Accepted Manuscript Canadian Cardiovascular Society Position Statement on the Management of Thoracic Aortic Disease Munir Boodhwani, MD, MMSc Gregor Andelfinger, MD, PhD Jonathan Leipsic, MD Thomas Lindsay, MD, MSc M. Sean McMurtry, MD, PhD Judith Therrien, MD Samuel C. Siu, MD PII:
S0828-282X(14)00112-3
DOI:
10.1016/j.cjca.2014.02.018
Reference:
CJCA 1128
To appear in:
Canadian Journal of Cardiology
Received Date: 8 November 2013 Revised Date:
1 February 2014
Accepted Date: 1 February 2014
Please cite this article as: Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC, Canadian Cardiovascular Society Position Statement on the Management of Thoracic Aortic Disease, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.02.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Canadian Cardiovascular Society Position Statement on the Management of Thoracic Aortic Disease
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Primary Panel: Munir Boodhwani1 MD, MMSc (Co-chair), Gregor Andelfinger2, MD, PhD, Jonathan Leipsic3, MD, Thomas Lindsay4,MD, MSc, M. Sean McMurtry5, MD, PhD, Judith Therrien6, MD, Samuel C. Siu7 MD (Co-chair)
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Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario Department of Pediatrics, University of Montreal, Montreal, Quebec 3 Department of Radiology, University of British Colombia, Vancouver British Colombia 4 Division of Vascular Surgery, University Health Network, Toronto, Ontario 5 Division of Cardiology, University of Alberta, Edmonton, Alberta 6 Division of Cardiology, McGill University, Montreal, Quebec 7 Division of Cardiology, Western University, London, Ontario
Corresponding Author:
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Munir Boodhwani, MD, MMSc H3405, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7 Phone: (613) 761-4313 Fax: (613) 761-5107 Email: [email protected] Word Count: 6,381 words
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Abstract:
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This Canadian Cardiovascular Society position statement aims to provide succinct perspectives on key issues in the management of thoracic aortic disease (TAD). This document is not a comprehensive overview of thoracic aortic disease and important elements of the epidemiology, presentation, diagnosis, and management of acute aortic syndromes are deliberately not discussed; readers are referred to the 2010 guidelines published by the American Heart Association, American College of Cardiology, American Association of Thoracic surgery and other stakeholders1. Rather, this document is a practical guide for clinicians managing adult patients with TAD. Topics covered include size thresholds for surgical intervention, emerging therapies, imaging modalities, medical and lifestyle management, and genetics of TAD. The primary panel consisted of experts from a variety of disciplines that are essential for comprehensive management of TAD patients. The methodology involved a focused literature review with an emphasis on updates since 2010 and the use of GRADE methodology to arrive at specific recommendations. The final document then underwent review by a secondary panel. This document aims to provide recommendations for most patients and situations. However, the ultimate judgement regarding the management of any individual patients should be made by their health care team.
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Brief Summary:
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This is the first Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Developed by a nationally representative, multi-disciplinary group, this document provides a succinct review of contemporary literature and practical recommendations on key aspects of management of patients with thoracic aortic disease including size thresholds for intervention, imaging modalities, medical and lifestyle management, and genetics. Brief perspectives on emerging therapies and models of care are also provided.
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Section 1. Size Thresholds for Elective Thoracic Aortic Intervention
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Thoracic Aortic aneurysms are largely asymptomatic until a sudden and catastrophic event, including aortic rupture or dissection, occurs, and is rapidly fatal in a large proportion of patients2, 3. Elective intervention on the thoracic aorta carries a much lower risk of mortality and morbidity, and prophylactic aortic surgery can be life-saving.
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The decision to perform aortic intervention is a balance between risks of natural history of the disease versus the risk of the surgical intervention itself and any additional longterms risks of treatment. The risk of aortic complications is influenced by a number of patient-related factors e.g. family history of aortic disease, history of smoking, etc. and disease-related factors e.g. true vs. false aneurysm, bicuspid valve aortopathy, connective tissue disorders, etc. (Table 1). Similarly, the risk of surgical intervention may be significantly influenced by comorbidities (e.g. COPD, coronary or valve disease, etc.) and anatomy (presence of dissection, aortic arch involvement).
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The risk related to intervention is an instantaneous risk whereas the risk of aortic complications accrues over time (e.g. 5-year risk of rupture is greater than 1-year risk of rupture). Therefore, it may be acceptable for patients to accept a one-time risk of intervention (e.g. 5%) to prevent the long-term consequences of aortopathy (e.g. 2 -3 %/year). Maximum aortic diameter is the most important predictor of aortic complications. However, since many factors influence the relationship between size and aortic complications, absolute size should not be used in isolation. There are occasionally long-term consequences that deserve consideration, such as minimizing the risk of valve-related complications in patients eligible for aortic valve sparing or repair surgery. Lastly, estimates of risk of aortic complications based on natural history studies are not well established in all subsets of TAD.
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The size threshold for considering aortic intervention has decreased successively over recent years, due to substantial reduction in morbidity and mortality for elective procedures. In experienced centers, elective repair of ascending aorta and aortic root aneurysms carries a mortality of 1%. Aneurysms involving the aortic arch and descending thoracic aorta typically carry a higher risk of mortality and neurologic morbidity. The International Registry of Aortic Dissection (IRAD) registry and other data have questioned the current threshold of aortic diameter of 5.5 cm for ascending aortic aneurysm, as the median diameter of patients presenting with type A and B aortic dissections was significantly less than 5.5 cm4, 5. With an intervention threshold of 5.5 cm, over half of type A aortic dissections would not be prevented. However, the number of patients in the general population with aortic diameters between 5.0 – 5.5 cm (and 4.5 – 5.0 cm) is large and their annual risk of aortic complications is not well characterized. Even with the low risk of elective aortic replacement, at some level, this number needed to treat (NNT) would be prohibitively high. 3
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Recommendation: “We recommend that the decision to perform prophylactic aortic intervention should be tailored to the individual patient and incorporate patientrelated and disease-related factors.” (Strong Recommendation, Moderate Quality of Evidence) Values and Preferences: The important factors influencing the risk of aortic complications and risk of operative intervention are listed in Table 1. Where there is uncertainty regarding decision making, patients should be referred to specialists in the management of thoracic aortic disease for consideration of operative intervention.
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Intervention Thresholds for Thoracic Aortic Aneurysms:
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Recommendation: “We recommend that surgical intervention be considered for thoracic aortic aneurysms according to the disease etiology and anatomic region affected as indicated in table 2.” (Strong Recommendation, Moderate Quality of Evidence)
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Certain factors confer increased risk and include (in increasing order of significance): bicuspid aortic valve aortopathy, Marfan syndrome, Familial Thoracic Aortic Disease, Ehlers Danlos (vascular type), Turner Syndrome and in particular, Loeys-Dietz syndrome . The size threshold for intervention is lower for these conditions. Patient body size is an important variable; a lower threshold may be used in females and patients of shorter stature.
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1. Degenerative Aneurysms: Patients with degenerative aortic aneurysms do not have connective tissue disorders, familial aortopathy, or bicuspid aortic valve aortopathy. They are typically older and have atherosclerotic risk factors, particularly hypertension and smoking. Increased aortic size has been linked to increased risk of dissection, rupture, and death, particularly when the size of the aneurysm exceeds 6.0 cm (7% annual risk of rupture or dissection and 12% annual risk of death)6. Surgical intervention is recommended at a diameter of 5.5 cm for the ascending aorta. For the descending thoracic aorta, surgical intervention is recommended at a diameter of 6.5 cm7. 2. Bicuspid Aortic Valve Aortopathy: Patients with bicuspid aortic valves have an increased risk of aortic dilation and molecular and histological changes suggesting an aortopathy independent of valve function8, 9. The risk of aortic dissection in BAV patients is higher than the general population but is lower than that for patients with Marfan syndrome or other genetic aortopathies10. Surgical intervention in this population should be considered when the size of the ascending aorta is between 5.0 – 5.5 cm, accounting for patient size, particularly in the presence of other risk factors.
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3. Marfan Syndrome: Marfan syndrome individuals are susceptible to thoracic aortic aneurysms with a higher incidence of aortic dissection11, 12. However, a low risk of aortic complications is noted in patients with an aortic size below 5.0 cm11. For the aortic root and ascending aorta, a size threshold of 5.0 cm is appropriate. For the descending thoracic aorta, a size threshold of 5.5 – 6.0 cm is recommended. Patients with a family history of premature aortic dissection warrant consideration of surgical intervention at smaller diameters.
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4. Familial Thoracic Aortic Aneurysm: These individuals have one or more relatives with thoracic aortic aneurysms with or without a previous history of aortic dissection. Aortic dilation progresses more rapidly in patients with familial aortopathy with e a higher risk of aortic complications13, 14. The threshold for surgical intervention may be guided by the aortic size at which other family members have had aortic complications, if known. If not known, then a size threshold of 4.5 – 5.0 for the ascending aorta and 5.5 – 6.0 for the descending thoracic aorta is reasonable.
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5. Non-Marfan Genetic Aortopathy: A number of genetic disorders including LoeysDietz, Turner and Ehlers Danlos (vascular type) are linked to thoracic aortic aneurysm and dissection. Because of the low prevalence of these syndromes, there is a paucity of data on the risk of aortic complications, it is significantly higher compared to degenerative aneurysms and Marfan syndrome. Patients with LoeysDietz syndrome have a high risk of aortic dissection at small diameters leading to limited life expectancy15. The threshold for surgical intervention is therefore lower than that for Marfan syndrome. Patients with vEDS can have a high risk of surgical complication due to poor quality of vascular tissue.
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In addition to size thresholds, the following factors deserve careful consideration:
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1. Presence of Symptoms: A small subset of patients will present with compressive symptoms, malperfusion, or pain, all of which are associated with poor outcome16 and surgical intervention should be considered in all symptomatic thoracic aortic aneurysms, regardless of absolute size. 2. Pseudoaneurysms: False aneurysms of the thoracic aorta may occur secondary to blunt trauma, prior aortic surgery, catheter based manipulation, or in association with penetrating atherosclerotic ulcers. Rates of aortic rupture for pseudoaneurysms are not well-characterized. Surgical intervention may be considered when the total diameter of the aorta (including the native aorta and the false aneurysm) meets the criteria in Table 2 or if the pseudoaneurysm is greater than 2 cm in maximum diameter.
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3. Rate of Growth: Typical growth rate of thoracic aortic aneurysms is 0.1 cm/year. Rapidly growing aneurysms (> 0.5 cm/year increase in diameter) are uncommon but are associated with increased aortic complications17. Surgical intervention should be considered in rapidly growing aneurysms regardless of absolute diameter.
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4. Concomitant Cardiac Surgical Procedures: Surgical intervention on the moderately dilated ascending aorta (> 4.5 cm) should be considered in patients undergoing open cardiac surgical procedures as it minimizes the long-term risk of dissection and rupture and avoids a future higher risk reoperation18-20. However, other factors including patient age, body size, co-morbidities, additional risk of procedure, and life expectancy must be considered in the decision making process. In some patients, aortic dilation below the thresholds recommended for surgical intervention may lead to aortic valve insufficiency due to cusp malcoaptation and a lower threshold for aortic resection is reasonable to facilitate aortic valve repair.
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5. Indexing for patient size: The normal thoracic aorta is smaller in females and in shorter individuals. In these individuals, aortic size index (maximum aortic diameter / body surface area) > 2.75 cm/m2 is a better predictor of aortic complications 21. Other investigators have suggested that the ratio between the cross-sectional area of the aorta (at its maximum diameter) divided by the patient’s height (m) is another useful method to adjust for differences in body size22. Indexed measurements are most useful for females, patients with short stature and certain genetic syndromes (e.g. Turner syndrome).
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Section 2. Emerging Interventions for Thoracic Aortic Disease A. Thoracic Endovascular Aneurysm Repair
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In contrast to open surgical repair, Thoracic Endovascular Aneurysm Repair (TEVAR) involves exclusion of the aneurysm sac with a covered stent. Compared to open surgical repair, TEVAR is associated with a lower procedural mortality and morbidity 23, 24, but a greater need for re-interventions and concerns remain regarding long-term outcome and late aneurysm-related mortality25.
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While TEVAR is used primarily for the descending thoracic aorta, alternate approaches to aortic arch disease in high-risk candidates include a combination of open and endovascular techniques, depending on anatomic suitability. Open surgical treatment is the standard of care for the ascending aorta26, 27.
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Type B dissections without complications are treated medically28, with surgery reserved for complications including malperfusion syndromes (visceral, renal or limb perfusion), rupture and rapid expansion. In the IRAD registry, TEVAR therapy for complicated, acute type B aortic dissections was associated with lower mortality and complications than open surgical intervention. The STABLE trial suggests this therapy is associated with increased true lumen size, and favorable clinical and anatomic results29. TEVAR may therefore offer better outcomes compared to open surgical approaches in complicated cases. For non-complicated type B dissections, the INSTEAD trial did not demonstrate any advantage for TEVAR in the short-term30, 31. However, longer-term follow-up suggests reduced aorta-specific mortality following TEVAR32.
