.05) and cardiac aldosterone production of hydrogel group was suppressed, and so did pulmonary congestion. Histological analysis indicated thicker scar, smaller infarct size, diminished cardiac fibrosis (collagen volume fraction 21.74±3.13% vs 33.38±3.08%, p &lt;0.01) and hypertrophy in hydrogel group. Higher Col3α1 mRNA (27.32±0.71 vs 14.29±1.37, p &lt;0.01) in infarct zone but lower Col3α1 mRNA (0.97±0.12 vs 9.06±1.04, p &lt;0.01) and ANP mRNA (10.03±1.49 vs 24.74±2.40, p &lt;0.01) in non-infarct zone (NIZ) were detected by RT-PCR in hydrogel group. These data proves that the intra-myocardial injection of DPHP hydrogel immediately after MI can improve cardiac function including diastolic function, decrease infarct size, and enhance fibrotic healing in the infarct area. On the other hand, this treatment suppresses reactive fibrosis and hypertrophy in NIZ and thus delays post-infarct VR and prevents HF. DPHP hydrogel implantation immediately after MI is an effective strategy to prevent abnormal cardiac remodeling and have a long term beneficial effect even after it has been biodegraded.

Cardiac Telocytes in Regeneration of Myocardium After Myocardial Infarction.

Recent research progress has revealed that a novel type of interstitial cells termed cardiac telocytes (CTs) is found in the interstitium of the heart. We demonstrated that CTs are distributed both longitudinally and within the cross network in the myocardium and that the density of CTs in the atrium-atria and base of the myocardium is higher than that in the middle of the myocardium, while the density of CTs in the epicardium is higher than that in the endocardium. In addition, we documented, for the first time, that the network of CTs in the infarct zone of the myocardium is destroyed during myocardial infarction (MI). This fact shows that, in addition to the death of cardiac myocytes, the previously unrecognized death of CTs is an important mechanism that contributes to the structural damage and poor healing and regeneration observed in the infarcted myocardium. Furthermore, we demonstrated, for the first time, that transplantation of CTs in cases of MI decreases the infarct size and improves myocardial function. The mechanisms behind the beneficial effects of CT transplantation are increased angiogenesis at the infarct site and the border zone, decreased fibrosis in the infarct and non-infarct zones, improved pathological reconstruction of the left ventricle, and increased regeneration of CTs in the infarct zone. Our findings reveal that CTs can be specifically identified by the following characteristics: very small cell bodies, extreme prolongation with some dilation, predisposition to cell death under ischemia, and expression of molecular markers such as c-Kit, CD34, vimentin, and PDGFR-β. CTs act as a structural and functional niche microenvironment in the myocardium and play an essential role in maintaining the integrity of the myocardium and in the regeneration of damaged myocardium.

Quantitative microstructural deficits in chronic phase of stroke with small volume infarcts: A diffusion tensor 3-D tractographic analysis

BackgroundNon-infarct zone white matter wallerian degeneration is well-documented in large volume territorial infarctions. However to what extent these abnormalities exist in small volume infarction is not known, particularly since routine T2/FLAIR MR images show minimal changes in such cases. We therefore utilized DTI based quantitative 3D tractography for quantitative assessment of white matter integrity in chronic phase of small volume anterior circulation infarcts. MethodsEleven chronic stroke subjects with small anterior circulation large vessel infarcts (≤10cm3 volume of primary infarct) were compared with 8 age matched controls. These infarcts had negligible to mild gliosis and encephalomalacia in the primary infarct territory without obvious wallerian degeneration on conventional MRI. Quantitative Diffusion Tensor 3-D tractography was performed for CST, genu and splenium of corpus callosum. Tract based Trace and fractional anisotropy (FA) were compared with age matched controls. ResultsOn univariate analysis, Chronic stroke subjects had significant elevation in Trace measurement in genu of corpus callosum (GCC), ipsilesional and contralesional CST, (p<0.05), compared to controls. After adjusting for smoking, hypertension (HTN) and non-specific white matter hyperintensities, (WMHs), there was significant elevation in trace within the ipsilesional CST (p=0.05). Contralesional CST FA correlated significantly with walking speed, r=0.67, p=0.03. ConclusionsStroke subjects with small volume infarcts demonstrate significant quantitative microstructural white matter abnormalities in chronic phase, which are otherwise subthreshold for detection on routine imaging. Ability to quantify these changes provides an important marker for assessing non-infarct zone neuroaxonal integrity in the chronic phase even in the setting of small infarction.

Computational modeling of acute myocardial infarction

Myocardial infarction, commonly known as heart attack, is caused by reduced blood supply and damages the heart muscle because of a lack of oxygen. Myocardial infarction initiates a cascade of biochemical and mechanical events. In the early stages, cardiomyocytes death, wall thinning, collagen degradation, and ventricular dilation are the immediate consequences of myocardial infarction. In the later stages, collagenous scar formation in the infarcted zone and hypertrophy of the non-infarcted zone are auto-regulatory mechanisms to partly correct for these events. Here we propose a computational model for the short-term adaptation after myocardial infarction using the continuum theory of multiplicative growth. Our model captures the effects of cell death initiating wall thinning, and collagen degradation initiating ventricular dilation. Our simulations agree well with clinical observations in early myocardial infarction. They represent a first step toward simulating the progression of myocardial infarction with the ultimate goal to predict the propensity toward heart failure as a function of infarct intensity, location, and size.

From culprit artery reperfusion to non-culprit revascularization: Will ECG play a bigger role in the evolving STEMI care?

STEMI evolves rapidly after culprit artery occlusion, causing acute infarct zone contractile dysfunction. With worse infarct zone contractility, greater “work stress” follows on the non-infarct zone with compensatory hyperkinesis to maintain stroke volume, and on the whole heart with compensatory (reflex) tachycardia to maintain cardiac output. This “stress test” tests the ability of the non-culprit arteries to supply the non-infarct zone during this special time of increased demand. The scale of this “stress test” is the extent of acute contractile dysfunction — the larger the incoming STEMI, the greater the stress on the non-infarct zone.

P10 miRNA-30 family inhibition protects against cardiac ischemic injury by regulating cystathionine-gamma-lyase expression

Background Myocardial infarction (MI) is a leading cause of death globally. MicroRNAs (miRs) have been identified as a novel class of MI injury regulators. Hydrogen sulfide (H2S) is a gaseous signaling molecule that regulates cardiovascular function. The purpose of this study was to explore the role of the miR-30 family in protecting against MI injury by regulating H2S production. Methods and Results Two days after coronary artery ligations in rats, the expression of miR-30 family was significantly upregulated in the non-infarct and border zone regions. However, the CSE expression was just the opposite. The overexpression of each miR-30 family member decreased mRNA and protein levels of CSE and reduced H2S production. In contrast, silencing the whole miR-30 family resulted in elevated CSE expression and increased H2S production. Forced expression of the miR-30 family aggravated hypoxia-induced myocardial cell injury. This was reversed by locked nucleic acid (LNA)-miR-30 family inhibitor transfection. Systemic delivery of a LNA-miR-30 family inhibitor correspondingly repressed the miR-30 family in mouse cardiac tissue and increased CSE expression and H2S production. The therapeutic targeting of the miR-30 family in mice reduced infarct size, decreased apoptotic cell number in the peri-infarct region, and improved cardiac function in response to MI, whereas miR-30b overexpression by lentivirus in vivo exacerbated MI injury. Conclusion The inhibition of miR-30 family expression in the heart can protect against mouse cardiac ischemic injury by increasing CSE expression and H2S production, indicating the therapeutic potential of miR-30 for cardiac diseases associated with MI injury.