Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart

Pathological cardiac hypertrophy aggravated myocardial infarction and is causally related to autophagy dysfunction and increased oxidative stress. Rapamycin is an inhibitor of serine/threonine kinase mammalian target of rapamycin (mTOR) involved in the regulation of autophagy as well as oxidative/nitrative stress. Here, we demonstrated that rapamycin ameliorates myocardial ischaemia reperfusion injury by rescuing the defective cytoprotective mechanisms in hypertrophic heart. Our results showed that chronic rapamycin treatment markedly reduced the phosphorylated mTOR and ribosomal protein S6 expression, but not Akt in both normal and aortic‐banded mice. Moreover, chronic rapamycin treatment significantly mitigated TAC‐induced autophagy dysfunction demonstrated by prompted Beclin‐1 activation, elevated LC3‐II/LC3‐I ratio and increased autophagosome abundance. Most importantly, we found that MI/R‐induced myocardial injury was markedly reduced by rapamycin treatment manifested by the inhibition of myocardial apoptosis, the reduction of myocardial infarct size and the improvement of cardiac function in hypertrophic heart. Mechanically, rapamycin reduced the MI/R‐induced iNOS/gp91^phox protein expression and decreased the generation of NO and superoxide, as well as the cytotoxic peroxynitrite. Moreover, rapamycin significantly mitigated MI/R‐induced endoplasmic reticulum stress and mitochondrial impairment demonstrated by reduced Caspase‐12 activity, inhibited CHOP activation, decreased cytoplasmic Cyto‐C release and preserved intact mitochondria. In addition, inhibition of mTOR also enhanced the phosphorylated ERK and eNOS, and inactivated GSK3β, a pivotal downstream target of Akt and ERK signallings. Taken together, these results suggest that mTOR signalling protects against MI/R injury through autophagy induction and ERK‐mediated antioxidative and anti‐nitrative stress in mice with hypertrophic myocardium.     

Cardioprotection through autophagy: Ready for clinical trial?

Interventions that reduce infarct size in animal models have largely failed to improve outcome in patients suffering acute myocardial infarction (MI), or 'heart attack'. Our group recently reported a reduction of infarct size by chloramphenicol treatment in a porcine in vivo model of acute MI, through a mechanism involving the induction of autophagy. Since 2005 several studies have implicated autophagy as a target for cardioprotection.     

Cardioprotection through autophagy

Interventions that reduce infarct size in animal models have largely failed to improve outcome in patients suffering acute myocardial infarction (MI), or ‘heart attack’. Our group recently reported a reduction of infarct size by chloramphenicol treatment in a porcine in vivo model of acute MI, through a mechanism involving the induction of autophagy. Since 2005 several studies have implicated autophagy as a target for cardioprotection.     

Mitochondrial ion channels as targets for cardioprotection

Acute myocardial infarction (AMI) and the heart failure (HF) that often result remain the leading causes of death and disability worldwide. As such, new therapeutic targets need to be discovered to protect the myocardium against acute ischaemia/reperfusion (I/R) injury in order to reduce myocardial infarct (MI) size, preserve left ventricular function and prevent the onset of HF. Mitochondrial dysfunction during acute I/R injury is a critical determinant of cell death following AMI, and therefore, ion channels in the inner mitochondrial membrane, which are known to influence cell death and survival, provide potential therapeutic targets for cardioprotection. In this article, we review the role of mitochondrial ion channels, which are known to modulate susceptibility to acute myocardial I/R injury, and we explore their potential roles as therapeutic targets for reducing MI size and preventing HF following AMI.     

Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure

The pharmacological inhibition or genetic ablation of cyclophilin-D (CypD), a critical regulator of the mitochondrial permeability transition pore (mPTP), confers myocardial resistance to acute ischemia-reperfusion injury, but its role in post-myocardial infarction (MI) heart failure is unknown. The aim of this study was to determine whether mitochondrial CypD is also a therapeutic target for the treatment of post-MI heart failure. Wild-type (WT) and CypD(-/-) mice were subjected to either sham surgery or permanent ligation of the left main coronary artery to induce MI, and were assessed at either 2 or 28 days to determine the long-term effects of CypD ablation. After 2 days, myocardial infarct size was smaller and left ventricular (LV) function was better preserved in CypD(-/-) mice compared to WT mice. After 28 days, when compared to WT mice, in the CypD(-/-) mice, mortality was halved, myocardial infarct size was reduced, LV systolic function was better preserved, LV dilatation was attenuated and in the remote non-infarcted myocardium, there was less cardiomyocyte hypertrophy and interstitial fibrosis. Finally, ex vivo fibroblast proliferation was found to be reduced in CypD(-/-) cardiac fibroblasts, and in WT cardiac fibroblasts treated with the known CypD inhibitors, cyclosporin-A and sanglifehrin-A. Following an MI, mice lacking CypD have less mortality, smaller infarct size, better preserved LV systolic function and undergo less adverse LV remodelling. These findings suggest that the inhibition of mitochondrial CypD may be a novel therapeutic treatment strategy for post-MI heart failure.     