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TEVAR may be associated with a number of complications including paralysis and paraperesis. Spinal CSF drains that allow drainage of CSF and improve spinal cord perfusion, 33, 34 intra operative monitoring of motor and sensory evoked potentials to monitor spinal cord function, and improved preoperative imaging to identify critical intercostals arteries are some techniques employed to minimize this complication 35. Stroke, renal failure and retrograde Type A dissection are other potential complications. B. Aortic Valve Preservation and Repair Patients with aortic root aneurysms, with or without associated aortic valve disease have traditionally been treated with composite aortic valve and root replacement with reimplantation of the coronary arteries (Bentall procedure). While this procedure is effective at treating the aortopathy, patients are left with the long-term risks associated with prosthetic heart valves which include thromboembolism, structural and nonstructural valve dysfunction, endocarditis, and anti-coagulant related hemorrhage for those with mechanical prostheses36. Since many of these patients have morphologically normal aortic valve leaflets, there has been increasing interest in valve sparing aortic
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root operations. Long-term observational cohort studies have demonstrated excellent outcome at over 15 years of follow-up37.
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The concepts, innovations38 and techniques39 in valve preserving operations have also been applied in patients with aortic insufficiency and bicuspid aortic valves and associated aortopathy with promising results40, 41, including a low risk of valve related complications42, 43. These benefits are most significant for young patients who are likely to accrue valve-related events over time. The likelihood of valve repair may be a consideration in determining the threshold for aortic replacement in these patients.
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Recommendation: “We recommend that patients with complex TAD that stand to benefit from the above emerging techniques and technologies be referred to teams experienced in these approaches.” (Conditional Recommendation, Low Quality of Evidence)
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Section 3: The Role of Imaging in Diagnosis and Surveillance
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Imaging is fundamental for diagnosis and surveillance of TAD. The test chosen should be determined by the presentation, location and patient age, with renal dysfunction, local expertise and access to imaging modalities as additional considerations. Height and weight should be recorded for calculation of body surface area. Strengths and weaknesses of the various imaging modalities are summarized in Table 3. Details on technical aspects of imaging are provided in Appendix 1. Overview of Imaging Modalities
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A. Multi-detector Computerized Tomography (CT) ECG gated scans are useful for imaging the ascending aorta enabling assessment of the aortic valve and at least the proximal coronary arteries (see Appendix 1). After aortic intervention, CT is also preferred to detect post procedural leaks or pseudoaneurysms as echocardiography (echo) is often limited by the presence of metallic devices and clips and transesophageal echocardiography is semi-invasive and thus not optimal for surveillance.
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Currently, external aortic diameters are reported for CT or magnetic resonance (MR) derived measurements. Echo-derived measurements are typically reported as luminal size; this difference is important in the descending thoracic aorta where mural thrombus is more prevalent. Pronounced arterial wall calcifications can lead to underestimation of the lumen. While the potential stochastic risk of radiation exposure drops significantly when patients reach the 5th decade of life, CT must be used with caution in neonates, children, and young adults in whom the risk of radiation-induced malignancy is the highest44-48.
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B. Magnetic Resonance Imaging (MRI) The avoidance of radiation or iodinated contrast exposure with MRI is a particularly valuable feature in younger patients and for serial follow up imaging. Disadvantages include longer scan times which is a particular issue in the setting of acute chest pain and claustrophobic patients, as well as issues related to the use of Gadolinium contrast agents in renal failure owing to concerns regarding nephrogenic systemic fibrosis and implanted cardiac devices. MRI may be particularly helpful in distinguishing mural thrombus from intramural blood in the setting of acute aortic syndromes with early potential being shown by new dual energy CT techniques 49, 50 . C. Transthoracic (TTE) and Transesophageal (TEE) Echocardiography Imaging of the aortic root and proximal ascending aorta is part of the standard TTE with images obtained at end diastole 51, 52. Three-dimensional echocardiography, particularly combined with TEE, has the potential of enhancing diagnostic utility53, but its aortic application has been focused on the proximal ascending aorta. TEE is superior to TTE for 9
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visualization of the thoracic aorta and has an important role in settings where CT or MR may not be available or feasible, such as the intensive care unit or the operating room. Criteria for TTE/TEE diagnosis of acute aortic dissection are: 1) Intimal or dissection flap seen on multiple views, 2) Independent motion of the intimal flap, 3) Differential colour flow in true and false lumens1. Echo is operator dependent, therefore serial examinations should be performed with standardized protocols and by experienced individuals in laboratories with quality assurance processes in place52.
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D. Cardiac catheterization and angiography The main use of angiography is in the evaluation of a suspected aortic syndrome while the patient is undergoing a cardiac catheterization procedure, but it has otherwise been replaced by CT, MR, and TEE.
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Recommendation: “For Acute Aortic Syndromes : A. We recommend CT as the preferred initial imaging test (Strong Recommendation, Moderate quality evidence) B. We suggest TEE as an appropriate alternative in the following situations (Conditional Recommendation, Moderate quality evidence) : a. An indeterminate CT examination b. When transport to CT is not feasible due to hemodynamic instability c. Intraoperative TEE when a dissection flap is seen on the initial TTE
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C. We suggest MR for characterizing acute intramural hematomas when CT is equivocal” (Conditional Recommendation, Low quality evidence)
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Values and Preferences: These recommendations are based on cohort studies, overviews, and expert opinion, as there are no contemporary studies comparing diagnostic accuracy of the imaging modalities. A systematic review concluded that TEE, helical CT, and MRI, yield clinically equally reliable diagnostic value for confirming or ruling out aortic dissection 54. There are no standards for the appropriate phase of the cardiac cycle to evaluate aortic size by CT or MR, therefore the phase (diastolic vs. systolic) used should be reported to allow for consistent serial measurements to assess interval changes. Recommendation: “For ongoing aortic surveillance in patients who are candidates for intervention, we suggest: A. For preoperative planning, the entire thoracic aorta should be imaged by CT or MR (Conditional Recommendation, Moderate quality evidence) B. For post repair surveillance in those without residual aortopathy, the entire aorta should be imaged by CT or MR at least once every 3-5 years after repair (Conditional Recommendation, Low quality evidence) 10
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C. MR should be considered the first line test of choice if serial repeat examinations are being considered in an adolescent or in the adult population below the age of 50 years (Conditional Recommendation, Low quality evidence) D. If dilation is established to only involve the root or proximal ascending aorta then TTE serves as a reasonable alternative, with TEE reserved for those with non-diagnostic TTE images (Conditional Recommendation, Low quality evidence)
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Values and Preferences: To reduce variability, serial aortic imaging should be performed using the same imaging protocols and modality, in the same laboratory. Follow up studies should be scheduled at 6-12 months following diagnosis, and then every 6 or 12 months thereafter depending on aortic size and the rate of change. In patients with stable dimensions between serial examinations, imaging intervals may be increased.
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Section 4: Medical Therapy and Lifestyle Considerations for Patients with Thoracic Aortic Disease
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A. Antihypertensive Therapy: The rationale for antihypertensive therapy is based on mechanistic and animal studies55, 56 , as well as observational reports linking aortic dissection with hypertension57, 58. Randomized controlled trials of antihypertensive therapies have not included patients with TAD per se or reported consistently on aortic endpoints.59, 60 While summaries of antihypertensive trials support treatment of hypertension when present, they do not offer specific guidance on the management of patients with thoracic aortic aneurysm, dissection, or aortopathy, either for choice of drug therapy or for blood pressure targets61-69.
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For Marfan syndrome, the available studies report surrogate outcomes, and are limited by small sample size, lack of blinding, and choice of comparator. Small randomized trials of beta blockers or losartan in addition to beta-blockers showed lower rates of aortic root dilation, with no difference in other clinical outcomes (Appendix 1, Table 2). No published trials compare beta-blocker monotherapy with ACE-inhibitor monotherapy, and in a recent trial of losartan only a subset were on losartan monotherapy70. In other subsets of TAD including BAV, Loeys-Dietz, Ehlers Danlos, and other genetic aortopathies, there are no randomized trials or observational studies.
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In patients with chronic aortic dissection, observational reports suggest lower risk for operative repair with beta-blocker therapy71. In a series of 722 and 579 patients with type A and type B aortic dissections respectively, beta-blockers were associated with improved survival in both groups, while ACE inhibitors were not associated with improved survival72. Use of calcium-channel blockers was associated with improved survival in type B aortic dissections72, as well as decreased aortic expansion in a smaller cohort of 191 type B aortic dissections73. A cohort of 78 consecutive type B aortic dissection cases identified an association between ACE inhibitor and better survival74. Poor blood pressure control (≥140/90 mmHg) has been linked with late mortality74, 75.
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Recommendation: “We recommend antihypertensive drug therapy for hypertensive patients with thoracic aortic disease to achieve a goal blood pressure of < 140/90 mmHg, or < 130/80 mmHg in those with diabetes, to reduce the risk of myocardial infarction, stroke, heart failure, and cardiovascular death76.” (Strong recommendation, moderate quality evidence) “We recommend beta-blocker or angiotensin receptor blocker therapy for patients with Marfan syndrome to reduce the rate of aortic dilation. If tolerated, we recommend consideration of additional therapy (ACE-inhibitor, angiotensin receptor blocker, or beta-blocker) for patients with Marfan syndrome to reduce the rate of aortic dilation.” (Strong recommendation, low quality of evidence)
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Values and Preferences: Though there are no randomized trials that support lower blood pressure targets (e.g. < 120/80 mmHg), aggressive therapy may be reasonable based on the physiologic rationale and patient-specific factors including type of aortopathy, prior patient or family history of acute aortic syndrome or sudden death, aortic aneurysm growth despite medical therapy, or patient preference. To date, there are no randomized trials supporting that monotherapy with a specific agent is superior to others for any form of TAD. B. Preventing hypertension and atherosclerosis:
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Diet and Smoking Cessation: Standard dietary advice for prevention of hypertension and atherosclerosis as well as smoking cessation are appropriate for most patients with thoracic aortic disease (Appendix 1).
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Lipid Lowering Therapy: Some observational studies suggest benefit and many patients with thoracic aortic disease have multiple atherosclerotic risk factors (Appendix 1). Lipid lowering, generally with statin drugs, should be offered according to general guidelines77.
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Exercise: Aortic dissection has been linked with severe physical exertion due to weight lifting78. The mean aortic diameter of these cases was 4.6 cm, therefore strenuous strength training may be dangerous for patients with TAD. The proposed mechanism is transiently elevated blood pressure associated with isometric exercise or valsalva maneuver79. Exercise-based cardiac rehabilitation for patients with coronary artery disease has been shown to reduce mortality in randomized controlled trials80, and exercise cardiac rehabilitation was found to be safe in a small series of survivors of type I aortic dissection81.
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Recommendation: “We recommend that patients with thoracic aortic disease be evaluated for risk for atherosclerotic vascular disease, and that recommendations for ameliorating this risk, whether by endurance exercise, dietary changes, smoking cessation, or medical therapy, be made in accordance with current general guidelines.” (Strong recommendation, low quality of evidence) Values and Preferences: Both patients and clinicians commonly require guidance with respect to these issues, and basing clinical decisions on the minimal observational data available, or extrapolating results from other populations, is a sensible compromise. Recommendation: “We suggest patients with thoracic aortic disease avoid strenuous resistance and isometric exercise.” Strong recommendation, very low quality of evidence.
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Values and Preferences: Though the data are minimal, the risks associated with strenuous isometric exercise 78 appear great enough to strongly recommend avoiding this exposure.
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Driving: Neither the Canadian Cardiovascular Society Conference nor the Canadian Medical Association (CMA) have made recommendations about fitness for driving in the context of thoracic aortic disease82. However, the CMA has recommended that patients with abdominal aortic aneurysm be precluded from driving when the rupture risk exceeds 10% per year. Based the best observational data available, these thresholds of risk occur for thoracic aortic aneurysms greater than 6.0 cm in the ascending aorta or arch, and greater than 6.5 cm in the descending aorta. A lower threshold for rupture risk is reasonable for commercial driving.82
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“We suggest that patients with thoracic aortic disease be precluded from private driving if the ascending aorta diameter is greater than 6.0 cm or the descending aorta diameter is greater than 6.5 cm, and restricted from commercial driving if the ascending thoracic aorta diameter is greater than 5.5 cm or the descending thoracic aorta is greater than 6.0 cm83. (Conditional recommendation, very low quality evidence).
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Values and preferences: These thresholds are based on the methodology of the CMA and Canadian Cardiovascular Society Consensus Conference on the assessment of the cardiac patient for fitness to drive and fly82 and the best available observational evidence. Risk thresholds may be reached at different aortic diameters for different aortopathies. Further studies are required to provide reliable estimates of rupture risk.
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“We suggest that patients return to private driving six weeks following and commercial driving three months following open aortic repair.” (Conditional recommendation, low quality evidence)
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Values and preferences: This practice is in accordance with current recommendations for patients after cardiac valve surgery. Patients undergoing endovascular aortic procedures may resume driving sooner based on assessment by their treating physician. Pregnancy: Information related to pregnancy in patients with TAD is provided in Appendix 1, Table 3.
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Section 5: Screening for family members of patients with genetic aortopathy
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A. Marfan syndrome Marfan Syndrome is an autosomal dominant disorder with high penetrance and varying phenotypic expression, which is associated with progressive aortopathy including dilation of the ascending aorta (sinuses of Valsalva) and can lead to dissection (usually type A) or rupture if not operated11. Clinical screening of patients suspected to have Marfan syndrome should be done using the revised Ghent criteria84. Routine CT or MRI for definite Marfan syndrome should be initiated in early adulthood or at surgery, whichever comes first.
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Screening of the first degree family members is indicated as the transmission rate is 50%. Genetic screening may help to clarify 1) the nature of the disease, 2) the risk to the patient when the clinical diagnosis is uncertain, 3) to ascertain sporadic cases or 4) prenatal diagnosis85. Imaging in family members suspected to have the disease should include at least a transthoracic echocardiogram to assess the ascending aorta and a baseline CT scan or MRI to assess the entire aorta. When dilation of the ascending aorta is found, a repeat transthoracic echo at 6 months should be performed to ascertain the rate of progression. If stable, a yearly echo should be done thereafter86. Any family member who has Marfan syndrome (clinically or genetically determined) with a normal size ascending aorta, should undergo yearly echocardiography 86.
