Myocardium In Myocardial Infarction Research Articles

Assessment of the alpha 7 nicotinic acetylcholine receptor as an imaging marker of cardiac repair-associated processes using NS14490

BackgroundCardiac repair and remodeling following myocardial infarction (MI) is a multifactorial process involving pro-reparative inflammation, angiogenesis and fibrosis. Noninvasive imaging using a radiotracer targeting these processes could be used to elucidate cardiac wound healing mechanisms. The alpha7 nicotinic acetylcholine receptor (ɑ7nAChR) stimulates pro-reparative macrophage activity and angiogenesis, making it a potential imaging biomarker in this context. We investigated this by assessing in vitro cellular expression of ɑ7nAChR, and by using a tritiated version of the PET radiotracer [18F]NS14490 in tissue autoradiography studies.Resultsɑ7nAChR expression in human monocyte-derived macrophages and vascular cells showed the highest relative expression was within macrophages, but only endothelial cells exhibited a proliferation and hypoxia-driven increase in expression. Using a mouse model of inflammatory angiogenesis following sponge implantation, specific binding of [3H]NS14490 increased from 3.6 ± 0.2 µCi/g at day 3 post-implantation to 4.9 ± 0.2 µCi/g at day 7 (n = 4, P < 0.01), followed by a reduction at days 14 and 21. This peak matched the onset of vessel formation, macrophage infiltration and sponge fibrovascular encapsulation. In a rat MI model, specific binding of [3H]NS14490 was low in sham and remote MI myocardium. Specific binding within the infarct increased from day 14 post-MI (33.8 ± 14.1 µCi/g, P ≤ 0.01 versus sham), peaking at day 28 (48.9 ± 5.1 µCi/g, P ≤ 0.0001 versus sham). Histological and proteomic profiling of ɑ7nAChR positive tissue revealed strong associations between ɑ7nAChR and extracellular matrix deposition, and rat cardiac fibroblasts expressed ɑ7nAChR protein under normoxic and hypoxic conditions.Conclusionɑ7nAChR is highly expressed in human macrophages and showed proliferation and hypoxia-driven expression in human endothelial cells. While NS14490 imaging displays a pattern that coincides with vessel formation, macrophage infiltration and fibrovascular encapsulation in the sponge model, this is not the case in the MI model where the ɑ7nAChR imaging signal was strongly associated with extracellular matrix deposition which could be explained by ɑ7nAChR expression in fibroblasts. Overall, these findings support the involvement of ɑ7nAChR across several processes central to cardiac repair, with fibrosis most closely associated with ɑ7nAChR following MI.

Application of High Molecular Hydrogel in The Treatment of Myocardial Infarction

Myocardial infarction (MI) is the world's leading disabling and fatal disease. Currently, clinical treatment methods mainly include drug therapy, angioplasty, and coronary artery bypass grafting. These traditional treatment methods are difficult to repair damaged myocardial tissue and cannot restore normal necrotic and fibrotic myocardium. Therefore, it is imperative to improve the efficacy of traditional treatment methods and find new treatment strategies. More and more studies have found that stem cell transplantation can repair damaged myocardium, but stem cells transplanted to the affected site undergo oxidative damage, compression loss, and low cell survival and retention rates. At present, there is an urgent need to seek new methods that can effectively repair damaged myocardium and restore cardiac function. In recent years, with the development of regenerative medicine engineering and the continuous optimization of polymer technology and the development of new biomaterials, it has become a reality to create lost or functionally damaged tissues and organs through theoretical methods of biology and engineering, enabling them to have the structure and function of normal tissues and organs. This article will focus on the latest progress in methods for repairing damaged myocardium in myocardial infarction through polymer hydrogel materials.

Microarray Analysis for Transcriptomic Profiling of Myocardium in Patients with Fatal Myocardial Infarction.

Transcriptomic evidence from human myocardium in myocardial infarction (MI) is still not sufficient. Thus, there is a need for studies on human cardiac samples in relation to the clinical data of patients. The purpose of our pilot study was to investigate the transcriptomic profile of myocardium in the infarct zone, in comparison to the remote myocardium, in patients with fatal MI, via microarray analysis. This study included four patients with fatal MI type 1. We selected histologically verified samples from within the infarct area (n = 4) and remote myocardium (n = 4). The whole transcriptome was evaluated using microarray analysis. Differentially expressed genes (DEGs) clustered in the infarct area and in the remote myocardium allowed their differentiation. We identified a total of 1785 DEGs (8.32%) in the infarct area, including 1692 up-regulated (94.79%) and 93 down-regulated (5.21%) genes. The top 10 up-regulated genes were TRAIL, SUCLA2, NAE1, PDCL3, OSBPL5, FCGR2C, SELE, CEP63, ST3GAL3 and C4orf3. In the infarct area, we found up-regulation of seventeen apoptosis-related genes, eleven necroptosis-related, and six necrosis-related genes. Transcriptome profiling of the myocardium in patients with MI remains a relevant area of research for the formation of new scientific hypotheses and a potential way to increase the translational significance of studies into myocardial infarction.

