Circulating microRNAs as novel and sensitive biomarkers of acute myocardial Infarction

Coronary artery disease and acute myocardial infarction (AMI) are the leading causes of death for both men and women. Serum cardiac-specific troponin level is now used for the "early" diagnosis of AMI. However, due to the "delayed" release of troponin, an earlier, more sensitive and specific biomarker is urgently demanded to further reduce AMI mortality. Recent studies have found that circulating microRNAs (miRNAs) are closely linked to myocardial injury. Due to the cell-specific physiological functions and the stability of miRNAs in plasma, serum, and urine, they are emerging as sensitive biomarkers of AMI. This review summarizes the latest insights into the identification and potential application of plasma and serum miRNAs as novel biomarkers for diagnosis and prognosis of AMI.     

microRNAs与心肌梗死

microRNAs（miRNAs）是一类内源性的非编码单链小分子RNA,约22个核苷酸。miRNAs通过调控其靶基因的表达,参与细胞发育、增殖、分化、凋亡等一系列重要的生理学途径。近些年的研究发现,miRNAs在心肌梗死的发生、发展过程中起着关键的作用。现就miRNAs在心肌梗死发生、发展过程中的作用机制进行阐述。     

Circulating microRNAs to predict heart failure after acute myocardial infarction in women

Left ventricular remodeling after acute myocardial infarction affects cardiac function and increases the risk of developing heart failure. Despite the emergence of biomarkers associated with remodeling, the ideal biomarker to accurately predict the risk of developing heart failure after acute myocardial infarction is still to be discovered. Female and male hearts cope differently with ischemic stress, leading to different consequences on cardiac morphology and function. As biomarkers reflect the pathogenesis of remodeling, utilization of sex-specific biomarkers might improve risk stratification. Expressed in cardiac and inflammatory cells, microRNAs regulate several biological pathways triggering the remodeling process. In addition, circulating microRNAs are associated with the risk of developing heart failure after acute myocardial infarction, hence their biomarker potential. Interestingly, multiple microRNAs display sex-specific expression profiles as they can be modulated by sexual hormones and escape X-inactivation, for those located on the X-chromosome. This review article aims to discuss the potential of circulating microRNAs to predict heart failure after acute myocardial infarction in a sex-specific manner.     

MicroRNA在心肌梗死临床诊疗中的应用进展

微小RNA(micro-ribonucleic acid,microRNA/miRNA)是一种小的非编码RNA,在调控基因的转录过程中起着重要作用。近年来研究发现,miRNA参与心肌细胞发育、增殖、凋亡等进程,可作为一种新型的生物标志物,在急性心肌梗死的早期诊断、预后甚至治疗等方面扮演重要角色。然而,目前miRNA在检测技术、机制研究及临床试验方面仍面临诸多问题和挑战。本文就上述系列内容作一综述。     

Pregnancy-associated plasma protein A: a biomarker in acute ST-elevation myocardial infarction (STEMI)

BACKGROUND: Elevated circulating levels of pregnancy-associated plasma protein A (PAPP-A), a novel marker of atherosclerotic plaque instability, are associated with increased risk of future cardiac events in patients with acute coronary syndromes (ACS). However, little is known of the kinetics or clinical significance of circulating PAPP-A after plaque rupture in acute ST-elevation myocardial infarction (STEMI). AIM: To evaluate the 48-hour release of pregnancy-associated plasma protein A (PAPP-A) and its association with 12-month outcome in patients with acute ST-elevation myocardial infarction (STEMI). METHODS: Sixty-two consecutive STEMI patients were included (40 men and 22 women, median age 67.5 years (range 34-84)), of whom 54 (87.1%) received reperfusion therapy. PAPP-A was measured at admission and 6-12, 24 and 48 hours thereafter. In 14 patients, samples were obtained also at 1, 2 and 4 hours. RESULTS: There was an early peak of circulating PAPP-A during the first 12 hours from symptom onset, followed by rapid normalization. A second, late PAPP-A elevation was noticed in 20/62 patients (32.3%). Admission PAPP-A >10.0 mIU/L (highest tertile) was associated (P = 0.049) with increased 12-month risk of cardiovascular death or non-fatal myocardial infarction. Moreover, the combination of failed early reperfusion together with late PAPP-A elevation was strongly (7/13 versus 10/49 patients, P = 0.016) associated with adverse outcome. Admission PAPP-A did not correlate with admission C-reactive protein or cardiac troponin I. CONCLUSIONS: PAPP-A is elevated early in STEMI and then declines rapidly, a pattern consistent with release from the ruptured plaque. The variability of PAPP-A kinetics at 48 hours reflects the success of reperfusion. This study also shows that PAPP-A may have prognostic value in STEMI.     

