See Article by Brangsch et al

In a recent international survey of vascular surgeons,¹ the discovery of new tests to predict and to identify fast-growing abdominal aortic aneurysm (AAA) was seen as a top research priority. Indeed, various international guidelines have also highlighted this as an important knowledge gap that needs to be addressed.^2,3 Such innovation would allow better targeted surveillance and preemptive surgery, which today relies almost solely on the overly simplistic dichotomous threshold of the maximum anteroposterior diameter of the AAA. It is against this backdrop that Brangsch et al⁴ report their novel imaging approach in the current edition of the Journal. The authors use a murine model to address one of the most pertinent questions in AAA research—how can we more accurately characterize the risk of aneurysm rupture? Brangsch et al⁴ have therefore offered us an interesting preclinical exploration into this topic, and their article has a number of important strengths.

The search for a more accurate prediction of aneurysm disease progression has gathered pace in recent times. The acknowledgment of staccato growth in AAA⁵ is mitigated by our lack of understanding as to the reasons why aneurysms do not grow predictably, and why some may rupture at small diameters (even while under surveillance), whereas many aneurysms reach a large size but never rupture. However, although we may not fully understand the biological reasons behind these phenomena, we are becoming increasingly able to evaluate it. The use of novel molecular and cellular imaging is flourishing in cardiovascular research and has recently shown great promise in aneurysm disease. We^6,7 and others^8,9 have reported the use of imaging biomarkers to predict future aneurysm disease progression.

As with many novel approaches, the question remains—where is the clinical relevance for such an expensive technique? Surely, in a world with a declining incidence of AAA disease, does this remain a priority? On the contrary—while the global incidence of AAA disease is indeed declining and the aneurysm-associated mortality has been reduced by the establishment of successful screening programs in many countries,¹⁰ there is a stubbornly high mortality associated with those aneurysms that do go on to rupture and there remains a lack of consensus around the world on whether, when, and how to treat patients with AAA.^11,12 It would therefore benefit patients and healthcare providers to understand and to predict disease progression more fully at an individual patient level. Moreover, the use of molecular and cellular imaging techniques has the potential to provide noninvasive serial assessments of the vasculature for use in interventional trials—providing early and measurable surrogate end points for clinical events that would otherwise take many months or years to manifest or cause devastating clinical sequelae. For example, cellular imaging techniques using magnetic resonance imaging have previously been used to evaluate the change in inflammation as a response to statin therapy in patients with carotid artery disease,¹³ demonstrating a reduction in macrophage-mediated inflammation with the use of high dose statin therapy for 3 months.

And so, this present study addresses a number of key issues pertaining to the assessment of aneurysm biology and its use beyond the preclinical arena. To date, the use of molecular and cellular imaging in aneurysm research has been limited to evaluating a single biomarker in clinical studies. However, aneurysm disease is in fact a multifactorial milieu of pathobiological activity, and this study explores 2 different—albeit closely interlinked—biological processes contemporaneously. Macrophage-mediated inflammation and extracellular matrix degradation are 2 key processes in aneurysm pathobiology, and their simultaneous evaluation has not previously been reported. This is a key strength of the study.

The authors use a clinically validated imaging probe to evaluate macrophage-mediated inflammation—ultrasmall superparamagnetic particles of iron oxide (in this case, ferumoxytol). In clinical studies of AAA, ultrasmall superparamagnetic particles of iron oxide–enhanced magnetic resonance imaging has been shown to track active macrophages¹⁴ and to predict future aneurysm growth^6,15,16 and the need for rupture or repair.^6,16 In addition, the gadolinium-based elastin-specific probe, ESMA, which evaluates elastin degradation, has been evaluated in preclinical studies^17,18 and shows great promise. However, by combining these 2 probes in the same sitting, the whole is greater than the sum of its parts and this is reflected in the results. In their longitudinal cohort study, magnetic resonance imaging with ultrasmall superparamagnetic particles of iron oxide or ESMA predicted aneurysm rupture with high sensitivity and specificity when each agent was used alone (sensitivity 80%, 80%; specificity 89%, 78%, respectively). However, when used in combination, these markers appeared to add incremental value and predicted events with near perfect accuracy: 100% sensitivity and 89% specificity. This suggests that macrophage-mediated inflammation and elastin breakdown in isolation or combination mediate nearly all the rupture events.

