钙化性主动脉瓣疾病的诊疗进展

随着社会老龄化进程的加快,钙化性主动脉瓣疾病发病率逐渐升高,相关的心力衰竭（心衰）等不良事件显著增加,给社会带来沉重负担,同时,目前对于严重的钙化性主动脉瓣的治疗方法和效果有限、并发症多,其原因是钙化性主动脉瓣疾病的发生机制不明确、缺少预防其发生发展的有效手段。因此,深入探究钙化性主动脉瓣疾病的发生机制,寻找干预其发生进展的分子靶点,对于降低钙化性主动脉瓣疾病的发生具有重要意义。本文针对钙化性主动脉瓣疾病的流行病学、发病机制和临床治疗的现状及进展进行综述。     

钙化性主动脉瓣狭窄发病机制的研究进展

钙化性主动脉瓣狭窄是老年人最常见的心脏瓣膜疾病,其病理特征主要是瓣叶的局灶性钙化和广泛纤维性增厚,发病机制过去一直被认为是退行性不可修复的劳损过程,近年来多项研究表明钙化性主动脉瓣狭窄是积极主动调控过程。目前发现主要有炎性细胞浸润、脂质沉积、凋亡结节形成、骨形成、细胞外基质的重塑、血管形成及肾素血管紧张素系统等机制参与。本文就钙化性主动脉瓣狭窄发病机制的研究进展及相应的治疗研究做简单的阐述。     

脂蛋白(a)与钙化性主动脉瓣疾病的研究进展

钙化性主动脉瓣疾病是常见的心血管疾病,随着人口老龄化的日益加剧其逐渐成为主要的医疗负担。瓣膜置换术是该病的主要治疗方法,但高龄群体手术风险较大,并发症发生率高。且目前仍缺少预防或减缓疾病进展的有效药物。研究发现,脂蛋白(a)在瓣膜钙化的病理过程中起关键作用,脂蛋白(a)水平升高是钙化性主动脉瓣疾病的重要危险因素,显著增加主动脉瓣狭窄的患病风险。本文综述了脂蛋白(a)在钙化性主动脉瓣疾病的病理机制中的作用及其与治疗方面的相关性。     

主动脉瓣钙化的机制研究进展

主动脉瓣钙化性狭窄是一种常见的引发主要不良心血管事件的心血管疾病，但目前尚无有效的医疗干预手段来延迟或阻止其进展。心脏代谢风险因素（包括吸烟和男性等）与主动脉瓣狭窄有关。近年的研究也明确了免疫和炎症反应（包括氧化脂质，各种细胞因子和生物矿化）对主动脉瓣钙化的重要调节作用。炎症和代谢通过调节骨形成相关的信号通路参与心血管系统中骨生成进而导致血管钙化。随着研究的深入，主动脉瓣钙化性疾病（CAVD）不再被认为是一种在高龄时发生的单纯的钙沉积被动过程，而是一个涉及瓣膜，循环，骨髓来源的细胞，巨噬细胞异质性以及遗传、生化和机械等因素的复杂调控过程。本综述主要讨论最近发现的促进CAVD的炎症和脂质代谢危险因素在主动脉瓣钙化形成机制的研究进展，这将为未来发展抑制CAVD进展的治疗策略提供理论基础。     

RAGE与主动脉瓣钙化发病机制的相关性研究

摘要：目的：本研究旨在证明RAGE与主动脉瓣钙化炎症机制、骨化机制具有相关性。方法：明确RAGE与主动脉瓣钙化过程中炎症机制的相关性（运用Elisa检测AGEs、sRAGE、TNF-α、IL-1β、IL-6在钙化主动脉瓣患者血清中的表达情况）。明确RAGE与主动脉瓣钙化过程中成骨机制的相关性（应用Western Blot、RT-PCR、免疫组化检测RAGE、BGP、BMP-2、TGF-β在钙化主动脉瓣中的表达情况）。结果：患者AGEs、sRAGE、TNF-α、IL-1β、IL-6在钙化主动脉瓣狭窄患者血清中较正常患者具有统计学差异（P＜0.05）。钙化主动脉瓣样本中定量PCR检测和Western实验中提示RAGE、BGP、BMP-2、TGF-βmRNA具有统计学差异（P＜0.01）。免疫组化提示：钙化组RAGE、BGP、BMP-2、TGF-β较对照组明显高表达。结论：主动脉瓣钙化患者血清中sRAGE降低、AGEs及相关炎症因子（TNF-α、IL-1β、IL-6）明显升高。钙化主动脉瓣中BGP、BMP-2、TGF-β及RAGE高表达。RAGE可能通过参与炎症反应及成骨作用促进主动脉瓣钙化。这对于该疾病治疗策略的选择及防治具有重要的临床意义。     