Circulating human megakaryocytes in cardiac diseases

Abstract Both bone marrow and circulating megakaryocytes may produce platelets. Changes in number and properties of the circulating megakaryocytes in cardiac diseases may provide information about thrombopoiesis in these disease states. Circulating megakaryocytes were obtained by retrograde aspiration through wedged pulmonary artery catheters from patients without cardiac abnormalities, patients with cardiac diseases and patients with disorders known to affect the megakaryocyte-platelet axis or marrowblood barrier. Their number, ploidy distribution and expression of the β₁-integrin adhesion antigens were estimated. We found evidence for an increased number of circulating megakaryocytes during acute myocardial infarction and in patients with triple vessel disease. A significantly higher proportion of circulating megakaryocytes obtained within 60 h after acute myocardial infarction, expressed CDw49b (α-chain of VLA2), CDw49e (α-chain of VLA5), and CDw49f (α-chain of VLA6) compared to megakaryocytes of patients without cardiac diseases. In myocardial infarction the increase in number of circulating megakaryocytes together with the higher proportion that expressed the β₁-integrin adhesion antigens favour the hypothesis that these megakaryocytes are acutely released from the bone marrow. This could reflect either a selective response to an increased demand for circulating platelets or be the result of an aselective mechanism resulting from damage to the marrow-blood barrier following the acute infarction or thrombolytic therapy administered.     

Circulating microRNAs: a novel class of biomarkers to diagnose and monitor human cancers

Specific and sensitive non-invasive biomarkers for the detection of human epithelial malignancies are urgently required to reduce the worldwide morbidity and mortality caused by cancer. MicroRNAs (miRNAs) are 19-24 nt noncoding RNAs that are frequently dysregulated in cancer and have shown great promise as tissue-based markers for cancer classification. Once thought to be unstable RNA molecules, miRNAs are now shown to be stably expressed in serum, plasma, urine, saliva, and other body fluids. Moreover, the unique expression patterns of these circulating miRNAs are correlated with certain human diseases, including various types of cancer. Therefore, tumor-derived miRNAs in serum or plasma are emerging as novel blood-based fingerprints for the detection of human cancers, especially at an early stage. This review presented newly uncovered cellular and molecular mechanisms of the sources and stability of circulating miRNAs, revealing their great potential as a class of highly specific and sensitive biomarkers for tumor classification and prognostication. Meanwhile, this review also addressed certain critical issues that hinder the wide application of this new approach. Some potential challenges for the transition of circulating miRNAs from a research setting to a clinical application were also highlighted, with a future perspective of the incorporation of circulating miRNAs in the field of clinical oncology, especially their great potential from diagnostic to prognostic and predictive applications.     

急性前壁心肌梗死并发急性心功能不全时休克指数的变化

目的：研究急性前壁心肌梗死致急性心功能不全时休克指数（SI,心率/收缩压）的变化,以探讨SI能否作为急性前壁心肌梗死时是否并发急性心功能不全的评价指标。方法：采用我院的数字化病案库,检索2011年以急性前壁心肌梗死作为第一诊断出院的患者,统计入院时的心率、血压以及Killip分级,根据Killip分级将患者分为心功能不全组以及非心功能不全组,分析两组的SI有无差异。结果：心功能不全组的平均SI大于非心功能不全组,且二者有统计学差异。结论：急性前壁心肌梗死时SI可以作为有无急性心功能不全的评价指标。     

The cardioprotective effects of mineralocorticoid receptor antagonists

Despite state-of-the-art reperfusion therapy, morbidity and mortality remain significant in patients with an acute myocardial infarction. Therefore, novel strategies to limit myocardial ischemia–reperfusion injury are urgently needed. Mineralocorticoid receptor (MR) antagonists are attractive candidates for this purpose, since several clinical trials in patients with heart failure have reported a survival benefit with MR antagonist treatment. MRs are expressed by several cells of the cardiovascular system, including cardiomyocytes, cardiac fibroblasts, vascular smooth muscle cells, and endothelial cells. Experiments in animal models of myocardial infarction have demonstrated that acute administration of MR antagonists, either before ischemia or immediately at the moment of coronary reperfusion, limits infarct size. This action appears to be independent of the presence of aldosterone and cortisol, which are the endogenous ligands for the MR. The cardioprotective effect is mediated by a nongenomic intracellular signaling pathway, including adenosine receptor stimulation, and activation of several components of the Reperfusion Injury Salvage Kinase (RISK) pathway. In addition to limiting infarct size, MR antagonists can improve scar healing when administered shortly after reperfusion and can reduce cardiac remodeling post myocardial infarction. Clinical trials are currently being performed studying whether early administration of MR antagonists can indeed improve prognosis in patients with an acute myocardial infarction, independent of the presence of heart failure.     

