REVIEWS Management of acute aortic syndrome Rachel E. Clough and Christoph A. Nienaber Abstract | Acute aortic syndrome (AAS) encompasses a group of severe, life-threatening disorders of the aorta, including acute aortic dissection, intramural haematoma (IMH), and penetrating aortic ulcer (PAU). The concept of AAS was developed to enable the early identification and definitive treatment of patients with chest pain from an aortic origin. Aortic dissection is the most common form of AAS, followed by IMH and PAU. Congenital cardiovascular defects, genetic syndromes, and nonsyndromic genetic variants have all been linked with the development of AAS. The diagnosis of AAS in the clinic can be made using imaging modalities such as CT, echocardiography, and MRI. The initial management of patients with AAS is focussed on the control of blood pressure to reduce aortic wall stress. A multidisciplinary team is required to assess each patient and decide whether endovascular or open surgical treatment, or further medical management is indicated. The optimal treatment of patients with AAS remains a challenging clinical dilemma, and further studies are required to fully characterize conditions within the AAS spectrum and to design individualized, patient-centred treatment plans. Clough, R. E. & Nienaber, C. A. Nat. Rev. Cardiol. 12, 103–114 (2015); published online 16 December 2014; doi:10.1038/nrcardio.2014.203

Department of Vascular Surgery, Division of Imaging Sciences, National Institute for Health Research Biomedical Research Centre of Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London, London SE1 7EH, UK (R.E.C.). Department of Internal Medicine I, Divisions of Cardiology, Pulmonology and Intensive Care Medicine, Heart Centre Rostock, Rostock School of Medicine, University Hospital Rostock, ErnstHeydemann-Strasse 6, 18057 Rostock, Germany (C.A.N.). Correspondence to: C.A.N. christoph.nienaber@ med.uni-rostock.de

Introduction

An overview of AAS

Competing interests The authors declare no competing interests.

Epidemiology The estimated incidence of aortic dissection is 2.6–3.5 cases per 100,000 person-years.5–7 Approximately 65% of patients are men, with an average age at presentation of 65 years. AAS is, therefore, becoming increasingly encountered as the population ages. Systemic hypertension is the most common risk factor for AAS, found in up to 72% of patients. Other risk factors include athero­ sclerosis, prior cardiac surgery, aortic aneurysm, and a family history of AAS.3 The epidemiology of aortic dissection is substantially different in patients 4.5 cm versus ≥5.0 cm).10 Physical findings highly suggestive of vascular-type Ehlers–Danlos syndrome include joint laxity and translucent skin. These features might also be present in patients with Loeys–Dietz syndrome, highlighting the importance of molecular testing for accurate diagnosis.9 Both Marfan syndrome and familial thoracic aortic dissection are characterized by an autosomal dominant pattern of inheritance, although familial thoracic aortic dissection has lower penetrance and variability in the age of onset than Marfan syndrome.15 Genetic counselling and testing should, therefore, be offered to first-degree 104  |  FEBRUARY 2015  |  VOLUME 12

relatives of patients with a confirmed or suspected genetic mutation associated with thoracic aortic dissection. Aortic imaging is also recommended for these family members, because genetic variations might lead to subtle phenotypic features that can be overlooked.10 Guidelines for surveillance of patients with these genetic syndromes include intervention thresholds based on echocardiographic measurements of the diameter of the aortic root and ascending aorta at the time of diagnosis, and the rate of aortic enlargement calculated 6 months after diagnosis.10

