Post-infarct Treatment Research Articles

Low n-6/n-3 PUFA ratio improves inflammation and myocardial ischemic reperfusion injury.

This study investigated the potential effect of n-6/n-3 polyunsaturated fatty acids (PUFA) on inflammation and myocardial ischemic reperfusion injury (MIRI) in rats, together with the underlying protective mechanisms, and screen out most effective ratio of n-6/n-3 within limits. The rats with pre-infarct treatment were distributed among 5 groups according to the n-6/n-3 ratio (36:1; 1:1, 5:1, 10:1, 50:1); for the post-infarct treatment, the rats were distributed among 6 groups, including the control group (36:1) which was subjected to a sham procedure; the model group (36:1); and 4 test groups (n-6/n-3 ratio: 1:1, 5:1, 10:1, 50:1). All of the rats were fed a purple perilla seed oil and safflower oil-based fatty emulsion. The serum levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were determined using enzyme-linked immunosorbent assay. Staining with triphenyl tetrazolium chloride, hematoxylin and eosin, or Masson's trichrome was performed for histological examination. Cardiomyocyte apoptosis was examined by TUNEL assay. Western blotting was performed to examine the expression levels of apoptosis-related proteins and signaling pathway proteins. Our data indicate that in both the pre-infarct treatment and post-infarct treatment, low ratios of n-6/n-3 PUFAs significantly inhibited the levels of serum inflammatory factors, the infarct size of MIRI rats, number of cardiomyocytes undergoing apoptosis, and the expression levels of caspase-3, Bcl-2, and Bax in the MIRI group. Thus a low ratio of n-6/n-3 PUFAs ameliorates inflammation and myocardial ischemic reperfusion injury.

Sumatriptan protects against myocardial ischaemia-reperfusion injury by inhibition of inflammation in rat model.

Ischemic heart disease is a leading cause of death on a global scale, placing major socio-economic burdens on health systems worldwide. Myocardial ischaemia and reperfusion (I/R)-induced tissue injury is associated with alteration in activity of inflammatory system and nitric oxide pathway. Sumatriptan, which is mainly used to relieve migraine headache, has recently been shown to exert anti-inflammatory properties. In this study, we aimed to assess the possible cardioprotective effect of sumatriptan in a rat model of I/R injury. Male Wistar rats were subjected to 30-min ligation of left anterior descending coronary artery and 120-min reperfusion. Animals were randomly divided into five groups: (1) Sham (2) I/R (3) I/R treated with sumatriptan (0.3 mg/kg i.p.) 20min after induction of I/R rats, (4) GR127935 (a selective antagonist of 5-HT1B/D serotonin receptors; 0.3mg/kg) 20min after induction of I/R, and (5) GR127935 (0.3mg/kg) 15min before administration of sumatriptan. Post-infarct treatment with sumatriptan increased left ventricular function, which was damaged in I/R animal's heart. Sumatriptan (0.3mg/kg) decreased lipid peroxidation, CK-MB and lactate dehydrogenase levels; tumor necrosis factor concentration; and Nf-ҡB' protein production. Treatment with sumatriptan significantly increased the endothelial nitric oxide synthase (eNOS) expression consequences nitric oxide metabolites' level in I/R rats. Also, injection of sumatriptan remarkably decreased myocardial tissue injury assessed by histopathological study. These findings suggest that sumatriptan may attenuate I/R injury via modulating the inflammatory responses and endothelial NOS activity. But therapeutic index of sumatriptan is narrow according to the result of this study.

Post-infarct treatment with [Pyr1]apelin-13 exerts anti-remodelling and anti-apoptotic effects in rats' hearts.

