Therapeutic potential of H11 kinase for the ischemic heart

H11 kinase (H11K) is a small heat shock protein expressed predominantly in the heart and skeletal muscle, which plays a critical role in the maintenance of cardiac cell survival and in promoting cell growth through the activation of complementary signaling pathways. An overexpression of H11K was detected in various forms of heart disease, both in animal models and in patients, including acute and chronic ventricular dysfunction, and myocardial hypertrophy. Overexpression of H11K was reproduced in a cardiac-specific transgenic model, which led to significant progress in understanding the role and mechanism of action of the protein. Increased expression of H11K confers a cardioprotection that is equivalent to ischemic preconditioning; it promotes cardiac hypertrophy while maintaining contractile function. The overexpression of H11K is sufficient to activate most of the signaling pathways involved in cardiac cell growth and survival, including the phosphatidylinositol-3-kinase/Akt pathway, the AMP-dependent protein kinase, the PKCepsilon pathway of ischemic preconditioning, the nitric oxide pathway of delayed cardioprotection, and the mTOR pathway of cell growth. As a result, the survival response triggered by H11K in the heart includes antiapoptosis, cytoprotection, preconditioning, growth, and metabolic stimulation. In addition to activating signaling pathways, H11K promotes the subcellular translocation and crosstalk of intracellular messengers. This review discusses the biological function of H11K, its molecular mechanisms of action, and its potential therapeutic relevance. In particular, we discuss how preemptive conditioning of the heart by H11K might be beneficial for patients with ischemic heart disease who would be at risk of further irreversible cardiac damage.     

Efficacy of metabolic modulators in ischemic heart disease: an overview

Myocardial ischemia results in a decrease in oxygen supply to the heart, leading to cardiac dysfunction. Present therapeutic strategies for treating myocardial ischemia or infarction focus on maintaining coronary artery patency by either fibrinolysis or primary percutaneous intervention. Although these approaches have dramatically improved the prognosis in patients with angina pectoris and myocardial infarction, the complication of myocardial ischemia remains a major cause of mortality and morbidity worldwide. A novel approach that entails improving and optimizing cardiac energy metabolism of the ischemic myocardium by pharmacologically manipulating different metabolic pathways in the heart holds promise in limiting myocardial damage. Metabolic support of the ischemic myocardium is aimed at increasing glycolysis and residual oxidative phosphorylation of glucose along with decreasing fatty acid oxidation. This review discusses the various metabolic modulators, both conventional and new, along with documented evidence in both acute and chronic angina.     

动态心电图对无症状性心肌缺血的诊断价值

目的 探讨24 h动态心电图检查对无症状性心肌缺血的诊断价值. 方法 应用24 h动态心电图对80例无症状心肌缺血冠心病（CHD）患者进行检测,并记录结果. 结果 在80例CHD患者中发生心肌缺血者75例,占93.75%,共发生缺血性ST段下移824阵次,每例发作1～23阵次,平均8.3阵次,平均ST段下移（0.15±0.06）mV;无症状心肌缺血大多发生在白天,发作高峰位于6～12 h出现最少;心率增快的高低与缺血的程度呈正相关,心率越快,ST段下移越明显,诱发的心肌缺血越严重. 结论 24 h动态心电图检查对元症状性心肌缺血病情评估和早期防治有重要意义.     

Poly(ADP-ribose) polymerase-mediated cell injury in acute renal failure.