NEU1 Regulates Mitochondrial Energy Metabolism and Oxidative Stress Post-myocardial Infarction in Mice via the SIRT1/PGC-1 Alpha Axis.

ObjectiveNeuraminidase 1 (NEU1) participates in the response to multiple receptor signals and regulates various cellular metabolic behaviors. Importantly, it is closely related to the occurrence and progression of cardiovascular diseases. Because ischemic heart disease is often accompanied by impaired mitochondrial energy metabolism and oxidative stress. The purpose of this study was to investigate the functions and possible mechanisms of NEU1 in myocardial remodeling and mitochondrial metabolism induced by myocardial infarction (MI).MethodsIn this study, the MI-induced mouse mode, hypoxia-treated H9C2 cells model, and hypoxia-treated neonatal rat cardiomyocytes (NRCMs) model were constructed. Echocardiography and histological analysis were adopted to evaluate the morphology and function of the heart at the whole heart level. Western blot was adopted to determine the related expression level of signaling pathway proteins and mitochondria. Mitochondrial energy metabolism and oxidative stress were detected by various testing kits.ResultsNeuraminidase 1 was markedly upregulated in MI cardiac tissue. Cardiomyocyte-specific NEU1 deficiency restored cardiac function, cardiac hypertrophy, and myocardial interstitial fibrosis. What is more, cardiomyocyte-specific NEU1 deficiency inhibited mitochondrial dysfunction and oxidative stress induced by MI. Further experiments found that the sirtuin-1/peroxisome proliferator-activated receptor γ coactivator α (SIRT1/PGC-1α) protein level in MI myocardium was down-regulated, which was closely related to the above-mentioned mitochondrial changes. Cardiomyocyte-specific NEU1 deficiency increased the expression of SIRT1, PGC-1α, and mitochondrial transcription factor A (TFAM); which improved mitochondrial metabolism and oxidative stress. Inhibition of SIRT1 activity or PGC-1α activity eliminated the beneficial effects of cardiomyocyte-specific NEU1 deficiency. PGC-1α knockout mice experiments verified that NEU1 inhibition restored cardiac function induced by MI through SIRT1/PGC-1α signaling pathway.ConclusionCardiomyocyte-specific NEU1 deficiency can alleviate MI-induced myocardial remodeling, oxidative stress, and mitochondrial energy metabolism disorder. In terms of mechanism, the specific deletion of NEU1 may play a role by enhancing the SIRT1/PGC-1α signaling pathway. Therefore, cardiomyocyte-specific NEU1 may provide an alternative treatment strategy for heart failure post-MI.

Assessment of the global work of the myocardium in myocardial infarction with ST segment elevation of various localization

Abstract Funding Acknowledgements Type of funding sources: None. Purpose To assess the degree of impairment of the global myocardial function of the left ventricle in different localization of myocardial infarction with ST segment elevation (STEMI) using speckle tracking echocardiography. Methods The study included 45 patients with primary STEMI aged 38 to 66 years (52.3 ± 7.4). Myocardial infarction was confirmed by ECG data, biomarkers (troponin T, CPK-MB) and by the results of coronary angiography with the presence of one infarct-related coronary artery in the absence of hemodynamically significant stenosis of other arteries. Echocardiography has been performed 7-9 days after STEMI on a Vivid GE 95 Healthcare ultrasound scanner (USA) using EchoPAC software version 202 (GE Healthcare). In the automatic mode, the indicators of myocardial work have been calculated: the index of global myocardial work (GWI, mm Hg%.), Global constructive work (GCW, mm Hg.%.), Global wasted work (GWW, mm Hg.%.) %.), global work efficiency (GWE,%). Statistical data processing has been performed using the Statistica 13.0 software package (StatSoft Inc., USA). Results Taking into account the localization of STEMI on the 7th-9th day, patients were divided into two groups: group 1, which included 29 patients (64.4%) with lesions of the anterior LV wall (LAD), group 2 - 16 patients (35, 6%) with LV posterior wall infarction (RCA and CA). The comparison of the indices of global myocardial work in the two groups, has found that the GWI in group 1 was 1219 [95% CI 1053.1; 1384.9] mm Hg%, in group 2 - 1550.8 [95% CI 1371.6; 1730] mm Hg%, (p = 0.02). The GWE parameter in group 1 was 88.2 [95% CI 85.5; 90.9]%, in group 2 - 94.3 [95% CI 92; 96.6]%, (p = 0.01). The GСW index had the following values: in group 1 - 1383 [95% CI 1205.1; 1560.9] mm Hg%, in group 2 - 1805.5 [95% CI 1576.2; 2034.8] mm Hg%, (p = 0.01). GWW in group 1 was 152.8 [95% CI 94.3; 211.3] mm Hg%, in group 1b - 73.3 [95% CI 47.6; 99.0] mm Hg%, (p = 0.02). Conclusion Thus, the localization of STEMI is reflected in the indicators of myocardial function. LV anterior wall infarction has lower GWI, GWE, and GCW values and higher GWW values than posterior wall infarction.