Ischaemic heart disease is the main cause of mortality in the world. After myocardial infarction (MI) cardiomyocytes apoptosis and ventricular remodelling have occurred. Apelin is a peptide that has been shown to exert cardioprotective effects. The aim of this study was to investigate the anti-apoptotic and anti-remodelling effects of [Pyr¹]apelin-13 in the rat model of post-MI. Thirty-six male Wistar rats were randomly divided into three groups: (1) sham, (2) MI, and (3) MI treated with [Pyr¹] apelin-13 (MI+Apel). MI animals were subjected to 30-min ligation of the left anterior descending coronary artery (LAD) and 14 days of reperfusion. Twenty-four hours after LAD ligation, [Pyr¹]apelin-13 (10 nmol/kg/day, i.p.) was administered for five consecutive days. Hypertrophic parameters, left ventricular (LV) remodelling, and gene expression of Apel, apelin receptor (Apelr), Bax, caspase-3 (Casp-3), and Bcl-2 by real-time polymerase chain reaction and cardiomyocytes apoptosis by TUNEL immunostaining were assessed on day 14 post-MI. Post-infarct treatment with [Pyr¹]apelin-13 improved myocardial hypertrophic and LV remodelling parameters and led to a significant increase in the expression of Apel, Apelr, and Bcl-2, and a decrease in the expression of Bax and Casp-3. Furthermore, treatment with [Pyr¹]apelin-13 decreased cardiomyocyte apoptosis. [Pyr¹]apelin-13 has anti-hypertrophic, anti-remodelling, and anti-apoptotic effects via overexpression of Apel, Apelr, and Bcl-2 and reduces gene expression of Bax and Casp-3 in the infarcted myocardium, which can in turn lead to repair myocardium.

Measurement and display of regional myocardial motion during post infarct treatment.

Quantitative assessment of 3-D regional heart motion has significant potential to provide more specific diagnosis of cardiac malfunction than currently possible. Using functional parametric mapping, regional myocardial motion during a cardiac cycle can be color-mapped onto a deformable heart model to provide better understanding of the structure-to-function relationships in the myocardium, including regional patterns of akinesis or dyskinesis associated with ischemia or infarction. In this study, 3-D reconstructions of human hearts were obtained from Electron-Beam Computed Tomography [1] (EB-CT), comparing stages of treatment after myocardial infarction.

Post-infarct treatment with [Pyr1]apelin-13 improves myocardial function by increasing neovascularization and overexpression of angiogenic growth factors in rats

Ischemic heart disease is the leading cause of mortality in the world. Angiogenesis is important for cardiac repair after myocardial infarction (MI) as restores blood supply to the ischemic myocardium and preserves cardiac function. Apelin is a peptide that has been recently shown to potentiate angiogenesis. The aim of this study was to investigate angiogenic effects of [Pyr1]apelin-13 in the rat model of post-MI. Male Wistar rats (n=36) were randomly divided into three groups: (1) sham (2) MI and (3) MI treated with [Pyr1]apelin-13 (MI+Apel). MI animals were subjected to 30min left anterior descending coronary artery (LAD) ligation and 14 days of reperfusion. Twenty-four hours after LAD ligation, [Pyr1]apelin-13 (10nmol/kg/day) was administered i.p. for 5 days. Hemodynamic functions by catheter introduced into the left ventricle (LV), myocardial fibrosis by Masson׳s trichrome staining, gene expression of vascular endothelial growth factor-A (VEGFA), VEGF receptor-2 (Kdr), Ang-1 (angiopoietin-1), Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2) and eNOS by Real-time polymerase chain reaction (Real-Time PCR) and myocardial angiogenesis by CD31 imunostaining were assessed at day 14 post-MI. Post-infarct treatment with [Pyr1]apelin-13 improved LV function and decreased myocardial fibrosis. [Pyr1]apelin-13 treatment led to a significant increase in the expression of VEGFA, Kdr, Ang-1, Tie2 and eNOS. Further, treatment with [Pyr1]apelin-13 promoted capillary density. [Pyr1]apelin-13 has angiogenic and anti-fibrotic activity via formation of new blood vessels and overexpression of VEGFA, Kdr, Ang-1, Tie2 and eNOS in the infarcted myocardium which could in turn repair myocardium and improve LV function.