Acute Renal Failure (ARF) is the most costly kidney disease in hospitalized patients and remains as a serious problem in clinical medicine. The mortality rate among ARF patients remains around 50% and no pharmaceutical agents are currently available to improve its clinical outcome. Although several successful therapeutic approaches have been developed in animal models of the disease, translation of the results to clinical ARF remains elusive. Understanding the cellular and molecular mechanisms of vascular and tubular dysfunction in ARF is important for developing acceptable therapeutic interventions. Following an ischemic episode, cells of the affected nephron undergo necrotic and/or apoptotic cell death. Necrotic cell death is widely considered to be a futile process that cannot be modulated by pharmacological means as opposed to apoptosis. However, recent reports from various laboratories including ours indicate that inhibition or absence of poly(ADP)-ribose polymerase (PARP), one of the molecules involved in cell death, provides remarkable protection in disease models such as stroke, myocardial infarction and renal ischemia which are characterized predominantly by necrotic type of cell death. Overactivation of PARP in conditions such as ischemic renal injury leads to cellular depletion of its substrate NAD+ and consequently ATP. The severely compromised cellular energetic state induces acute cell injury and diminishes renal functions. PARP activation also enhances the expression of proinflammatory agents and adhesion molecules in ischemic kidneys. Pharmacological inhibition and gene ablation of PARP-1 decreased energy depletion, inflammatory response and improved renal functions in the setting renal ischemia/reperfusion injury. The biochemical pathways and the cellular and molecular mechanisms mediated by PARP-1 activation in eliciting the energy depletion and inflammatory responses in ischemic kidney are not fully elucidated. Dissecting the molecular mechanisms by which PARP activation contributes to oxidant-induced cell death will provide new strategies to interfere in those pathways to modulate cell death in renal ischemia. The current review evaluates the experimental evidences in animal and cell culture models implicating PARP as a pathophysiological modulator of acute renal failure with particular emphasis on ischemic renal injury.     

无症状性心肌缺血的动态心电图分析

目的 探讨动态心电图对无症状心肌缺血的诊断价值.方法 应用holter对238例冠心病患者进行检测.结果 218例有缺血型ST改变（91.6％）,其中72.48％的缺血性ST改变阵次为无症状心肌缺血.有症状心肌缺血发生占27.52％.结论 holter是检测无症状心肌缺血的重要方法,临床上应高度重视无症状心肌缺血的发生并积极治疗.     

The hedgehog signaling pathway, a new therapeutic target for treatment of ischemic heart disease

The hedgehog (Hh) protein is involved in angiogenesis and cardiovascular development via activation of the classical ligand-dependent signaling transduction. So its potential therapeutic meaning of Hh signaling proteins to the ischemic heart diseases has been greatly explored. Recent studies show that up-regulated expression of hypoxia-induced factor-1 (HIF-1) and inflamemation in ischemic tissues activate the Hh signaling cascade in a GLI-dependent or independent way, resulting in elevated expression levels of pro-angiogenic and agiogenic factors to facilitate angiogenesis. In addition, Hh signaling pathway activation can promote residual myocardial progenitors, endogenous EPCs and MSCs differentiating into cardiomyocytes, inhibit cardiomyocyte apoptosis; thirdly, high level of exogenous Hh signaling can reduce myocardial ischemic/reperfusion injuries(I/R). In conclusion, three kinds of mechanisms induced by Hh signaling pathway participate in the heart repair after myocardial ischemia. Therefore, Hh agonists including Hh protein, Hh gene transfer and small molecule agonist could be part of a potential therapeutic strategy for acute or chronic ischemic heart disease.     

2017—2019年天津市第五中心医院重症肺炎病原菌分布及耐药性分析

冠心病是常见缺血性心血管疾病的一种,因冠状动脉粥样硬化导致的心肌缺血、缺氧所致,可引发心绞痛,致使患者病情进一步加重。冠心病、心绞痛的治疗以药物为主,注射用丹参多酚酸是用丹参提取物制成的中药注射剂,具有抗氧化应激、减轻心肌缺血损伤、抗炎等多个方面的药理作用,可有效缓解冠心病、心绞痛症状,促进患者预后改善。对近年来注射用丹参多酚酸盐治疗冠心病、心绞痛的作用机制与临床疗效的研究进展进行综述。     