Post-infarct cardiac injury,protection and repair:roles of non-cardiomyocyte multicellular and acellular components

Following myocardial infarction(MI), cardiomyocytes and infarct size are the focus of our attention when evaluating the extent of cardiac injury, efficacy of therapies or success in repairing the damaged heart by stem cell therapy. Numerous interventions have been shown by pre-clinical studies to be effective in limiting infarct size, and yet clinical trials designed accordingly have yielded disappointing outcomes. The ultimate goal of cardiac protection is to limit the adverse cardiac remodeling. Accumulating studies have revealed that post-infarct remodeling can be attenuated without infarct size limitation. To reconcile this, one needs to appreciate the significance of various cellular and acellular myocardial components that, like cardiomyocytes, undergo significant damage and dysfunction, which impact the ultimate cardiac injury and remodelling. Microvascular injury following ischemia-reperfusion may influence infarct size and promote inflammation. Myocardial injury evokes innate immunity with massive inflammatory infiltration that, although essential for the healing process, exacerbates myocardial injury and damage to extracellular matrix leading to dilative remodeling. It is also important to consider the multiple non-cardiomyocyte components in evaluating therapeutic efficacy. Current research indicates the pivotal role of these components in achieving cardiac regeneration by cell therapy. This review summarizes findings in this field, highlights a broad consideration of therapeutic targets,and recommends cardiac remodeling as the ultimate target.     

Ghrelin对心肌梗死大鼠恶性心律失常和早期左室重构的影响(英文)

目的:本文主要研究ghrelin对心肌梗死大鼠恶性心律失常和早期左室重构的影响。方法:心肌梗死大鼠模型每天两次注射ghrelin(100μg/kg)或生理盐水。通过超声心动图评估大鼠的心脏重量并且观察大鼠的血流动力学。使用酶免疫分析法测定血清胰岛素生长因子I(IGF-1)、血浆肾上腺素、去甲肾上腺素和多巴胺的浓度。注射药物前后分析大鼠的神经功能。结果:与对照组相比,ghrelin治疗的心肌梗死模型大鼠生存率显著增加(P0.05),心脏功能增强,但心肌梗死面积差异不大(P0.05)。结论:Ghrelin能够提高心肌梗死模型大鼠的生存率、缓解心肌梗死大鼠心率失常、改善心肌梗死大鼠左心室重构。     

Myocardial Connective Tissue Growth Factor (CCN2/CTGF) Attenuates Left Ventricular Remodeling after Myocardial Infarction

Aims

Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV) remodeling after myocardial infarction (MI) remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI.

Methods and Results

Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate controls (NLC) were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk) 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42) admitted to hospital for percutaneous coronary intervention (PCI) serum-CTGF levels (s-CTGF) were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15.

Conclusion

Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis.     

Inhibition of MAPK signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through reduction of inflammation

Endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) may play an important role in attenuating cardiac remodeling and apoptosis after myocardial infarction. However, the anti-inflammation effects of eNOS in infarcted myocardium and the role of MAPK signaling in eNOS/NO mediated cardiac remodeling have not yet been elucidated. Adenovirus carrying Human eNOS gene was delivered locally into heart 4 days prior to induction of myocardial infarction (MI) by left anterior descending coronary artery ligation. Monocyte/macrophage infiltration was detected by ED-1 immunohistochemistry. Western blot was employed to examine the activation of MAPK. eNOS gene transfer significantly reduced myocardial infarct size and improved cardiac contractility as well as left ventricle (LV) diastolic function at 7 days after MI. In addition, eNOS gene transfer decreased monocyte/macrophage infiltration in the infarct region of the heart. Phosphorylation of MAPK after MI were also dramatically reduced by eNOS gene transfer. All the protective effects of eNOS were blocked by N(ω)-nitro-l-arginine methyl ester (L-NAME) administration, indicating a NO-mediated event. These results demonstrate that the eNOS/NO system provides cardiac protection after MI injury through inhibition of inflammation and suppression of MAPK signaling.     