体液microRNA作为新的无创伤性生物标志物的意义

microRNA（miRNA）是一类能降解靶mRNA或抑制靶mRNA翻译从而在转录后水平调控基因表达的非编码RNA。miRNA在多种生理、病理过程中发挥重要作用,组织细胞miRNA表达谱与多种病理尤其是肿瘤密切相关。最近的研究发现,血循环及其他体液中也存在丰富而稳定的miRNA,并且在某些疾病状态下,体液中的一些miRNA表达量会发生特异性改变,提示体液miRNA作为一种新的无创伤性生物标志物的潜力和良好的临床应用前景。本文就体液miRNA与疾病关系的研究进展作一综述。     

Inhalation of NO during myocardial ischemia reduces infarct size and improves cardiac function

Purpose

Bioactive NO carriers in circulating blood formed during NO inhalation selectively distribute blood flow to areas in need, and may thus improve collateral perfusion to the area-at-risk in acute myocardial infarction (AMI). Here, we tested the hypothesis that NO inhalation during the ischemic phase of AMI may improve left ventricular function and reduce infarct size in rats.

Methods

Following left anterior descending coronary artery (LAD) occlusion, rats received 50?ppm NO for 2?h of ischemia, during subsequent 3?h of reperfusion, or for 5?h of ischemia and reperfusion. Effects of inhaled NO were compared to those of intravenous nitrite as a putative carrier formed during NO inhalation. Downstream signaling via soluble guanylate cyclase was tested by inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ).

Results

NO inhalation during myocardial ischemia increased left ventricular systolic pressure, contractility, relaxation, and cardiac output, and reduced myocardial infarction size and area-at-risk as compared to untreated controls. NO inhalation during the reperfusion phase caused a comparable protective effect. Combined inhalation during ischemia and reperfusion did not further improve left ventricular hemodynamics, but had an additive protective effect on the myocardial area-at-risk. NO inhalation increased circulating nitrite levels, and mimicking of this effect by intravenous nitrite infusion achieved similar protection as NO inhalation during myocardial ischemia, while ODQ blocked the protective NO effect.

Conclusions

Inhalation of NO during myocardial ischemia improves left ventricular function and reduces infarct size by mechanisms that increase levels of circulating nitrite and involve soluble guanylate cyclase. NO inhalation may represent a promising early intervention in AMI.     

Apelin in acute myocardial infarction and heart failure induced by ischemia

Apelin is a recently isolated novel endogenous ligand for the angiotensin-like 1 receptor (APJ). Initial experiments in animal models indicate that the cardiovascular system is the main target of the apelin-APJ system. Apelin plays an opposite role to the renin-angiotensin-aldosterone system as a compensatory mechanism. It is reduced in patients with heart failure, also of ischemic origin. However, only animal studies concern the role of the apelin-APJ system in myocardial ischemia. Less is known about the function of this adipokine in an acute phase of myocardial infarction in human. The apelin-APJ system could perhaps be involved in myocardial protection during acute myocardial ischemia. In the current review we have summarized recent data concerning the role of apelin in acute myocardial infarction and heart failure induced by ischemia.     

Cell therapy for acute myocardial infarction

Evidence suggesting that bone marrow and circulating blood may harbor myocardial and vascular progenitor cells was the basis for pre-clinical studies of cell therapy for acute myocardial infarction (MI). Rapid initiation of clinical trials has since followed, with regional myocardial delivery of autologous cells being tested as adjunctive therapies for both acute and chronic left ventricular dysfunction. While clinical cell transplantation trials originally began with the explicit goal of myocardial regeneration, more recently the emphasis has shifted to attempted modulation of myocardial remodeling through other processes, such as mechanical strengthening of scar tissue and promotion of myocardial tissue survival through cellular paracrine effects. This article discusses the scientific rationale for cell therapy strategies in acute MI and provides an overview of the clinical studies that have been undertaken to date.     