Extracorporeal Shock Wave Therapy for Ischemic Cardiovascular Disorders

Ischemic heart disease is the leading cause of death and a major cause of hospital admissions, with the number of affected patients increasing worldwide. The current management of ischemic heart disease has three major therapeutic options: medication, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). However, the prognosis for patients with severe ischemic heart disease without indications for PCI or CABG still remains poor due to the lack of effective treatments. It is therefore crucial to develop alternative therapeutic strategies for severe ischemic heart disease. Extracorporeal shock wave (SW) therapy was introduced clinically more than 20 years ago to fragment kidney stones, which has markedly improved the treatment of urolithiasis. We found that a low-energy SW (about 10% of the energy density used for urolithiasis) effectively increases the expression of vascular endothelial growth factor (VEGF) in cultured endothelial cells. Based on this in vitro study, we initiated in vivo studies and have demonstrated that extracorporeal cardiac SW therapy with a low-energy SW up-regulates the expression of VEGF, induces neovascularization, and improves myocardial ischemia in a porcine model of chronic myocardial ischemia, without any adverse effects in vivo. On the basis of promising results in animal studies, we performed a series of clinical studies in patients with severe coronary artery disease without indication for PCI or CABG, including, firstly, an open trial followed by a placebo-controlled, double-blind study. In both studies, our extracorporeal cardiac SW therapy improved symptoms, exercise capacity, and myocardial perfusion in patients with severe coronary artery disease. Importantly, no procedural complications or adverse effects were noted. The SW therapy was also effective in ameliorating left ventricular remodeling after acute myocardial infarction (MI) in pigs and in enhancing angiogenesis in hind-limb ischemia in rabbits. Based on these animal studies, we are also conducting clinical studies in patients with acute MI and in those with peripheral artery disease. Thus, our extracorporeal cardiac SW therapy appears to be an effective, safe, and non-invasive angiogenic approach in cardiovascular medicine and its indication could be extended to a variety of ischemic diseases in the near future. In this article, we briefly summarize our work in animals and humans, and discuss the advantages and perspectives of our extracorporeal SW therapy.     

表观遗传调控在心肌缺血作用机制中的研究进展

随着现代生活方式的转变,缺血性心脏病已成为全球心血管疾病患者的主流死亡因素。迅速恢复血流灌注是治疗心肌缺血的重要途径,然而血流再灌注会诱发心肌梗死,甚至会引起无法逆转的心肌细胞死亡,因此寻找新的途径治疗心肌缺血迫在眉睫。DNA甲基化、组蛋白乙酰化与非编码RNA等表观遗传调控是后基因时代的重点研究对象,越来越多的证据表明表观遗传学调控直接影响心脏的发育,参与多种缺血性心脏病的发生与发展过程,对心肌缺血的诊断和治疗具有重要意义。对近年来DNA甲基化、组蛋白乙酰化与非编码RNA在心肌缺血中的作用机制做一综述。     

动态心电图对冠心病无症状性心肌缺血的诊断价值

目的探讨动态心电图对冠心病无症状性心肌缺血的临床诊断价值。方法随机抽取220例本院心内科收治的冠心病患者,采用动态心电图对其连续观测1d,然后回放分析ST段的位移值等指标。结果 220例患者中发生心肌缺血者201例（91.36%）,共检测出心肌缺血671次,其中心肌缺血为568次（84.65%）,显著高于有症状的心肌缺血（15.35%）,P〈0.05。心肌缺血阈变异性在早8点至晚6点之间和晚6点至早6点之间差异显著（P〈0.05）。心肌缺血发作前后心率发生了显著差异变化。而ST下移也是在发作后显著大于发作前。结论动态心电图是诊断无痛心肌性缺血的较为理想的手段,是一种无创的辅助检查手段,对于冠心病患者的回访和疗效的评价有着重要的意义,值得推广。     