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Recommendations for Marfan syndrome:
“We recommend clinical and genetic screening for suspected Marfan syndrome to clarify the nature of the disease and provide a basis for individual counselling”. (Strong recommendation, high quality of evidence)
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“We recommend echocardiographic screening be performed at diagnosis to measure aortic root and ascending aorta diameters, and repeated 6 months thereafter to determine rate of progression. If aortic diameters remain stable, annual imaging is recommended. If the aortic diameter exceeds 45 mm or if significant deviation from baseline studies occurs, more frequent imaging should be considered.” (Strong recommendation, high quality of evidence) “We recommend that women with Marfan syndrome who want to become pregnant be considered for aortic root and ascending aorta replacement if the diameter reaches 41 to 45 mm). These women should undergo surgery at centres with expertise in aortic valve sparing surgery (see recommendation from section 2B)”. (Conditional recommendation, low quality of evidence) B. Loeys-Dietz syndrome Loeys-Dietz syndrome (LDS) associated with arterial tortuosity and aggressive, progressive dilation of the ascending aorta; although the aorta at any level can be 15
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affected. Cerebral aneurysms are common in LDS. Accompanying craniofacial involvement can include bifid uvula, cleft palate, craniosynostosis and hypertelorism. It is autosomal dominant with a 50% transmission rate. First degree family members should undergo clinical as well as genetic screening. In affected family members, an initial transthoracic echocardiogram is recommended with a repeat at 6 months if aortic dilation is present or at 1 year if aorta is not dilated86. Prophylactic aortic root surgery is recommended in these patients when the ascending aorta reaches 42mm87. A MRI from the base of the neck to the pelvis is also recommended every 18-24 months to assess the degree of arterial tortuosity and presence of arterial aneurysms, or more frequently if specific pathology is followed 88
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C. Bicuspid aortic valve Bicuspid Aortic Valve (BAV) is the most common cardiac malformation with a prevalence of 1-2% in the general population. BAV is a heritable disorder with a significantly increased recurrence risk in first-degree relatives (5-30%) 89-93. Although autosomal dominant transmission with reduced penetrance and variable expression has been reported, it is likely a complex genetic trait influenced by several loci. Fifty percent of patients with BAV have an associated aortopathy that can involve the proximal aorta, usually the mid ascending aorta. Some affected family members may not have BAV but may have aortopathy 89, 94, 95. Because of its high risk of recurrence, clinical screening of first degree relatives is suggested with a transthoracic echo to ascertain the presence of BAV and/or ascending aorta dilation. CT scan or MRI may be indicated to completely visualize the ascending aorta and arch 96. Echocardiographic screening of first degree relatives in the pediatric age range may be useful.
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D. Familial thoracic aortic aneurysm Familial Thoracic Aortic Aneurysm (FTAA) is a genetic disease that occurs in “non syndromic” patients with aortopathy and a family history of aortic aneurysm. The majority of FTAA demonstrate an autosomal dominant inheritance with decreased penetrance and variable expression. A positive family history for TAA should prompt a search for signs of syndromic disease. To date, a number of genetic mutations have been identified which explain 20% of the FTAA.. Imaging of the aorta of first degree relatives to identify asymptomatic aneurysm is critical. Transthoracic echocardiogram is recommended, with additional CT scan or MRI if the entire aorta needs imaging. E. Aneurysm-Osteoarthritis Syndrome Aneurysm-osteoarthritis syndrome is an autosomal dominant trait with aneurysms of the arterial tree, skeletal and cutaneous anomalies97, 98. Phenotypic overlap with LDS encompasses hypertelorism and abnormal palate/uvula, and velvety skin. Early-onset osteoarthritis and intervertebral disc degeneration are present. Arterial disease mostly presents as aneurysm of the aortic root, but can also affect the thoracic aorta and the remainder of the arterial tree with an aggressive course99. Imaging of the entire vascular tree and genetic testing should be performed in such patients. First-degree relatives of
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patients with AOS should be screened for arterial disease and genetic testing be offered when a causal mutation is identified in the index case.
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F. Vascular Ehlers-Danlos syndrome (vEDS) vEDS is an autosomal dominant disorder caused by a mutation in the COL3A1 gene 100. The ensuing deficiency in collagen III formation results in connective tissue fragility including aneurysms, arteriovenous fistulae, spontaneous vascular dissections and ruptures, as well as bowel and uterus ruptures. Patients present with easy bruising, translucent skin and spontaneous arterial bleeding. Typically, aneurysms involve any medium-to-large sized muscular artery including branch vessels in the head, neck, thorax, abdomen and extremities. Dilation of the ascending aorta may occur. Surgical complications are common, with high procedural mortality101. Surgery should be avoided unless a lesion is considered to be imminently life-threatening. Clinical and genetic screening is recommended for first degree relatives. Widespread imaging modalities should be performed to document anatomy of the entire vascular tree 100.
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G. Turner syndrome Turner syndrome is a chromosomal anomaly in which one sex chromosome is lacking in a female, most commonly in the form of monosomy X (45, X). Salient features are short stature, ovarian failure, and cardiovascular disease. Between 10% - 25% of females with Turner syndrome have bicuspid aortic valve, and approximately 8% have coarctation. The risk of aortic dissection is increased in women with Turner syndrome 102, and occurs in young individuals at smaller aortic diameters than in the general population or other forms of genetically triggered aortopathy. The absence of aortic valve or other cardiac malformations reduces the risk of aortic dissection. Data from the international Turner syndrome aortic dissection registry suggest that individuals with Turner syndrome who are >18 years of age with an ascending aortic size index >2.5 cm/m2 should be considered for an aortic operation to prevent aortic dissection103.
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Recommendations for Non-Marfan, Genetic forms of aortic disease:
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“We recommend aortic imaging for first-degree relatives of patients with genetic forms of TAD to identify asymptomatic carriers.” (Strong recommendation, moderate quality of evidence) “We recommend cardiac imaging in adult first-degree relatives of patients with BAV to identify asymptomatic carriers.” (Strong recommendation, moderate quality of evidence) “We recommend screening for TAD-associated genes in non-BAV aortopathy index cases to clarify the origin of disease and improve clinical and genetic counselling”. (Strong recommendation, moderate quality evidence)
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“We recommend that genetic counselling and testing be offered to first-degree relatives of patients in whom a causal mutation of a TAD-associated gene is identified. We recommend that aortic imaging be offered only to mutation carriers”. (Strong recommendation, Low quality evidence)
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“We recommend complete aortic imaging at initial diagnosis and at 6 months for patients with Loeys-Dietz syndrome or a confirmed genetic aortopathy (e.g. TGFBR1/2, TGFB, SMAD3, ACTA2, or MYH11) to establish if enlargement is occurring.” (Strong recommendation, moderate quality evidence)
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“We recommend that patients with Loeys-Dietz syndrome have whole body magnetic resonance imaging every 18-24 months to assess progression of vascular disease, or more frequently if specific pathology is followed”. (Strong recommendation, moderate quality of evidence)
Section 6: Knowledge Gaps
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“We recommend that patients with Turner syndrome should have a complete assessment of cardiac and aortic structures. If normal, repeat imaging should be performed every 5 years. If abnormalities are detected, annual imaging should be performed. In children, annual imaging may be recommended.” (Strong recommendation, moderate quality of evidence)
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Most of the epidemiology and natural history of TAD is based on: 1) Surgical series from selected populations, 2) Retrospective cohorts of acute aortic syndromes, 3) Single center studies of patients with inherited or degenerative forms of TAD, and 4) Extrapolation from non TAD patients, leaving important knowledge gaps in this patient population. Future research should be focused on these key knowledge gaps in the pathophysiology, natural history, and treatment of patients with TAD, including but not limited to: 1. Contemporary natural history data on the risks of aortic complications. 2. Predictors of aortic complications (other than size) in patients with moderate aortic dilation. 3. Genetic, epigenetic, and imaging determinants of the development and progression of the various forms of TAD and predictors of acute aortic syndromes. 4. Prevalence of TAD in susceptible populations and the role of age in development of disease 5. The efficacy of screening strategies and the psychological, social and legal consequences of such screening 6. The efficacy of risk factor modification on preventing TAD or attenuating its progression. 7. The outcomes and impact of emerging therapies in the management of TAD
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Section 7: Multi-disciplinary Care and Quality Indicators
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Comprehensive management of thoracic aortic disease spans multiple disciplines including but not limited to cardiac surgery, vascular surgery, cardiology, genetics, imaging, and adult congenital heart disease. Therefore, care for these patients is best provided in such a multi-disciplinary environment and clinics are currently emerging across major cardiac centers in Canada. These may also be an important source of critical natural history data on thoracic aortic pathologies, and facilitate prospective clinical trials and mechanistic studies to help advance care for these patients.
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Assessment of quality of care indicators for TAD may include 1) timely referral for surgery (as per propsed size thresholds), 2) appropriate imaging surveillance, and 3) risk factor management (anti-hypertensives, smoking cessation, etc.).
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Acknowledgements:
The authors would like to thank the members of the secondary panel listed below for their thorough review of the manuscript draft and insightful comment that helped shape the final document
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Secondary Panel: Hal Dietz1 MD, Francois Dagenais2 MD, Christopher Fiendel3 MD, Raymond Kwong4 MD, PhD, Erwin Oechslin5 MD 1
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McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA 2 Division of Cardiac Surgery, Laval University, Quebec City, Quebec 3 Division of Cardiac Surgery, University Health Network, Toronto, Ontario 4 Division of Cardiology, Brigham and Women’s Hospital, Harvard University, Boston, MA, USA 5 Division of Cardiology, University of Toronto, Toronto, Ontario
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Tables Table 1: Factors* determining increased risk of aortic complications and of increased risk of surgical intervention. Factors Associated with Increased Risk of Surgical Intervention Aortic Arch Pathology Descending Thoracic Aortic Pathology Chronic Obstructive Pulmonary Disease Renal Dysfunction Previous Cardiac Surgery Advanced Age Left Ventricular Dysfunction
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Factors Associated with Increased Risk of Aortic Complications Aortic size Connective Tissue Disorder Family History of Aortopathy Bicuspid Aortic Valve Smoking History Aneurysm related symptoms Rapid Growth (> 0.5 cm/year) Concomitant Aortic Valve Disease Uncontrolled Hypertension
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* Additional factors may be relevant for risk stratification in some patients
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Table 2: Recommended Size thresholds for Intervention for Asymptomatic Thoracic Aortic Aneurysms*
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Aortic Root Ascending Arch Descending Degenerative 5.5 cm 5.5 cm 6.0 cm 6.5 cm Bicuspid Aortic Valve 5.0 – 5.5 cm 5.0 – 5.5 cm 5.5 cm 6.5 cm Marfan Syndrome 5.0 cm*** 5.0 cm 5.5 – 6.0 cm 5.5 – 6.0 cm Familial Aortopathy 4.5 – 5.0 cm 4.5 – 5.0 cm 5.5 – 6.0 cm 5.5 – 6.0 cm Other Genetic Syndromes** 4.0 – 5.0 cm 4.2 – 5.0 cm 5.5 – 6.0 cm 5.5 – 6.0 cm Undergoing Cardiac Surgery 4.5 cm * Size thresholds for intervention should take into consideration patient body size either empirically or using proposed formulas for adjustment ** Loeys-Dietz, Turner, Ehlers-Danlos *** For women anticipating pregnancy, the threshold is 4.1-4.5 cm.
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Table 3: Advantages and disadvantages of various modalities for thoracic aortic Imaging
CT
• • • • • •
Availability Imaging of aorta, neck vessels, and thorax Short image acquisition time Able to define coronary anatomy Tissue characterization No radiation
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Portable Readily Available Excellent visualization
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Transesophageal • echocardiography • •
Disadvantages • Limited acoustical access, particularly in obese or postoperative patients • Best for visualization of proximal portion of ascending aorta • Operator Dependent • Limited visualization of distal ascending aorta • Reduced diagnostic accuracy for intramural hematoma • Operator dependent • Radiation exposure • Renal insufficiency may require restriction in contrast administration *
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Modality Advantages Transthoracic • Portable echocardiography • Readily available • Established role in evaluation of structural cardiac disease
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Long acquisition time Cannot be performed in unstable patients or patients with renal dysfunction*, pacemakers/AICD
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CT – Computed Tomography, MR – Magnetic Resonance Imaging *See online supplement for options in patients with mild to moderate renal dysfunction
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Table 4: Screening for patients and family members with genetic aortopathy
Gene(s) involved
Transmission Part of Screening of Imaging mode aorta family modality affected members Marfan FBN1 Autosomal Asc: ++ Clinical: Ghent Echo + syndrome Dominant Arch: + criteria CT vs. with Desc: + Genetic: in MRI different some cases phenotypic Imaging: yes expression Loeys-Dietz TGFBR1 Autosomal Asc: ++ Clinical: yes Echo + syndrome TGFBR2 Dominant Arch: + Genetic: yes CT vs. SMAD3 with variable Desc: + Imaging: yes MRI TGFB2 expression $ AneurysmAutosomal Asc:++ Clinical: yes Echo + osteoarthritis SMAD3 dominant Desc: + Genetic: yes CT vs. syndrome $ Imaging: yes MRI Ehlers-Danlos Autosomal Asc:+ Clinical: yes Echo + Type IV COL3A1 dominant Desc: + Genetic: yes CT vs. $ Imaging: yes MRI Bicuspid aortic Likely Complex Asc: ++ Clinical: yes Echo + valve multiple trait Arch: + Genetic: no CT vs. genes Familial Desc: Imaging: yes MRI clustering Familial TGFB2 Autosomal Asc: ++ Clinical: yes Echo + thoracic aortic TGFBR1 Dominant Arch: + Genetic: yes CT vs. aneurysm TGFBR2 with reduced Desc: + Imaging: yes MRI MYH11 penetrance SMAD3 and variable ACTA2 expression CT – Computed Tomography, Echo – echocardiogram, MRI – Magnetic Resonance Imaging, Asc – Ascending Aorta, Desc – Descending Thoracic Aorta $: See text for imaging of other vessels.