Inhibition of NF-{kappa}B improves left ventricular remodeling and cardiac dysfunction after myocardial infarction

Several studies have demonstrated that NF-kappaB is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-kappaB is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of IkappaB that acts via inhibition of IKK-beta, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group (P < 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV end-diastolic area: vehicle, 74.13 +/- 3.57 mm(2); IMD-0354, 55.00 +/- 3.73 mm(2); P < 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 +/- 0.26; IMD-0354, 2.61 +/- 0.24; P < 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 +/- 14.87 pg/ml; IMD-0354, 110.75 +/- 6.41 pg/ml; P < 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-beta1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-kappaB activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI.     

Resveratrol reduces infarct size and improves ventricular function after myocardial ischemia in rats

The purpose of this study was to investigate the effect of resveratrol, a polyphenol present in grapes and red wine, on ventricular remodeling after myocardial infarction (MI) in rats. After permanent ligation of the left anterior descending artery, surviving rats were randomly allocated to three groups and treated with 1 mg/kg/day resveratrol (R-1 group), 0.1 mg/kg/day resveratrol (R-0.1 group), or vehicles (control group) administered by intraperitoneal injection once daily for four weeks. We examined the effects of resveratrol by echocardiography, hemodynamic studies, histologic examinations, and real-time quantitative polymerase chain reaction. The R-1 group had significantly increased fractional shortening of the left ventricle, ameliorated left ventricular dilatation, reduced left ventricular end-diastolic pressure, and reduced infarct size. In contrast, the R-0.1 group experienced no beneficial effects on myocardial infarction. The R-1 group also had significantly attenuated expression of myocardial atrial natriuretic peptide and transforming growth factor-beta1 mRNAs. This study indicates that resveratrol is a potent cardioprotective agent in MI rats. Its cardioprotective effects may be due to a reduction of atrial natriuretic peptide and transforming growth factor-beta1, which are known to protect the heart from detrimental remodeling.     

Deficiency of Capn4 Gene Inhibits Nuclear Factor-κB (NF-κB) Protein Signaling/Inflammation and Reduces Remodeling after Myocardial Infarction

Calpain has been implicated in acute myocardial injury after myocardial infarction (MI). However, the causal relationship between calpain and post-MI myocardial remodeling has not been fully understood. This study examined whether deletion of Capn4, essential for calpain-1 and calpain-2 activities, reduces myocardial remodeling and dysfunction following MI, and if yes, whether these effects of Capn4 deletion are associated with NF-κB signaling and inflammatory responses in the MI heart. A novel mouse model with cardiomyocyte-specific deletion of Capn4 (Capn4-ko) was employed. MI was induced by left coronary artery ligation. Deficiency of Capn4 dramatically reduced the protein levels and activities of calpain-1 and calpain-2 in the Capn4-ko heart. In vivo cardiac function was relatively improved in Capn4-ko mice at 7 and 30 days after MI when compared with their wild-type littermates. Deletion of Capn4 reduced apoptosis, limited infarct expansion, prevented left ventricle dilation, and reduced mortality in Capn4-ko mice. Furthermore, cardiomyocyte cross-sectional areas and myocardial collagen deposition were significantly attenuated in Capn4-ko mice, which were accompanied by down-regulation of hypertrophic genes and profibrotic genes. These effects of Capn4 knock-out correlated with restoration of IκB protein and inhibition of NF-κB activation, leading to suppression of proinflammatory cytokine expression and inflammatory cell infiltration in the Capn4-ko heart after MI. In conclusion, deficiency of Capn4 reduces adverse myocardial remodeling and myocardial dysfunction after MI. These effects of Capn4 deletion may be mediated through prevention of IκB degradation and NF-κB activation, resulting in inhibition of inflammatory responses.     