Biomaterials based cardiac patches for the treatment of myocardial infarction

• Biomaterials used for cardiac patches are classified according to their sources. • The required properties for the biomaterials to make cardiac patches are introduced. • The specific advantages and shortcomings of different types of cardiac patches are discussed. • The development tendency of biomaterials based cardiac patches is prospected. Myocardial infarction (MI) is one of the common cardiovascular diseases that occurs with a blockage in one or more of the coronary arteries to lead to the damage of the myocardium, resulting in a life-threatening condition. To repair the damaged myocardium in MI, researchers are looking forwards to new ways to postpone the progression of myocardial injury. Cardiac patches, the scaffolds layered on the heart surface, can provide mechanical support for the infarction site and improve cardiac function by delivering various bioactive factors or cells, showing considerable curative effect in the treatment of MI. Biomaterials with certain biocompatibility and mechanical properties have received widespread attention for the application in cardiac patches. In this review, we focus on the recent progress on these biomaterials-based cardiac patches, which could be categorized into two types according to the sources of materials including (ⅰ) natural materials and (ⅱ) synthetic materials. The major advantages and current challenges of each type are discussed and a brief perspective on the future research directions is presented.

A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction.

Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype, and function of so-called tissue Tregs in the heart remain unclear. In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury, or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or ischemia/reperfusion injury. Photoconversion, parabiosis, single-cell T-cell receptor sequencing, and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin-33/suppression of tumorigenicity 2 axis and Sparc (secreted acidic cysteine-rich glycoprotein), a molecule upregulated in heart Tregs, was further evaluated in functional assays. We showed that Tregs were highly enriched in the myocardium of MI, ischemia/reperfusion injury, and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts in comparison with their lymphoid counterparts, including heart-draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly because of recruitment from the circulating Treg pool, whereas local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected T-cell receptor of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, HelioshighNrp-1high phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4+ T cells, proved by the analysis of T-cell receptor repertoires and conventional CD4+ T cells adoptive transfer experiments. The interleukin-33/suppression of tumorigenicity 2 axis was essential for sustaining heart Treg populations. Last, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone. We identified and characterized a phenotypically and functionally unique population of heart Tregs that may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.

Endothelial cell HSPA12B and yes-associated protein cooperatively regulate angiogenesis following myocardial infarction

Angiogenesis is essential for cardiac functional recovery after myocardial infarction (MI). HSPA12B is predominately expressed in endothelial cells and required for angiogenesis. Yes-associated protein (YAP) plays an important role in tumor angiogenesis. This study investigated the cooperative role of HSPA12B and YAP in angiogenesis after MI. Silencing of either HSPA12B or YAP impaired hypoxia-promoted endothelial cell proliferation and angiogenesis. Deficiency of HSPA12B suppressed YAP expression and nuclear translocation after hypoxia. Knockdown of YAP attenuated hypoxia-stimulated HSPA12B nuclear translocation and abrogated HSPA12B-promoted endothelial cell angiogenesis. Mechanistically, hypoxia induced an interaction between endothelial HSPA12B and YAP. ChIP assay showed that HSPA12B is a target gene of YAP/transcriptional enhanced associated domain 4 (TEAD4) and a coactivator in YAP-associated angiogenesis. In vivo studies using the MI model showed that endothelial cell–specific deficiency of HSPA12B (eHspa12b–/–) or YAP (eYap–/–) impaired angiogenesis and exacerbated cardiac dysfunction compared with WT mice. MI increased YAP expression and nuclear translocation in WT hearts but not eHspa12b–/– hearts. HSPA12B expression and nuclear translocation were upregulated in WT MI hearts but not eYap–/– MI myocardium. Our data demonstrate that endothelial HSPA12B is a target and coactivator for YAP/TEAD4 and cooperates with YAP to regulate endothelial angiogenesis after MI.