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Appendix 1: Supplementary Materials 1. Supplementary Information for endovascular treatment of thoracic aortic disease
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Thoracic Endovascular Aneurysm Repair (TEVAR) requires normal caliber aorta (~ 2 cm) proximal and distal to the aneurysm to achieve a seal and complete aneurysm exclusion. Seal zones have been expanded by proximal subclavian coverage and revascularization of the left subclavian artery (LSA) is recommended1. Treatment strategy for TEVAR is largely determined based on the location of the pathology and the suitability of adjacent aortic segments where the stents can be placed (Figure 1). The greatest experience with TEVAR has been accrued for descending thoracic aortic pathology.
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To facilitate TEVAR with zone 1 and zone 2 proximal landing zones, debranching of arch vessels can be performed either via sternotomy or in an extra-anatomic fashion (carotid-carotid and carotid-subclavian bypass) followed by stent implantation. Chimney grafts have also been described for the aortic arch2. This technique involves the placement of stents (covered or uncovered) parallel to a TEVAR graft to perfuse the arch vessels to avoid surgical debranching or bypassing these arch vessels. This technique adds sealing zone length while maintaining perfusion to the artery of interest. Some very short endografts have been produced for therapy of type A aortic dissections in poor operative candidates and a few published series exist3, 4.
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Placement of any endovascular device requires a sufficiently large femoral/external iliac artery for delivery or a surgically-created iliac conduit may be required. Tortuous arterial anatomy may complicate device delivery to the site of desired deployment. Accurate placement of proximal thoracic grafts has been facilitated with either the use of intraoperative hypotension induced by pharmacologic means (adenosine, esmolol) or rapid ventricular pacing using a right ventricular pacing wire. The ventricular pacing technique allows rapid onset and reversal of hypotension for accurate graft deployment.
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While the results of endovascular treatment of selected thoracic aortic pathologies are promising, these results are achieved by those with advanced experience, skills and access to the multiple additional technologies (e.g. Intravascular ultrasound) that aid in therapy of these complex patients. The use of TEVAR for genetic conditions associated with a generalized impairment of vessel wall integrity remains highly controversial and requires further study. The concern relates to maintenance of vessel wall and stent integrity at the loading zones. In addition, initiation and propagation of dissection can still occur within or immediately adjacent to the vascular region isolated by the stent. Currently TEVAR should be considered a temporizing measure that can be used (largely in the descending aorta) in specialized emergent situations or to bridge vascular segments that have already been replaced by Dacron grafts. 1
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2. Supplementary information for imaging in thoracic aortic disease
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The following suggestions are provided so that practitioners can utilize imaging modalities to achieve the most diagnostic value and to facilitate communication between providers and centres.
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Thoracic Aortic Assessment with CT • CT examinations should be performed with iodinated contrast • Multiplanar reformation or centerline reconstruction should be used to achieve cross-sectional visualization. o From these reconstructed images, the minimal luminal diameter along the course of the vascular access should be determined o Aortic Dimensions should be measured orthogonal to the direction of blood flow in systole and reflect the external aortic diameter (Figure) • CT with the implementation of modern dose reduction strategies may be a reasonable imaging option particularly in those over the age of 50 • ECG Gating should be considered for all cases when heart rate and scanner technology available will permit it. o If serial surveillance is performed with CT this should be optimally performed with ECG gating to ensure optimal image quality so changes in aortic dimension can be adequately identified
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Thoracic Aorta Assessment in the setting of Abnormal renal function • Echocardiographic assessment of aortic size is the first line test where the concerns lie in the ascending aorta • MR alternatives include: o Non-Gadolinium enhanced MRI with bright blood or black blood sequences o non-contrast based MR angiography o reduced dose of gadolinium in patients with mild to moderate renal insufficiency (GFR> 30) • Depending on the severity of renal impairment, CT with the use of contrast reduction strategies such as dual energy CT and high pitch helical acquisitions are also alternatives
Standard Report Elements for Thoracic Aortic Disease Evaluation • Anatomical location(s) and extent where the aorta is dilated • Maximum diameter of the dilated segment from the outer vessel margin in addition to the length of the dilated segment. Measurements must be performed in the short axis of the vessel • The presence of either calcified or non-calcified aortic atherosclerosis 2
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Atherosclerosis must be distinguished from intramural hematoma Measurements of the aortic root, annulus, sinuses, and tubular aorta in patients with suspected or confirmed genetic conditions Involvement of aortic branch vessels including dissection or dilatation as well as any secondary evidence of end-organ injury (e.g., renal or bowel hypoperfusion) When a prior examination is available, direct comparison should be performed to allow for the image measurements to be performed by the same interpreting physician to determine if there has been interval change Evidence of aortic rupture, including periaortic and mediastinal hematoma, pericardial and pleural fluid, and contrast extravasation from the aortic lumen
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3. Supplementary Information for Medical Therapy and Lifestyle Considerations
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Anti-Hypertensive Therapy: Table 2 summarizes the clinical trials of anti-hypertensive therapy in patients with Marfan Syndrome. These trials show lower rates of aortic root dilation with treatment, and no difference in other clinical outcomes
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Diet: There are no studies of dietary interventions in patients with thoracic aortic disease. However, a diet rich in fruits and vegetables with reduced saturated and total fat (DASH diet) reduces blood pressure in a randomized controlled trial5. The combination of sodium reduction with the DASH diet has been shown to be more effective in lowering blood pressure than either dietary intervention alone6. Nationwide programs to reduce dietary sodium have been associated with improvements in blood pressure and decreases in deaths from strokes and coronary artery disease.7, 8 In addition, a Mediterranean diet, rich in fruits, vegetables, and supplemented with extra virgin olive oil or nuts, was associated with lower risk for cardiovascular events (myocardial infarction, stroke, or death from a cardiovascular cause) in a randomized controlled trial9.
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Smoking Cessation: Tobacco smoking has been associated with increased rate of growth of thoracic aortic aneurysm in an observational study10. Moreover, tobacco smoking is associated with increased mortality from cancer, chronic obstructive pulmonary disease, coronary artery disease, and stroke, and smoking cessation at any age is linked with reduced death rates11-13. Lipid Lowering Therapy: Trials of lipid lowering therapies have generally not included patients with thoracic aortic disease nor have they reported on thoracic aortic aneurysm or acute aortic syndromes.14, 15 Moreover, many forms of thoracic aortic aneurysm appear unrelated to dyslipidemia. A small, underpowered, observational study of patients with thoracic aortic aneurysm (n = 59) did not show a mortality benefit for statin therapy16. An intriguing observational report of 147 patients with bicuspid aortic valve reported smaller ascending aortic sizes in those taking statins17. Another series of 649 patients with thoracic aortic aneurysm, of whom 147 were taking statins, found that 3
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statin use was associated with better survival and lower risk for aneurysm repair18. Though there are no good data which support that statins alter the course of thoracic aortic disease, statin drugs are safe and effective for reducing all cause mortality, major vascular events (myocardial infarction, stroke), and revascularizations in patients without prior cardiovascular disease and at relatively low (< 1% per year) cardiovascular risk, and many patients with thoracic aortic aneurysms have risk factors for atherosclerosis.19, 20
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Driving: The Canadian Medical Association has not addressed driving recommendations for patients with thoracic aortic disease, but did recommend patients with infrarenal abdominal aortic aneurysms with annual rupture risk greater than 10% be precluded from driving21. The Canadian Cardiovascular Society Consensus Conference on the assessment of the cardiac patient for fitness to drive and fly also did not address patients with thoracic aortic disease22, but did suggest a return to driving after valve surgery, assuming no thromboembolic complications, normal functional capacity, and absence of severe left ventricular dysfunction (left ventricular ejection fraction ≥ 35%), at six weeks for private driving and three months for commercial driving. Rates of rupture or acute dissection for ascending aortic aneurysms ≥ 6.0 cm are 36.2% (95% CI 5.1-85.6%) and 6.6% (95% CI 1.3-27%) for ascending thoracic aortic aneurysms between 5.0 and 5.9 cm23. Similarly, for descending thoracic aneurysms ≥ 7.0 cm the incidence of rupture or aortic dissection was 47.1% (95% CI 12.6-84.8%) and 12.2% (95% 1.2-59.8%) %) for descending thoracic aortic aneurysms between 6.0 and 6.9 cm. The rupture risk for a given aortic size may be higher for some forms of aortic disease, including aortopathies associated with bicuspid aortic valve, connective tissue disorders, or familial aortic aneurysm syndromes.23, 24
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Pregnancy: Information related to pregnancy in various subsets of patients with TAD is outlined in Table 3.
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Table 1: Possible Approaches to Endovascular management of thoracic aortic aneurysms
Zone 2
a) Thoracic EVAR with or without LSA reconstruction using insitu fenestration of graft b) Thoracic EVAR with LSA branch c) Chimney graft for LSA and TEVAR Thoracic EVAR
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Sternotomy with debranching for innominate, LCC and LSA (several configurations) followed by TEVAR placed ante or retrograde Carotid-Carotid bypass with or without LSA reconstruction and TEVAR to edge of innominate artery (possible use of custom graft with scallop for innominate for extra fixation) Thoracic EVAR with bypass to re-attach LSA by extra anatomic technique
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Zone 1
a) Aortic Arch graft (branches for innominate and LCC) with or without LSA reconstruction b) Chimney graft(s) and TEVAR graft Chimney graft for LCC and/or LSA with TEVAR graft (or without LSA reconstruction)
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Possible Approaches to Repair TEVAR alone Hybrid (Open and TEVAR)
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TEVAR – Thoracic Endovascular Aneurysm Repair, LSA – Left Subclavian Artery, LCC – Left Common Carotid
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Table 2: Summary of trials of anti-hypertensive therapy in Marfan Syndrome
Propranolol vs. no therapy
Groenink et 26 al
233
Ahimastos et al27
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Investigator Blinding
Outcome
Main Finding
Yes
No
Rate of increase in aortic ratio
Slower increase in aortic ratio in propranolol group (0.023 vs. 0.084 per year, P < 0.001)
Losartan plus usual care vs. usual care (73% on βblockers)
3.1 years
Yes
No
Aortic root dilatation root
Lower aortic root dilatation in losartan group (0.77 ± 1.36 vs. 1.35 ± 1.55 mm, P < 0.014)
17
Perindopril plus betablocker vs. beta-blocker
24 weeks
Yes
Yes
Mean change in aortic root diameter
Lower aortic root diameter change with perindopril (2.3 ± 0.5 mm vs. 0.4 ± 0.1, p < 0.001)
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Losartan plus beta-blocker vs. betablocker
35 month s
Yes
No
Annual aortic root dilatation rate
Lower annual aortic root dilatation rate in losartan treated subjects (0.10 mm/yr vs 0.89 mm/yr; P=.02)
155
Beta-blockers vs. no betablockers
1.3 years
No
No
Annual aortic root dilatation rate
Lower annual aortic root dilatation rate in beta-blocker treated subjects (1.05 mm/yr vs 1.15 mm/yr; P < 0.001)
ARB (no control group; historical control only)
12 to 47 month s
No
No
Annual aortic root dilatation rate before and after ARB
Annual aortic root dilatation rate 3.54 ±2.87 mm/yr before and 0.46 ± 0.62 mm/yr after angiotensin receptor blocker
Losartan (no control group; historical control only)
33.2 month s
No
No
Mean normalized aortic root diameter change
Mean normalized aortic root diameter change -3.0 ± 2.8 mm/m2, p 45 mm 32, 33 Relative CID if aorta > 40 mm 32, 33 Increased rate of aortic growth during pregnancy 32 BB during pregnancy BP control TTE every 4-6 weeks Assisted delivery (outlet forcep or vacuum) if aorta < 40mm Consider Cesarian delivery if aorta > 40mm 34 50% transmission rate to offspring CID if any aortic dilatation 35 BP control* TTE q4-6 weeks Consider elective Cesarian delivery at 34-36 weeks 36 50% transmission rate to offspring CID for risk arterial and uterine rupture 35 Consider elective Cesarian delivery at 34-36 weeks 37 + DDAVP to diminish perioperative bleed 34 50% transmission rate to offspring CID if ascending aorta > 50 mm Relative CID if aorta > 45mm 38 BP control* TTE q4-6 weeks Consider elective Cesarian delivery at 34-36 weeks if aorta dilated CID if ascending aorta > 50 mm CID if family history of aortic dissection at normal aortic size BP control* TTE q4-6 weeks Consider elective Cesarian delivery at 34-36 weeks if aorta dilated CID if ascending aorta > 55 mm BP control* TTE q 4-6 weeks if ascending aneurysm TEE or MRI if descending aortic aneurysm Consider elective Cesarian delivery at 34-36 weeks if aorta dilated CID
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Aortopathy Marfan
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Acquired
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Chronic dissection
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BB- Beta adrenergic blockade CID – Contraindicated; BP – Blood pressure; TTE – transthoracic echocardiogram; TEE – transesophageal echocardiogram; MRI – magnetic resonance imaging *lowering the upper limit of acceptable systolic blood pressure to
S0828-282X(14)00112-3
DOI:
10.1016/j.cjca.2014.02.018
Reference:
CJCA 1128
To appear in:
Canadian Journal of Cardiology
Received Date: 8 November 2013 Revised Date:
1 February 2014
Accepted Date: 1 February 2014
Please cite this article as: Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC, Canadian Cardiovascular Society Position Statement on the Management of Thoracic Aortic Disease, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.02.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Canadian Cardiovascular Society Position Statement on the Management of Thoracic Aortic Disease
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Primary Panel: Munir Boodhwani1 MD, MMSc (Co-chair), Gregor Andelfinger2, MD, PhD, Jonathan Leipsic3, MD, Thomas Lindsay4,MD, MSc, M. Sean McMurtry5, MD, PhD, Judith Therrien6, MD, Samuel C. Siu7 MD (Co-chair)
1
Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario Department of Pediatrics, University of Montreal, Montreal, Quebec 3 Department of Radiology, University of British Colombia, Vancouver British Colombia 4 Division of Vascular Surgery, University Health Network, Toronto, Ontario 5 Division of Cardiology, University of Alberta, Edmonton, Alberta 6 Division of Cardiology, McGill University, Montreal, Quebec 7 Division of Cardiology, Western University, London, Ontario
Corresponding Author:
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Munir Boodhwani, MD, MMSc H3405, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7 Phone: (613) 761-4313 Fax: (613) 761-5107 Email: [email protected] Word Count: 6,381 words
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Abstract:
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This Canadian Cardiovascular Society position statement aims to provide succinct perspectives on key issues in the management of thoracic aortic disease (TAD). This document is not a comprehensive overview of thoracic aortic disease and important elements of the epidemiology, presentation, diagnosis, and management of acute aortic syndromes are deliberately not discussed; readers are referred to the 2010 guidelines published by the American Heart Association, American College of Cardiology, American Association of Thoracic surgery and other stakeholders1. Rather, this document is a practical guide for clinicians managing adult patients with TAD. Topics covered include size thresholds for surgical intervention, emerging therapies, imaging modalities, medical and lifestyle management, and genetics of TAD. The primary panel consisted of experts from a variety of disciplines that are essential for comprehensive management of TAD patients. The methodology involved a focused literature review with an emphasis on updates since 2010 and the use of GRADE methodology to arrive at specific recommendations. The final document then underwent review by a secondary panel. This document aims to provide recommendations for most patients and situations. However, the ultimate judgement regarding the management of any individual patients should be made by their health care team.