瓣膜间质细胞异质性在钙化性主动脉瓣疾病中的作用

钙化性主动脉瓣疾病(CAVD)是一种表现为主动脉瓣增厚、钙化的疾病,随病情发展可出现瓣膜硬化,进而引起一系列血流动力学的异常改变,最终可导致慢性心力衰竭和死亡。主动脉瓣膜间质细胞是构成主动脉瓣膜的主要细胞亚群,在CAVD的发生发展中起重要的作用。当前,单细胞测序等技术让研究者对间质细胞的起源、表型和功能异质性有了新的理解。文章对间质细胞的异质性在钙化性主动脉瓣疾病中所起的作用进行综述,为靶向间质细胞延缓CAVD进程提供新的思路。     

从DNA甲基化探讨钙化性主动脉瓣膜疾病的发病机制

随着我国风湿热发病率逐年下降,钙化性主动脉瓣膜病(CAVD)已成为老年人最常见的心脏瓣膜病。钙化性主动脉瓣疾病是指各种原因引起的以主动脉瓣钙化为主要病理改变的疾病总称。早期的病变机制,是与动脉粥样硬化相类似的、经典的"损伤应答假说",最近的研究发现,CAVD是涉及内皮损伤、脂质浸润、慢性炎症、基质重构、细胞分化、钙盐沉积及新生血管形成等复杂变化的多信号通路参与的主动过程,而并非年龄导致的不可避免的结果。随着人们生活方式、人口老龄化、科学技术和健康产业的发展,CAVD呈现出逐年增长的趋势,对其分子学机制的研究也成为目前的热点。DNA甲基化是一种重要的表观遗传调控方式,可在转录前水平调节基因的表达,异常的DNA甲基化模式是许多疾病共同的分子学基础,目前已广泛应用于各种肿瘤疾病、糖尿病、骨性关节炎、帕金森等疾病发病机制的研究中,在心血管疾病如动脉粥样硬化及主动脉瓣钙化中也发现了表观遗传修饰的证据。因此从DNA甲基化修饰探讨CAVD的发病机制为分子学水平的研究提供了新途径,从而对疾病的预防及治疗提供更有效的手段,有可能使药物治疗延缓或逆转钙化性主动脉瓣疾病的发展成为可能。     

钙化性主动脉瓣狭窄的预防及治疗展望

主动脉瓣疾病,特别是钙化性主动脉瓣狭窄是目前老年人中最为常见的心脏瓣膜病。中国渐入老龄化社会,再加之人们生活质量的提高和平均寿命的增加,钙化性主动脉瓣狭窄在中国的发病率及患病率逐年上升。钙化性主动脉瓣狭窄的平均病程在8年左右,一旦出现症状若不及时有效地进行主动脉瓣置换术,患者的生存率将极大缩短。由于患者高龄,合并多种疾病,往往错过手术最佳时期,而药物治疗对严重钙化的主动脉瓣往往难以奏效。因此,研究该病的相关危险因素及发病机制对预防、早期药物干预治疗及延缓瓣膜钙化的进展尤为重要。     