IB-MECA and cardioprotection

The adenosine A(3) receptor plays an important role in ischemic preconditioning. Activation of the adenosine A(3) receptor with its agonists induces both early and late pharmacological preconditioning through various mechanisms. As the first potent and selective adenosine A(3) receptor agonist, IB-MECA (N(6)-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide) has been demonstrated to induce cardioprotection against myocardial ischemia/reperfusion injury when given before onset of ischemia by triggering pharmacological preconditioning. More importantly, IB-MECA can also protect the heart even when administered at the onset of reperfusion after ischemia, indicating a strong likelihood that the drug may be useful for the treatment of patients with acute myocardial infarction. However, since IB-MECA has been reported to have lethal effects at higher concentrations, and may cause systemic hypertension in some species, further studies are needed to find the best treatment strategy to increase its therapeutic potential.     

动态心电图在无症状性心肌缺血冠心病诊断中的价值

目的探讨动态心电图（DCG）对检测冠心病患者无症状性心肌缺血的临床价值。方法用DCG记录96例冠心病患者ST段下移阵次数、ST段下移持续时间、当时有无症状、发作昼夜时间规律及发作前后心率的变化。结果缺血性ST段下移336阵次,其中无症状发作246阵次,有症状发作90阵次;无症状性心肌缺血持续时间（5.4～12）min/次,有症状性心肌缺血持续时间（14～24.6）min/次,两者比较差异有统计学意义（P〈0.05）。结论 DCG是临床上诊断心肌缺血尤其是无症状性心肌缺血（SMI）的敏感性、特异性、准确性都较高,大大提高了SMI的检出率,为目前较理想的非创伤性检查方法。     

动态心电图无症状心肌缺血的诊断价值研究

目的对动态心电图无症状心肌缺血的诊断价值进行研究与探讨。方法2012年10月。2013年11月我院共收治了112例无症状心肌缺血患者,采用回顾性的分析方式,对这112例患者的病例进行研究与分析。结果79例患者符合心肌缺血性ST段压低发作的要求,约占总例数的70．5％。在这79例患者中,共发生缺血性ST-T改变362阵次,其中症状性心肌缺血发生率明显低于SMI发生率,两者差异显著,具有统计学意义（P〈0．05）。结论在临床治疗无症状心肌缺血的过程中,使用动态心电图对患者进行检查,可以收到较为理想的效果,是比较好的检查方法,在临床诊断与治疗冠心病中具有非常重大的意义,值得大力推广使用。     

Modulation of cardiovascular remodeling with statins: fact or fiction?

The concept of cardiac remodeling implies a complex mixture of myocardial ischemia, and increased wall stress that results in molecular, cellular and interstitial changes in the heart. Clinically, cardiac remodeling is manifested as a change in size, shape and function of the heart. Morphologically the key feature of remodeling is myocyte hypertrophy, myocyte loss from necrosis or apoptosis, as well as interstitial cell growth especially fibroblast proliferation leading to myocardial fibrosis. Cardiac remodeling is influenced by hemodynamic load, neurohumoral activation, and other factors that can further affect the remodeling process. Despite advances in the management of heart failure, morbidity and mortality still present major health care issues in these patients. Statins (HMG Coenzyme A reductase inhibitors) play a key role in the management of ischemic heart disease. Recent studies indicate that statins may modulate cardiac remodeling by affecting signals that cause fibroblast growth, and myocyte hypertrophy and loss. In this paper we review the mechanisms of cardiac remodeling and the mechanisms of potential beneficial effects of statins on cardiac remodeling.     