Post-infarct Treatment with MicroRNA145 Protects the Heart against Myocardial Ischemia-reperfusion Injury Through Acceleration of Myocyte Autophagy

Post-infarct Treatment with MicroRNA145 Protects the Heart against Myocardial Ischemia-reperfusion Injury Through Acceleration of Myocyte Autophagy

Abstract 9434: Post-infarct Treatment With Microrna145 Protects the Heart Against Myocardial Ischemia-reperfusion Injury Through Acceleration of Myocyte Autophagy

Background: We previously reported that microRNA145 (miRNA145) attenuates the ischemia-reperfusion injury. However, the mechanism how miRNA145 reduces the myocardial infarct size is still unclear. Objective: We aimed to investigate whether post-infarct treatment with miRNA145 reduces myocardial infarct size and its precise mechanism in a rabbit model of myocardial infarction. Methods: Male Japanese white rabbits underwent 30 min of coronary occlusion followed by 14 days of reperfusion. Rabbits received intravenous injection of saline (control group, n=7) or 0.035 mg/kg of miRNA145 encapsulated with liposome (miRNA145 group, n=7) immediately after reperfusion. At 14 days after reperefusion, rabbits were sacrificed and the hearts were removed. The area at risk and infarct areas were measured by evans blue dye and TTC staining, respectively. The infarct size was calculated as a percentage of the risk area of the left ventricle. Heart tissues were sampled and the morphological changes were investigated by electron microscopy, and the expression of LC3B, an indicator of autophagy, was assessed by western blot analysis. In another series of experiments, rat myoblast H9C2 were treated with 20 nM of miRNA145 and investigated the morphological changes by electron microscopy and the expression of LC3B by western blot analysis. Results: Post-infarct treatment with miRNA145 significantly reduced the myocardial infarct size (16.0±3.1 %) as compared to the control (28.7±6.1 %) group. Post-infarct treatment with miRNA145 significantly improved LV remodeling and improved ±dp/dt as compared to the control group. Both in vitro myoblast and in vivo experiments, treatment with miRNA145 induced autophagic changes such as autophagosome and autolysosome, and activated LC3B. Conclusions: It is suggested that post-infarct treatment with miRNA145 attenuated ischemia-reperfusion injury through acceleration of myocyte autophagy. The miRNA145 may be a promising strategy for treatment of acute myocardial infarction.

Post-infarct Treatment with MicroRNA145 Protects the Heart Against Myocardial Ischemia-reperfusion Injury through Acceleration of Myocyte Autophagy

Background: We previously reported that microRNA145 (miR-145) significantly reduced the myocardial infarct size and improved the function of left ventricle. It has been reported that autophagy is activated in cardiomyocytes in ischemic heart disease. We investigated whether miR-145 would reduce the myocardial infarct size through acceleration of autophagy. Objective: We aimed to investigate whether administration of miR-145 would affect myocyte autophagy in a rabbit model of myocardial infarction (MI). Methods: Male Japanese white rabbits underwent 30 min of coronary occlusion followed by 2 and 14 days of reperfusion. Saline or miR-145 (0.035 mg/kg) was intravenous injected immediately after reperfusion. Some of the rabbits treated with miR-145 were administered chloroquine that acts by inhibiting vacuolar H+-ATPase and autophagosome fusion to prevent the final digestion step during autophagy immediately after reperfusion followed by 30 min of coronary ligation. On day 2 and day 14 post-MI, rabbits were sacrificed and the hearts were removed. Heart tissues were sampled and devided into three area; remote area, borderline area and infarct area. The morphological changes were assessed by electron microscopy, and the expressions of LC3B, Akt, phosphorylated (p)-Akt, ERK and p-ERK were assessed by western blot analysis. Results: The MI size as a percentage of area at risk was significantly smaller in the miR-145 group than that in the control group. Treatment with chloroquine blocked the infarct size-reducing effect of miR-145. These were observed both in 2days and 14days reperfusion groups. Electron microscopic findings showed the autophagic change in cardiomyocytes in both the control and miRNA145 groups on day 2 and day 14 post-MI. Western blot analysis showed that transition from LC3B-I to LC3B-II was significantly stronger in the miR-145 group than in the control group. The expression of p-Akt in the ischemic area was upregulated in the miR-145 group on day 2 post-MI. However, there was no significant difference in the expression of Akt, ERK and p-ERK between 2 groups on day 2 and day 14 post-MI. Conclusions: It is suggested that post-infarct treatment with miR-145 attenuated ischemia-reperfusion injury through acceleration of myocyte autophagy.

