Post-infarction Cardiac Remodeling Research Articles

Human erythropoietin gene delivery for cardiac remodeling of myocardial infarction in rats

Considerable efforts have been made to exploit cardioprotective drugs and gene delivery systems for myocardial infarction (MI). The promising cardioprotective effects of recombinant human erythropoietin (rHuEPO) protein in animal experiments have not been consistently reproduced in clinical human trials of acute MI; however, the mechanisms underlying the inconsistent discrepancies are not yet fully understood. We hypothesized that the plasmid human erythropoietin gene (phEPO) delivered by our bioreducible polymer might produce cardioprotective effects on post-infarct cardiac remodeling. We demonstrated that intramyocardial delivery of phEPO by an arginine-grafted poly(disulfide amine) (ABP) polymer in infarcted rats preserves cardiac geometry and systolic function. The reduced infarct size of phEPO/ABP delivery was followed by decrease in fibrosis, protection from cardiomyocyte loss, and down-regulation of apoptotic activity. In addition, the increased angiogenesis and decreased myofibroblast density in the border zone of the infarct support the beneficial effects of phEPO/ABP administration. Furthermore, phEPO/ABP delivery induced prominent suppression on Ang II and TGF-β activity in all subdivisions of cardiac tissues except for the central zone of infarct. These results of phEPO gene therapy delivered by a bioreducible ABP polymer provide insight into the lack of phEPO gene therapy translation in the treatment of acute MI to human trials.

Increased expression of Dock180 protein in the noninfarcted myocardium in rats

The integrin β1 subunit and its downstream molecule focal adhesion kinase have been identified as critical molecules for the inhibition of postinfarction cardiac remodeling, ischemic cardiomyopathy, and heart failure. However, as a component of the integrin pathway, it is still unclear whether Dock180 (dedicator of cytokinesis 1) protein is expressed in the noninfarcted myocardium of the peri-infarct zones. In this study, experimental myocardial infarction (MI) and sham-operation (sham) models were established in Sprague Dawley rats and the expression of Dock180 protein in the myocardium of the sham group and in the noninfarcted myocardium of the peri-infarct zones of the MI group was detected by Western blot technique. The Dock180 protein expression in the myocardium was as follows: postsham 24-hour group, 0.10 ± 0.04 (n = 8); post-MI 24-hour group, 0.13 ± 0.03 (n = 8); postsham 12-week group, 0.11 ± 0.05 (n = 8); and post-MI 12-week group 0.17 ± 0.04 (n = 8). The Dock180 protein expression in the myocardium in the post-MI 12-week group was significantly higher than that in the postsham 12-week group (p = 0.019), in the postsham 24-hour group (p = 0.004), and in the post-MI 24-hour group (p = 0.040). We conclude that Dock180 protein is expressed in the myocardium in rats. Furthermore, its expression is significantly increased in the noninfarcted myocardium of the peri-infarct zones.

Elevated expression of C3G protein in the peri-infarct myocardium of rats

BackgroundThe integrin β1 subunit and its downstream molecules such as integrin-linked kinase (ILK) and focal adhesion kinase (FAK) are indispensable to the inhibition of postinfarction cardiac remodeling, ischemic cardiomyopathy, and heart failure. As a component of the integrin pathway, C3G (Crk SH3-domain-binding guanine nucleotide exchange factor) protein may also participate in postinfarction cardiac remodeling, ischemic cardiomyopathy, and heart failure.Material/MethodsExperimental myocardial infarction (MI) and sham-operation (sham) models were set up in Sprague-Dawley rats. C3G protein expression in the myocardium in the sham group and in the non-infarcted myocardium of the peri-infarct zones in the MI group was examined by Western blot.ResultsThe C3G protein expression in the myocardium was 0.22±0.06, n=8 in the post-sham 24-hour group; 0.29±0.10, n=8 in the post-MI 24-hour group; 0.22±0.07, n=8 in the post-sham 12-week group; and 0.56±0.14, n=8 in the post-MI 12-week group. The C3G protein expression in the myocardium in the post-MI 12-week group was significantly elevated compared to that in the post-sham 12-week group (p=0.0002), in the post-sham 24-hour group (p=0.0002), and in the post-MI 24-hour group (p=0.0006).ConclusionsC3G protein expression exhibits in the myocardium of rats. Furthermore, C3G protein expression is significantly elevated in the non-infarcted myocardium of the peri-infarct zones. The elevated C3G protein expression could participate in postinfarction cardiac remodeling, ischemic cardiomyopathy, and heart failure.