Exogenous IL-4 shuts off pro-inflammation in neutrophils while stimulating anti-inflammation in macrophages to induce neutrophil phagocytosis following myocardial infarction

IntroductionMacrophages and neutrophils are primary leukocytes involved in the inflammatory response to myocardial infarction (MI). While interleukin (IL)-4 is an in vitro anti-inflammatory stimulus, the MI myocardium does not express a considerable amount of IL-4 but does express IL4 receptors. We hypothesized that continuous exogenous IL-4 infusion starting 24 h after MI would promote a polarization switch in inflammatory cells towards a reparative phenotype. MethodsC57BL/6J male mice (3–6 months of age) were subcutaneously infused with either saline (n = 17) or IL-4 (20 ng/g/day; n = 17) beginning 24 h after MI and evaluated at MI day 3. ResultsMacrophages and neutrophils were isolated ex vivo from the infarct region and examined. Exogenous IL-4 decreased pro-inflammatory Ccl3, Il12a, Tnfa, and Tgfb1 in neutrophils and increased anti-inflammatory Arg1 and Ym1 in macrophages (all p < .05). Tissue clearance by IL-4 treated neutrophils was not different, while selective phagocytosis of neutrophils doubled in IL-4 treated macrophages (p < .05). Of 24,339 genes examined by RNA-sequencing, 2042 genes were differentially expressed in macrophages from IL-4 stimulated infarct (all FDR p < .05). Pdgfc gene expression was ranked first, increasing 3-fold in macrophages stimulated with IL-4 (p = 1 × 10−9). Importantly, changes in macrophage physiology and transcriptome occurred in the absence of global LV effects. Bone marrow derived monocytes stimulated with mouse recombinant PDGF-CC protein (10 μg/ml) or PDGF-CC blocking antibody (200 ng/ml) did not change Arg1 or Ym1 expression, indicating the in vivo effect of IL-4 to stimulate macrophage anti-inflammatory gene expression was independent of PDGF-CC. ConclusionsOur results indicate that exogenous IL-4 promotes inflammation resolution by turning off pro-inflammation in neutrophils while stimulating anti-inflammation in macrophages to mediate removal of apoptotic neutrophils.

Exogenous IL‐4 Promotes Myocardial Infarction Repair by Turning off Pro‐Inflammation in Neutrophils while Stimulating Anti‐Inflammation in Macrophages to Induce Neutrophil Phagocytosis

Macrophages and neutrophils are primary leukocytes involved in the inflammatory response to myocardial infarction (MI). While IL‐4 is an in vitro stimulus for anti‐inflammation, the MI myocardium does not express IL‐4. We hypothesized that continuous exogenous IL‐4 infusion starting 24 h after MI would promote a polarization switch in inflammatory cells towards a reparative phenotype. C57BL/6J male mice (3–6 months of age) were subcutaneously infused with either saline (n=17) or IL‐4 (20 ng/g/day; n=17) and evaluated at MI day 3. Macrophages and neutrophils were isolated ex vivo from the infarct region and examined for pro‐inflammatory genes (Ccl3, Ccl5, Il1b, Il12a, and Tnfa) and anti‐inflammatory genes (Arg1, Ym1, Mrc1, Il10, and Tgfb, Il6). Exogenous IL‐4 decreased pro‐inflammatory Ccl3, IL‐12a, Tnfa, and Tgfb1 in neutrophils while increasing anti‐inflammatory Arg1 and Ym1 in macrophages (all p&lt;0.05); none of the other markers were different. Tissue clearance by IL‐4 treated neutrophils was not different, while phagocytosis of neutrophils, but not myocytes, doubled in IL‐4 treated macrophages (p&lt;0.05). Because macrophage cell physiology was influenced by IL‐4, whole transcriptome analysis of macrophages isolated from the infarct regions of IL‐4 (n=10) or saline (n=11) treated mice was performed by RNA‐sequencing. Of the 24,341 genes sequenced, 2,042 genes were differentially expressed with IL‐4 stimulation (all p&lt;0.05). Pdgfc gene expression was ranked first by p value, increasing from 1.8±0.3 in saline treated macrophages to 5.4±0.2 FPKM units in macrophages stimulated with IL‐4 (p=1×10−9). Importantly, changes in macrophage physiology and transcriptome occurred before differences in cardiac physiology evaluated by echocardiography, which allowed the isolation of effects in cell phenotype not induced by global myocardial effects. Bone marrow derived monocytes stimulated with mouse recombinant PDGF‐CC protein (10 μg/ml) or PDGF‐CC blocking antibody (10 μg/ml) revealed no effect on Arg1 or Ym1 expression, indicating the in vivo effect of IL‐4 to stimulate macrophage gene expression was independent of PDGF‐CC. Altogether, our results indicate that exogenous IL‐4 promotes inflammation resolution by turning off pro‐inflammation in neutrophils while stimulating anti‐inflammation in macrophages to induce neutrophil phagocytosis.Support or Funding InformationNational Institutes of Health under Award Numbers HL075360, HL129823, and HL137319, Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development under Award Numbers 5I01BX000505