A further strength of this study is the use of repeated imaging over 4 weeks of aneurysm development to chronicle the changes in the vasculature. This is one of the great advantages of imaging biomarkers—serial measurements of biological activity can be obtained. The authors observed that the early stage of AAA development was characterized by elastic fiber dissection, intramural hematoma, and dilatation of the aortic wall, followed by an increase in macrophage activity and further dilatation. In the later stages, there was intense remodeling at sites of rupture. To provide further validation of their findings, the authors compared in vivo markers of biological activity with ex vivo histological findings. They demonstrated the ability to characterize temporal changes of the vasculature in great detail. Importantly, the authors were able to demonstrate that there was no confounding effect from using the 2 probes when used simultaneously and performed competition experiments to verify the binding specificity of ESMA. This is a key step in the development of dual probe imaging.

The major limitation of this study is the use of an inherently imperfect animal model of aneurysm disease. While the angiotensin II–infused apolipoprotein E–deficient mouse is one of the commonest models of human aneurysm disease, its limitations are well recognized. The mice typically form aneurysms in the suprarenal aorta, whereas 80% of human AAA are infrarenal. In addition, the animals tend to form aneurysms as a consequence of hypertension-induced aortic dissection and intramural hematoma, whereas the vast majority of AAA disease in humans is unrelated to dissection or intramural hematoma. Moreover, the pathogenesis of human disease is dominated by the combination of smoking and hypertension, with smoking being the strongest modifiable risk factor for disease progression. Nevertheless, the appeal of the article by Brangsch et al is that the authors have taken one step further and proven that it is mechanistically possible to evaluate more than one biological process at the same time using molecular magnetic resonance imaging. They have provided evidence of the independent value of the 2 imaging probes, but importantly, the improvement in rupture prediction when the assessment of macrophage-mediated inflammation and extracellular matrix degradation are combined.

The ability to predict accurately an individual aneurysm’s future disease activity would be invaluable on many levels—surveillance programs could be tailored to an individual patient, intervention thresholds could be adapted according to biological as well as clinical risk, and difficult decision-making could be guided by integrated assessment of all known risk factors. However, no molecular or cellular imaging biomarker has to date given us the whole answer, but certainly we should be looking toward dual or multiprobe imaging to assess the various disease processes that interlink in human aortic aneurysm disease more comprehensively. With studies like these, we will hopefully soon see the development of imaging approaches that will predict disease progression and help us avoid the often devastating and fatal consequences of AAA rupture.

The authors are supported by the British Heart Foundation (CH/09/002; RE/18/5/34216), Wellcome Trust (WT103782AIA), and Medical Research Council (11/20/03).

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

参见Brangsch等人的文章

在最近的一项有关血管外科医师的国际调查中，[ ^1]发现新的预测和识别快速增长的腹主动脉瘤（AAA）的检测方法被认为是研究的重中之重。确实，各种国际准则也强调了这一点，这是需要解决的重要知识鸿沟。^2,3这种创新将允许更好地进行有针对性的监视和抢先式手术，而如今，这些手术几乎完全依赖于AAA最大前后直径的过于简单的二分法阈值。正是在这种背景下，Brangsch等人⁴在最新版的《华尔街日报》上报道他们的新颖成像方法。作者使用鼠模型来解决AAA研究中最相关的问题之一-我们如何才能更准确地表征动脉瘤破裂的风险？因此，Brangsch等人⁴为我们提供了对该主题的有趣的临床前探索，他们的文章具有许多重要的优势。

近来，寻求更准确地预测动脉瘤疾病进展的研究已经加快了步伐。由于我们缺乏对为什么动脉瘤无法预测生长的原因以及为什么一些可能在小直径处破裂（即使在监视下）的破裂的了解，而对许多病灶的大小却很大，但从没有破裂，我们对AAA ⁵断断续续生长的认识得到了缓解。破裂。但是，尽管我们可能无法完全理解这些现象背后的生物学原因，但我们越来越能够对其进行评估。新型分子和细胞成像技术在心血管研究中正在蓬勃发展，并且最近在动脉瘤疾病中显示出了广阔的前景。我们^6,7和其他人^8,9 已经报道了使用成像生物标记物来预测未来的动脉瘤疾病的进展。

与许多新颖的方法一样，问题仍然存在：这种昂贵的技术在临床上的意义在哪里？当然，在一个AAA疾病发病率不断下降的世界中，这仍然是优先事项吗？相反，尽管在许多国家建立成功的筛查计划，全球AAA疾病的发病率确实在下降，与动脉瘤相关的死亡率已降低，但¹⁰与确实如此的动脉瘤相关的死亡率仍然很高破裂，在全世界是否，何时以及如何治疗AAA患者方面仍缺乏共识。^11,12因此，这将使患者和医疗保健提供者从个体患者的角度更全面地了解和预测疾病的进展。此外，分子和细胞成像技术的使用有潜力提供用于介入试验的脉管系统的非侵入性连续评估-为临床事件提供早期且可测量的替代终点，否则将需要数月或数年才能表现出来或造成破坏性后果临床后遗症。例如，之前使用磁共振成像的细胞成像技术已被用于评估炎症变化，作为对颈动脉疾病患者对他汀类药物治疗的反应[ ^13]。 证实使用大剂量他汀类药物治疗3个月可减少巨噬细胞介导的炎症。