Pathophysiological role of neutrophils in acute myocardial infarction

The pathogenesis of acute myocardial infarction is known to be mediated by systemic, intraplaque and myocardial inflammatory processes. Among different immune cell subsets, compelling evidence now indicates a pivotal role for neutrophils in acute coronary syndromes. Neutrophils infiltrate coronary plaques and the infarcted myocardium and mediate tissue damage by releasing matrix-degrading enzymes and reactive oxygen species. In addition, neutrophils are also involved in post-infarction adverse cardiac remodelling and neointima formation after angioplasty. The promising results obtained in preclinical modelswith pharmacological approaches interfering with neutrophil recruitment or function have confirmed the pathophysiological relevance of these immune cells in acute coronary syndromes and prompted further studies of these therapeutic interventions. This narrative review will provide an update on the role of neutrophils in acute myocardial infarction and on the pharmacological means that were devised to prevent neutrophil-mediated tissue damage and to reduce post-ischaemic outcomes.

Resveratrol Reverses Remodeling in Hearts with Large, Old Myocardial Infarctions through Enhanced Autophagy-Activating AMP Kinase Pathway

We investigated the effect of resveratrol, a popular natural polyphenolic compound with antioxidant and proautophagic actions, on postinfarction heart failure. Myocardial infarction was induced in mice by left coronary artery ligation. Four weeks postinfarction, when heart failure was established, the surviving mice were started on 2-week treatments with one of the following: vehicle, low- or high-dose resveratrol (5 or 50 mg/kg/day, respectively), chloroquine (an autophagy inhibitor), or high-dose resveratrol plus chloroquine. High-dose resveratrol partially reversed left ventricular dilation (reverse remodeling) and significantly improved cardiac function. Autophagy was augmented in those hearts, as indicated by up-regulation of myocardial microtubule-associated protein-1 light chain 3-II, ATP content, and autophagic vacuoles. The activities of AMP-activated protein kinase and silent information regulator-1 were enhanced in hearts treated with resveratrol, whereas Akt activity and manganese superoxide dismutase expression were unchanged, and the activities of mammalian target of rapamycin and p70 S6 kinase were suppressed. Chloroquine elicited opposite results, including exacerbation of cardiac remodeling associated with a reduction in autophagic activity. When resveratrol and chloroquine were administered together, the effects offset one another. In vitro, compound C (AMP-activated protein kinase inhibitor) suppressed resveratrol-induced autophagy in cardiomyocytes, but did not affect the events evoked by chloroquine. In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart.

Impaired post-infarction cardiac remodeling in chronic kidney disease is due to excessive renin release

The complex pathophysiological interactions between heart and kidney diseases are collectively known as cardiorenal syndrome. The renin–angiotensin system (RAS) may have a pivotal role in the development of cardiorenal syndrome. The aim of this study was to elucidate the RAS activity responsible for adverse post-infarction remodeling and prognosis in mice with renal failure. To establish the type IV cardiorenal syndrome model, 5/6 nephrectomy (NTX) was performed in a surgical procedure, followed by the induction of myocardial ischemia (MI) by a coronary artery ligation 4 weeks later. NTX and MI resulted in deteriorated left ventricular remodeling and RAS activation, which was improved by an aliskiren that appeared to be independent of renal function and blood pressure (BP). Moreover, MI induced in renin and angiotensinogen double-transgenic (Tg) mice showed comparable effects to MI plus NTX mice, including advanced ventricular remodeling and enhancement of RAS, oxidative stress, and monocytes chemoattractant protein (MCP)-1. Aliskiren suppressed these changes in the MI-induced Tg mice. In in vitro study, Nox2 expression was elevated by the stimulation of plasma from NTX mice in isolated neonatal cardiomyocytes. However, Nox2 upregulation was negated when we administered plasma from aliskiren-treated-NTX mice or isolated cardiomyocytes from AT1-deficient mice. Primary mononuclear cells also showed an upregulation in the expression of Nox2 and MCP-1 by stimulation with plasma from NTX mice. Our data suggest that renal disorder results in ventricular dysfunction and deteriorates remodeling after MI through excessive RAS activation. Moreover, renin inhibition improved the changes caused by cardiorenal syndrome.