Prognostic implications of left ventricular end-diastolic pressure during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: Findings from the Assessment of Pexelizumab in Acute Myocardial Infarction study

Left ventricular end-diastolic pressure (LVEDP) is frequently measured during primary percutaneous coronary intervention (PCI). However, little is known of this measurement's utility in predicting outcomes or informing treatment decisions. We sought to determine the prognostic value of LVEDP measured during primary PCI for ST-segment elevation myocardial infarction (STEMI). We studied 1,909 (33.2%) of 5,745 STEMI patients in whom LVEDP was measured during primary PCI in the APEX-AMI trial. Cox regression analysis was used to evaluate whether LVEDP was an independent predictor of mortality and the composite of death, cardiogenic shock, or congestive heart failure (CHF) at 90 days. The median (25th, 75th percentiles) LVEDP level was 22 mm Hg (16, 29); compared with patients with LVEDP ≤ 22 mm Hg, those with LVEDP > 22 mm Hg had higher rates of CHF (7.3% vs 3.1%, P < .001), cardiogenic shock (4.6% vs 1.7%, P < .001), and death (4.1% vs 2.2%, P = .014) at 90 days. After multivariable adjustment, LVEDP was associated with increased risk of mortality through 90 days (adjusted hazard ratio 1.22, 95% CI 1.02-1.46, per 5-mmHg increase, P = .044) and the composite of death, cardiogenic shock, or CHF within the first 2 days (adjusted hazard ratio 1.40, 95% CI 1.23-1.59, per 5-mm Hg increase, P < .001), but not from day 3 to 90 (P = .25). Left ventricular end-diastolic pressure measured during primary PCI for STEMI is an independent predictor of inhospital and longer term cardiovascular outcomes. Measuring LVEDP may be useful to stratify patient risk and guide postinfarct treatment.

Post-infarct treatment with microRNA145 reduces myocardial infarct size through acceleration of myocyte autophagy in rabbits

Background: We previously reported that microRNA145 (miRNA145) attenuates the ischemia-reperfusion injury. However, it is not still unclear how miRNA145 attenuates the ischemia-reperfusion injury. Objective: We aimed to investigate whether post-infarct treatment with miRNA145 reduces myocardial infarct size and its precise mechanism in a rabbit model of myocardial infarction. Methods: Male Japanese white rabbits underwent 30 min of coronary occlusion followed by 14 days of reperfusion. Rabbits received intravenous injection of saline (control group, n=7) or 0.035 mg/kg of miRNA145 encapsulated with liposome (miRNA145 group, n=7) immediately after reperfusion. At 14 days after reperfusion, rabbits were sacrificed and the hearts were removed. The area at risk and infarct areas were measured by evans blue dye and TTC staining, respectively, and the infarct size was calculated as a percentage of the risk area of the left ventricle. In another series of experiments, rat myoblast H9C2 were treated with 20 nM of miRNA145 and investigated the morphological changes by electron microscopy and signals by western blot analysis such as LC3B. Results: Post-infarct treatment with miRNA145 significantly reduced the myocardial infarct size (16.0±3.1%) as compared to the control (28.7±6.1%) group. Post-infarct treatment with miRNA145 significantly improved LV remodeling and improved ±dp/dt as compared to the control group. In the myoblast experiment, treatment with miRNA145 caused autophagic changes such as autophagosome and autolysosome, and caused activation of LC3B. Conclusions: It is suggested that post-infarct treatment with miRNA145 attenuated ischemia-reperfusion injury through acceleration of myocyte autophagy. The miRNA145 may be a promising strategy for treatment of acute myocardial infarction.

Post-infarct treatment with [Pyr1]-apelin-13 reduces myocardial damage through reduction of oxidative injury and nitric oxide enhancement in the rat model of myocardial infarction