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Brief Summary:
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This is the first Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Developed by a nationally representative, multi-disciplinary group, this document provides a succinct review of contemporary literature and practical recommendations on key aspects of management of patients with thoracic aortic disease including size thresholds for intervention, imaging modalities, medical and lifestyle management, and genetics. Brief perspectives on emerging therapies and models of care are also provided.
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Section 1. Size Thresholds for Elective Thoracic Aortic Intervention
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Thoracic Aortic aneurysms are largely asymptomatic until a sudden and catastrophic event, including aortic rupture or dissection, occurs, and is rapidly fatal in a large proportion of patients2, 3. Elective intervention on the thoracic aorta carries a much lower risk of mortality and morbidity, and prophylactic aortic surgery can be life-saving.
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The decision to perform aortic intervention is a balance between risks of natural history of the disease versus the risk of the surgical intervention itself and any additional longterms risks of treatment. The risk of aortic complications is influenced by a number of patient-related factors e.g. family history of aortic disease, history of smoking, etc. and disease-related factors e.g. true vs. false aneurysm, bicuspid valve aortopathy, connective tissue disorders, etc. (Table 1). Similarly, the risk of surgical intervention may be significantly influenced by comorbidities (e.g. COPD, coronary or valve disease, etc.) and anatomy (presence of dissection, aortic arch involvement).
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The risk related to intervention is an instantaneous risk whereas the risk of aortic complications accrues over time (e.g. 5-year risk of rupture is greater than 1-year risk of rupture). Therefore, it may be acceptable for patients to accept a one-time risk of intervention (e.g. 5%) to prevent the long-term consequences of aortopathy (e.g. 2 -3 %/year). Maximum aortic diameter is the most important predictor of aortic complications. However, since many factors influence the relationship between size and aortic complications, absolute size should not be used in isolation. There are occasionally long-term consequences that deserve consideration, such as minimizing the risk of valve-related complications in patients eligible for aortic valve sparing or repair surgery. Lastly, estimates of risk of aortic complications based on natural history studies are not well established in all subsets of TAD.
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The size threshold for considering aortic intervention has decreased successively over recent years, due to substantial reduction in morbidity and mortality for elective procedures. In experienced centers, elective repair of ascending aorta and aortic root aneurysms carries a mortality of 1%. Aneurysms involving the aortic arch and descending thoracic aorta typically carry a higher risk of mortality and neurologic morbidity. The International Registry of Aortic Dissection (IRAD) registry and other data have questioned the current threshold of aortic diameter of 5.5 cm for ascending aortic aneurysm, as the median diameter of patients presenting with type A and B aortic dissections was significantly less than 5.5 cm4, 5. With an intervention threshold of 5.5 cm, over half of type A aortic dissections would not be prevented. However, the number of patients in the general population with aortic diameters between 5.0 – 5.5 cm (and 4.5 – 5.0 cm) is large and their annual risk of aortic complications is not well characterized. Even with the low risk of elective aortic replacement, at some level, this number needed to treat (NNT) would be prohibitively high. 3
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Recommendation: “We recommend that the decision to perform prophylactic aortic intervention should be tailored to the individual patient and incorporate patientrelated and disease-related factors.” (Strong Recommendation, Moderate Quality of Evidence) Values and Preferences: The important factors influencing the risk of aortic complications and risk of operative intervention are listed in Table 1. Where there is uncertainty regarding decision making, patients should be referred to specialists in the management of thoracic aortic disease for consideration of operative intervention.
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Intervention Thresholds for Thoracic Aortic Aneurysms:
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Recommendation: “We recommend that surgical intervention be considered for thoracic aortic aneurysms according to the disease etiology and anatomic region affected as indicated in table 2.” (Strong Recommendation, Moderate Quality of Evidence)
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Certain factors confer increased risk and include (in increasing order of significance): bicuspid aortic valve aortopathy, Marfan syndrome, Familial Thoracic Aortic Disease, Ehlers Danlos (vascular type), Turner Syndrome and in particular, Loeys-Dietz syndrome . The size threshold for intervention is lower for these conditions. Patient body size is an important variable; a lower threshold may be used in females and patients of shorter stature.
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1. Degenerative Aneurysms: Patients with degenerative aortic aneurysms do not have connective tissue disorders, familial aortopathy, or bicuspid aortic valve aortopathy. They are typically older and have atherosclerotic risk factors, particularly hypertension and smoking. Increased aortic size has been linked to increased risk of dissection, rupture, and death, particularly when the size of the aneurysm exceeds 6.0 cm (7% annual risk of rupture or dissection and 12% annual risk of death)6. Surgical intervention is recommended at a diameter of 5.5 cm for the ascending aorta. For the descending thoracic aorta, surgical intervention is recommended at a diameter of 6.5 cm7. 2. Bicuspid Aortic Valve Aortopathy: Patients with bicuspid aortic valves have an increased risk of aortic dilation and molecular and histological changes suggesting an aortopathy independent of valve function8, 9. The risk of aortic dissection in BAV patients is higher than the general population but is lower than that for patients with Marfan syndrome or other genetic aortopathies10. Surgical intervention in this population should be considered when the size of the ascending aorta is between 5.0 – 5.5 cm, accounting for patient size, particularly in the presence of other risk factors.
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3. Marfan Syndrome: Marfan syndrome individuals are susceptible to thoracic aortic aneurysms with a higher incidence of aortic dissection11, 12. However, a low risk of aortic complications is noted in patients with an aortic size below 5.0 cm11. For the aortic root and ascending aorta, a size threshold of 5.0 cm is appropriate. For the descending thoracic aorta, a size threshold of 5.5 – 6.0 cm is recommended. Patients with a family history of premature aortic dissection warrant consideration of surgical intervention at smaller diameters.
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4. Familial Thoracic Aortic Aneurysm: These individuals have one or more relatives with thoracic aortic aneurysms with or without a previous history of aortic dissection. Aortic dilation progresses more rapidly in patients with familial aortopathy with e a higher risk of aortic complications13, 14. The threshold for surgical intervention may be guided by the aortic size at which other family members have had aortic complications, if known. If not known, then a size threshold of 4.5 – 5.0 for the ascending aorta and 5.5 – 6.0 for the descending thoracic aorta is reasonable.
Other Considerations:
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5. Non-Marfan Genetic Aortopathy: A number of genetic disorders including LoeysDietz, Turner and Ehlers Danlos (vascular type) are linked to thoracic aortic aneurysm and dissection. Because of the low prevalence of these syndromes, there is a paucity of data on the risk of aortic complications, it is significantly higher compared to degenerative aneurysms and Marfan syndrome. Patients with LoeysDietz syndrome have a high risk of aortic dissection at small diameters leading to limited life expectancy15. The threshold for surgical intervention is therefore lower than that for Marfan syndrome. Patients with vEDS can have a high risk of surgical complication due to poor quality of vascular tissue.
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In addition to size thresholds, the following factors deserve careful consideration:
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1. Presence of Symptoms: A small subset of patients will present with compressive symptoms, malperfusion, or pain, all of which are associated with poor outcome16 and surgical intervention should be considered in all symptomatic thoracic aortic aneurysms, regardless of absolute size. 2. Pseudoaneurysms: False aneurysms of the thoracic aorta may occur secondary to blunt trauma, prior aortic surgery, catheter based manipulation, or in association with penetrating atherosclerotic ulcers. Rates of aortic rupture for pseudoaneurysms are not well-characterized. Surgical intervention may be considered when the total diameter of the aorta (including the native aorta and the false aneurysm) meets the criteria in Table 2 or if the pseudoaneurysm is greater than 2 cm in maximum diameter.
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3. Rate of Growth: Typical growth rate of thoracic aortic aneurysms is 0.1 cm/year. Rapidly growing aneurysms (> 0.5 cm/year increase in diameter) are uncommon but are associated with increased aortic complications17. Surgical intervention should be considered in rapidly growing aneurysms regardless of absolute diameter.
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4. Concomitant Cardiac Surgical Procedures: Surgical intervention on the moderately dilated ascending aorta (> 4.5 cm) should be considered in patients undergoing open cardiac surgical procedures as it minimizes the long-term risk of dissection and rupture and avoids a future higher risk reoperation18-20. However, other factors including patient age, body size, co-morbidities, additional risk of procedure, and life expectancy must be considered in the decision making process. In some patients, aortic dilation below the thresholds recommended for surgical intervention may lead to aortic valve insufficiency due to cusp malcoaptation and a lower threshold for aortic resection is reasonable to facilitate aortic valve repair.
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5. Indexing for patient size: The normal thoracic aorta is smaller in females and in shorter individuals. In these individuals, aortic size index (maximum aortic diameter / body surface area) > 2.75 cm/m2 is a better predictor of aortic complications 21. Other investigators have suggested that the ratio between the cross-sectional area of the aorta (at its maximum diameter) divided by the patient’s height (m) is another useful method to adjust for differences in body size22. Indexed measurements are most useful for females, patients with short stature and certain genetic syndromes (e.g. Turner syndrome).
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Section 2. Emerging Interventions for Thoracic Aortic Disease A. Thoracic Endovascular Aneurysm Repair
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In contrast to open surgical repair, Thoracic Endovascular Aneurysm Repair (TEVAR) involves exclusion of the aneurysm sac with a covered stent. Compared to open surgical repair, TEVAR is associated with a lower procedural mortality and morbidity 23, 24, but a greater need for re-interventions and concerns remain regarding long-term outcome and late aneurysm-related mortality25.
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While TEVAR is used primarily for the descending thoracic aorta, alternate approaches to aortic arch disease in high-risk candidates include a combination of open and endovascular techniques, depending on anatomic suitability. Open surgical treatment is the standard of care for the ascending aorta26, 27.
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Type B dissections without complications are treated medically28, with surgery reserved for complications including malperfusion syndromes (visceral, renal or limb perfusion), rupture and rapid expansion. In the IRAD registry, TEVAR therapy for complicated, acute type B aortic dissections was associated with lower mortality and complications than open surgical intervention. The STABLE trial suggests this therapy is associated with increased true lumen size, and favorable clinical and anatomic results29. TEVAR may therefore offer better outcomes compared to open surgical approaches in complicated cases. For non-complicated type B dissections, the INSTEAD trial did not demonstrate any advantage for TEVAR in the short-term30, 31. However, longer-term follow-up suggests reduced aorta-specific mortality following TEVAR32.
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TEVAR may be associated with a number of complications including paralysis and paraperesis. Spinal CSF drains that allow drainage of CSF and improve spinal cord perfusion, 33, 34 intra operative monitoring of motor and sensory evoked potentials to monitor spinal cord function, and improved preoperative imaging to identify critical intercostals arteries are some techniques employed to minimize this complication 35. Stroke, renal failure and retrograde Type A dissection are other potential complications. B. Aortic Valve Preservation and Repair Patients with aortic root aneurysms, with or without associated aortic valve disease have traditionally been treated with composite aortic valve and root replacement with reimplantation of the coronary arteries (Bentall procedure). While this procedure is effective at treating the aortopathy, patients are left with the long-term risks associated with prosthetic heart valves which include thromboembolism, structural and nonstructural valve dysfunction, endocarditis, and anti-coagulant related hemorrhage for those with mechanical prostheses36. Since many of these patients have morphologically normal aortic valve leaflets, there has been increasing interest in valve sparing aortic
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root operations. Long-term observational cohort studies have demonstrated excellent outcome at over 15 years of follow-up37.