Diagnosis The abrupt onset of severe pain is the most important symptom of patients presenting with AAS, and is independent of age, sex, or other associated clinical features.16,17 Pooled data from >1,000 patients with AAS showed that acute aortic dissection is perceived as abrupt pain in 84% of patients, with 90% of these patients rating their pain as severe.4,18–20 The location of the pain and associated symptoms reflects the site of initial intimal disruption and might shift as the dissection extends further along the aorta or involves other arteries or organs.18–20 The presence of pain radiating to the neck, throat, and/or jaw suggests involvement of the ascending aorta, particularly when associated with aortic regurgitation, differential pulses, or symptoms of tamponade or myocardial ischaemia.18–20 Conversely, pain in the back or abdomen might indicate dissection of the descending aorta. Pericardial effusion occurs in 8%, syncope in 4%, and circulatory shock in 3% of patients.3 The clinical features of IMH and PAU are similar to those of acute aortic dissection (Table 1) and differentiation between these AAS manifestations solely by clinical means can be difficult or even impossible. Moreover, some authors have documented a clear overlap between the conditions that constitute AAS, suggesting that one pathological process can progress to another (Figure 2).1 For example, PAU might act as an initiation site for aortic dissection, or IMH might evolve into aortic dissection. If the diagnosis of an AAS is overlooked, a patient with aortic dissection might receive anticoagulant therapy to treat suspected myocardial ischaemia or pulmonary embolism, which can complicate surgical repair and, in the context of rupture, might have devastating consequences. Prompt exclusion of cardiac and pulmonary causes of chest pain is essential, which can be assisted by a combination of blood tests, electrocardiography, and imaging. However, clinical acumen is required in i­nterpreting the results of these investigations.21,22 Imaging Approximately half of all patients with AAS have normal findings on a chest X‑ray, and approximately one-third of patients have a widened mediastinum. 3 However, the availability of modern noninvasive imaging equipment in hospital emergency departments has enabled confident and early diagnosis of even subtle forms of AAS. CT, echocardiography, and MRI have become the standard diagnostic options for AAS in clinical



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REVIEWS practice (Table 1). The degree of haemodynamic instability of the patient and local expertise often dictate the choice of imaging modality used. In the International Registry of Aortic Dissection (IRAD), CT was the diagnostic modality of choice in 62% of patients, followed by t­ransoesophageal echocardiography in 32% and MRI in 1%.4 CT is the standard first-line imaging modality used in patients with a high clinical probability of having AAS, owing to the fast acquisition of images with high spatial resolution.23 Unenhanced CT scans should be included to provide information regarding the presence of IMH, mediastinal haemorrhage, or haemorrhagic pericardial effusion and calcification.23 A combined unenhanced and contrast-enhanced CT protocol has a sensitivity approaching 95% and a specificity of 87–100% for the detection of AAS.24 A triple rule-out CT protocol can also be used to differentiate between different causes of chest pain, namely AAS, ACS, and pulmonary embolism. 25,26 The delayed venous phase images obtained using this protocol can help to characterize the status of thrombosis in the false lumen of aortic dissection, and can aid in the differentiation of IMH from frank dissection.27 Post-acquisition reformatting of images by multiplanar reconstruction and maximum intensity projection can improve the detection, characterization, and evaluation of AAS.28 One of the main disadvantages of CT imaging is the need for contrast agents, which are associated with contrast-induced nephropathy.29 Furthermore, the use of sequential CT scans exposes the patient to substantial doses of ionizing radiation, which are particularly harmful in young patients.30,31 Electrocardiography-gated CT angiography is especially useful for avoiding motion artefacts that might prevent accurate assessment of the aortic root and the ascending aorta, particularly in aortic dissection with involvement of the coronary ostia. 32 Electrocardiographic gating can be performed either retrospectively or prospectively. In prospective gating, images are usually only acquired during late diastole, whereas in retrospective gating, images are acquired throughout the cardiac cycle. Consequently, retrospective gating provides more comprehensive data than prospective gating, albeit at the expense of increased radiation exposure.27 Unlike CT and MRI machines, modern ultrasonographic equipment is portable, and image acquisition can, therefore, be performed at the bedside for u­nstable patients in an emergency setting. Transthoracic echocardiography is useful for identifying aortic valve dys­ function, proximal dissections extending into the aortic root, pericardial tamponade, and wall motion abnormalities. 33 Transthoracic echocardiography is of limited use for assessment of the distal ascending aorta, aortic arch and descending thoracic aorta due to the presence of over-lying structures and a poor acoustic window.34 The sensitivity of this modality for detecting type A and type B dissections are 78–100% and 31–55%, respectively. 34 Technological advances in ultrasonography, including the development of