Apelin is a newly discovered peptide that has been recently shown to have cardioprotective effects in the animal model of myocardial infarction (MI) and ischemia/reperfusion (I/R) injuries. The aim of the present study was to investigate the long term cardioprotective effect of [Pyr1]-apelin-13 in the rat model of MI. Male Wistar rats (n=22) were randomly divided into three groups: (1) sham operated group (2) control MI group and (3) MI treated with apelin (MI-AP group). MI animals were subjected to 30min of left anterior descending coronary artery (LAD) ligation and 14 days of reperfusion. 24h after LAD ligation, apelin (10nmol/kg/day) was administered i.p. for 5 days. Blood sampling was performed at days 1, 3, 5 and 7 after MI for determination of serum changes of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), malondialdehyde (MDA) and nitric oxide (NO). Myocardial infarct size (IS) and hemodynamic function were also measured at the end of the study at day 14. We found out that post infarct treatment with apelin decreases infarct size, serum levels of LDH, CK-MB and MDA and increases heart rate and serum level of NO in the consecutive days, but there were no significant differences in blood pressure in the MI-AP group in comparison with MI. In conclusion, apelin has long term cardioprotective effects against myocardial infarction through attenuation of cardiac tissue injury and lipid peroxidation and enhancement of NO production.

Development of cardiac support bioprostheses for ventricular restoration and myocardial regeneration

Ventricular constraint devices made of polyester and nitinol have been used to treat heart failure patients. Long-term follow-up has not demonstrated significant benefits, probably due to the lack of effects on myocardial tissue and to the risk of diastolic dysfunction. The goal of this experimental study is to improve ventricular constraint therapy by associating stem cell intrainfarct implantation and a cell-seeded collagen scaffold as an interface between the constraint device and the epicardium. In a sheep ischaemic model, three study groups were created: Group 1: coronary occlusion without treatment (control group). Group 2: postinfarct ventricular constraint using a polyester device (Acorn CorCap). Group 3: postinfarct treatment with stem cells associated with collagen matrix and the polyester device. Autologous adipose mesenchymal stem cells cultured in hypoxic conditions were injected into the infarct and seeded into the collagen matrix. At 3 months, echocardiography showed the limitation of left ventricular end-diastolic volume in animals both treated with constraint devices alone and associated with stem cells/collagen. In Group 3 (stem cell + collagen treatment), significant improvements were found in ejection fraction (EF) and diastolic function evaluated by Doppler-derived mitral deceleration time. In this group, histology showed a reduction of infarct size, with focuses of angiogenesis and minimal fibrosis interface between CorCap and the epicardium due to the interposition of the collagen matrix. Myocardial infarction treated with stem cells associated with a collagen matrix and ventricular constraint device improves systolic and diastolic function, reducing adverse remodelling and fibrosis. The application of bioactive molecules and the recent development of nanobiotechnologies should open the door for the creation of a new semi-degradable ventricular support bioprosthesis, capable of controlled stability or degradation in response to physiological conditions of the left or right heart.

Abstract 8567: Combination of Active Targeting Erythropoietin-Liposome with Sialyl Lewis X and G-CSF, is Markedly Protective against Ischemia Reperfusion Injury via EPCs Mobilization and Upregulation of p-Akt and p-ERK

Purpose: We previously reported that erythropoietin(EPO)-containing nano-size liposome with Sialyl Lewis X (SLX) and G-CSF prevent cardiac remodeling and improve cardiac function, respectively. Then we hypothesized that combination of EPO-liposome with SLX and G-CSF might be more protective against ischemia reperfusion injury than EPO-liposome with SLX or G-CSF alone. Methods: Japanese white rabbits (n=40) were subjected to 30-minute coronary occlusion followed by 14 days of reperfusion. Rabbits were administered saline (control group, i.v., n=10), G-CSF (G group, 10μ g/kg/day, i.c., for 5days, n=10), EPO-liposome with SLX (LE group, i.v., 5000IU/ml of EPO, 1ml, n=10), G-CSF + EPO-liposome with SLX (LE+G group, n=10) after reperfusion. Myocardial infarct size was calculated as a percentage of the risk area of the left ventricle. Western blot-analysis examined phosphorylation of Akt and ERK, and expression of E- and P-selectin in the ischemic myocardium at 14days of reperfusion. We also performed fluorescence-activated cell sorter (FACS) analysis of endothelial progenitor cells (EPCs) to evaluate CD34 + /CXCR4 + cell mobilization at 7 days after reperfusion. Results: The infarct size was significantly smaller in the LE+G group (14.0±2.5%) than in the control group (29.0±5.4%), G group (20.3±5.6%) or LE group (18.7±3.7%). Western blot-analysis showed a higher expression of phosphorylated(p)-Akt and p-ERK and expression of E- and P-selectin in the infarct area of the LE+G group than the others. Serum SDF-1 level at 2 days after reperfusion was higher in the G group and the LE+G group than in the Control group or the LE group. The percentages of CD34 + /CXCR4 + cells among total peripheral blood mononuclear cells of G group and LE+G group were higher than the others. Conclusions: Combination of post-infarct treatment with G-CSF and EPO-liposome with SLX markedly reduced the infarct size via EPCs mobilization and upregulation of p-Akt and p-ERK in the ischemic myocardium. This combination therapy may provide a new strategy for the treatment of myocardial infarction.

