New therapeutic targets in cardiology: arrhythmias and Ca2+/calmodulin-dependent kinase II (CaMKII).
New therapeutic targets in cardiology: arrhythmias and Ca2+/calmodulin-dependent kinase II (CaMKII).
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DOI：
10.1161/circulationaha.112.124990
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发表时间：
2012-10-23
期刊：
影响因子：
37.8
通讯作者：
Anderson ME
中科院分区：
文献类型：
--
作者：
Rokita AG;Anderson ME
心律失常是一个主要的流行病学和公共卫生问题，并严重导致心脏性猝死、心力衰竭、中风、痛苦、衰弱和医疗费用。仅在美国，心源性猝死估计每年造成25万至40万人死亡。1大多数猝死是由心律失常引起的，2室性心动过速和室颤是院外心脏骤停中最常见的（80%）心律。3在结构性心脏病患者中，大多数是由心肌梗死病史引起的，心律失常是死亡的主要原因。4心房颤动（AF）和窦房结功能障碍（SND）是最常见的持续性心律失常。在美国，AF影响230万患者，5并且由于AF的患病率随着年龄的增长而增加，预计到2050年将增加2.5倍。6房颤患者的死亡率约为窦性心律患者的两倍，6卒中的发生率增加2- 7倍。AF是一种昂贵的疾病，在美国每年造成的公共卫生负担估计为60亿至260亿美元。8 SND与心源性猝死增加相关，特别是在心力衰竭患者中，心力衰竭住院患者的大部分（40%）死亡率可能继发于SND。在美国每年植入的180000个心脏起搏器中，60%的适应症是SND，2004年这项手术的费用为20亿美元。心律失常对人类健康和医疗经济的负面影响是建立新的有效治疗方法的主要推动因素。心律失常是细胞膜过度兴奋（自动和触发性快速性心律失常的原因）、冲动形成缺陷（SND的原因）或正常细胞间电耦合减少（传导系统“阻滞”的原因和大多数心律失常中由折返回路支持的慢传导区的组成部分）的结果。离子通道是具有细胞跨膜传导通路的大分子蛋白质复合物，是膜兴奋性的基本单位，并且离子通道的罕见先天性缺陷或许多药物的促心律失常脱靶作用可能足以促进心律失常风险。然而，大多数心律失常不是由单基因缺陷或药物引起的，而是在各种促心律失常因素的生物学背景下发生的，如高龄、氧化应激增加、缺血、组织损伤、炎症和全身性疾病（如高血压、糖尿病、心力衰竭）。这些促心律失常因素似乎有利于心脏组织的结构重塑，并使某些离子通道易于引发或维持心律失常。不幸的是，离子通道拮抗剂药物尚未被证明是广泛适用的、安全的或有效的抗肿瘤剂。因此，科学和工业的主要目标是确定导致常见和危及生命的心律失常的分子途径和机制，以开发新的和改进的疗法。多功能Ca 2/钙调素非依赖性蛋白激酶II（CaMKII）已成为一种高度验证的分子机制，有可能将“上游”致心律失常因素（例如氧化）与“下游”反应（例如离子通道过度活跃、细胞内Ca 2稳态缺陷）联系起来。、组织损伤和促进心律失常的疤痕形成。在这里，我们回顾了现代概念的CaMKII分子生理学的背景下，基本的心律失常机制，并认为证据表明，CaMKII抑制可能是一个广谱的…
Cardiac arrhythmias are a major epidemiological and public health problem and contribute significantly to sudden cardiac death, heart failure, stroke, suffering, debilitation, and healthcare expenses. In the United States alone, sudden cardiac death is estimated to kill 250 000 to 400 000 people annually. 1 Most sudden death is due to cardiac arrhythmias, 2 with ventricular tachycardia and fibrillation as the most commonly (80%) recorded rhythms in out-ofhospital cardiac arrests. 3 In patients with structural heart disease, mostly resulting from a history of myocardial infarction, arrhythmias are the main cause of death. 4 Atrial fibrillation (AF) and sinus node dysfunction (SND) are the most common sustained arrhythmias. AF affects 2.3 million patients in the United States, 5 and because the prevalence of AF increases with age, it is predicted to increase by 2.5-fold by 2050. 6 Patients with AF have approximately twice the mortality rate of patients in sinus rhythm, 6 and the incidence of stroke is increased by 2-to 7-fold. 7 AF is a costly disease and causes a public health burden estimated at $6.0 to $26.0 billion annually in the United States. 8 SND is associated with increased sudden cardiac death, particularly in patients with heart failure, and a large portion (40%) of mortality in hospitalized patients with heart failure may be secondary to SND. 9 SND is the indication for 60% of the 180000 pacemakers implanted in the United States each year, a procedure that in 2004 accounted for $2 billion in expenses. 10, 11 The negative impact of arrhythmias on human health and medical economics is a major motivating factor for establishing new and effective therapeutic approaches. Cardiac arrhythmias are the result of cell membrane hyperexcitability (the cause of automatic and triggered tachyarrhythmias), defective impulse formation (the cause of SND), or reduction in normal cell-to-cell electric coupling (the cause of conduction system “block” and a component of the zone of slow conduction in most arrhythmias supported by a reentrant circuit). Ion channels, macromolecular protein complexes with a cell membrane–spanning conductance pathway, are the fundamental units of membrane excitability, and rare congenital defects in ion channels or proarrhythmic off-target actions of many drugs can be sufficient to promote arrhythmia risk. However, most arrhythmias are not attributable to monogenic defects or drugs and occur in the biological context of various proarrhythmic factors such as advanced age, increased oxidant stress, ischemia, tissue injury, inflammation, and systemic disease (eg, hypertension, diabetes, heart failure). These proarrhythmic factors appear to favor structural remodeling of cardiac tissue and to predispose certain ion channels to initiate or sustain arrhythmias. Unfortunately, ion channel antagonist drugs have not proved to be broadly applicable, safe, or effective antiarrhythmic agents. 12, 13 Thus, a major goal for science and industry is to define molecular pathways and mechanisms that cause common and life-threatening arrhythmias to develop new and improved therapies. The multifunctional Ca2/calmodulindependent protein kinase II (CaMKII) has emerged as a highly validated molecular mechanism with the potential to connect “upstream” proarrhythmic factors such as oxidation with “downstream” responses such as ion channel hyperactivity, defective intracellular Ca2 homeostasis, tissue damage, and scar formation that promote arrhythmias. Here, we review modern concepts of CaMKII molecular physiology in the context of fundamental arrhythmia mechanisms and consider evidence that CaMKII inhibition could be a broadspectrum …