因此，本研究解决了与评估动脉瘤生物学及其在临床前领域以外的用途有关的许多关键问题。迄今为止，在动脉瘤研究中使用分子和细胞成像技术仅限于评估临床研究中的单个生物标志物。但是，动脉瘤病实际上是病理生物学活动的多因素环境，该研究同时探索了两种不同的（尽管密切相关的）生物学过程。巨噬细胞介导的炎症和细胞外基质降解是动脉瘤病理生物学中的两个关键过程，并且它们的同时评估以前尚未见报道。这是这项研究的关键优势。

作者使用经过临床验证的成像探针评估巨噬细胞介导的炎症-超小超顺磁性颗粒的氧化铁（在这种情况下为阿魏酸）。在AAA的临床研究中，氧化铁增强的磁共振成像的超小超顺磁性颗粒已显示出可追踪活性巨噬细胞¹⁴并预测未来动脉瘤的生长^6,15,16以及是否需要破裂或修复。^6,16此外，在临床前研究中已评估了基于的弹性蛋白特异性探针ESMA（可评估弹性蛋白降解）^17,18并显示出巨大的希望。但是，通过将这两个探针在相同的位置组合在一起，整体大于其各个部分的总和，这在结果中得到了反映。在他们的纵向队列研究中，使用超细超顺磁性氧化铁或ESMA进行的磁共振成像可预测当单独使用每种药物时，动脉瘤破裂具有高敏感性和特异性（敏感性分别为80％，80％；特异性89％，78％）。但是，当组合使用这些标记物时，它们似乎以近乎完美的准确性增加了增量值和预测事件：100％的敏感性和89％的特异性。这表明，巨噬细胞介导的炎症和弹性蛋白的分解在孤立或组合中介导了几乎所有破裂事件。

这项研究的另一个优势是在4周的动脉瘤发展过程中使用重复成像来记录脉管系统的变化。这是对生物标志物进行成像的巨大优势之一-可以对生物活性进行串行测量。作者观察到，AAA发展的早期阶段的特征是弹性纤维剥离，壁内血肿和主动脉壁扩张，然后巨噬细胞活性增加和进一步扩张。在后期，破裂部位进行了强烈的重塑。为了进一步证实他们的发现，作者将生物活性的体内标记物与离体组织学发现进行了比较。他们展示了表征血管系统暂时变化的能力。重要的，这组作者能够证明，同时使用两种探针并进行竞争实验以验证ESMA的结合特异性不会产生混淆作用。这是双探针成像技术发展的关键步骤。

这项研究的主要局限性是使用了一种天生不完美的动脉瘤动物模型。尽管注入血管紧张素II的载脂蛋白E缺陷型小鼠是人类动脉瘤疾病最常见的模型之一，但其局限性已得到公认。小鼠通常在肾上主动脉中形成动脉瘤，而人类AAA的80％位于肾下。另外，由于高血压引起的主动脉夹层和壁内血肿，动物倾向于形成动脉瘤，而人中的绝大多数AAA疾病与夹层或壁内血肿无关。此外，人类疾病的发病机理主要是吸烟和高血压的结合，吸烟是疾病进展的最强可改变风险因素。尽管如此，Brangsch等人的文章的吸引力在于，作者进一步迈出了一步，并证明使用分子磁共振成像可以同时评估多个生物过程在机械上是可能的。他们提供了两种成像探针的独立价值的证据，但重要的是，当结合巨噬细胞介导的炎症和细胞外基质降解的评估时，破裂预测的改善。

准确预测单个动脉瘤未来疾病活动的能力在许多层面上都是无价的-可以针对单个患者制定监视计划，可以根据生物学和临床风险调整干预阈值，并可以指导困难的决策通过对所有已知风险因素的综合评估。然而，迄今为止，尚无分子或细胞成像生物标记物能为我们提供完整的答案，但是我们当然应该考虑采用双探针或多探针成像技术，以更全面地评估与人类主动脉瘤疾病相互联系的各种疾病过程。通过此类研究，我们有望很快看到影像学方法的发展，这些影像学可预测疾病的进展并帮助我们避免AAA破裂经常造成毁灭性和致命的后果。

作者得到英国心脏基金会（CH / 09/002; RE / 18/5/34216），惠康基金会（WT103782AIA）和医学研究理事会（11/20/03）的支持。

本文表达的观点不一定是编辑者或美国心脏协会的观点。