Acute induction of autophagy as a novel strategy for cardioprotection: getting to the heart of the matter

There is no question that necrosis and apoptosis contribute to cardiomyocyte death in the setting of myocardial ischemia-reperfusion. Indeed, considerable effort and resources have been invested in the development of novel therapies aimed at attenuating necrotic and apoptotic cell death, with the ultimate goal of applying these strategies to reduce infarct size and improve outcome in patients suffering acute myocardial infarction (MI) or ‘heart attack’. However, an issue that remains controversial is the role of autophagy in determining the fate of ischemic-reperfused cardiomyocytes: i.e., is induction of autophagy detrimental or protective? Recent data from our group obtained in the clinically relevant, in vivo swine model of acute MI provide novel evidence of a positive association between pharmacological upregulation of autophagy (achieved by administration of chloramphenicol succinate (CAPS)) and increased resistance to myocardial ischemia-reperfusion injury.Key words: myocardial ischemia, myocardial infarction, ischemia-reperfusion injury, autophagy, chloramphenicolOngoing controversy concerning the role of autophagy in myocardial ischemia-reperfusion injury (pro-survival versus pro-death) may be an example of the ‘Goldilocks Principle’: uncontrolled ‘pathophysiological’ induction of autophagy in response to an extreme or prolonged stress reportedly contributes to cardiac cell death, whereas a modest ‘physiological’ upregulation of autophagy may be beneficial. Indeed, in support of this latter concept, a growing body of evidence obtained in isolated cardiomyocytes and rodent models has revealed that acute, pre-ischemic induction of autophagy can confer a cardioprotective phenotype. The objective of our recent publication was to extend this paradigm to a clinically relevant, large animal (swine) model and establish whether pharmacological upregulation of autophagy would render the heart resistant to lethal ischemia-reperfusion injury and thus limit myocardial infarct size.To test this concept, anesthetized pigs were assigned to receive our candidate drug, chloramphenicol succinate (CAPS) or placebo and, at 10 min after treatment, underwent 45 min of coronary artery occlusion followed by 3 h of reperfusion. Administration of CAPS results in a rapid and robust upregulation in molecular markers of autophagy: at 10 min post-treatment (the time corresponding to the onset of the sustained ischemic insult), we observed a 2.4- and 6.2-fold increase in expression of Beclin 1 and LC3-II, respectively, versus baseline. However, most notably, CAPS-treated pigs displayed a profound, ~50% reduction in infarct size when compared with placebo-controls. To investigate whether the favorable effect of CAPS was retained when administered in a more clinically relevant manner, an additional cohort of pigs received CAPS at 15 min before the onset of reperfusion. Efficacy was maintained (albeit attenuated) with delayed treatment, with mean infarct size reduced by ~27% versus controls.The novel aspect of our study is the unequivocal documentation of a significant infarct-sparing effect of CAPS in a well-established pre-clinical model of ischemia-reperfusion injury, thereby bringing the concept of cardioprotection via pharmacological upregulation of autophagy one step closer to future clinical evaluation. Nonetheless, our use of the swine model has an inherent weakness: although we have shown compelling evidence of an association between induction of autophagy and reduction of infarct size, the pig is not amenable to the application of genetic and molecular tools that would yield definitive documentation of cause-and-effect.As acknowledged in our recent publication, an issue of particular relevance in establishing the mechanism by which CAPS confers cardioprotection is the tight and complex interaction between autophagy and the PtdIns3K-Akt-mTOR signaling pathway. Specifically, class III PtdIns3K is an activator of autophagy and, via its interaction with Beclin 1, plays a pivotal role in initiating autophagosome formation, whereas class I PtdIns3K purportedly suppresses autophagy. Interaction at the level of mTOR is multifaceted, bi-directional and has been reported to exert both positive and negative feedback; i.e., while activation of mTOR is associated with inhibition of autophagy, there is evidence of self-regulation of autophagy by autophagy-induced inhibition of mTOR and, in at least one model, co-activation of autophagy and mTOR. PtdIns3K-Akt-mTOR are also components of the ‘Reperfusion Injury Salvage Kinase’ or RISK pathway, a canonical cardioprotective signal transduction pathway that, when activated, has been shown in multiple models to attenuate lethal ischemia-reperfusion injury. Akt signaling is upregulated by a host of protective strategies including ischemic preconditioning (considered the ‘gold standard’ of cardioprotection) and pharmacological preconditioning-mimetic agents. It is therefore perhaps not surprising that administration of CAPS is accompanied by an increase in expression of phospho-Akt.If CAPS treatment is associated with both an induction of autophagy (as documented in our study) and, as with many cardioprotective strategies, upregulation of Akt signaling, this raises two intriguing and interrelated possibilities. First, autophagy and PtdIns3K-Akt-mTOR signaling may yield additive benefit. Second, we speculate that co-activation of the Akt signaling pathway may, by these complex bi-directional interactions, assist in establishing an appropriate balance and maintaining autophagy in a favorable, pro-survival ‘Goldilocks’ state. Our data clearly demonstrate that CAPS is cardioprotective, and may, via induction of autophagy, provide a novel and clinically relevant therapy to attenuate myocardial ischemia-reperfusion injury. However, detailed molecular investigation will be required to ‘get to the heart’ of the mechanisms underlying the reduction of infarct size seen with CAPS treatment.     

Heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in rats with experimental myocardial infarction

The importance of heart rate for left ventricular remodeling and prognosis after myocardial infarction is not known. We examined the contribution of heart rate reduction by zatebradine, a direct sinus node inhibitor without negative inotropic effects on left ventricular function and dilatation, on mortality, energy metabolism, and neurohormonal changes in rats with experimental myocardial infarction (MI). Thirty minutes after left coronary artery ligation or sham operation, the rats were randomized to receive either placebo or zatebradine (100 mg x kg(-1) x day(-1) per gavage) continued for 8 wk. Mortality during 8 wk was 33.3% in the placebo and 23.0% in the zatebradine group (P < 0.05); MI size was 36 +/- 2% and 30 +/- 1% (means +/- SE, P < 0.05), respectively. Zatebradine improved stroke volume index in all treated rats but increased left ventricular volume in rats with small MI (2.43 +/- 0.10 vs. 1.81 +/- 0.10 ml/kg, P < 0.05) but not in rats with large MI (2.34 +/- 0.09 vs. 2.35 +/- 0.11 ml/kg, not significant). Zatebradine reduced left and right ventricular norepinephrine and increased left and right ventricular 3,4-dihydroxyphenyl ethylene glycol-to-norepinephrine ratio suggesting aggravation of cardiac sympathetic activation by zatebradine after MI. Creatine kinase and lactate dehydrogenase isoenzymes in rats with MI remained unchanged by zatebradine. Lowering heart rate per se reduces mortality and MI size in this model but induces adverse effects on left ventricular remodeling in rats with small MI.     

猪冠状动脉前降支结扎位点和左室功能的线性回归

目的探讨猪冠状动脉前降支(LAD)结扎百分位点和心梗体积、左室射血分数的关系,以期指导研究者能够根据急性心肌梗死模型的心功能要求选择合适的LAD结扎百分位点。方法将47只小型猪开胸结扎心脏LAD中远段约30%~75%的不同百分位点,分别于术前、术后1 h心脏超声检查左室射血分数(LVEF),术后3 d进行常规冠状动脉造影,4周处死测量前降支结扎位点和梗死体积,最后用简单直线回归模型分析LAD结扎百分位点和心梗体积、左室射血分数回归方程和相关系数。结果47例动物手术过程中死亡8只,剩余39只存活动物冠状动脉造影均显示LAD中远段结扎部位处完全闭塞,表明手术成功。LAD结扎百分位点和术后1 h LVEF、术后1 hLVEF下降值、梗死心肌体积均明显相关(相关系数r分别为0.87、0.78和0.90,P均<0.001),其回归方程分别为:术后LVEF(%)=65.88-0.55x结扎百分位点;术后LVEF下降值(%)=0.12 0.59x结扎百分位点;心肌梗死体积(%)=0.53x结扎百分位点-5.43。结论猪LAD结扎百分位点和术后左室功能、梗死心肌体积均存在显著的相关性,可根据实验目的和对心功能的要求选择合适的结扎百分位点。     

Atorvastatin therapy during the peri-infarct period attenuates left ventricular dysfunction and remodeling after myocardial infarction

Although statins impart a number of cardiovascular benefits, whether statin therapy during the peri-infarct period improves subsequent myocardial structure and function remains unclear. Thus, we evaluated the effects of atorvastatin on cardiac function, remodeling, fibrosis, and apoptosis after myocardial infarction (MI). Two groups of rats were subjected to permanent coronary occlusion. Group II (n = 14) received oral atorvastatin (10 mg/kg/d) daily for 3 wk before and 4 wk after MI, while group I (n = 12) received equivalent doses of vehicle. Infarct size (Masson''s trichrome-stained sections) was similar in both groups. Compared with group I, echocardiographic left ventricular ejection fraction (LVEF) and fractional area change (FAC) were higher while LV end-diastolic volume (LVEDV) and LV end-systolic and end-diastolic diameters (LVESD and LVEDD) were lower in treated rats. Hemodynamically, atorvastatin-treated rats exhibited significantly higher dP/dt_max, end-systolic elastance (Ees), and preload recruitable stroke work (PRSW) and lower LV end-diastolic pressure (LVEDP). Morphometrically, infarct wall thickness was greater in treated rats. The improvement of LV function by atorvastatin was associated with a decrease in hydroxyproline content and in the number of apoptotic cardiomyocyte nuclei. We conclude that atorvastatin therapy during the peri-infarct period significantly improves LV function and limits adverse LV remodeling following MI independent of a reduction in infarct size. These salubrious effects may be due in part to a decrease in myocardial fibrosis and apoptosis.     