Box 1 | Differential diagnosis of chest pain ■■ ■■ ■■ ■■ ■■ ■■ ■■

Aortic dissection Intramural haematoma Penetrating ulcer Acute coronary syndrome Pulmonary embolism Pneumothorax Oesophageal perforation

high-resolution probes and the introduction of harmonic imaging, are expected to greatly improve the quality of transthoracic echocardiography.35 The European Cooperative Study Group and others have shown that transoesophageal echocardiography has a sensitivity of 99% and specificity of 89%, with a positive predictive accuracy of 89% and negative predictive accuracy of 99% for AAS.24,36–38 Transoesophageal echocardiography is a useful tool for the detection of aortic valve regurgitation and pericardial effusion.33 In addition, it can be used intraoperatively to confirm whether intravascular devices are located in the true or false aortic lumen, and to identify aortic side branches. Intimal tears can be localized in >78% of patients.39–41 However, visualization of the distal ascending aorta and proximal arch is limited, owing to interposition of the air-filled trachea and the main bronchus, and transoesophageal echocardiography does not provide any information below the diaphragm. Transoesophageal echocardiography is an invasive imaging modality and consequently poorly suited to surveillance. Intravascular ultrasonography is a useful adjunct to endovascular repair of AAS, but is not commonly used for early diagnosis.25 MRI is a highly accurate, non-invasive imaging modality with sensitivity of 88–95% and specificity of 94–98% for detection of AAS.42 Nonetheless, MRI is rarely used during the initial stages of suspected AAS owing to the relatively long duration of examinations (in the region of 20–30 min for a typical aortic protocol). The MRI suite is also not readily compatible with the life support and monitoring equipment usually required for critically ill patients. Consequently, MRI is generally reserved for situations where the avoidance of ionizing radiation is important, such as serial follow-up studies, especially in young patients.30,31 Angiography with intravenous gadolinium contrast has emerged as the most common MRI technique for imaging the aorta,43 whereas black-blood T1-weighted and T2-weighted images are used to assess aortic lumen calibre, aortic wall thickness, and aortic wall signal.25,44 The age of an IMH can be estimated by measuring the signal (related to haemoglobin breakdown products) on T1-weighted and T2-weighted images.45 Dynamic steady-state free precession sequences can be used to assess the function of the aortic valve and the calibre of the aortic root.44 MRI protocols for the identification and assessment of acute and chronic aortic disease should be adapted according to local expertise to answer specific questions about the target of interest. For example, the protocol used in the acute setting to diagnose AAS, when a short scan time is important, might

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REVIEWS Table 1 | A comparison of the three main forms of AAS Form of AAS

Aortic dissection Type A

IMH

PAU

Type B

Type

Most common form of AAS (62–88%) Two out of three cases is type A; the rest is type B

Second most common form of AAS (10–30%)

Least common form of AAS (2–8%)

Risk factors

Hypertension Connective tissue disease (particularly in young patients) Bicuspid aortic valve

Hypertension

Hypertension Male sex Atherosclerotic disease

Clinical features

Abrupt onset of pain* High blood pressure Aortic insufficiency Tamponade Myocardial ischaemia Stroke Aortic rupture

Abrupt onset of pain* High blood pressure Visceral, renal, or leg ischaemia Paraplegia Aortic rupture

Abrupt onset of pain* High blood pressure Aortic insufficiency Pericardial effusion Pleural effusion High blood pressure

Abrupt onset of pain* High blood pressure Typically affects the descending thoracic aorta (rare in the ascending aorta)

Prognosis

24% of patients die within 24 h, 90% die within 1‑year without treatment

84% of patients with uncomplicated disease are alive at 1‑year

Progression to aortic dissection more common with proximal than distal IMH Development of ulcer-like projections associated with poor prognosis

High risk of aortic rupture, even at normal aortic diameter Highly symptomatic patients have the worst prognosis

Preferred imaging modality

CT (acute) Echocardiography (acute) MRI (surveillance)

CT (acute) MRI (surveillance)

CT MRI (surveillance)