Caloric Restriction Enhances Cardiomyocyte Autophagy to Improve Energy Status and Ameliorates Left Ventricular Remodeling in the Postinfarction Heart

We previously reported that cardiomyocyte autophagy is an innate mechanism which prevents postinfarction cardiac remodeling. In this study, we examined effect of caloric restriction (CR), a potent inducer of autophagy, on postinfarction cardiac remodeling. Myocardial infarction (MI) was induced in mice. After one week of MI, mice were randomly divided into the following four groups. The control group was fed ad libitum (100%). Others were fed restricted diet respectively 80%, 60%, and 40% of the control mice's total calorie.

Activation of Natural Killer T Cells Ameliorates Postinfarct Cardiac Remodeling and Failure in Mice

Chronic inflammation in the myocardium is involved in the development of left ventricular (LV) remodeling and failure after myocardial infarction (MI). Invariant natural killer T (iNKT) cells have been shown to produce inflammatory cytokines and orchestrate tissue inflammation. However, no previous studies have determined the pathophysiological role of iNKT cells in post-MI LV remodeling. The purpose of this study was to examine whether the activation of iNKT cells might affect the development of LV remodeling and failure. After creation of MI, mice received the injection of either α-galactosylceramide (αGC; n=27), the activator of iNKT cells, or phosphate-buffered saline (n=31) 1 and 4 days after surgery, and were followed during 28 days. Survival rate was significantly higher in MI+αGC than MI+PBS (59% versus 32%, P<0.05). LV cavity dilatation and dysfunction were significantly attenuated in MI+αGC, despite comparable infarct size, accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis. The infiltration of iNKT cells were increased during early phase in noninfarcted LV from MI and αGC further enhanced them. It also enhanced LV interleukin (IL)-10 gene expression at 7 days, which persisted until 28 days. AntienIL-10 receptor antibody abrogated these protective effects of αGC on MI remodeling. The administration of αGC into iNKT cell-deficient Jα18(-/-) mice had no such effects, suggesting that αGC was a specific activator of iNKT cells. iNKT cells play a protective role against post-MI LV remodeling and failure through the enhanced expression of cardioprotective cytokines such as IL-10.

MT1-MMP–Dependent Remodeling of Cardiac Extracellular Matrix Structure and Function Following Myocardial Infarction

The myocardial extracellular matrix (ECM), an interwoven meshwork of proteins, glycoproteins, proteoglycans, and glycosaminoglycans that is dominated by polymeric fibrils of type I collagen, serves as the mechanical scaffold on which myocytes are arrayed for coordinated and synergistic force transduction. Following ischemic injury, cardiac ECM remodeling is initiated via localized proteolysis, the bulk of which has been assigned to matrix metalloproteinase (MMP) family members. Nevertheless, the key effector(s) of myocardial type I collagenolysis both in vitro and in vivo have remained unidentified. In this study, using cardiac explants from mice deficient in each of the major type I collagenolytic MMPs, including MMP-13, MMP-8, MMP-2, MMP-9, or MT1-MMP, we identify the membrane-anchored MMP, MT1-MMP, as the dominant collagenase that is operative within myocardial tissues in vitro. Extending these observations to an in vivo setting, mice heterozygous for an MT1-MMP-null allele display a distinct survival advantage and retain myocardial function relative to wild-type littermates in an experimental model of myocardial infarction, effects associated with preservation of the myocardial type I collagen network as a consequence of the decreased collagenolytic potential of cardiac fibroblasts. This study identifies MT1-MMP as a key MMP responsible for effecting postinfarction cardiac ECM remodeling and cardiac dysfunction.