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The concepts, innovations38 and techniques39 in valve preserving operations have also been applied in patients with aortic insufficiency and bicuspid aortic valves and associated aortopathy with promising results40, 41, including a low risk of valve related complications42, 43. These benefits are most significant for young patients who are likely to accrue valve-related events over time. The likelihood of valve repair may be a consideration in determining the threshold for aortic replacement in these patients.
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Recommendation: “We recommend that patients with complex TAD that stand to benefit from the above emerging techniques and technologies be referred to teams experienced in these approaches.” (Conditional Recommendation, Low Quality of Evidence)
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Section 3: The Role of Imaging in Diagnosis and Surveillance
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Imaging is fundamental for diagnosis and surveillance of TAD. The test chosen should be determined by the presentation, location and patient age, with renal dysfunction, local expertise and access to imaging modalities as additional considerations. Height and weight should be recorded for calculation of body surface area. Strengths and weaknesses of the various imaging modalities are summarized in Table 3. Details on technical aspects of imaging are provided in Appendix 1. Overview of Imaging Modalities
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A. Multi-detector Computerized Tomography (CT) ECG gated scans are useful for imaging the ascending aorta enabling assessment of the aortic valve and at least the proximal coronary arteries (see Appendix 1). After aortic intervention, CT is also preferred to detect post procedural leaks or pseudoaneurysms as echocardiography (echo) is often limited by the presence of metallic devices and clips and transesophageal echocardiography is semi-invasive and thus not optimal for surveillance.
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Currently, external aortic diameters are reported for CT or magnetic resonance (MR) derived measurements. Echo-derived measurements are typically reported as luminal size; this difference is important in the descending thoracic aorta where mural thrombus is more prevalent. Pronounced arterial wall calcifications can lead to underestimation of the lumen. While the potential stochastic risk of radiation exposure drops significantly when patients reach the 5th decade of life, CT must be used with caution in neonates, children, and young adults in whom the risk of radiation-induced malignancy is the highest44-48.
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B. Magnetic Resonance Imaging (MRI) The avoidance of radiation or iodinated contrast exposure with MRI is a particularly valuable feature in younger patients and for serial follow up imaging. Disadvantages include longer scan times which is a particular issue in the setting of acute chest pain and claustrophobic patients, as well as issues related to the use of Gadolinium contrast agents in renal failure owing to concerns regarding nephrogenic systemic fibrosis and implanted cardiac devices. MRI may be particularly helpful in distinguishing mural thrombus from intramural blood in the setting of acute aortic syndromes with early potential being shown by new dual energy CT techniques 49, 50 . C. Transthoracic (TTE) and Transesophageal (TEE) Echocardiography Imaging of the aortic root and proximal ascending aorta is part of the standard TTE with images obtained at end diastole 51, 52. Three-dimensional echocardiography, particularly combined with TEE, has the potential of enhancing diagnostic utility53, but its aortic application has been focused on the proximal ascending aorta. TEE is superior to TTE for 9
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visualization of the thoracic aorta and has an important role in settings where CT or MR may not be available or feasible, such as the intensive care unit or the operating room. Criteria for TTE/TEE diagnosis of acute aortic dissection are: 1) Intimal or dissection flap seen on multiple views, 2) Independent motion of the intimal flap, 3) Differential colour flow in true and false lumens1. Echo is operator dependent, therefore serial examinations should be performed with standardized protocols and by experienced individuals in laboratories with quality assurance processes in place52.
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D. Cardiac catheterization and angiography The main use of angiography is in the evaluation of a suspected aortic syndrome while the patient is undergoing a cardiac catheterization procedure, but it has otherwise been replaced by CT, MR, and TEE.
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Recommendation: “For Acute Aortic Syndromes : A. We recommend CT as the preferred initial imaging test (Strong Recommendation, Moderate quality evidence) B. We suggest TEE as an appropriate alternative in the following situations (Conditional Recommendation, Moderate quality evidence) : a. An indeterminate CT examination b. When transport to CT is not feasible due to hemodynamic instability c. Intraoperative TEE when a dissection flap is seen on the initial TTE
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C. We suggest MR for characterizing acute intramural hematomas when CT is equivocal” (Conditional Recommendation, Low quality evidence)
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Values and Preferences: These recommendations are based on cohort studies, overviews, and expert opinion, as there are no contemporary studies comparing diagnostic accuracy of the imaging modalities. A systematic review concluded that TEE, helical CT, and MRI, yield clinically equally reliable diagnostic value for confirming or ruling out aortic dissection 54. There are no standards for the appropriate phase of the cardiac cycle to evaluate aortic size by CT or MR, therefore the phase (diastolic vs. systolic) used should be reported to allow for consistent serial measurements to assess interval changes. Recommendation: “For ongoing aortic surveillance in patients who are candidates for intervention, we suggest: A. For preoperative planning, the entire thoracic aorta should be imaged by CT or MR (Conditional Recommendation, Moderate quality evidence) B. For post repair surveillance in those without residual aortopathy, the entire aorta should be imaged by CT or MR at least once every 3-5 years after repair (Conditional Recommendation, Low quality evidence) 10
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C. MR should be considered the first line test of choice if serial repeat examinations are being considered in an adolescent or in the adult population below the age of 50 years (Conditional Recommendation, Low quality evidence) D. If dilation is established to only involve the root or proximal ascending aorta then TTE serves as a reasonable alternative, with TEE reserved for those with non-diagnostic TTE images (Conditional Recommendation, Low quality evidence)
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Values and Preferences: To reduce variability, serial aortic imaging should be performed using the same imaging protocols and modality, in the same laboratory. Follow up studies should be scheduled at 6-12 months following diagnosis, and then every 6 or 12 months thereafter depending on aortic size and the rate of change. In patients with stable dimensions between serial examinations, imaging intervals may be increased.
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Section 4: Medical Therapy and Lifestyle Considerations for Patients with Thoracic Aortic Disease
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A. Antihypertensive Therapy: The rationale for antihypertensive therapy is based on mechanistic and animal studies55, 56 , as well as observational reports linking aortic dissection with hypertension57, 58. Randomized controlled trials of antihypertensive therapies have not included patients with TAD per se or reported consistently on aortic endpoints.59, 60 While summaries of antihypertensive trials support treatment of hypertension when present, they do not offer specific guidance on the management of patients with thoracic aortic aneurysm, dissection, or aortopathy, either for choice of drug therapy or for blood pressure targets61-69.
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For Marfan syndrome, the available studies report surrogate outcomes, and are limited by small sample size, lack of blinding, and choice of comparator. Small randomized trials of beta blockers or losartan in addition to beta-blockers showed lower rates of aortic root dilation, with no difference in other clinical outcomes (Appendix 1, Table 2). No published trials compare beta-blocker monotherapy with ACE-inhibitor monotherapy, and in a recent trial of losartan only a subset were on losartan monotherapy70. In other subsets of TAD including BAV, Loeys-Dietz, Ehlers Danlos, and other genetic aortopathies, there are no randomized trials or observational studies.
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In patients with chronic aortic dissection, observational reports suggest lower risk for operative repair with beta-blocker therapy71. In a series of 722 and 579 patients with type A and type B aortic dissections respectively, beta-blockers were associated with improved survival in both groups, while ACE inhibitors were not associated with improved survival72. Use of calcium-channel blockers was associated with improved survival in type B aortic dissections72, as well as decreased aortic expansion in a smaller cohort of 191 type B aortic dissections73. A cohort of 78 consecutive type B aortic dissection cases identified an association between ACE inhibitor and better survival74. Poor blood pressure control (≥140/90 mmHg) has been linked with late mortality74, 75.
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Recommendation: “We recommend antihypertensive drug therapy for hypertensive patients with thoracic aortic disease to achieve a goal blood pressure of < 140/90 mmHg, or < 130/80 mmHg in those with diabetes, to reduce the risk of myocardial infarction, stroke, heart failure, and cardiovascular death76.” (Strong recommendation, moderate quality evidence) “We recommend beta-blocker or angiotensin receptor blocker therapy for patients with Marfan syndrome to reduce the rate of aortic dilation. If tolerated, we recommend consideration of additional therapy (ACE-inhibitor, angiotensin receptor blocker, or beta-blocker) for patients with Marfan syndrome to reduce the rate of aortic dilation.” (Strong recommendation, low quality of evidence)
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Values and Preferences: Though there are no randomized trials that support lower blood pressure targets (e.g. < 120/80 mmHg), aggressive therapy may be reasonable based on the physiologic rationale and patient-specific factors including type of aortopathy, prior patient or family history of acute aortic syndrome or sudden death, aortic aneurysm growth despite medical therapy, or patient preference. To date, there are no randomized trials supporting that monotherapy with a specific agent is superior to others for any form of TAD. B. Preventing hypertension and atherosclerosis:
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Diet and Smoking Cessation: Standard dietary advice for prevention of hypertension and atherosclerosis as well as smoking cessation are appropriate for most patients with thoracic aortic disease (Appendix 1).
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Lipid Lowering Therapy: Some observational studies suggest benefit and many patients with thoracic aortic disease have multiple atherosclerotic risk factors (Appendix 1). Lipid lowering, generally with statin drugs, should be offered according to general guidelines77.
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Exercise: Aortic dissection has been linked with severe physical exertion due to weight lifting78. The mean aortic diameter of these cases was 4.6 cm, therefore strenuous strength training may be dangerous for patients with TAD. The proposed mechanism is transiently elevated blood pressure associated with isometric exercise or valsalva maneuver79. Exercise-based cardiac rehabilitation for patients with coronary artery disease has been shown to reduce mortality in randomized controlled trials80, and exercise cardiac rehabilitation was found to be safe in a small series of survivors of type I aortic dissection81.
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Recommendation: “We recommend that patients with thoracic aortic disease be evaluated for risk for atherosclerotic vascular disease, and that recommendations for ameliorating this risk, whether by endurance exercise, dietary changes, smoking cessation, or medical therapy, be made in accordance with current general guidelines.” (Strong recommendation, low quality of evidence) Values and Preferences: Both patients and clinicians commonly require guidance with respect to these issues, and basing clinical decisions on the minimal observational data available, or extrapolating results from other populations, is a sensible compromise. Recommendation: “We suggest patients with thoracic aortic disease avoid strenuous resistance and isometric exercise.” Strong recommendation, very low quality of evidence.
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Values and Preferences: Though the data are minimal, the risks associated with strenuous isometric exercise 78 appear great enough to strongly recommend avoiding this exposure.
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Driving: Neither the Canadian Cardiovascular Society Conference nor the Canadian Medical Association (CMA) have made recommendations about fitness for driving in the context of thoracic aortic disease82. However, the CMA has recommended that patients with abdominal aortic aneurysm be precluded from driving when the rupture risk exceeds 10% per year. Based the best observational data available, these thresholds of risk occur for thoracic aortic aneurysms greater than 6.0 cm in the ascending aorta or arch, and greater than 6.5 cm in the descending aorta. A lower threshold for rupture risk is reasonable for commercial driving.82
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“We suggest that patients with thoracic aortic disease be precluded from private driving if the ascending aorta diameter is greater than 6.0 cm or the descending aorta diameter is greater than 6.5 cm, and restricted from commercial driving if the ascending thoracic aorta diameter is greater than 5.5 cm or the descending thoracic aorta is greater than 6.0 cm83. (Conditional recommendation, very low quality evidence).
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Values and preferences: These thresholds are based on the methodology of the CMA and Canadian Cardiovascular Society Consensus Conference on the assessment of the cardiac patient for fitness to drive and fly82 and the best available observational evidence. Risk thresholds may be reached at different aortic diameters for different aortopathies. Further studies are required to provide reliable estimates of rupture risk.
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“We suggest that patients return to private driving six weeks following and commercial driving three months following open aortic repair.” (Conditional recommendation, low quality evidence)
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Values and preferences: This practice is in accordance with current recommendations for patients after cardiac valve surgery. Patients undergoing endovascular aortic procedures may resume driving sooner based on assessment by their treating physician. Pregnancy: Information related to pregnancy in patients with TAD is provided in Appendix 1, Table 3.
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Section 5: Screening for family members of patients with genetic aortopathy
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A. Marfan syndrome Marfan Syndrome is an autosomal dominant disorder with high penetrance and varying phenotypic expression, which is associated with progressive aortopathy including dilation of the ascending aorta (sinuses of Valsalva) and can lead to dissection (usually type A) or rupture if not operated11. Clinical screening of patients suspected to have Marfan syndrome should be done using the revised Ghent criteria84. Routine CT or MRI for definite Marfan syndrome should be initiated in early adulthood or at surgery, whichever comes first.
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Screening of the first degree family members is indicated as the transmission rate is 50%. Genetic screening may help to clarify 1) the nature of the disease, 2) the risk to the patient when the clinical diagnosis is uncertain, 3) to ascertain sporadic cases or 4) prenatal diagnosis85. Imaging in family members suspected to have the disease should include at least a transthoracic echocardiogram to assess the ascending aorta and a baseline CT scan or MRI to assess the entire aorta. When dilation of the ascending aorta is found, a repeat transthoracic echo at 6 months should be performed to ascertain the rate of progression. If stable, a yearly echo should be done thereafter86. Any family member who has Marfan syndrome (clinically or genetically determined) with a normal size ascending aorta, should undergo yearly echocardiography 86.