CT MRI (surveillance)

Specific imaging findings

True and false lumen dimensions Extent of dissection Location of entry tears False lumen thrombosis Involvement of aortic valve, coronary arteries, or arch vessels Pericardial fluid Aortic rupture

True and false lumen dimensions Extent of dissection Location of entry tears False lumen thrombosis Involvement of visceral, renal, or iliac arteries Pleural fluid Aortic rupture

Smooth cresentic or circular aortic wall thickening (≥5 mm) Aortic wall attenuation 39–72 HU Aortic rupture

Outpouching with irregular margins Intimal calcification Further PAU lesions Generalised aortic atherosclerotic changes Aortic rupture

Treatment strategy

Open surgery

Medical therapy with endovascular intervention for patients with complications

Open surgery or medical therapy‡

Urgent open surgery for type A symptomatic PAU Endovascular surgery for symptomatic type B Otherwise, medical management

*Site of pain is dependent upon location of lesion. ‡Differs between North America, Europe, and Asia. Abbreviations: AAS, acute aortic syndromes; IMH, intramural haematoma; PAU penetrating aortic ulcer.

be different to the protocol used for surveillance, when the patient is stable and the focus of imaging examination is to identify high-risk features, such as blood flow patterns (Figure 3).46 Blood biomarkers The presence of blood outside the intravascular space results in activation of the coagulation and fibrinolytic systems. High plasma levels of d‑dimer, a product of plasmin fibrinolysis, can be found in AAS. In a metaanalysis of seven studies with a total of 298 patients, plasma d‑dimer level 5.5 cm.68 Approximately 30% of type B dissections are classed as complicated at initial presentation.69

Prognosis In the absence of immediate surgical repair, medical management of type A aortic dissection is associated with substantial mortality: nearly 24% at day 1, 29% at day 2, 44% at day 7, and 50% after 2 weeks.4 Less than 10% of patients with untreated proximal aortic dissection survive for 1 year, and almost all die within 10 years (Table 1). Acute aortic dissection of the descending aorta is less frequently lethal. Patients with uncomplicated type B dissections have good survival: 89% at 1 month, 84% at 1 year, and 80% at 5 years.4,70 More than 60% of deaths associated with acute type B aortic dissection result from local aortic rupture, usually of the false lumen. 71 Continued patency of the false 108  |  FEBRUARY 2015  |  VOLUME 12

lumen is also associated with aneurysmal dilatation. By contrast, complete thrombosis is an independent predictive factor of false lumen stability.72 However, the IRAD investigators reported that partial thrombosis of the false lumen was a stronger independent predictor of post­discharge mortality than either complete thrombosis or no thrombosis; patients with partial thrombosis had a relative risk of death 2.7 times that of patients with a patent false lumen.73 In the IRAD study, thrombus in the distal false lumen could impede outflow, increasing the mean intraluminal pressure and leading to aneurysmal expansion and rupture.73 However, the extent of thrombosis in the false lumen can be difficult to assess a­ccurately using current imaging technology.74 Visceral branches arising partially or completely from the false lumen, re-entry tears, and a large maximum diameter of the false lumen in the abdominal aorta are all risk factors for incomplete thrombosis of the false lumen.75 Furthermore, an aortic diameter ≥40 mm, or a false lumen diameter ≥22 mm in the proximal descending thoracic aorta at initial imaging are both predictors of poor outcome.76–78 In a multiple logistic regression analysis of IRAD data, refractory pain or hypertension, and an age ≥70 years were independent predictors of in-hospita­l mortality (OR 3.3 and 5.1, respectively).79 High-risk patients can also be identified by the presence of a large proximal entry tear.80 Other factors such as a small initial aortic diameter and white ethnicity have been associated with increased aortic expansion during follow-up, but require further investigation.81 Simulation tools have been developed to model intraaortic haemodynamics in patients with aortic dissection.82,83 These parameters can also be measured in vivo using MRI.46 Our research group reported that blood flow velocity, helicity, and stroke volume—measured using four-dimensional phase contrast MRI—were all associated with the rate of aortic expansion in patients with aortic dissection (Figure 3).46