Effect of erythropoietin on bone marrow mononuclear cells

Stem/progenitor cells are considered an alternative method of heart failure therapy by promoting regeneration of damaged myocardium in myocardial infarction. Effectiveness of cell therapy depends on the population composition and functional activity of the cell graft, and, in turn, it depends on the conditions of microenvironment. Cultivation of stem/progenitor cells with erythropoietin stimulates proliferative potential causing in vitro resistance to hypoxia, and in vivo stimulation of angiogenesis. We aimed for assessing effects of erythropoietin upon hematopoietic cells. We studied some effects of short-term incubation of bone marrow mononuclear cells (BM-MNCs) in patients with coronary heart disease (CHD) with erythropoietin upon cellular phenotype, cell cycle, apoptosis and their proliferative potential. BM-MNCs were isolated from bone marrow aspirate from patients with CHD in a density gradient, then incubated for 60 minutes with erythropoietin (33.4 IU/ml). Using flow cytometric assay of the total BM-MNCs pool, we have shown there endothelial progenitor cells at different stages of maturation and differentiation, mesenchymal stem cells are. Their total number did not exceed 30%. Short-term incubation of BM-MNCs with erythropoietin reduces expression of CD184 “homing receptor” molecules on CD34+ cells, and causes increase of CD184 on CD31+ cells in the BM-MNCs pool (p &amp;lt; 0.05). In addition, erythropoietin has been shown to cause a delay of CD34+ cells in the resting phase (G0G1), reduce a proportion of cells in the synthetic phase (S) and mitosis (G2/M) (p&amp;lt;0.05), and does not affect apoptosis, as shown by Annexin V-FITC Apoptosis Detection Kit. Erythropoietin had no significant effects on expression on BM-MNCs surface molecules involved in providing adhesion, such as CD18, CD29, CD44, CD49a, CD54, CD62E, CD146, and CD202b. MTT-method has shown that the short-term preincubation of BM-MNCs with erythropoietin contributed to a significant decrease in proliferative activity of BM-MNCs (p &amp;lt; 0.05). However, there was a tendency towards increased resistance of erythropoietin-pretreated BM-MNCs to oxidative stress induced by hydrogen peroxide. We have also revealed a correlation between the numbers of endothelial progenitor cells at different stages of differentiation, and numbers of hematopoietic stem cells in the total BM-MNCs pool. The number of CD34+/CD133+, CD34- / CD31+, CD45+/EpoR+, and CD34+/EpoR+ in BM-MNCs pool are dependent on the age of patients. Hence, a short-term incubation of BM-MNCs with erythropoietin promotes the cells to be retained in resting phase of the cell cycle, thus, in turn, helping to reduce proliferative potential of BM-MNCs.

Abstract 260: Adverse Transverse-Tubule Remodeling in a Rat Model of Heart Failure is Attenuated by Triiodothyronine (T3) Treatment

Pre-clinical animal studies have shown that triiodothyronine (T3) replacement therapy improves cardiac contractile function after myocardial infarction (MI). We hypothesized that T3 treatment could prevent adverse post-MI cardiomyocyte remodeling by maintaining T-tubule (TT) organization, thus improving contractility. Methods: Coronary artery ligation (MI) or sham surgeries were performed on female Sprague-Dawley rats (aged 12 wks), followed by treatment with T3 (5ug/kg/d) or vehicle in drinking water for 16 wks (10/gp). After echocardiographic/hemodynamic analyses, ventricular myocytes were isolated by collagenase digestion and plated on laminin-coated glass coverslips for TT analysis or analyzed for contractility using IonOptix’s edge-detection method. Live cell staining with wheat germ agglutinin (WGA)-488 or di-8-ANNEPS labeled sarcolemma and TT, and multiple z-stack images were captured by scanning confocal microscopy and TT organization measured using TTorg program. Ventricular RNA was analyzed by qPCR. Results: Echocardiography and in vivo hemodynamic measurements showed significantly improved systolic and diastolic function in T3- vs vehicle-treated MI rats. IonOpix analysis of isolated ventricular myocytes showed significant dysfunction in measures of relaxation in MI myocytes compared to sham, and improvements with T3: max relaxation velocity (Vmax), 2.98±1.41 vs 1.59±0.33, p&lt;0.05; time to Vmax (sec), 0.23±0.04 vs 0.31±0.02, p&lt;0.001, MI+T3 vs MI). Similarly, time to peak contraction was shortened by T3 treatment (0.16±0.02 vs 0.20±0.01 sec., MI+T3 vs MI; p&lt;0.01. TT power measured by TTorg analysis of WGA-488 or di-8-ANNEPS labeled myocytes showed significant disorganization of the TT system in MI myocytes that was normalized by T3-treatment (TTpower = 82±7 sham, 74±8 MI and 79±6 MI+T3; sham vs MI p&lt;0.0001; MI vs MI+T3, p&lt;0.0001). qPCR results indicated that reduced expression of Bin1, Jph2, RyR2 and LTCC in the MI myocardium was normalized by T3. In conclusion, T3 treatment prevented TT disorganization in the post-MI cardiomyocyte, normalized contractile and relaxation parameters and improved cardiac output, thus supporting the therapeutic potential of T3 in heart failure.