Plasma Uric Acid is Associated with Postinfarction Cardiac Remodeling in Elderly with Old Myocardial Infarction

The increased plasma uric acid has been documented in ischemic cardiomyopathy (ICM) and heart failure in other age ranges in human and in animal models. However, it remains incompletely clear whether plasma uric acid is associated with cardiac remodeling, ischemic cardiomyopathy and heart failure in elderly. So, the objective of the study was to investigate whether plasma uric acid was associated with postinfarction cardiac remodeling in elderly with a previous myocardial infarction. Data of 246 elderly aged 60 years and older with angiography-confirmed coronary heart disease and myocardial infarction were analyzed. Among the patients, 89 had ICM defined as left ventricular end-diastolic diameter [men > 55 mm, women > 50 mm (60.74 ± 5.79 mm)] measured by echocardiography. Difference in plasma uric acid was analyzed between patients with and without ICM. There was significant increase in plasma uric acid in ICM compared with non-ICM (444.66 ± 160.97 umol/L vs. 372.59 ± 131.31 umol/L, p = 0.000), and plasma uric acid was significantly positively related to left ventricular end-diastolic diameter ( r = 0.312, p = 0.000). Plasma uric acid is significantly increased in elderly with ICM complicated with previous myocardial infarction as well as with those elderly patients who have postinfarction cardiac remodeling and previous myocardial infarction.

Postinfarct cardiac remodeling and the substrate for sudden cardiac death: role of oxidative stress and myocardial fibrosis

“…in a heart with well-coupled myocytes, a greater number of myocytes with simultaneous early afterdepolarization and delayed afterdepolarization are required to overcome the electrotonic sink effect…” The biological changes that occur after myocardial infarction (MI) produce gross structural abnormalities in the heart, such as scar tissue, hypertrophy and chamber dilatation, which may be followed by functional deterioration and the clinical symptoms of heart failure or ventricular arrhythmia. Heart failure is a well-known risk factor for ventricular arrhythmia that is associated with significantly higher car diovascular mortality. It may be too late to cure a dysfunctional heart. Therefore, understanding the molecular mechanisms and signaling pathways involved in postMI remodeling can provide useful insights for the very important period of time that follows infarction (the ‘golden therapeutic window’). Infarcted hearts show several important pathological changes that are arrhythmogenic, such as nerve sprouting [1], action potential duration (APD) alternans [2] and a decreased cardiac sodium current [3]. Among the underlying pathophysiologic changes, oxidative stress and myocardial fibrosis are particularly impor tant for several reasons. First, there is strong experimental and clinical evidence for their arrhythmogenicity. Second, there are potential therapeutic options to prevent them. Also, oxidative stress promotes cardiac fibrosis. Finally, oxidative stress and cardiac fibrosis potentiate the arrhyth mogenic effect of each other. This article highlights the role of oxidative stress and myocardial fibrosis in providing the sub strate for sudden cardiac death in infarcted hearts.

Direct Renin Inhibition Exerts an Anti-hypertrophic Effect Associated with Improved Mitochondrial Function in Post-infarction Heart Failure in Diabetic Rats

Background: In addition to hypertension control, direct renin inhibition has been shown to exert direct beneficial effects on the heart in post-infarction cardiac remodeling. This study elucidates the possible contribution of mitochondria to the anti-hypertrophic effects of the direct renin inhibitor aliskiren in post-infarction heart failure complicated with diabetes in rats. Methods: Diabetes was induced in male Sprague-Dawley rats by a single injection of streptozotocin (IP, 65 mg/kg body weight). After 7 days, the animals were randomly assigned to 4 groups: sham, heart failure, sham+aliskiren, and heart failure+aliskiren. Post-infarction HF was induced by coronary artery ligation for 4 weeks. Results: showed that heart failure reduced ejection fraction and cardiac output by 41% (P<0.01) and 42% (P<0.05), respectively, compared to sham-operated hearts. Cardiac dysfunction was associated with suppressed state 3 respiration rates and respiratory control index in mitochondria, and increased mitochondrial permeability transition pore (PTP) opening. In addition, heart failure reduced expression of the major mitochondrial sirtuin, SIRT3 and increased acetylation of cyclophilin D, a regulatory component of the PTP. Aliskiren significantly improved cardiac function and abrogated mitochondrial perturbations. Conclusion: Our results demonstrate that aliskiren attenuates post-infarction remodeling which is associated with its beneficial effects on mitochondria.

Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction

Cellular FLICE-inhibitory protein (cFLIP) is a member of the tumour necrosis factor signalling pathway and a regulator of apoptosis, and it has a role in cardiac remodelling following myocardial infarction (MI) that remains largely uncharacterised. This study aimed to determine the function of cFLIP as a potential mediator of post-infarction cardiac remodelling. Our results show diminished cFLIP expression in failing human and murine post-infarction hearts. Genetically engineered cFLIP heterozygous (cFLIP+/-, HET) mice, cardiac-specific cFLIP-overexpressing transgenic (TG) mice and their respective wild-type (WT) and non-transgenic controls were subjected to MI by permanent ligation of their left anterior descending artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Apoptosis, inflammation, angiogenesis, and fibrosis were evaluated in the myocardium. The HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and remodelling compared with WT mice 28 days after MI. Impaired LV function in the HET mice was associated with increases in infarct size, hypertrophy, apoptosis, inflammation, and interstitial fibrosis, and reduced capillary density. The TG mice displayed the opposite phenotype after MI. Moreover, adenovirus-mediated overexpression of cFLIP decreased LV dilatation and improved LV function and remodelling in both HET and WT mice. Further analysis of signalling events suggests that cFLIP promotes cardioprotection by interrupting JNK1/2 signalling and augmenting Akt signalling. In conclusion, our results indicate that cFLIP protects against the development of post-infarction cardiac remodelling. Thus, cFLIP gene delivery shows promise as a clinically powerful and novel therapeutic strategy for the treatment of heart failure after MI.

The cardioprotective effects of metformin

In patients with type 2 diabetes mellitus, treatment with metformin is associated with a lower cardiovascular morbidity and mortality, compared with alternative glucose-lowering drugs. It has been suggested that metformin might exert direct protective effects on the heart. This review appraises recent experimental animal studies on the effect of metformin on myocardial ischaemia-reperfusion injury and remodeling. In murine models of myocardial infarction, the administration of metformin potently limits infarct size. Activation of adenosine monophosphate-activated protein kinase, increased formation of adenosine, and the prevention of opening of the mitochondrial permeability transition pore at reperfusion all contribute to this cardioprotective effect. In addition, metformin therapy attenuates postinfarction cardiac remodeling. There is evidence that activation of adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase, and a reduced collagen expression are crucial for this effect. The finding that metformin limits myocardial infarct size and remodeling in animal models of myocardial infarction suggests that patients suffering from myocardial ischaemia could benefit from treatment with metformin, even when these patients do not have diabetes. Currently, several clinical trials are being performed to test this hypothesis.

Abstract 9424: Caloric Restriction Augments Cardiomyocyte Autophagy to Mitigate Postinfarction Cardiac Remodeling and Heart Failure

We previously reported that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodeling. In the present study, we examined effect of caloric restriction (CR), a potent inducer of autophagy, on post infarction cardiac remodeling. Myocardial infarction (MI) was induced in mice by ligating the left coronary artery. After one week of MI, mice were randomly divided into the following four groups. The control group was fed ad libitum (100%). Others were fed restricted diet: 80%, 60%, and 40% of the total calorie which was taken by control mice. The water was provided ad libitum. Three weeks later, we performed echocardiography and catheter to evaluate the left ventricular (LV) function. There was no mouse that died through the period. The body weight was decreased in CR groups (post/pre ratio: 1.08±0.01 in control, 0.83±0.01 in 80% CR, 0.76±0.01 in 60% CR, 0.70±0.01 in 40% CR, p&lt;0.001). However, there was no difference in heart/body weight ratio. The dilatation and hypofunction of the LV were apparent in the control group: left ventricular diastolic dimension (LVDd) = 4.9±0.1 mm; left ventricular ejection fraction (LVEF) = 27±3.3%; and dP/dT = 4677±277 mmHg/s. However, both dilatation and hypofunction were significantly mitigated in groups undergoing CR: in 80%, 60%, and 40% CR, respectively, LVDd = 4.0±0.1 mm, 3.4±0.2 mm and 4.0±0.1 mm; LVEF = 36±2.8%, 51±4.3% and 43±1.5%; and dP/dT = 6849±221 mmHg/s, 7758±638 mmHg/s and 6923±553 mmHg/s, among which the 60% CR group showed the strongest therapeutic effect on postinfarction cardiac remodeling (control vs. 60% CR: p&lt;0.001). Cardiomyocyte autophagy was markedly activated in CR groups as evidenced by the overexpressed microtubule-associated protein 1 light chain 3-II (LC3-II) and specific ultrastructural findings including autophagosome formation. In conclusion, caloric restriction enhances cardiomyocyte autophagy and mitigates postinfarction cardiac remodeling and dysfunction; the optimal caloric restriction is suggested to be 60%. These findings suggest an important clinical implication that a dietary protocol can be a preventive strategy against progression of postinfarction left ventricular remodeling and heart failure.