Treatment Type A aortic dissection Acute type A aortic dissection is associated with several potentially lethal complications, including aortic rupture, coronary ischaemia, stroke, visceral ischaemia, cardiac tamponade, and circulatory failure.4 Open surgery is the mainstay of treatment for such patients. The procedure involves excision of the intimal tear and obliteration of the entry site of blood into the false lumen. The aorta is then reconstructed using a synthetic graft. Reimplantation of the coronary arteries might also be required, depending on the extent and position of the dissection.8 In addition, patients with aortic valve insufficiency require valve repair or replacement procedures to restore aortic valve competence. Operative mortality for ascending aortic dissections is 10–35% at highvolume­centres; this value is considerably lower than the 50% mortality rate after 2 weeks that is associated with patients who receive medical therapy only.84 Endovascular treatment of type A aortic dissections might be feasible for highly selected patients, such as



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REVIEWS those with suitable aortic anatomy who are not fit for surgery, although this approach is restricted by unique anatomical factors and remains under development.85,86 Endovascular repair can been suitable for patients with a distal entry tear and retrograde extension of the d­issection to involve the ascending aorta.87 Type B aortic dissection The IRAD registry data suggest that in-hospital mortality of patients with acute type B aortic dissection is strongly influenced by the type of treatment they receive. 88 Medical management of uncomplicated type B dissection results in ~90% survival to hospital discharge and, therefore, constitutes the current standard of care for these patients.89 For patients with complicated type B dissection, open surgery or endovascular treatment is available. Open surgery involves a prosthetic graft replacement of the descending thoracic aorta and is associated with considerable in-hospital mortality and morbidity, particularly stroke and paraplegia.90,91 Mortality related to emergency open surgery for complicated type B aortic dissection has improved over the past 5 years, but still remains high; IRAD data show that operative mortality for type B aortic dissection complicated by renal or mesenteric ischaemia can be as high as 50–88%.92,93 The risk of spinal cord ischaemia and stroke are 5.9% and 3.3%, respectively.67 Since the 1990s, endovascular stent grafts have been established as an alternative to open surgical treatment in high-risk patients with complicated type B aortic dissection.94,95 In the USA, ~25% of type B dissection repairs use an endovascular approach, which has reduced mortality and morbidity compared with open surgical repair.96 In a meta-analysis of outcomes after endovascular treatment of acute type B aortic dissections, the in-hospital mortality was 9% and a major complication rate was 8% (including stroke in 3.1%, paraplegia in 1.9%, conversion to type A dissection in 2%, bowel infarction in 0.9% and major amputation in 0.2%).97 The 5‑year results of the INSTEAD randomized controlled trial62 in patients with uncomplicated type B aortic dissection showed a reduction in death from aortic-related causes and delayed disease progression with thoracic endo­ vascular aortic repair and optimum medical therapy, compared with optimum medical therapy alone.62 Data from the ADSORB randomized controlled trial98 after 1 year demonstrated that uncomplicated type B aortic dissection can be safely treated using a stent graft, and that this treatment strategy was associated with improved aortic remodelling.98 Bare-metal stents can also be inserted distally if further remodelling of the aorta is required after placement of a stent graft in the proximal descending thoracic aorta.99 However, patients who received both a proximal stent graft and distal bare-metal stent in the acute setting exhibited considerable dilatation of the abdominal seg­ ment below the bare stent.100 Other endovascular strategies have been developed to increase the rate of false lumen thrombosis, such as the knickerbocker technique, which involves relining the true lumen of the descending

Box 2 | Classification of AAS63,64 The DeBakey system for classifying aortic dissection ■■ Type I: Dissection in the ascending aorta, propagates at least to the aortic arch and often to the descending aorta ■■ Type II: Dissection in the ascending aorta only ■■ Type IIIa: Dissection in the descending thoracic aorta only ■■ Type IIIb: Dissection originates in the descending aorta and propagates distally The Stanford system* ■■ Type A: Involves the ascending aorta (includes DeBakey types I and II aortic dissection) ■■ Type B: Does not involve the ascending aorta (includes DeBakey type III aortic dissection) *The Stanford system can be used to classify aortic dissection, intramural haematoma, and penetrating aortic ulcer.