0053: Incidence of cardiovascular events following myocardial infarction in France: an observational analysis using a claims database

To describe the characteristics and treatments of patients having a myocardial infarction (MI) and estimate the incidence of cardiovascular events following the index MI, in the French Health Insurance database. A cohort of patients who had a MI in France between 2007 and 2011 was extracted from a claim database: the Echantillon Généraliste de Bénéficiaires (a 1% representative sample of subjects covered by the general health insurance (?600,000 patients). The incidence of cardiovascular events following the index MI was estimated using the Kaplan Meier method. 1,977 subjects were identified with an index myocardial MI: 2/3 were males, mean age=67.2 y, 20.6% had diabetes, 37.6% hypercholesterolemia and 82.4% hypertension. Cumulative incidence rates for outcomes are shown in the table. All cause mortality at 3 years (including in-hospital death) was 27% (95% CI: 25.8-29.1). This incidence was high in the 3 months following the index MI stabilized thereafter. Despite high prescription rates of post-MI treatments, rates of all-cause mortality and CV events remained high following MI. This underscores the need to improve secondary prevention. Abstratct 0053 – Table % patients treated 6 months before index MI 6 months after index MI Statins 30.7% 91.1% Ezetimibe 3.6% 4.9% Aspirine (Alone) 59.9% 11.6% Aspirine+P2Y12-I * 23.9% 76.0% Class III Antiarrhytmic 2.4% 8.4% Oral Anticoagulant 5.1% 10.1% Non-Thiazide Diuretics 19.1% 32.9% ACE Inhibitors 18.6% 71.0% Beta-Blockers 26.5% 86.0% Nitrates 9.9% 46.4% Other Antihypertensives ** 40.2% 30.3% Cumulative incidence rate (95%CI) 1 year 2 year 3 year All cause deaths *** 17.8% (16.0%;19.5%) 21.6% (20.7%;23.5%) 27.0% (25.8%;29.1%) Recurrent MI 3.1% (2.3%;3.8%) 4.1% (3.2%;5.0%) 4,7% (3.7%;5.7%) Stroke orTIA 1.9% (1.3%;2.5%) 3.1% (2.3%;3.9%) 4.1% (3.1%;5.0%) Composite of death *** / reinfarction/stroke 20.7% (18.9%;22.5%) 26.0% (24.0%;28.0%) 32.1% (29.8%;34.3%) * mostly clopidogrel ** thiazide diuretics, angiotensin II receptor blockers, CCBs *** including in-hospital deaths

ECG imaging of altered electrical properties of myocardium in myocardial infarction

Temporal complexity of depolarization indicates myocardial sympathetic denervation and predicts sudden cardiac arrest in patients with ischemic cardiomyopathy and poor left ventricular ejection fraction Salah Al-Zaiti, CRNP, PhD, Amit Sethi, OTR/L, PhD, Mary Carey, RN, PhD, FAHA, John Canty,MD, FAHA, James Fallavollita, MD, FAHA University of Pittsburgh, Pittsburgh, PA, USA University of Rochester Medical Center, Rochester NY, USA VA WNY Health Care System at Buffalo, Buffalo, NY, USA The Center for Research in Cardiovascular Medicine, Buffalo, NY, USA The State University of New York at Buffalo, Buffalo, NY, USA

Augmented Cardiac Formation of Oxidatively-Induced Carbonylated Proteins Accompanies the Increased Functional Severity of Post-Myocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus

Heart failure (HF) is a dominant cause for the higher mortality of diabetics after myocardial infarction (MI). In the present investigation, we have discovered that higher levels of oxidative stress (OS)-induced carbonylated proteins accompany worsening post-MI HF in the presence of type 1 diabetes. These findings provide a mechanistic link between amplified OS and exacerbation of post-infarction HF in diabetes. Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) manifest an increased incidence of subsequent heart failure (HF). We have previously shown that after MI, type 1 DM is associated with accentuated myocardial oxidative stress (OS) and concomitant worsening of left ventricular (LV) function. However, the precise mechanisms whereby type 1 DM-enhanced OS adversely affects HF after MI remain obscure. As carbonylation of proteins is an irreversible post-translational modification induced only by OS that often leads to the loss of function, we analyzed protein-bound carbonyls in the surviving LV myocardium of MI and DM+MI rats in relation to residual LV function. Type 1 DM was induced in rats via administration of streptozotocin. Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by coronary artery ligation. Residual LV function and remodeling was assessed at 4 weeks post-MI by echocardiography. Myocardial carbonylated proteins were detected through OxyBlot analysis, and identified by mass spectrometry. Compared with MI rats, DM+MI rats exhibited significantly poorer residual LV systolic function and elevated wet to dry weight ratios of the lungs. Protein carbonyl content in cardiac tissue and isolated heart mitochondria of DM+MI rats was 20% and 48% higher, respectively, versus MI rats. Anti-oxidative enzymes and fatty acid utilization proteins were among the carbonylated protein candidates identified. These findings implicate myocardial protein carbonylation as part of the molecular pathophysiology of aggravated HF in the type 1 diabetic post-infarction heart.