Abstract 8274: Resveratrol Brings About Reverse Remodeling In The Heart With A Large Old Myocardial Infarction Through Autophagy Activating amp Kinase Pathway

We previously reported that autophagy is activated during postmyocardial infarction and compensates for the lack of energy in cardiomyocytes by digesting and recycling own constituents. Resveratrol is a popular natural polyphenolic compound, abundantly contained in the skin of grapes and red wine, and is recently reported to have not only an anti-oxidant property but also autophagy-accelerating action. We here investigated the effect of resveratrol on established heart failure due to a large old myocardial infarction. Myocardial infarction was induced in mice by the left coronary artery ligation. Four weeks post-infarction, the surviving mice were assigned to four groups: control (saline, n=15); resveratrol (50 mg/kg/day, n=15); chroloquine (an autophagy inhibitor, 10 mg/kg/day, n=15); and combination (resveratrol, 50 mg/kg/day plus chroloquine, 10 mg/kg/day, n=15). The agents were administered for 2 weeks using osmotic mini pump. Resveratrol significantly attenuated and partially reversed left ventricular dilatation (reverse remodeling) and improved function: left ventricular end-diastolic diameter, 4.1±0.2 mm vs. 4.9±0.3 mm in controls; and ejection fraction, 46.9±3.3 % vs. 35.8±3.3 % in controls (p&lt;0.05), accompanying reduction of ventricular expression of atrial natriuretic peptide. In those hearts, autophagic findings were augmented as shown by upregulation of microtubule-associated protein-1 light chain 3-II (LC3-II) and by electron microscopic findings of autophagic vacuoles. The activation of AMP-activated protein kinase was enhanced in the hearts treated with resveratrol while the activation of mammalian target of rapamycin complex 1 (mTORC1) and p70S6 kinase (a direct down-stream target of mTORC1) was suppressed compared to vehicle. Chroloquine brought about an opposite result, including aggravation of cardiac dysfunction and remodeling progression, where autophagic activity was diminished. A combined treatment with resveratrol and chroloquine offset each effect on the postinfarction heart. Any treatment did not affect apoptosis in the infarcted heart. The present findings suggest that resveratrol is new pharmacological strategy -i.e., manipulation of autophagy, against postinfarction cardiac remodeling.

Caloric Restriction Enhances Cardiomyocyte Autophagy and Mitigates Postinfarction Cardiac Remodeling and Dysfunction

We previously reported that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodeling. In the present study, we examined effect of caloric restriction (CR), a potent inducer of autophagy, on post infarction cardiac remodeling. Myocardial infarction (MI) was induced in mice by ligating the left coronary artery. After one week of MI, mice were randomly divided into the following four groups. The control group was fed ad libitum (100%). Others were fed restricted diet respectively 80%, 60%, and 40% of the total calorie which was taken by control mice.

OPC-28326, a Selective Peripheral Vasodilator with Angiogenic Action, Attenuates Postinfarction Cardiac Remodeling

Although OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, was originally developed as a selective peripheral vasodilator, this reagent was recently reported to have an additional angiogenic activity on ischemic tissue. We hypothesized that such properties of OPC-28326, vasodilatation and angiogenesis, might benefit postinfarction hearts. The mice with myocardial infarction were randomly assigned into the 2 groups after coronary artery ligation: a normal diet group; and a 0.05% OPC-28326-containing diet (OPC) group. The survival rate of mice was better 4 weeks postinfarction in the OPC group (82% vs. control: 44%, p&gt0.05) and the left ventricular remodeling and dysfunction were significantly mitigated. Histologically, the OPC group showed a significantly greater infarct wall thickness, compared with the control group, which might contribute to reduction of wall stress (Laplace's law). The thickened infarct wall contained more abundant nonmyocytes including vessels, not only capillaries but also small arteries, and myofibroblasts. Five days postinfarction, proliferating cells in the granulation tissue were more abundant while apoptotic cells were fewer in the OPC group, accompanying activation of myocardial Akt and endothelial nitric oxide synthase. Hypoxia of the infarct issue was markedly attenuated in the OPC group. In conclusion, OPC-28326 increased cell proliferation while decreased apoptosis of the infarct tissue, probably through the vasodilatating and angiogenetic actions, to alter the infarct tissue dynamics and attenuate postinfarction cardiac remodeling.