aorta with an oversized thoracic tubular endograft.101 Controlled rupture of the dissection membrane using a large compliant balloon allows expansion of the stent graft midsection into the false lumen, thus occluding the false lumen and inhibiting perfusion through distal entry tears.101 However, off-label usage of devices for endo­vascular thoracic aortic repair is associated with s­ubstantially higher mortality.102

Intramural haematoma

IMH is a haemorrhage contained within the aortic wall, in the absence of a detectable intimal tear and, therefore, without communication with the aortic lumen (Figure 1).8 IMH is thought to originate from rupture of the vasa vasorum with subsequent aortic wall infarction, but can also occur as a result of blunt trauma.103 Histologically, the haematoma typically extends within the media but it might also be subadventitial. IMH appears as a smooth crescentic or circular thickening in the aorta of ≥5 mm in diameter.25 The haematoma might encroach into the aortic lumen and centrally displace any intimal calcification that might be present. IMH typically have an attenuation of 39–72 HU, and aortic wall attenuation measurements outside this range have a high negative predictive value for IMH.24,104 An increase in the thickness of IMH during imaging surveillance suggests progression of the lesion, and surgical intervention should be performed to prevent rupture.8 In the past 10 years, some researchers have suggested that IMH represents a subcategory of aortic dissections in which the intimal tear cannot readily be detected and flow in the false lumen is limited.24 However, an intimal defect can now often be detected in patients with IMH using high-resolution multidetector CT.105

Clinical features Unlike other forms of AAS, IMH is not commonly associated with Marfan syndrome or bicuspid aortic valve. 8 Stanford type A IMH involves the ascending aorta, with or without descending aortic involvement, whereas Stanford type B IMH do not involve the ascending aorta (Box 2). IMH of the ascending aorta is often

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REVIEWS complicated by pericardial effusion, pleural effusion, and aortic insufficiency. As shown in the IRAD3 and Korean AAS registry,93 IMH tends to occur more frequently in the descending than the ascending aorta. Data from the IRAD registry also show that patients with IMH were more likely to be male (60.3%), and were older than those with aortic dissection (69.7 versus 60.5 years).24 Disparities are present in the natural history of IMH, as demonstrated in findings from studies from North America and Europe compared with studies from Japan and South Korea. For example, in IRAD, which is composed predominantly of data from centres in North America and Europe, the incidence of IMH was 6% (58 of 1,010 identified patients with AAS).25 However, two large studies from Japan and Korea reported an incidence of IMH of 28.3% and 29%, respectively.24,106,107

Prognosis Progression of IMH to complete dissection occurs in 28–47% of patients, and early aneurysm formation or contained rupture occurs in 20–45% of patients.24,103,108 The progression of IMH lesions to both localized dissection and aneurysmal dilatation is more common in proximal than distal IMH.106,107 Development of ulcer-like projections during follow-up is a predictor of poor prognosis in patients with both proximal and distal IMH.109,110 Other predictors of disease progression include age >70 years (in type B IMH), cardiac tamponade, maximum haematoma thickness ≥10 mm, and an aortic diameter ≥50 mm (in type A IMH).106,109 Expansion and rupture were observed in up to 47% of patients with IMH in Western studies, and only 50% of patients survived to hospital discharge.111 By contrast, in a study of IMH performed in South Korea in 124 patients, resorption occurred in 67% of patients with type A IMH and 78% of patients with type B IMH.112,113 In a series of patients in Japan with type A IMH, rates of early (within 30 days) and late (≥30 days) progression to aortic dissection or increase in haematoma size were 30% and 10%, respectively.106 These differences in prognosis might be related to discrepancies in the medical ­management of these patients between the clinical centres. Treatment The different clinical experiences in Japan and Korea compared with USA and Europe have led to contrasting recommendations for the management of IMH. The Stanford group, based on their experience, recommends surgery for type A IMH and medical treatment for type B IMH, and a group of Western centres reported early mortality of 8% for surgery versus 55% with medical treatment.111,114–116 By contrast, in a meta-analysis of 12 studies, nine of which were performed in Asia, no difference in early mortality for patients with type A IMH was seen between surgical (10.1%) and medical treatment (14.4%) strategies.117 However, other studies including individuals from Asia have found high rates of progression, and mortality of 32% in Chinese patients with medically treated type A IMH, which prompted the investigators to ­recommend surgical resection for this group.118 110  |  FEBRUARY 2015  |  VOLUME 12