Abstract 9111: Augmented Cardiac Formation of Oxidatively-Induced Carbonylated Proteins Accompanies the Increased Functional Severity of Post-Myocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher cardiovascular mortality than those without DM. We have previously shown that after MI, type 1 DM is associated with accentuated myocardial oxidative stress (OS) and concomitant worsening of left ventricular (LV) function. However, the precise mechanisms whereby type 1 DM-enhanced OS adversely affects HF after MI remain obscure. As carbonylation of proteins is an irreversible post-translational modification induced only by OS that often leads to the loss of function, we analyzed protein-bound carbonyls in the viable LV myocardium of MI and DM + MI rats in relation to residual LV function at 4 weeks post-MI. Type 1 DM was induced in male Sprague-Dawley rats by a single injection of streptozotocin (65 mg/kg i.p.). Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by left coronary artery ligation. Residual LV function was assessed by echocardiography. Carbonylated proteins were detected through oxyblot analysis, and identified by mass spectrometry. Mortality following induction of MI was higher among the DM + MI group compared to the MI group (47% vs. 33%, respectively). Compared with MI rats, DM + MI rats exhibited significantly greater LV systolic dysfunction as well as elevated wet to dry weight ratios of the lungs (Table), indicating an increased functional severity of HF among the DM + MI group. No difference in the weight of myocardial scar caused by the infarction was observed between the MI and DM + MI groups (Table). Protein carbonyl content in cardiac tissue and isolated mitochondria of DM + MI rats was 20% and 48% higher, respectively, than in MI rats (n=4/group). Anti-oxidative enzymes and fatty acid utilization proteins were the predominant carbonylated proteins identified. The findings of this in vivo study implicate protein carbonylation as part of the molecular pathophysiology of aggravated HF in the type 1 diabetic post-infarction heart.

Abstract 17546: No Decrease in the Incidence of Heart Failure Following Acute Myocardial Infarction in the Years 1994-2006

Objectives: Heart failure (HF) is a common serious complication following acute myocardial infarction (MI). We studied whether improvements in MI treatment had an impact on the incidence of post-MI HF. Methods: We used data from the Myocardial Infarction Data Acquisition System (MIDAS) database, selecting all first myocardial infarctions admitted to non-federal hospitals in the state of New Jersey between 1994 and 2006. We studied the incidence of HF during admission, within 28 days of admission, and 28 days to one year from admission. Using a multivariate model, we assessed which clinical characteristics had an impact on the incidence of HF. Results: A total of 185,483 patients were admitted with a first MI. The incidence of HF within one year was 38.2% in 1994 and remained stable through 2006 (range 37.6% - 41.0%). The incidence of HF in patients with subendocardial MI was also stable and significantly higher than that observed in transmural MI (43.7% vs. 30.9%, p&lt;0.0001). However, among patients with transmural MI, HF incidence within one year declined from 32.8% in 1994 to 26.3% in 2006 (p&lt;0.0001), mainly due to a decline in HF during the index admission. HF incidence after discharge remained stable in transmural MI and increased in subendocardial MI. By multivariate modeling, older age, female gender, black race, diabetes, atrial fibrillation, renal disease, and chronic obstructive pulmonary disease were associated with higher incidence of HF (p&lt;0.0001 for all). Patient age and the rates of diabetes, hypertension, renal disease, cancer, and anemia increased during the period of observation (p&lt;0.0001). Conclusions: Despite major advances in management of acute myocardial MI, the incidence of post-MI HF remained stable. The only decline observed was in HF during an index admission for transmural MI. Subendocardial MI was associated with a higher HF incidence. These findings may be due to the increasing age and rates of comborbidities among patients with first MI.