Depression Increases Sympathetic Activity and Exacerbates Myocardial Remodeling after Myocardial Infarction: Evidence from an Animal Experiment

Depression is an independent risk factor for cardiovascular events and mortality in patients with myocardial infarction (MI). Excessive sympathetic activation and serious myocardial remodeling may contribute to this association. The aim of this study was to discuss the effect of depression on sympathetic activity and myocardial remodeling after MI. Wild-type (WT) rats were divided into a sham group (Sham), a myocardial infarction group (MI), a depression group (D), and a myocardial infarction plus depression group (MI+D). Compared with controls, the MI+D animals displayed depression-like behaviors and attenuated body weight gain. The evaluation of sympathetic activity showed an increased level in plasma concentrations of epinephrine and norepinephrine and higher expression of myocardial tyrosine hydroxylase in the MI+D group than the control groups (p<0.05 for all). Cardiac function and morphologic analyses revealed a decreased fractional shortening accompanied by increased left ventricular dimensions, thinning myocardium wall, and reduced collagen repair in the MI+D group compared with the MI group (p<0.05 for all). Frequent premature ventricular contractions, prolonged QT duration and ventricular repolarization duration, shorted effective refractory period, and increased susceptibility to ventricular arrhythmia were displayed in MI+D rats. These results indicate that sympathetic hyperactivation and exacerbated myocardial remodeling may be a plausible mechanism linking depression to an adverse prognosis after MI.     

Tissue kallikrein infusion prevents cardiomyocyte apoptosis, inflammation and ventricular remodeling after myocardial infarction

We investigated the effect of tissue kallikrein infusion on cardiac protection at acute and sub-acute phases after myocardial infarction (MI). Immediately after MI, rats were infused with purified tissue kallikrein, with or without icatibant (a kinin B2 receptor antagonist). Intramyocardial injection of kallikrein reduced myocardial infarct size and inhibited cardiomyocyte apoptosis at 1 day after MI associated with increased nitric oxide levels, Akt and glycogen synthase kinase-3beta phosphorylation and decreased caspase-3 activation. Kallikrein infusion for 7 days improved cardiac function, normalized left ventricular wall thickness and decreased monocyte/macrophage infiltration in the infarct heart. Kallikrein treatment reduced NADH oxidase expression and activity, superoxide formation and malondialdehyde levels, and reduced MAPK and Ikappa-Balpha phosphorylation, NF-kappaB activation and MCP-1 and VCAM-1 expression. Kallikrein's effects were all blocked by icatibant. These results indicate that kallikrein through kinin B2 receptor activation prevents apoptosis, inflammation and ventricular remodeling by increased nitric oxide formation and suppression of oxidative stress-mediated signaling pathways.     

Effects of hydrogel injection on borderzone contractility post-myocardial infarction

Injectable hydrogels are a potential therapy for mitigating adverse left ventricular (LV) remodeling after myocardial infarction (MI). Previous studies using magnetic resonance imaging (MRI) have shown that hydrogel treatment improves systolic strain in the borderzone (BZ) region surrounding the infarct. However, the corresponding contractile properties of the BZ myocardium are still unknown. The goal of the current study was to quantify the in vivo contractile properties of the BZ myocardium post-MI in an ovine model treated with an injectable hydrogel. Contractile properties were determined 8 weeks following posterolateral MI by minimizing the difference between in vivo strains and volume calculated from MRI and finite element model predicted strains and volume. This was accomplished by using a combination of MRI, catheterization, finite element modeling, and numerical optimization. Results show contractility in the BZ of animals treated with hydrogel injection was significantly higher than untreated controls. End-systolic (ES) fiber stress was also greatly reduced in the BZ of treated animals. The passive stiffness of the treated infarct region was found to be greater than the untreated control. Additionally, the wall thickness in the infarct and BZ regions was found to be significantly higher in the treated animals. Treatment with hydrogel injection significantly improved BZ function and reduced LV remodeling, via altered MI properties. These changes are linked to a reduction in the ES fiber stress in the BZ myocardium surrounding the infarct. The current results imply that injectable hydrogels could be a viable therapy for maintaining LV function post-MI.