The timing of surgery is important. In a study from the USA, immediate surgery following diagnosis of type A IMH was associated with mortality of 14.3%, compared with 7.1% in those managed with optimal medical management followed by delayed (>72 h) surgery.119 In this series, one-third of patients with type A IMH progressed to aortic dissection (although none progressed within the first 72 h after diagnosis).119 At present, limited evidence exists to support endovascular treatment of IMH.120–122 Small case series cite good procedural success rates and few complications, but the study cohorts are highly selected, and the investigators have not reported the number and type of patients who were excluded.122–124 No evidence from randomized trials confirms the superi­ ority of endovascular repair of IMH over best medical treatment or surgery.

Penetrating aortic ulcer

PAU is thought to be caused by a rupture of the intima that allows blood through the internal elastic lamina.123 Over time, this leakage can result in the formation of a pseudoaneurysm or rupture. Computational fluidstructure analysis suggests that wall shear stress might be one of the major haemodynamic factors influencing the structural fragility of the ulcer wall.123 PAU can present with acute pain, aortic dissection, or perforation. 108 Local inflammation generated by the ulcer might lead to fusion of the degenerated aortic layers that prevents passage of the blood through the layers of the aortic wall and p­rogression to aortic dissection or IMH.

Clinical features The Stanford classification system can also be applied to PAU (Box 2). Lesions predominantly occur in the descending thoracic aorta (in ~90%) but might also be present in the arch and abdominal aorta; PAU rarely occurs in the ascending aorta.124,125 PAU can be an incidental finding; in up to 27.8% of asymptomatic patients, PAU is associated with a saccular aneurysm, and in 14% with IMH.126 The typical radiological features of PAU are an out-pouching with irregular margins, intimal calcification, and localized IMH.25 Multiple lesions are often present, and can be 2–25 mm in diameter and 4–30 mm in depth.127,128 Risk factors for the development of PAU include advanced age, hypertension, atherosclerosis, and smoking. Patients with PAU typically present with severe chest or back pain but without signs of aortic regurgitation or malperfusion. The severity and duration of recurrent or refractory pain is considered one of the most important clinical features to determine the appropriateness of intervention. PAU involving the ascending aorta have an especially high risk of rupture and require urgent intervention.108 Prognosis Patients with PAU are at high risk of aortic rupture, which might occur even when aortic diameter is normal. The incidence of aortic rupture in patients with PAU is 42%, among the highest across all forms of AAS.129 Predictors of disease progression include sustained or recurrent



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REVIEWS pain, increasing pleural effusion, and maximum PAU dimensions above the recommended intervention t­hresholds of 20 mm diameter and 10 mm depth.130

Treatment Few studies have addressed the optimal management of patients with PAU. The quality of available evidence is poor and primarily involves small numbers of retrospectively reviewed patients with various clinical presentations.93 A conservative approach to the treatment of PAU is generally recommended, with open or endovascular surgery reserved for symptomatic patients who have persistent pain, an increase in lesion size, aortic expansion, or rupture. Urgent surgical repair is recommended for type A PAU, although the majority of patients might not be suitable for conventional open surgery owing to the presence of cardiovascular and respiratory comorbidities.8 As type B PAU are frequently segmental and well-localized, this lesion represents an ideal target for endovascular stent graft treatment. Endovascular treatment of type B PAU has yielded good perioperative results with no reported intraprocedural or 30-day deaths.128,131