Thyroid status in patients after acute myocardial infarction

Subjects followed serially after acute myocardial infarction demonstrated a rapid and sustained fall in serum total tri-iodothyronine (T3) concentration and a rise in reverse tri-iodothyronine (rT3) concentration. There was a transient fall in total thyroxine (T4) concentration. Thyroxine binding globulin (TBG) levels were unchanged after acute myocardial infarction but prolonged falls were observed in thyroxine binding prealbumin (TBPA) and albumin concentrations. In contrast to the fall in total T4, both measured and calculated free T4 concentrations were unchanged but measured and calculated free T3 concentrations fell as did total T3. Despite the observed fall in T3, basal thyrotrophin (TSH) concentrations did not rise. The reduction in circulating T3 levels after acute myocardial infarction suggests that a hypothyroid state exists. Until tissue thyroid status can be assessed directly, however, this conclusion must remain in doubt.     

实时PCR法验证心肌梗死大鼠模型正常组织及心肌梗死组织与血管新生途径相关差异基因的表达

背景：研究表明急性心肌梗死后血管新生过程受众多基因调控。目的：观察急性心肌梗死后与血管新生途径相关的差异基因的表达。方法：建立急性大鼠心肌梗死模型,在基因芯片结果基础上选取5个特定的表达差异基因：分泌磷酸蛋白1、趋化因子受体2、人血管生成素样蛋白4、CXC趋化因子配体5和白细胞介素1β。采用实时PCR法验证5个基因在心肌梗死大鼠模型正常组织及心肌梗死组织中的表达。结果与结论：分泌磷酸蛋白1、趋化因子受体2和人血管生成素样蛋白4在心肌梗死急性期表达上升显著（P〈0.05）,呈时间依赖性。CXC趋化因子配体5和白细胞介素1β基因表达水平呈低位波动,变化不显著。其中分泌磷酸蛋白1与趋化因子受体2与急性心肌梗死后炎性、细胞黏附、迁移和趋化相关,而人血管生成素样蛋白4与血管新生和细胞分化相关。     

Diagnosis of acute myocardial infarct with ventricular paced rhythm

Management of acute myocardial ischaemia is dependent upon interpretation of the 12‐lead electrocardiogram. The presence of ventricular pacing and acute myocardial infarction makes electrocardiogram interpretation difficult. This may impact upon patient management if treating staff are unaware of the expected electrocardiogram morphology or do not have a rapidly available means to make the diagnosis. This case highlights the difficulty with diagnosis of acute myocardial infarction in the presence of ventricular paced rhythm and demonstrates the electrocardiogram changes that occur with myocardial infarction.     

Acute myocardial infarction and renal failure following naphtha ingestion

We present a case of a non-Q wave myocardial infarction and acute renal failure following an ingestion of naphtha, a petroleum distillate composed primarily of hydrocarbons. The patient's renal, metabolic, and cardiac status improved over several days with aggressive volume replacement and bicarbonate therapy. Acute cardiotoxic effects of hydrocarbon exposure generally manifest as dysrhythmias, secondary to myocardial sensitization to circulating catecholamines, or, possibly, coronary vasospasm. Ischemia from associated hypotension or direct myocardial toxicity are other potential causes of naphtha-related cardiac injury.     

MicroRNAs: role in cardiovascular biology and disease

miRNAs (microRNAs) comprise a novel class of endogenous, small, non-coding RNAs that negatively regulate gene expression via degradation or translational inhibition of their target mRNAs. Recent studies have demonstrated that miRNAs are highly expressed in the cardiovascular system. Although we are currently in the initial stages of understanding how this novel class of gene regulators is involved in cardiovascular biological functions, a growing body of exciting evidence suggests that miRNAs are important regulators of cardiovascular cell differentiation, growth, proliferation and apoptosis. Moreover, miRNAs are key modulators of both cardiovascular development and angiogenesis. Consequently, dysregulation of miRNA function may lead to cardiovascular diseases. Indeed, several recent reports have demonstrated that miRNAs are aberrantly expressed in diseased hearts and vessels. Modulating these aberrantly expressed miRNAs has significant effects on cardiac hypertrophy, vascular neointimal lesion formation and cardiac arrhythmias. Identifying the roles of miRNAs and their target genes and signalling pathways in cardiovascular disease will be critical for future research. miRNAs may represent a new layer of regulators for cardiovascular biology and a novel class of therapeutic targets for cardiovascular diseases.