Natural history of thoracic aortic aneurysms

Transcription

1 Peter F. Lawrence, MD, Section Editor EVIDENCE SUMMARY Natural history of thoracic aortic aneurysms Gregory A. Kuzmik, BA, Adam X. Sang, BA, and John A. Elefteriades, MD, New Haven, Conn Understanding the natural history of thoracic aortic aneurysms (TAAs) is essential to patient care and surgical decision making. In this evidence summary we discuss some of the most clinically relevant features of the disease. The true incidence of TAAs is likely to be higher than currently reported because of the inherently silent nature of TAAs. However, TAAs can become rapidly lethal once dissection or rupture occurs, highlighting the need for more robust screening. The impressive discovery of familial patterns and novel genetic loci for TAAs challenges the idea that most TAAs are simply sporadic. Although the aorta grows in an indolent manner, its rate of growth and its current diameter both have important clinical implications. Biomechanical studies have supported clinical findings of 6.0 cm as a dangerous threshold. Surgical extirpation of TAAs is currently the mainstay of effective treatment. Although endovascular TAA repair is becoming increasingly common, long-term safety remains unproven. We still need more data to support the concept that any medical therapy is effective. (J Vasc Surg 2012;56: ) The Centers for Disease Control and Prevention reports that aortic aneurysms (thoracic and abdominal) are the 15 th leading cause of death in individuals aged 55 years and the 19 th leading cause of death overall. 1 Although the prevalence of thoracic aortic aneurysms (TAAs) is likely lower than the reported prevalence of abdominal aortic aneurysms (AAAs), TAAs represent an important component of vascular disease due to their particularly lethal nature. 2 We highlight in this evidence summary the following specific characteristics of the natural history of TAAs. EVIDENCE SUMMARY TAA is likely to be much more common than we recognize. The epidemiology of TAAs is challenging to study because it is a clinically silent disease. Approximately 60% of TAAs occur in the root or ascending aorta, 10% in the arch, 40% in the descending aorta, and 10% in the thoracoabdominal aorta; however, an aneurysm may involve multiple aortic segments. 3 TAAs are asymptomatic in 95% of cases, meaning most TAAs remain undetected unless incidentally discovered. 2 In addition, many fatal TAA ruptures or dissections are misdiagnosed as myocardial infarction, thereby underestimating the true prevalence of TAAs. The prevalence of asymptomatic TAAs has been measured at between 0.16% and 0.34% 4,5 ; however, these studies defined TAA as aortic diameters 5 cm, thereby From the Aortic Institute at Yale-New Haven Hospital. Author conflict of interest: none. Reprint requests: J.A. Elefteriades, Section of Cardiac Surgery, 330 Cedar St, BB204, New Haven, CT ( john.elefteriades@yale.edu). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline to review of any manuscript for which they may have a conflict of interest /$36.00 Copyright 2012 by the Society for Vascular Surgery. overlooking potentially clinically significant aneurysms sized between 4 and 5 cm. The annual incidence of TAAs has been assessed at approximately six to 10 cases/100,000 patient-years. 6,7 Interestingly, the incidence of TAAs appears to be increasing, although it is not understood to what degree this observation is explained by an aging population or more frequent imaging. 2 On the basis of data from communities where the population is stable and postmortem examinations are done routinely, there appears to be a bona fide increase in the true incidence of TAAs during the past several decades. 7,8 TAA appears to have a larger familial component than previously thought. Recent clinical series looking at the Mendelian patterns in families of TAA patients have disclosed definite familial patterns. 9 In fact, 21% of patients with TAAs have at least one family member with a known aneurysm of some sort; many more family members likely harbor unknown, undiagnosed aneurysms. Of these familial forms, 77% are inherited in an autosomal-dominant manner with variable expressivity and penetrance (Fig 1). 9,10 TAAs can also occur as part of complex genetic syndromes, including Marfan syndrome (most common), Ehlers-Danlos syndrome, Loeys-Dietz syndrome, and Turner syndrome. However, these syndromes are just the tip of the iceberg. Increasing numbers of genetic loci linked to nonsyndromic TAAs are being identified. 11 These novel loci, and the inherent incompleteness of pedigrees, suggest that the true proportion of familial TAAs is 21%. Therefore, physicians should be cognizant of screening family members of TAA patients. Of note, patients with familial TAAs generally present at an earlier age (56.8 years) than patients with sporadic TAAs (64.3 years). 10 Mutations causing TAAs can also underlie the formation of other types of aneurysm. For example, we have 565