Stem Cell Therapy for the Treatment of Myocardial Infarction

Despite timely reperfusion and subsequent optimal postinfarct pharmacotherapy and device-based treatment, the outcome in patients with severe myocardial infarction remains unfavourable. Myocardial salvage is incomplete, resulting in adverse left ventricular remodeling with concomitant morbidity and mortality. The combined risk of recurrent myocardial infarction, death or readmission for heart failure amounts to 25 % within the first year, highlighting the need for additional treatment strategies. Recent and rapidly evolving insights in cardiac biology, recognizing endogenous repair capabilities of the adult human heart, paved the path towards progenitor or stem cell based cardiac protection and repair strategies following ischemic injury. We critically report on the major randomized controlled clinical trials published so far concerning intracoronary transfer of autologous bone marrow cells in the setting of acute myocardial infarction. Moreover, underlying mechanisms, practical aspects, remaining questions and future challenges are highlighted. Taken together, these trials confirm the safety and feasibility of intracoronary progenitor cell transfer in the setting of myocardial infarction. Efficacy data suggests its potential to improve left ventricular function recovery beyond current state of the art therapy, but results are mixed, modest at best and do not support true cardiomyogenesis. Hence, due to its complexity, costs and remaining uncertainties, it is still too early to implement progenitor cell therapy in its current form in standard treatment strategies for ischemic heart disease. Future studies on strategies for cardiomyocyte regeneration in combination with myocardial protection are needed.

Postinfarct Treatment With Oxytocin Improves Cardiac Function and Remodeling via Activating Cell-survival Signals and Angiogenesis

We investigated whether postinfarct treatment with oxytocin (OT) improves left ventricular (LV) function and remodeling via cardiac repair of myocardial ischemia-reperfusion injury. Experiments were performed with 30 minutes of coronary occlusion and 2 or 14 days of reperfusion rabbit model of myocardial infarction. LV function and remodeling were significantly improved in the OT group. The infarct size was significantly reduced in the OT group. The number of CD31-positive microvessels was increased significantly in the OT group. There were no Ki67-positive myocytes in either group. The expression of the OT receptor, phosphorylated (p)-Akt protein kinase, p-extracellular signal-regulated protein kinase, p-enodthelial NO synthase, p-signal transducer and activator of transcription 3, vascular endothelial growth factor, B-cell lymphoma 2, and matrix metalloproteinase-1 (MMP-1) were markedly increased in the OT group days 2 and 14 post myocardial infarction. Postinfarct treatment with OT reduces myocardial infarct size and improves LV function and remodeling by activating OT receptors and prosurvival signals and by exerting antifibrotic and angiogenic effects through activation of MMP-1, endothelial NO synthase, and vascular endothelial growth factor. These findings provide new insight into therapeutic strategies for ischemic heart disease.

Post-infarct treatment with an erythropoietin-gelatin hydrogel drug delivery system for cardiac repair

We investigated the effect of an erythropoietin (EPO)-gelatin hydrogel drug delivery system (DDS) applied to the heart on myocardial infarct (MI) size, left ventricular (LV) remodelling and function. Experiments were performed in a rabbit model of MI. The infarct size was reduced, and LV remodelling and function were improved 14 days and 2 months after MI but not at 2 days after MI in the EPO-DDS group. The number of cluster of differentiation 31(CD31)-positive microvessels and the expression of erythropoietin receptor (EPO-R), phosphorylated-Akt (p-Akt), phosphorylated glycogen synthase kinase 3beta (p-GSK-3beta), phosphorylated extracellular signal-regulated protein kinase (p-ERK), phosphorylated signal transducer and activator of transcription 3 (p-Stat3), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-1 (MMP-1) were significantly increased in the myocardium of the EPO-DDS group. Post-MI treatment with an EPO-DDS improves LV remodelling and function by activating prosurvival signalling, antifibrosis, and angiogenesis without causing any side effect.