钙化性主动脉瓣疾病的研究进展

大量研究显示,随着人口老龄化的加剧,钙化性主动脉瓣疾病发病率逐年上升。目前研究发现其是一类涉及内皮损伤、基质重塑、血管生成、钙化、骨形成及多种血管活性肽等参与的主动过程,其中血管活性肽较受关注。而且,目前尚无有效的药物治疗方案。近年来,他汀类药物及肾素-血管紧张素抑制剂的疗效备受关注,但结论尚不一致。基于此,现就钙化性主动脉瓣疾病的研究进展及治疗做一综述。     

钙化性主动脉瓣疾病:一个新的挑战

钙化性主动脉瓣疾病(CAVD)是一个涉及脂质沉积、慢性炎症调控及进展性钙化的主动过程,其病理过程与动脉粥样硬化相似。CAVD是心血管高危风险的标志,他汀类药物虽推迟CAVD合并高脂血症患者的病程,但其治疗仍是一个新的挑战。经导管主动脉瓣植入术日益受到青睐;主动脉瓣钙化的病因、病理、治疗及转归正受到关注。     

Statin therapy of calcific aortic stenosis: hype or hope?

Calcific aortic stenosis, with a prevalence of 3-9%, is the most frequent heart valve disease and the main cause for valve replacement in patients over 60 years of age. Once thought to be caused by a passive calcium precipitate within the aortic valve leaflets, there is now increasing evidence that development and progression of calcific aortic valve disease may be triggered by underlying genetic and cardiovascular risk factors, and is regulated by an active cellular process involving inflammatory pathways. Targeted drug therapy to prevent the progression of calcific aortic valve disease should ideally be based on the knowledge of risk factors and the molecular pathogenesis of the disease. Conflicting data exists on the potency of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e. statins) to influence both risk factors and inflammatory pathways by lowering lipid levels and exerting anti-inflammatory properties, respectively. In this review, various aspects of the molecular pathogenesis of calcific aortic stenosis will be summarized and connected with recent experimental and clinical studies that address the potential benefit of the targeted drug therapy by statins in order to prevent the progression of the disease.     

Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis

Calcific aortic valve stenosis (AS), the main heart valve disease in the elderly, is characterized by extensive remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) are upregulated in calcific AS and might modulate matrix remodeling. The regulatory mechanisms are unclear. As recent studies have suggested that calcific AS might result from an inflammatory process involving leukocyte invasion and activation, the present study aimed to elucidate the role of the pro-inflammatory cytokine interleukin (IL)-1β on MMP expression and cell proliferation in human aortic valves. Immunohistochemistry for leukocytes, IL-1β and MMP-1 was performed on aortic valves with (n=6) and without (n=6) calcification obtained at valve replacement or autopsy. Stenotic valves showed marked leukocyte infiltration and associated expression of IL-1β and MMP-1. In control valves only scattered leukocytes, low staining for MMP-1 and no staining for IL-1β were present. Double-label immunostaining localized IL-1β expression mainly to leukocytes and MMP-1 expression to myofibroblasts. Stimulation of cultured human aortic valve myofibroblasts with IL-1β lead to a time-dependently increased expression of MMP-1 and MMP-2 by Western blotting and zymography, whereas MMP-9 remained unchanged. Cell proliferation was increased by IL-1β as determined by bromodesoxyuridine incorporation. Thus, IL-1β may regulate remodeling of the extracellular matrix in calcific AS.     

Calcific aortic stenosis: an update

Calcific aortic stenosis in the elderly is the number one cause of surgical valve replacement in the US and Europe. The incidence of calcific aortic stenosis is increasing as the general age of the population increases. For many years, rheumatic heart disease was the main cause of aortic valve disease. Over the last half century, however, there has been a change from a rheumatic etiology to a 'degenerative' mechanism because of the increase in access to health care in developed countries and the increasing age of the population in the US and Europe. For many years 'degenerative' aortic stenosis was thought to be caused by the passive accumulation of calcium on the surface of the aortic valve leaflet. Recent studies have demonstrated, however, that the etiology of aortic valve disease has a similar pathophysiology to that of vascular atherosclerosis, and that the treatment of this disease could be similar to that of chronic vascular atherosclerosis. This Review will discuss our current understanding of the pathophysiology, risk factors, cellular mechanisms, diagnosis and finally, future medical therapies for calcific aortic stenosis.     