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Recommendations for Marfan syndrome:
“We recommend clinical and genetic screening for suspected Marfan syndrome to clarify the nature of the disease and provide a basis for individual counselling”. (Strong recommendation, high quality of evidence)
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“We recommend echocardiographic screening be performed at diagnosis to measure aortic root and ascending aorta diameters, and repeated 6 months thereafter to determine rate of progression. If aortic diameters remain stable, annual imaging is recommended. If the aortic diameter exceeds 45 mm or if significant deviation from baseline studies occurs, more frequent imaging should be considered.” (Strong recommendation, high quality of evidence) “We recommend that women with Marfan syndrome who want to become pregnant be considered for aortic root and ascending aorta replacement if the diameter reaches 41 to 45 mm). These women should undergo surgery at centres with expertise in aortic valve sparing surgery (see recommendation from section 2B)”. (Conditional recommendation, low quality of evidence) B. Loeys-Dietz syndrome Loeys-Dietz syndrome (LDS) associated with arterial tortuosity and aggressive, progressive dilation of the ascending aorta; although the aorta at any level can be 15
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affected. Cerebral aneurysms are common in LDS. Accompanying craniofacial involvement can include bifid uvula, cleft palate, craniosynostosis and hypertelorism. It is autosomal dominant with a 50% transmission rate. First degree family members should undergo clinical as well as genetic screening. In affected family members, an initial transthoracic echocardiogram is recommended with a repeat at 6 months if aortic dilation is present or at 1 year if aorta is not dilated86. Prophylactic aortic root surgery is recommended in these patients when the ascending aorta reaches 42mm87. A MRI from the base of the neck to the pelvis is also recommended every 18-24 months to assess the degree of arterial tortuosity and presence of arterial aneurysms, or more frequently if specific pathology is followed 88
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C. Bicuspid aortic valve Bicuspid Aortic Valve (BAV) is the most common cardiac malformation with a prevalence of 1-2% in the general population. BAV is a heritable disorder with a significantly increased recurrence risk in first-degree relatives (5-30%) 89-93. Although autosomal dominant transmission with reduced penetrance and variable expression has been reported, it is likely a complex genetic trait influenced by several loci. Fifty percent of patients with BAV have an associated aortopathy that can involve the proximal aorta, usually the mid ascending aorta. Some affected family members may not have BAV but may have aortopathy 89, 94, 95. Because of its high risk of recurrence, clinical screening of first degree relatives is suggested with a transthoracic echo to ascertain the presence of BAV and/or ascending aorta dilation. CT scan or MRI may be indicated to completely visualize the ascending aorta and arch 96. Echocardiographic screening of first degree relatives in the pediatric age range may be useful.
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D. Familial thoracic aortic aneurysm Familial Thoracic Aortic Aneurysm (FTAA) is a genetic disease that occurs in “non syndromic” patients with aortopathy and a family history of aortic aneurysm. The majority of FTAA demonstrate an autosomal dominant inheritance with decreased penetrance and variable expression. A positive family history for TAA should prompt a search for signs of syndromic disease. To date, a number of genetic mutations have been identified which explain 20% of the FTAA.. Imaging of the aorta of first degree relatives to identify asymptomatic aneurysm is critical. Transthoracic echocardiogram is recommended, with additional CT scan or MRI if the entire aorta needs imaging. E. Aneurysm-Osteoarthritis Syndrome Aneurysm-osteoarthritis syndrome is an autosomal dominant trait with aneurysms of the arterial tree, skeletal and cutaneous anomalies97, 98. Phenotypic overlap with LDS encompasses hypertelorism and abnormal palate/uvula, and velvety skin. Early-onset osteoarthritis and intervertebral disc degeneration are present. Arterial disease mostly presents as aneurysm of the aortic root, but can also affect the thoracic aorta and the remainder of the arterial tree with an aggressive course99. Imaging of the entire vascular tree and genetic testing should be performed in such patients. First-degree relatives of
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patients with AOS should be screened for arterial disease and genetic testing be offered when a causal mutation is identified in the index case.
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F. Vascular Ehlers-Danlos syndrome (vEDS) vEDS is an autosomal dominant disorder caused by a mutation in the COL3A1 gene 100. The ensuing deficiency in collagen III formation results in connective tissue fragility including aneurysms, arteriovenous fistulae, spontaneous vascular dissections and ruptures, as well as bowel and uterus ruptures. Patients present with easy bruising, translucent skin and spontaneous arterial bleeding. Typically, aneurysms involve any medium-to-large sized muscular artery including branch vessels in the head, neck, thorax, abdomen and extremities. Dilation of the ascending aorta may occur. Surgical complications are common, with high procedural mortality101. Surgery should be avoided unless a lesion is considered to be imminently life-threatening. Clinical and genetic screening is recommended for first degree relatives. Widespread imaging modalities should be performed to document anatomy of the entire vascular tree 100.
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G. Turner syndrome Turner syndrome is a chromosomal anomaly in which one sex chromosome is lacking in a female, most commonly in the form of monosomy X (45, X). Salient features are short stature, ovarian failure, and cardiovascular disease. Between 10% - 25% of females with Turner syndrome have bicuspid aortic valve, and approximately 8% have coarctation. The risk of aortic dissection is increased in women with Turner syndrome 102, and occurs in young individuals at smaller aortic diameters than in the general population or other forms of genetically triggered aortopathy. The absence of aortic valve or other cardiac malformations reduces the risk of aortic dissection. Data from the international Turner syndrome aortic dissection registry suggest that individuals with Turner syndrome who are >18 years of age with an ascending aortic size index >2.5 cm/m2 should be considered for an aortic operation to prevent aortic dissection103.
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Recommendations for Non-Marfan, Genetic forms of aortic disease:
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“We recommend aortic imaging for first-degree relatives of patients with genetic forms of TAD to identify asymptomatic carriers.” (Strong recommendation, moderate quality of evidence) “We recommend cardiac imaging in adult first-degree relatives of patients with BAV to identify asymptomatic carriers.” (Strong recommendation, moderate quality of evidence) “We recommend screening for TAD-associated genes in non-BAV aortopathy index cases to clarify the origin of disease and improve clinical and genetic counselling”. (Strong recommendation, moderate quality evidence)
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“We recommend that genetic counselling and testing be offered to first-degree relatives of patients in whom a causal mutation of a TAD-associated gene is identified. We recommend that aortic imaging be offered only to mutation carriers”. (Strong recommendation, Low quality evidence)
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“We recommend complete aortic imaging at initial diagnosis and at 6 months for patients with Loeys-Dietz syndrome or a confirmed genetic aortopathy (e.g. TGFBR1/2, TGFB, SMAD3, ACTA2, or MYH11) to establish if enlargement is occurring.” (Strong recommendation, moderate quality evidence)
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“We recommend that patients with Loeys-Dietz syndrome have whole body magnetic resonance imaging every 18-24 months to assess progression of vascular disease, or more frequently if specific pathology is followed”. (Strong recommendation, moderate quality of evidence)
Section 6: Knowledge Gaps
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“We recommend that patients with Turner syndrome should have a complete assessment of cardiac and aortic structures. If normal, repeat imaging should be performed every 5 years. If abnormalities are detected, annual imaging should be performed. In children, annual imaging may be recommended.” (Strong recommendation, moderate quality of evidence)
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Most of the epidemiology and natural history of TAD is based on: 1) Surgical series from selected populations, 2) Retrospective cohorts of acute aortic syndromes, 3) Single center studies of patients with inherited or degenerative forms of TAD, and 4) Extrapolation from non TAD patients, leaving important knowledge gaps in this patient population. Future research should be focused on these key knowledge gaps in the pathophysiology, natural history, and treatment of patients with TAD, including but not limited to: 1. Contemporary natural history data on the risks of aortic complications. 2. Predictors of aortic complications (other than size) in patients with moderate aortic dilation. 3. Genetic, epigenetic, and imaging determinants of the development and progression of the various forms of TAD and predictors of acute aortic syndromes. 4. Prevalence of TAD in susceptible populations and the role of age in development of disease 5. The efficacy of screening strategies and the psychological, social and legal consequences of such screening 6. The efficacy of risk factor modification on preventing TAD or attenuating its progression. 7. The outcomes and impact of emerging therapies in the management of TAD
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Section 7: Multi-disciplinary Care and Quality Indicators
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Comprehensive management of thoracic aortic disease spans multiple disciplines including but not limited to cardiac surgery, vascular surgery, cardiology, genetics, imaging, and adult congenital heart disease. Therefore, care for these patients is best provided in such a multi-disciplinary environment and clinics are currently emerging across major cardiac centers in Canada. These may also be an important source of critical natural history data on thoracic aortic pathologies, and facilitate prospective clinical trials and mechanistic studies to help advance care for these patients.
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Assessment of quality of care indicators for TAD may include 1) timely referral for surgery (as per propsed size thresholds), 2) appropriate imaging surveillance, and 3) risk factor management (anti-hypertensives, smoking cessation, etc.).
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Acknowledgements:
The authors would like to thank the members of the secondary panel listed below for their thorough review of the manuscript draft and insightful comment that helped shape the final document
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Secondary Panel: Hal Dietz1 MD, Francois Dagenais2 MD, Christopher Fiendel3 MD, Raymond Kwong4 MD, PhD, Erwin Oechslin5 MD 1
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McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA 2 Division of Cardiac Surgery, Laval University, Quebec City, Quebec 3 Division of Cardiac Surgery, University Health Network, Toronto, Ontario 4 Division of Cardiology, Brigham and Women’s Hospital, Harvard University, Boston, MA, USA 5 Division of Cardiology, University of Toronto, Toronto, Ontario
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Tables Table 1: Factors* determining increased risk of aortic complications and of increased risk of surgical intervention. Factors Associated with Increased Risk of Surgical Intervention Aortic Arch Pathology Descending Thoracic Aortic Pathology Chronic Obstructive Pulmonary Disease Renal Dysfunction Previous Cardiac Surgery Advanced Age Left Ventricular Dysfunction
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Factors Associated with Increased Risk of Aortic Complications Aortic size Connective Tissue Disorder Family History of Aortopathy Bicuspid Aortic Valve Smoking History Aneurysm related symptoms Rapid Growth (> 0.5 cm/year) Concomitant Aortic Valve Disease Uncontrolled Hypertension
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* Additional factors may be relevant for risk stratification in some patients
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Table 2: Recommended Size thresholds for Intervention for Asymptomatic Thoracic Aortic Aneurysms*
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Aortic Root Ascending Arch Descending Degenerative 5.5 cm 5.5 cm 6.0 cm 6.5 cm Bicuspid Aortic Valve 5.0 – 5.5 cm 5.0 – 5.5 cm 5.5 cm 6.5 cm Marfan Syndrome 5.0 cm*** 5.0 cm 5.5 – 6.0 cm 5.5 – 6.0 cm Familial Aortopathy 4.5 – 5.0 cm 4.5 – 5.0 cm 5.5 – 6.0 cm 5.5 – 6.0 cm Other Genetic Syndromes** 4.0 – 5.0 cm 4.2 – 5.0 cm 5.5 – 6.0 cm 5.5 – 6.0 cm Undergoing Cardiac Surgery 4.5 cm * Size thresholds for intervention should take into consideration patient body size either empirically or using proposed formulas for adjustment ** Loeys-Dietz, Turner, Ehlers-Danlos *** For women anticipating pregnancy, the threshold is 4.1-4.5 cm.
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Table 3: Advantages and disadvantages of various modalities for thoracic aortic Imaging
CT
• • • • • •
Availability Imaging of aorta, neck vessels, and thorax Short image acquisition time Able to define coronary anatomy Tissue characterization No radiation
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Portable Readily Available Excellent visualization
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Transesophageal • echocardiography • •
Disadvantages • Limited acoustical access, particularly in obese or postoperative patients • Best for visualization of proximal portion of ascending aorta • Operator Dependent • Limited visualization of distal ascending aorta • Reduced diagnostic accuracy for intramural hematoma • Operator dependent • Radiation exposure • Renal insufficiency may require restriction in contrast administration *
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Modality Advantages Transthoracic • Portable echocardiography • Readily available • Established role in evaluation of structural cardiac disease
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Long acquisition time Cannot be performed in unstable patients or patients with renal dysfunction*, pacemakers/AICD
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CT – Computed Tomography, MR – Magnetic Resonance Imaging *See online supplement for options in patients with mild to moderate renal dysfunction
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Table 4: Screening for patients and family members with genetic aortopathy
Gene(s) involved
Transmission Part of Screening of Imaging mode aorta family modality affected members Marfan FBN1 Autosomal Asc: ++ Clinical: Ghent Echo + syndrome Dominant Arch: + criteria CT vs. with Desc: + Genetic: in MRI different some cases phenotypic Imaging: yes expression Loeys-Dietz TGFBR1 Autosomal Asc: ++ Clinical: yes Echo + syndrome TGFBR2 Dominant Arch: + Genetic: yes CT vs. SMAD3 with variable Desc: + Imaging: yes MRI TGFB2 expression $ AneurysmAutosomal Asc:++ Clinical: yes Echo + osteoarthritis SMAD3 dominant Desc: + Genetic: yes CT vs. syndrome $ Imaging: yes MRI Ehlers-Danlos Autosomal Asc:+ Clinical: yes Echo + Type IV COL3A1 dominant Desc: + Genetic: yes CT vs. $ Imaging: yes MRI Bicuspid aortic Likely Complex Asc: ++ Clinical: yes Echo + valve multiple trait Arch: + Genetic: no CT vs. genes Familial Desc: Imaging: yes MRI clustering Familial TGFB2 Autosomal Asc: ++ Clinical: yes Echo + thoracic aortic TGFBR1 Dominant Arch: + Genetic: yes CT vs. aneurysm TGFBR2 with reduced Desc: + Imaging: yes MRI MYH11 penetrance SMAD3 and variable ACTA2 expression CT – Computed Tomography, Echo – echocardiogram, MRI – Magnetic Resonance Imaging, Asc – Ascending Aorta, Desc – Descending Thoracic Aorta $: See text for imaging of other vessels.