2 566 Kuzmik et al JOURNAL OF VASCULAR SURGERY August 2012 Fig 1. Selected pedigrees of thoracic aortic aneurysm (TAA) patients, demonstrating multiple inheritance patterns and levels of penetrance. Recent discoveries of novel loci underlying familial TAAs supplement our understanding of the proportion of TAAs that are genetic. Reproduced with permission from Albornoz et al. 9 shown that 9% of TAA patients harbor concurrent intracranial aneurysms, a prevalence that is significantly higher than that in the general population. 12 The aorta grows in an indolent manner. The average ascending aneurysmal aorta expands by 0.10 cm annually, whereas descending TAAs grow by 0.29 cm annually. 13 Aneurysms with larger diameters tend to grow more rapidly. 13 It is important to appreciate that such measurements fall within the margin of error for most computed tomography (CT) scanners, and therefore, physicians should be cautious about relying too heavily on these measurements. 14 In addition, the innate geometry of the aorta, particularly as it dilates and becomes more tortuous, poses inherent challenges in obtaining accurate measurements from radiographic studies. The lack of standardization regarding axis of measurement and inclusion of the vessel wall further complicates the issue. When determining the rate of TAA growth, comparison must be made not with the most recent CT scan but with the earliest CT scan available so that small changes accruing over time can be fully appreciated. 15 Reports of rapid growth usually represent measurement error due to comparison of nonequivalent aortic segments or tangential measurement across an oblique segment of aorta. 14 Patients with familial TAAs have faster growth rates of 0.21 cm/y (combined ascending and descending TAA) compared with patients with sporadic TAAs (0.16 cm/y) and thus present earlier. 9 Syndromic TAA growth rates vary as well. Marfan aortas grow at 0.1 cm/y, whereas TAAs of the especially malignant Loeys-Dietz syndrome can grow faster than 1.0 cm/y, resulting in mean age of death at 26 years. 9,16 TAA is silent and lethal. Before an acute event, 95% of TAAs are asymptomatic. 2 A diastolic murmur secondary to aortic regurgitation may be audible with advanced disease, but only if the aneurysm involves the ascending aorta. As a result, most aneurysms are detected incidentally through imaging for an unrelated problem (eg, a CT scan for a lung nodule, or echocardiography for a murmur). Once aneurysms become symptomatic or painful, however,