Postinfarct treatment with granulocyte colony-stimulating factor improves cardiac function in patients with acute myocardial infarction

Postinfarct treatment with granulocyte colony-stimulating factor improves cardiac function in patients with acute myocardial infarction

Cyclophosphamide Improves the Function of Post-Infarct Hearts by Reducing Old Infarct Area and Accelerating the Mobilization of CD34+ Cells

Myelosuppressives such as cyclophosphamide (Cy) and 5-fluorouracil (5FU), which can increase circulating CD34+ cells, may have a beneficial effect in the post-infarct heart. Twenty-four hours after 30-min ischemia-reperfusion, rabbits were intravenously treated with Cy (20 mg/kg), 5FU (15 mg/kg) or saline (S). Cy significantly improved cardiac function and remodeling and decreased the old infarct area 1 month after infarction, compared with those given S. The number of circulating CD34+ cells was higher and neovascularization and matrix metalloproteinase-1 was induced in the Cy group. Cy has potential for post-infarct treatment.

Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage.

Granulation tissue cells at the subacute stage of myocardial infarction (MI) are eliminated by apoptosis to finally make a scar at the chronic stage. We hypothesized that postinfarct inhibition of apoptosis might preserve myofibroblasts and endothelial cells in granulation and modulate chronic left ventricular (LV) remodeling and heart failure. A pancaspase inhibitor, Boc-Asp-fmk (BAF, 10 micromol/kg per day), or vehicle (control) was given to rats with experimental large MI. The treatment was started on the third day after MI and continued until 4-week-old MI. Two weeks later, the apoptosis of granulation tissue cells was significantly reduced and conversely, the cell population was greater in BAF. Twelve weeks later, BAF showed significantly greater survival rates (84% versus 42%) with significantly smaller LV cavity, lower LV end-diastolic pressure and central venous pressure, and higher LV dP/dt, which indicated improvement of LV remodeling and dysfunction. A scar was established in old infarct of control subjects, but in BAF, the infarct wall was thicker because of greater old infarct area, which contained abundant myofibroblasts and vessels. Surprisingly, many of the alpha-smooth muscle actin-positive myofibroblast-like cells in BAF, making bundles and running parallel to the survived cardiomyocytes, were ultrastructurally mature smooth muscle cells with contractile phenotype. Cardiomyocyte apoptosis in the infarct area was equally rare in each group. The postinfarct treatment with BAF improved LV remodeling and dysfunction through inhibition of granulation tissue cell apoptosis. These findings imply a new therapeutic strategy against postinfarct heart failure.

Relative importance of improved hospital treatment and primary prevention. Results from 20 years of the Myocardial Infarction Register, Göteborg, Sweden.

To analyse to what extent declines in incidence and mortality of coronary artery disease can be attributed to improved hospital and post-hospital treatment in contrast to how much is due to primary prevention. A register for non-fatal and fatal myocardial infarction and sudden coronary death registered in in-hospital as well as out-of-hospital events between 1975 and 1994. City of Göteborg, Sweden, with 450,000 inhabitants. Seventy-one per cent of the decline in attacks could be attributed to a decline in first infarctions. Of the decrease in coronary deaths, 63% was due to a decline in out-of-hospital mortality. Previous registrations for myocardial infarction were considerably more common amongst people who died in hospital (29%) than amongst those who died out-of-hospital (11-16%) or who survived an infarction (11-13%). Out-of-hospital resuscitation contributed to about half of the reduction in out-of-hospital mortality. Thus, most of the decline in incidence and about half of the decline in sudden coronary deaths was due to primary preventive measures. Population data on risk factors indicate a decline of 37% between 1963 and 1995 in coronary risk amongst consecutive cohorts of 50-year-old men in the community. Out-of-hospital resuscitation, treatment in coronary care units and post-infarct treatment improved considerably, but changes in primary risk factors were also of major importance for the decline in incidence and mortality.