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Appendix 1: Supplementary Materials 1. Supplementary Information for endovascular treatment of thoracic aortic disease
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Thoracic Endovascular Aneurysm Repair (TEVAR) requires normal caliber aorta (~ 2 cm) proximal and distal to the aneurysm to achieve a seal and complete aneurysm exclusion. Seal zones have been expanded by proximal subclavian coverage and revascularization of the left subclavian artery (LSA) is recommended1. Treatment strategy for TEVAR is largely determined based on the location of the pathology and the suitability of adjacent aortic segments where the stents can be placed (Figure 1). The greatest experience with TEVAR has been accrued for descending thoracic aortic pathology.
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To facilitate TEVAR with zone 1 and zone 2 proximal landing zones, debranching of arch vessels can be performed either via sternotomy or in an extra-anatomic fashion (carotid-carotid and carotid-subclavian bypass) followed by stent implantation. Chimney grafts have also been described for the aortic arch2. This technique involves the placement of stents (covered or uncovered) parallel to a TEVAR graft to perfuse the arch vessels to avoid surgical debranching or bypassing these arch vessels. This technique adds sealing zone length while maintaining perfusion to the artery of interest. Some very short endografts have been produced for therapy of type A aortic dissections in poor operative candidates and a few published series exist3, 4.
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Placement of any endovascular device requires a sufficiently large femoral/external iliac artery for delivery or a surgically-created iliac conduit may be required. Tortuous arterial anatomy may complicate device delivery to the site of desired deployment. Accurate placement of proximal thoracic grafts has been facilitated with either the use of intraoperative hypotension induced by pharmacologic means (adenosine, esmolol) or rapid ventricular pacing using a right ventricular pacing wire. The ventricular pacing technique allows rapid onset and reversal of hypotension for accurate graft deployment.
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While the results of endovascular treatment of selected thoracic aortic pathologies are promising, these results are achieved by those with advanced experience, skills and access to the multiple additional technologies (e.g. Intravascular ultrasound) that aid in therapy of these complex patients. The use of TEVAR for genetic conditions associated with a generalized impairment of vessel wall integrity remains highly controversial and requires further study. The concern relates to maintenance of vessel wall and stent integrity at the loading zones. In addition, initiation and propagation of dissection can still occur within or immediately adjacent to the vascular region isolated by the stent. Currently TEVAR should be considered a temporizing measure that can be used (largely in the descending aorta) in specialized emergent situations or to bridge vascular segments that have already been replaced by Dacron grafts. 1
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2. Supplementary information for imaging in thoracic aortic disease
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The following suggestions are provided so that practitioners can utilize imaging modalities to achieve the most diagnostic value and to facilitate communication between providers and centres.
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Thoracic Aortic Assessment with CT • CT examinations should be performed with iodinated contrast • Multiplanar reformation or centerline reconstruction should be used to achieve cross-sectional visualization. o From these reconstructed images, the minimal luminal diameter along the course of the vascular access should be determined o Aortic Dimensions should be measured orthogonal to the direction of blood flow in systole and reflect the external aortic diameter (Figure) • CT with the implementation of modern dose reduction strategies may be a reasonable imaging option particularly in those over the age of 50 • ECG Gating should be considered for all cases when heart rate and scanner technology available will permit it. o If serial surveillance is performed with CT this should be optimally performed with ECG gating to ensure optimal image quality so changes in aortic dimension can be adequately identified
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Thoracic Aorta Assessment in the setting of Abnormal renal function • Echocardiographic assessment of aortic size is the first line test where the concerns lie in the ascending aorta • MR alternatives include: o Non-Gadolinium enhanced MRI with bright blood or black blood sequences o non-contrast based MR angiography o reduced dose of gadolinium in patients with mild to moderate renal insufficiency (GFR> 30) • Depending on the severity of renal impairment, CT with the use of contrast reduction strategies such as dual energy CT and high pitch helical acquisitions are also alternatives
Standard Report Elements for Thoracic Aortic Disease Evaluation • Anatomical location(s) and extent where the aorta is dilated • Maximum diameter of the dilated segment from the outer vessel margin in addition to the length of the dilated segment. Measurements must be performed in the short axis of the vessel • The presence of either calcified or non-calcified aortic atherosclerosis 2
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Atherosclerosis must be distinguished from intramural hematoma Measurements of the aortic root, annulus, sinuses, and tubular aorta in patients with suspected or confirmed genetic conditions Involvement of aortic branch vessels including dissection or dilatation as well as any secondary evidence of end-organ injury (e.g., renal or bowel hypoperfusion) When a prior examination is available, direct comparison should be performed to allow for the image measurements to be performed by the same interpreting physician to determine if there has been interval change Evidence of aortic rupture, including periaortic and mediastinal hematoma, pericardial and pleural fluid, and contrast extravasation from the aortic lumen
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3. Supplementary Information for Medical Therapy and Lifestyle Considerations
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Anti-Hypertensive Therapy: Table 2 summarizes the clinical trials of anti-hypertensive therapy in patients with Marfan Syndrome. These trials show lower rates of aortic root dilation with treatment, and no difference in other clinical outcomes
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Diet: There are no studies of dietary interventions in patients with thoracic aortic disease. However, a diet rich in fruits and vegetables with reduced saturated and total fat (DASH diet) reduces blood pressure in a randomized controlled trial5. The combination of sodium reduction with the DASH diet has been shown to be more effective in lowering blood pressure than either dietary intervention alone6. Nationwide programs to reduce dietary sodium have been associated with improvements in blood pressure and decreases in deaths from strokes and coronary artery disease.7, 8 In addition, a Mediterranean diet, rich in fruits, vegetables, and supplemented with extra virgin olive oil or nuts, was associated with lower risk for cardiovascular events (myocardial infarction, stroke, or death from a cardiovascular cause) in a randomized controlled trial9.
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Smoking Cessation: Tobacco smoking has been associated with increased rate of growth of thoracic aortic aneurysm in an observational study10. Moreover, tobacco smoking is associated with increased mortality from cancer, chronic obstructive pulmonary disease, coronary artery disease, and stroke, and smoking cessation at any age is linked with reduced death rates11-13. Lipid Lowering Therapy: Trials of lipid lowering therapies have generally not included patients with thoracic aortic disease nor have they reported on thoracic aortic aneurysm or acute aortic syndromes.14, 15 Moreover, many forms of thoracic aortic aneurysm appear unrelated to dyslipidemia. A small, underpowered, observational study of patients with thoracic aortic aneurysm (n = 59) did not show a mortality benefit for statin therapy16. An intriguing observational report of 147 patients with bicuspid aortic valve reported smaller ascending aortic sizes in those taking statins17. Another series of 649 patients with thoracic aortic aneurysm, of whom 147 were taking statins, found that 3
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statin use was associated with better survival and lower risk for aneurysm repair18. Though there are no good data which support that statins alter the course of thoracic aortic disease, statin drugs are safe and effective for reducing all cause mortality, major vascular events (myocardial infarction, stroke), and revascularizations in patients without prior cardiovascular disease and at relatively low (< 1% per year) cardiovascular risk, and many patients with thoracic aortic aneurysms have risk factors for atherosclerosis.19, 20
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Driving: The Canadian Medical Association has not addressed driving recommendations for patients with thoracic aortic disease, but did recommend patients with infrarenal abdominal aortic aneurysms with annual rupture risk greater than 10% be precluded from driving21. The Canadian Cardiovascular Society Consensus Conference on the assessment of the cardiac patient for fitness to drive and fly also did not address patients with thoracic aortic disease22, but did suggest a return to driving after valve surgery, assuming no thromboembolic complications, normal functional capacity, and absence of severe left ventricular dysfunction (left ventricular ejection fraction ≥ 35%), at six weeks for private driving and three months for commercial driving. Rates of rupture or acute dissection for ascending aortic aneurysms ≥ 6.0 cm are 36.2% (95% CI 5.1-85.6%) and 6.6% (95% CI 1.3-27%) for ascending thoracic aortic aneurysms between 5.0 and 5.9 cm23. Similarly, for descending thoracic aneurysms ≥ 7.0 cm the incidence of rupture or aortic dissection was 47.1% (95% CI 12.6-84.8%) and 12.2% (95% 1.2-59.8%) %) for descending thoracic aortic aneurysms between 6.0 and 6.9 cm. The rupture risk for a given aortic size may be higher for some forms of aortic disease, including aortopathies associated with bicuspid aortic valve, connective tissue disorders, or familial aortic aneurysm syndromes.23, 24
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Pregnancy: Information related to pregnancy in various subsets of patients with TAD is outlined in Table 3.
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Table 1: Possible Approaches to Endovascular management of thoracic aortic aneurysms
Zone 2
a) Thoracic EVAR with or without LSA reconstruction using insitu fenestration of graft b) Thoracic EVAR with LSA branch c) Chimney graft for LSA and TEVAR Thoracic EVAR
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Sternotomy with debranching for innominate, LCC and LSA (several configurations) followed by TEVAR placed ante or retrograde Carotid-Carotid bypass with or without LSA reconstruction and TEVAR to edge of innominate artery (possible use of custom graft with scallop for innominate for extra fixation) Thoracic EVAR with bypass to re-attach LSA by extra anatomic technique
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a) Aortic Arch graft (branches for innominate and LCC) with or without LSA reconstruction b) Chimney graft(s) and TEVAR graft Chimney graft for LCC and/or LSA with TEVAR graft (or without LSA reconstruction)
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Possible Approaches to Repair TEVAR alone Hybrid (Open and TEVAR)
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TEVAR – Thoracic Endovascular Aneurysm Repair, LSA – Left Subclavian Artery, LCC – Left Common Carotid
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Table 2: Summary of trials of anti-hypertensive therapy in Marfan Syndrome
Propranolol vs. no therapy
Groenink et 26 al
233
Ahimastos et al27
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Ladouceur
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Investigator Blinding
Outcome
Main Finding
Yes
No
Rate of increase in aortic ratio
Slower increase in aortic ratio in propranolol group (0.023 vs. 0.084 per year, P < 0.001)
Losartan plus usual care vs. usual care (73% on βblockers)
3.1 years
Yes
No
Aortic root dilatation root
Lower aortic root dilatation in losartan group (0.77 ± 1.36 vs. 1.35 ± 1.55 mm, P < 0.014)
17
Perindopril plus betablocker vs. beta-blocker
24 weeks
Yes
Yes
Mean change in aortic root diameter
Lower aortic root diameter change with perindopril (2.3 ± 0.5 mm vs. 0.4 ± 0.1, p < 0.001)
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Losartan plus beta-blocker vs. betablocker
35 month s
Yes
No
Annual aortic root dilatation rate
Lower annual aortic root dilatation rate in losartan treated subjects (0.10 mm/yr vs 0.89 mm/yr; P=.02)
155
Beta-blockers vs. no betablockers
1.3 years
No
No
Annual aortic root dilatation rate
Lower annual aortic root dilatation rate in beta-blocker treated subjects (1.05 mm/yr vs 1.15 mm/yr; P < 0.001)
ARB (no control group; historical control only)
12 to 47 month s
No
No
Annual aortic root dilatation rate before and after ARB
Annual aortic root dilatation rate 3.54 ±2.87 mm/yr before and 0.46 ± 0.62 mm/yr after angiotensin receptor blocker
Losartan (no control group; historical control only)
33.2 month s
No
No
Mean normalized aortic root diameter change
Mean normalized aortic root diameter change -3.0 ± 2.8 mm/m2, p 45 mm 32, 33 Relative CID if aorta > 40 mm 32, 33 Increased rate of aortic growth during pregnancy 32 BB during pregnancy BP control TTE every 4-6 weeks Assisted delivery (outlet forcep or vacuum) if aorta < 40mm Consider Cesarian delivery if aorta > 40mm 34 50% transmission rate to offspring CID if any aortic dilatation 35 BP control* TTE q4-6 weeks Consider elective Cesarian delivery at 34-36 weeks 36 50% transmission rate to offspring CID for risk arterial and uterine rupture 35 Consider elective Cesarian delivery at 34-36 weeks 37 + DDAVP to diminish perioperative bleed 34 50% transmission rate to offspring CID if ascending aorta > 50 mm Relative CID if aorta > 45mm 38 BP control* TTE q4-6 weeks Consider elective Cesarian delivery at 34-36 weeks if aorta dilated CID if ascending aorta > 50 mm CID if family history of aortic dissection at normal aortic size BP control* TTE q4-6 weeks Consider elective Cesarian delivery at 34-36 weeks if aorta dilated CID if ascending aorta > 55 mm BP control* TTE q 4-6 weeks if ascending aneurysm TEE or MRI if descending aortic aneurysm Consider elective Cesarian delivery at 34-36 weeks if aorta dilated CID
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Chronic dissection
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BB- Beta adrenergic blockade CID – Contraindicated; BP – Blood pressure; TTE – transthoracic echocardiogram; TEE – transesophageal echocardiogram; MRI – magnetic resonance imaging *lowering the upper limit of acceptable systolic blood pressure to