The role of nitric oxide in A3 adenosine receptor‐mediated cardioprotection

1 Limiting the impact of ischemia reperfusion‐related cell death is of vital importance given the enormous figures of heart related mortality in the world. 2 Coronary heart disease (CHD) is responsible for over 100 000 deaths in the UK each year, and is the most common cause of premature death in the UK and as a whole it is estimated that there are just over 1.5 million men, and 1.1 million women, who have suffered CHD in the form of either angina or myocardial infarction ( http://www.heartstats.org ). 3 In patients undergoing standard clinical reperfusion treatment today such as thrombolysis, percutaneous coronary angioplasty (primary PCTA), and bypass surgery, there remains an underscored need for novel therapies and strategies to reduce post‐ischemic infarct size. 4 This review focuses on some of the intracellular signalling pathways that have been proposed to be coupled to A3 adenosine receptors in order to reduce post‐ischemic infarct size, in particular the role of nitric oxide in A3 adenosine receptor‐mediated cardioprotection is discussed.     

The potential role of sphingolipid-mediated cell signaling in the interaction between hyperglycemia, acute myocardial infarction and heart failure

INTRODUCTION: Patients with acute myocardial infarction or heart failure frequently have abnormalities of glucose metabolism and insulin resistance, both of which are associated with a poor outcome. Sphingolipids are a class of lipids, which play important roles in cellular biological processes including insulin resistance and myocardial ischemia. AREAS COVERED: This review examines the available evidence linking abnormalities in sphingolipids, glucose tolerance and insulin resistance to acute myocardial infarction and heart failure. EXPERT OPINION: Pharmacological and genetic activation of enzymes controlling key sphingolipids synthesis, such as sphingosine-1-phosphate, increases insulin sensitivity in rodents and increases myocardial tolerance to ischemia. Major projects are being realized to develop clinical strategies to manipulate sphingolipid metabolism in this clinical settings, with the ultimate goal of increasing insulin sensitivity and augmenting myocardial tolerance to ischemia. Thus, a clear understanding of the sphingolipid-mediated signaling in ischemic heart disease is required to devise strategies to develop novel agents and technologies that directly target this signaling pathway.     

心肌缺血再灌注损伤的分子修复机制及其抑制剂的研究进展

目前缺血性心脏病的发病率位于原发性心脏病之首,其中心肌缺血再灌注损伤约占50%以上。因此,开发治疗心肌缺血再灌注损伤的多靶点药物对防治心脏疾病具有重大价值和意义。研究MIRI的分子机制并开发针对各种靶点的MIRI抑制剂,以此调控多种信号通路,为进一步阐明MIRI分子机制及研发相关药物提供了新的思路。     

Role of Metabolically Active Drugs in the Management of Ischemic Heart Disease

This article reviews the fundamentals of myocardial energy metabolism and selectively outlines the use of several metabolically active drug therapies in the treatment of ischemic heart disease. These drugs — ranolazine, trimetazidine, dichloroacetate (DCA), glucose-insulin-potassium (GIK) solutions, and L-carnitine — have mechanisms of action distinct from traditional anti-ischemic drugs. These agents work by shifting myocardial energy metabolism away from fatty acids toward glucose as a source of fuel. Because these agents are well tolerated and do not affect heart rate or blood pressure, they conceivably could supplement traditional anti-ischemic drug therapy with little risk. The background, rationale for use, and published literature on each agent is reviewed, and the outcomes of pertinent clinical trials are discussed. In the case of ranolazine, data suggest benefit in the treatment of stable angina pectoris, particularly with sustained release formulations. Trimetazidine appears to have similar physiologic effects to ranolazine, and it is effective as monotherapy and as additive therapy in patients with chronic ischemic heart disease. DCA improves acidosis in critically ill patients and, likewise, improves myocardial hemodynamics in those with chronic coronary artery disease and congestive heart failure; however, its metabolism is variable and clinical data on its use in chronic ischemic heart disease are limited. GIK solutions have been shown to be beneficial in animal and human models of ischemia and acute myocardial infarction, and they offer an inexpensive means by which to improve the oxidation of glucose in the heart. Lastly, a large body of literature suggests a benefit with L-carnitine in a number of cardiovascular illnesses, including ischemic heart disease. Clinical trial data in acute myocardial infarction are promising and have prompted the initiation of a large-scale mortality trial.