Long-term management of AAS

In patients with AAS, 1‑year survival is 81% and 5‑year survival is 63%.132 Secondary aortic interventions are frequently required and long-term surveillance is, therefore, important.133,134 Ongoing medical therapy, including β‑blocker administration, is needed to minimize aortic wall stress. Serial imaging studies (CT or MRI, depending upon local expertise) to detect signs of progression should be performed at 1 month, 3 months, 6 months, and 12 months post-diagnosis, and if the lesions remain stable, annually thereafter.10 The choice of imaging modality and clinic where imaging is performed should ideally be consistent throughout follow-up, to ensure that image quality is similar and direct comparisons can be made. Each patient should be referred to a multidisciplinary team consisting of cardiothoracic and vascular surgeons, cardio­ logists, radiologists, and allied health professionals, who should take into account the patient’s age, life expectancy, 1.

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Patel, P. J., Grande, W. & Hieb, R. A. Endovascular management of acute aortic syndromes. Semin. Intervent. Radiol. 28, 10–23 (2011). Brinster, D. R. Endovascular repair of the descending thoracic aorta for penetrating atherosclerotic ulcer disease. J. Card. Surg. 24, 203–208 (2009). Cho, J. R. et al. Clinical characteristics of acute aortic syndrome in Korean patients: from the Korean multi-center registry of acute aortic syndrome. Korean Circ. J. 42, 528–537 (2012). Hagan, P. G. et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA 283, 897–903 (2000). Meszaros, I. et al. Epidemiology and clinicopathology of aortic dissection. Chest 117, 1271–1278 (2000). Bickerstaff, L. K. et al. Thoracic aortic aneurysms: a population-based study. Surgery 92, 1103–1108 (1982).

and general fitness when deciding whether medical management, open surgery, or endovascular treatment is appropriate.135 Patients who are not candidates for either intervention (because of short life expectancy, advanced medical comorbidities, or personal preference) do not require close follow-up. However, inclusion of all patients in AAS registries is desirable and facilitates subsequent auditing of procedures and outcomes.

Conclusions

A benefit of grouping the conditions comprising AAS into a single disease entity is to facilitate the early identification of patients at risk, and to promote the use of specific treatment algorithms in centres that specialize in aortic intervention. However, the optimal treatment of patients with AAS still remains a challenging clinical dilemma. With the advent of minimally invasive endovascular techniques, treatment paradigms in AAS are no longer limited to the choice between open surgery or medical therapy alone. The current challenge for clin­icians is to identify the patient populations who are best suited to surgical (open or endovascular) treatment rather than medical therapy alone. Additional studies are required to further characterize the conditions within the spectrum of AAS and design patient-centred and i­ndividualized treatment plans. Review criteria We undertook a comprehensive search of the PubMed database using the following keywords: “aortic dissection”, “intramural hematoma”, “penetrating ulcer”, “medical”, “endovascular”, and “surgery”. Articles published in English within the past 10 years were reviewed, including full-text research articles, reviews, editorials, and correspondence. We primarily selected publications from the past 5 years, but did not exclude well-referenced and highly regarded publications over 5 years old. We also searched the reference lists of identified articles for further relevant material. We prioritized the inclusion of randomized controlled trials and meta-analyses, over smaller studies and case series.

7.

Clouse, W. D. et al. Acute aortic dissection: population-based incidence compared with degenerative aortic aneurysm rupture. Mayo Clin. Proc. 79, 176–180 (2004). 8. Coady, M. A. et al. Surgical management of descending thoracic aortic disease: open and endovascular approaches. A scientific statement from the American Heart Association. Circulation 121, 2780–2804 (2010). 9. LeMaire, S. A. & Russell, L. Epidemiology of thoracic aortic dissection. Nat. Rev. Cardiol. 8, 103–113 (2011). 10. Hiratzka, L. F. et al. 2010 ACCF/AHA/AATS/ACR/ ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for

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Acknowledgements R.E.C. is supported by the Academy of Medical Sciences through funding from the Wellcome Trust, Medical Research Council UK, and British Heart Foundation. Author contributions Both authors contributed equally to researching data for the article, discussion of content, writing, editing, and reviewing the manuscript before submission.

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