Effects of Levosimendan on Cardiac Gene Expression Profile and Post-Infarct Cardiac Remodelling in Diabetic Goto-Kakizaki Rats

The calcium sensitizer levosimendan has shown beneficial effects on cardiac remodelling in spontaneously diabetic Goto-Kakizaki (GK) rats 12 weeks after experimental myocardial infarction (MI). However, the short-term effects and the cellular mechanisms remain partially unresolved. The aim was to study the effects of oral levosimendan treatment on the myocardial gene expression profile in diabetic GK rats 4 weeks after MI/sham operation. MI was induced to diabetic GK rats. Twenty-four hours after surgery, rats were randomized into four groups: MI, MI +levosimendan (1 mg/kg/day), sham-operated and sham-operated +levosimendan. Cardiac function and histology were examined 1, 4 and 12 weeks after MI. The effects of levosimendan on cardiac gene expression profile were investigated by microarray analysis. Levosimendan ameliorated post-infarct heart failure and cardiac remodelling. Levosimendan altered the expression of 264 of MI and sham rats, respectively; these changes were associated with alterations in two Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Levosimendan up-regulated 3 genes in the renin-angiotensin system pathway [angiotensin receptor 1 (Agtr1), chymase 1 (Cma1) and thimet oligopeptidase 1 (Thop1)] and down-regulated 3 genes in the glycerolipid metabolism pathway [diacylglycerol kinase gamma (Dgkg), carboxyl ester lipase (Cel) and Diacylglycerol kinase iota]. Levosimendan induced opposite effects on the gene expression of pleckstrin homology (PH) domain containing family f (Plekhf1), carboxymethylenebutenolidase homologue (Cmbl) (up-regulation) and hydroxyprostaglandin dehydrogenase 15 (Hpgd) (down-regulation) as compared with MI. MI versus sham affected 420 genes and was associated with alterations in 12 KEGG pathways. The beneficial effects of levosimendan on cardiac hypertrophy in sham-operated GK rats was associated with altered expression in 522 genes and associated with three KEGG pathways including purine metabolism, cell cycle pathway and pathways in cancer. Levosimendan protects against post-infarct heart failure and cardiac remodelling. Analysis of the cardiac transcriptome revealed several genes that are regulated by levosimendan. These genes may represent novel drug targets for heart failure and diabetic cardiomyopathy.

A combined cell therapy and in-situ tissue-engineering approach for myocardial repair

Myocardial cell-replacement strategies are hampered by limited sources for human cardiomyocytes and by significant cell loss following transplantation. We tested the hypothesis that a combined delivery of cardiomyocytes with an in-situ polymerizable hydrogel into a post-MI rat heart will result in better functional outcomes than each intervention alone. A photopolymerizable, biodegradable, PEGylated-fibrinogen (PF) hydrogel matrix was used as the carrier for the cardiomyocytes [neonatal rat ventricular cardiomyocytes (NRVCMs) or human embryonic stem cell-derived cardiomyocytes (hESC-CMs)]. Infarcted rat hearts (LAD ligation) were randomized to injection of saline, NRVCMs, biopolymer, or combined biopolymer-cell delivery. Echocardiography revealed typical post-infarction remodeling after 30 days in the saline-injected control group [deterioration of fractional shortening (FS) by 31.0 ± 3.6%]. Injection of NRVCMs or PF alone significantly (p < 0.01) altered this remodeling process (slightly increasing FS by 3.1 ± 6.6% and 0.5 ± 5.3% respectively). Co-injection of the NRVCMs with PF matrix resulted in a significant increase in the cell-graft area (by 144%) and in the highest improvements in FS (by 26.3 ± 6.6%). Finally, feasibility studies were performed with the PF matrix and hESC-CMs. We conclude that an injectable in-situ forming hydrogel can act as a cardiomyocyte cell-carrier and add to the beneficial effects of the grafted cells in preventing unfavorable post-infarction cardiac remodeling.