3 JOURNAL OF VASCULAR SURGERY Volume 56, Number 2 Kuzmik et al 567 Fig 2. Effects of aortic aneurysm size on risk of complications for the (A) ascending and (B) descending aorta. Reproduced with permission from Coady et al. 13 surgical intervention is usually indicated regardless of aneurysm size. 17 Given that the 5-year survival of untreated TAA 6cm falls to 54%, 18 we cannot overemphasize the clinical need for a robust screening test. Echocardiography is not sensitive for aneurysms beyond the proximal ascending aorta, and CT is too costly and harmful to serve as a generalized screening test. We are currently researching gene expression profiles and other biomarkers as potential screening modalities. 19,20 Screening is especially important for highrisk patients who have concurrent intracranial aneurysms or AAAs, a family history of sudden death, persistent atypical chest pain, or for relatives of patients with known aneurysm. We can predict the risk of rupture or dissection based on aortic size. Data from our institution has shown that the risk of natural complications (rupture, dissection) from TAAs rises with increasing aortic diameter. The annual risk of rupture or dissection is 2% for TAAs between 4.0 and 4.9 cm, while reaching nearly 7% for TAAs 6.0 cm. 18 We have also found that there is a drastic increase in the risk of rupture or dissection beyond a diameter of 6.0 cm for an ascending TAA and 7.0 cm for a descending TAA (Fig 2). 13 Accordingly, preemptive surgical intervention is necessary before the aorta reaches these dangerous thresholds. 17 However, other factors, such as the presence of acute symptoms, a concomitant bicuspid aortic valve, a connective tissue disease such as Marfan Syndrome, or a rapidly enlarging aortic diameter, often warrant earlier intervention at smaller aortic sizes. 21 Once dissection or rupture occurs, short-term and long-term outcomes diminish rapidly. The excruciating chest pain or sudden death caused by acute aortic events is frequently the first and only signs of a TAA. However, physicians must also respect dissection as a great masquerader that presents with variable or even absent symptoms. 22 Aortic dissection and rupture occur with approximately the same incidence of 3.5/100,000 patient-years. 23 The prognosis for acute aortic dissection is poor. Data from the International Registry of Acute Aortic Dissection (IRAD) indicate that overall in-hospital mortality for acute thoracic aortic dissection is 27.4%. 24 In-hospital mortality for acute type A dissection is 35% (26% in patients undergoing surgical repair and 58% in patients managed nonoperatively due to age or comorbidities). 24 Acute type B dissections have a more favorable in-hospital mortality of 12%, with mortality rates of 29%, 11%, and 10% for patients receiving surgical, endovascular, and medical management, respectively. 25 In cases of chronic dissection, or even after successful partial aortic replacement, the residual aorta will grow at an accelerated rate. 26 As a consequence, these patients have a severely compromised long-term outlook: nearly 40% will suffer fatal rupture or require additional intervention. 27 The prognosis for TAA rupture is worse than dissection. One study found that only 41% of patients with TAA rupture reach a hospital alive. 28 For those patients who do survive to operation, data from a nationwide study indicate that the perioperative mortality of surgical repair of the descending aorta is 28.6%, whereas the mortality of endovascular repair is 23.4% (risk-adjusted mortality and complication rates were not significantly different between the two treatments). 29 Because of the potential misdiagnosis of rupture-related death as cardiac arrest, aortic ruptures likely have an even higher mortality rate than we suspect. These dismal statistics underscore the need for early recognition of TAAs in the general population. Mechanical properties of the aorta correlate well with its clinical behavior. We have shown that the clinical danger threshold for rupture mirrors the innate physical limits of the aortic wall. As the aorta approaches 6.0 cm, its distensibility rapidly falls. 30 At this size, the aorta loses its natural elasticity and effectively becomes a rigid tube. Pressure on the vessel wall therefore cannot be dissipated and results directly in increased wall stress. Indeed, once the aorta reaches 6.0 cm, the measurable wall stress markedly rises (Fig 3). 30 At a blood pressure of 200 mm Hg, easily achieved through strenuous exercise or emotional distress,

4 568 Kuzmik et al JOURNAL OF VASCULAR SURGERY August 2012 Fig 3. Relationship between wall stress and aortic size in ascending aortic aneurysms. The bars show wall stress at blood pressures of 100 mm Hg (dark bars) and 200 mm Hg (light bars). The dashed lines represent maximum tensile strength of aortic tissue. Reproduced with permission from Koullias et al. 30 Fig 4. Kaplan-Meier survival after elective surgery, medical management, and emergency surgery. Reproduced with permission from Davies et al. 18 the wall stress in a 6.0-cm aorta reaches the maximum tensile strength of aortic tissue. 30 It is therefore not surprising that 6.0 cm represents the danger threshold for rupture and dissection. Surgical extirpation of TAAs restores life expectancy. Although TAA is often a lethal disease if left untreated, early surgical intervention provides good longterm outcomes. Elective surgical treatment of TAAs not only improves survival over medical management alone but also achieves a survival curve approaching that of the healthy, age-matched population (Fig 4). 18 The 5-year survival after elective extirpation of a TAA is 85%. In contrast, emergency surgical intervention does not yield such favorable outcomes, with a 5-year survival of 37%. 18