重视老年钙化性主动脉瓣狭窄的防治研究

钙化性主动脉瓣狭窄(CAVS)是老年人的多发病,由于其无症状期漫长,先前一直被认为是"良性的"被动性老年退变现象。新近研究发现,CAVS的病变实际上是主动的发展过程,最终并可导致严重后果。到后期,一旦出现症状,病情很快恶化,致死率很高,此时只能进行外科换瓣手术解除狭窄,抢救和延长生命。目前尚无其他有效办法防止CAVS的发生、发展,亟待深入研究。     

Association of Paget's disease of bone with calcific aortic valve disease

To test the hypothesis that Paget's disease of bone is associated with a greater incidence of calcific aortic valve disease, a computer-generated list was obtained of all autopsy subjects from the Johns Hopkins Hospital in whom Paget's disease was diagnosed (n = 92). The severity of Paget's disease and cardiac valvular lesions was graded on a scale of 0 to 3, with 3 as the most severe. Two control cases were obtained for each case of Paget's disease. Each was the case either immediately before or after the Paget's case, and was matched for age, race, sex, and extent of autopsy. The incidences of moderate (10.9 percent) and severe (5.4 percent) calcific aortic valve disease were both fourfold greater than in the control group (chi-square analysis, p less than 0.01 and p less than 0.05, respectively). Additionally, the frequency of advancing grades of calcific aortic valve disease was greater in more advanced stages of Paget's disease. In fact, there was a dose-response effect of Paget's disease upon calcific aortic valve disease (trend analysis for proportion, p less than 0.01). These data therefore support the hypothesis that Paget's disease is associated with calcific aortic valve disease in a dose-response manner.     

Genetics of Calcific Aortic Stenosis – Time to Move Forward

Knowledge of the genetic determinants of aortic stenosis (AS) could help elucidate the underlying mechanisms leading to clinical valvular heart disease and could potentially aid in the development of new therapies to prevent or retard valvular heart disease. However, despite the large burden of disease due to AS, no large-scale genetic studies of AS have been reported. Research on the genetics of valvular heart disease remains at least several years behind that of myocardial infarction, coronary artery disease and several other cardiovascular diseases. To date, with few important exceptions, human genetic research in calcific aortic valve disease has been quite limited. This review will provide a summary of the genetic literature on human calcific AS and provide future directions for genetic research in aortic valve disease.     

Hemodynamic changes pre- and post-pacing with complete heart block and aortic valve stenosis and regurgitation

Conduction disturbances in the setting of calcific aortic valve disease have been well documented in the literature. In this report we describe a case of a patient who presented in complete heart block and dyspnea on exertion. Subsequent non-invasive and invasive studies revealed moderate aortic stenosis and regurgitation with preserved left ventricular function. Hemodynamically important physiological pressure waveform changes occurred before and after pacing the ventricles and are highlighted here. © 1996 Wiley-Liss, Inc.     

Pathology of calcific aortic stenosis

With the aging of the general population in industrialized nations, calcific aortic stenosis (CAS) is becoming an increasingly important medical problem. The etiology is for the most part, dependent on the age at presentation; the two predominant causes in the western world are calcific aortic valve disease arising in a tricuspid aortic valve and bicuspid aortic valve (BAV). CAS is a progressive disease, exhibiting a spectrum of pathologic findings, ranging from valvular sclerosis to severe nodular calcification. Aortic valve replacement is the recommended treatment for severe disease but tissue valves may also calcify over time. Various atherosclerotic risk factors have been linked to aortic stenosis and there are mechanistic similarities between atherosclerosis and CAS. The precise pathologic mechanisms underlying aortic stenosis are poorly understood.     

Retinal artery embolization: A rare presentation of calcific aortic stenosis

Retinal artery embolization is an unusual but serious complication of calcific aortic stenosis. However, it is rare for retinal embolization to be the presenting feature of aortic stenosis. This report describes a young patient who presented with an acute retinal artery occlusion secondary to calcific aortic valve disease, and discusses the rationale for early surgical intervention.