Targeting Sarcoplasmic Reticulum Ca 2+ Uptake to Improve Heart Failure

The association between disturbed Ca2+ handling within cardiac myocytes and heart failure has been established in many studies of human myocardium from patients with end-stage heart failure undergoing heart transplantation.1–3 The causality is more difficult to prove at this late time point.4 Yet, the observed reduction in the Ca2+ available for myofilament activation and reduced Ca2+ reuptake in the sarcoplasmic reticulum (SR) are obvious targets to improve myocyte contraction and relaxation and, thus, cardiac pump function. Early pharmacotherapy mimicked adrenergic stimulation, the physiological boost of contraction and relaxation, by raising cAMP. Although this worked well, and still does, for acute treatment, the long-term results showed an increase in mortality. Alternative therapy to enhance myofilament sensitivity seems a safer alternative.5,6 Many animal models have been designed to reproduce heart failure in humans allowing study of myocyte remodeling at different stages of disease. The most extensively studied are genetic predisposition (the cardiomyopathic hamster), pressure overload (hypertensive models, aortic banding), myocardial infarction (MI), and tachycardia pacing (in dog or rabbit). Except for genetic model, obvious discrepancies with human disease are the fast time course of the disease and the relative lack of complexity, as, for example, the absence of atherosclerosis in most models of MI. Nevertheless these models have been very useful to demonstrate that very often in vivo cardiac dysfunction paralleled changes in Ca2+ handling, suggesting causality. It should be pointed out that disturbed Ca2+ handling is not always the one or only cause of in vivo heart failure. Loss of myocardium in MI, increased loading on healthy myocardium by the scar tissue, reduced perfusion distal to coronary stenosis, suboptimal preload because of stiffness of the ventricle with hypertrophy, and matrix remodeling are but a few factors that can contribute to global cardiac dysfunction …

Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen

We tested the hypothesis that chronically reducing the heart rate in infarcted middle-aged rats using ivabradine (IVA) would induce arteriolar growth and attenuate perivascular collagen and, thereby, improve maximal perfusion and coronary reserve in the surviving myocardium. Myocardial infarction (MI) was induced in 12-mo-old male Sprague-Dawley rats, which were then treated with either IVA (10.5 mg.kg(-1).day(-1); MI + IVA) or placebo (MI) via intraperitoneal osmotic pumps for 4 wk. Four weeks of IVA treatment limited the increase in left ventricular end-diastolic pressure and the decrease in ejection fraction but did not affect the size of the infarct, the magnitude of myocyte hypertrophy, or the degree of arteriolar and capillary growth. However, treatment reduced interstitial and periarteriolar collagen in the surviving myocardium of MI + IVA rats. The reduced periarteriolar collagen content was associated with improvement in maximal myocardial perfusion and coronary reserve. Although the rates of proliferation of periarteriolar fibroblasts were similar in the MI and MI + IVA groups, the expression levels of the AT(1) receptor and transforming growth factor (TGF)-beta(1) in the myocardium, as well as the plasma level of the ANG II peptide, were lower in treated rats 14 days after MI. Therefore, our data reveal that improved maximal myocardial perfusion and coronary reserve in MI + IVA rats are most likely the result of reduced periarteriolar collagen rather than enhanced arteriolar growth.

Evaluation of transmural distribution of viable muscle by myocardial strain profile and dobutamine stress echocardiography

Transmural distribution of viable myocardium in the ischemic myocardium has not been quantified and fully elucidated. To address this issue, we evaluated transmural myocardial strain profile (TMSP) in dogs with myocardial infarction using a newly developed tissue strain imaging. TMSP was obtained from the posterior wall at the epicardial left ventricular short-axis view in 13 anesthetized open-chest dogs. After control measurements, the left circumflex coronary artery was occluded for 90 min to induce subendocardial infarction (SMI). Subsequently, latex microbeads (90 microm) were injected in the same artery to create transmural infarction (TMI). In each stage, measurements were done before and after dobutamine challenge (10 microg.kg(-1).min(-1) for 10 min) to estimate transmural myocardial viability. Strain in the subendocardium in the control stage increased by dobutamine (from 53.6 +/- 17.1 to 73.3 +/- 21.8%, P < 0.001), whereas that in SMI and TMI stages was almost zero at baseline and did not increase significantly by dobutamine [from 0.8 +/- 8.8 to 1.3 +/- 7.0%, P = not significant (NS) for SMI, from -3.9 +/- 5.6 to -1.9 +/- 6.0%, P = NS for TMI]. Strain in the subepicardium increased by dobutamine in the control stage (from 23.9 +/- 6.1 to 26.3 +/- 6.4%, P < 0.05) and in the SMI stage (from 12.4 +/- 7.3 to 27.1 +/- 8.8%, P < 0.005), whereas that in the TMI stage did not change (from -1.0 +/- 7.8 to -0.7 +/- 8.3%, P = NS). In SMI, the subendocardial contraction was lost, but the subepicardium showed a significant increase in contraction with dobutamine. However, in TMI, even the subepicardial increase was not seen. Assessment of transmural strain profile using tissue strain imaging was a new and useful method to estimate transmural distribution of the viable myocardium in myocardial infarction.