5 JOURNAL OF VASCULAR SURGERY Volume 56, Number 2 Kuzmik et al 569 Fig 5. Convergence of several molecular mechanisms of aneurysm formation. Candidate medical therapies target many of these mechanisms in principle, although clinical benefit has yet to be demonstrated for all of these candidates for general aneurysm management. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; AT1, angiotensin 1; MMP, matrix metalloproteinase; NADH, reduced nicotinamide adenine dinucleotide; NADPH, reduced nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; TGF, transforming growth factor. Reproduced with permission from Danyi et al. 41 The benefits of surgical management are reinforced by the safety of TAA repair procedures relative to the lifelong risks of rupture or dissection. At our institution, the surgical mortality rates are 3.0% for elective ascending/arch repair and 2.9% for descending TAA repair. 31 The rates of serious perioperative complications are similarly low. Endovascular techniques are being used for descending TAA repair, with encouraging results. Perioperative mortality for various devices is between 5.8% and 6.1%, with mortality and complication rates that are often lower than those for surgical comparison groups. 32,33 Successful endovascular or hybrid approaches to repair ascending TAAs have also been reported. 34 Nonetheless, there are concerns regarding the long-term durability and safety of endovascular TAA repair in contrast to surgical repair. 35 Overall, these outcomes strongly reinforce the need to repair a TAA before it reaches the dangerous thresholds of 6.0 cm for the ascending aorta and 7.0 cm for the descending aorta, at which the risk of rupture increases sharply (Fig 2). We recommend repairing an ascending TAA once it reaches 5.5 cm and a descending TAA at 6.5 cm, although intervention is indicated at smaller diameters in patients with symptomatic aneurysms, rapidly enlarging aneurysms, or those with connective tissue disease. 17 The presence of a bicuspid aortic valve, which represents the most common congenital heart condition, also warrants aortic repair at smaller diameters (we recommend 5.0 cm) due to the increased risk of dissection. 2 Evidence for effectiveness of medical therapy for TAA is scant. -Blockers were initially proposed as medical therapy for TAAs based on their ability to reduce blood pressure, cardiac inotropy, and shear stress on the aorta (Fig 5). 36 However, clinical benefit of -blockers has been demonstrated in only one study of Marfan patients. 37 No studies to date have confirmed this finding on non-marfan TAA patients. Some studies, in fact, suggest that -blockers do not protect against TAA growth. 38 Statins were studied as treatment for AAAs based on their lipid-lowering and antioxidative effects. Yet, the largest, most recent study to date found no benefit of statins on AAA growth. 39 A recent study from our institution, however, did find a substantial benefit from statins in preventing rupture, dissection, death, and need for surgical intervention in patients with TAAs (Fig 6). 40 This exciting finding needs further corroboration. Studies on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have reported conflicting results. 41 Losartan may have a protective effect by antagonizing the activity of transforming growth factor-. 42 A multicenter randomized controlled trial (COzaar in Marfan Patients Reduces aortic Enlargement [COMPARE]) is underway to confirm these findings. CONCLUSIONS At present, we believe surgery remains the mainstay of TAA treatment. Although endovascular techniques hold promise, particularly for descending and thoracoabdominal

6 570 Kuzmik et al JOURNAL OF VASCULAR SURGERY August 2012 Fig 6. Kaplan-Meier curves are shown for survival free of the composite end point of death, rupture, dissection, or aneurysm repair for 649 patients with thoracic aortic aneurysms stratified according to statin intake. The table at the bottom shows the number of patients at risk. Reproduced with permission from Jovin et al. 40 TAAs, long-term safety and durability have yet to be proven; recent data from a large nationwide study indicate that survival for endovascular repair after 1 and 5 years is worse than open surgical repair. 33,35 We also recommend smoking cessation and avoidance of stressful activity for TAA patients. 43 Understanding the natural history of TAA is contributing to rational, evidence-based surgical decision making and helping us to tame this virulent disease. AUTHOR CONTRIBUTIONS Conception and design: GK, AS, JE Analysis and interpretation: GK, AS, JE Data collection: GK, AS, JE Writing the article: GK, AS Critical revision of the article: GK, AS, JE Final approval of the article: GK, AS, JE Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: JE GK and AS contributed equally to this article. REFERENCES 1. Centers for Disease Control and Prevention (CDC). National Center for Injury Prevention and Control. WISQARS leading causes of death reports. Atlanta: CDC; Elefteriades JA, Rizzo J. Epidemiology, prevalence, incidence, trends. In: Elefteriades JA, editor. Acute aortic disease. 1 st ed. New York: Informa; p Isselbacher EM. Thoracic and abdominal aortic aneurysms. Circulation 2005;111: Itani Y, Watanabe S, Masuda Y, Hanamura K, Asakura K, Sone S, et al. 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