Portal de Periódicos da CAPES

Medical management of thoracic aortic aneurysm disease

2012; Elsevier BV; Volume: 145; Issue: 3 Linguagem: Inglês

10.1016/j.jtcvs.2012.11.062

1097-685X

Alan C. Braverman,

Connective tissue disorders research

The patient with thoracic aortic aneurysm disease requires careful evaluation and management over his or her lifetime. This includes assessment for the presence of an underlying genetic disorder, such as Marfan syndrome, bicuspid aortic valve disease, or a familial aortic aneurysm syndrome. Screening family members is necessary, inasmuch as up to 20% of first-degree relatives of the patient with a thoracic aortic aneurysm will also have aneurysm disease. Medical therapy is often prescribed, and beta-blocker therapy to reduce the stress on the aortic wall is usually recommended. However, very few clinical trials of pharmacologic therapy in humans with thoracic aortic aneurysm disease have been conducted. Mouse models have led to important discoveries and insight into the pathogenesis of aneurysm syndromes, and there is hope these may lead to effective therapy in people. Several studies are ongoing that examine the role of angiotensin receptor blockers in Marfan syndrome. Lifestyle modification is also important for patients with thoracic aortic aneurysm, including restrictions on physical activity, weight lifting, and recommendations about the management of pregnancy. Long-term surveillance of the aorta, even after successful surgery, is necessary for timing of prophylactic surgery and to evaluate for late complications. The patient with thoracic aortic aneurysm disease requires careful evaluation and management over his or her lifetime. This includes assessment for the presence of an underlying genetic disorder, such as Marfan syndrome, bicuspid aortic valve disease, or a familial aortic aneurysm syndrome. Screening family members is necessary, inasmuch as up to 20% of first-degree relatives of the patient with a thoracic aortic aneurysm will also have aneurysm disease. Medical therapy is often prescribed, and beta-blocker therapy to reduce the stress on the aortic wall is usually recommended. However, very few clinical trials of pharmacologic therapy in humans with thoracic aortic aneurysm disease have been conducted. Mouse models have led to important discoveries and insight into the pathogenesis of aneurysm syndromes, and there is hope these may lead to effective therapy in people. Several studies are ongoing that examine the role of angiotensin receptor blockers in Marfan syndrome. Lifestyle modification is also important for patients with thoracic aortic aneurysm, including restrictions on physical activity, weight lifting, and recommendations about the management of pregnancy. Long-term surveillance of the aorta, even after successful surgery, is necessary for timing of prophylactic surgery and to evaluate for late complications. Thoracic aortic aneurysm (TAA) is due to multiple disorders (Table 1) and has an estimated incidence of approximately 10 per 100,000 person-years.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar The natural history and treatment strategy depend on the location of the aneurysm and its underlying cause.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar Although aneurysms reaching a certain size are generally treated with surgery or endovascular therapy, many aspects of medical management of TAA disease are worth emphasizing.Table 1Etiology of thoracic aortic aneurysmsGenetically triggered diseases Marfan syndrome Loeys-Dietz syndrome Bicuspid aortic valve aortopathy Familial thoracic aortic aneurysm syndromes Vascular Ehlers-Danlos syndrome Turner syndromeDegenerative diseases Atherosclerosis HypertensionInflammatory diseases Giant cell arteritis Nonspecific aortitis Takayasu arteritis Reiter syndrome Kawasaki disease Behcet syndromeMechanical Aortic dissection and variants TraumaInfectious diseases Bacterial aortitis (staphylococcus, salmonella) Syphilis Aspergillus Infected thoracic endovascular aortic repair Open table in a new tab First, when evaluating the patient with TAA disease, it is essential to make a correct diagnosis of the underlying condition. Genetically triggered diseases may have overlapping phenotypes, and accurate diagnosis is important for surgical decision making and for identifying affected relatives.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar, 2Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar Much of the data regarding pharmacologic therapy for TAA disease is derived from mouse model studies, such as fibrillin-1–deficient (Marfan) mice. There are few studies on the pharmacologic treatment of TAA disease in humans. Lifestyle modification (such as that related to exercise, pregnancy, and work) is essential in the management of patients with TAA disease. Finally, long-term surveillance of the aorta is required before and after surgery for patients with TAA disease. When the individual with TAA disease is being evaluated, there may be clues from the history, family history, and physical examination that assist in the diagnosis of the correct underlying disease.2Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar, 3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Not only is it important to evaluate the subject with TAA for these findings, but it is also helpful to inquire as to whether any family members have features of an underlying connective tissue disease or aortopathy. In some instances, an affected family member will have more striking features of the underlying disease, and this will assist with the correct diagnosis. A family history of TAA, bicuspid aortic valve (BAV), cerebral aneurysm, aortic dissection, or features of an underlying connective tissue disorder should be queried. Marfan syndrome is due to mutations in the FBN1 gene and leads to multisystem findings including skeletal features (tall stature, scoliosis, pectus deformities, elongated fingers and toes, hyperflexibility), ocular involvement (lens dislocation, high myopia), and cardiovascular disease (aortic root aneurysm, aortic dissection, mitral valve prolapse).2Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar Loeys-Dietz syndrome is due to mutations in TGFBR1 and TGFBR2 genes and has a characteristic triad of craniofacial features (craniosynostosis, bifid uvula, hypertelorism), aortic root and branch vessel aneurysm and dissection, and arterial tortuosity.4Loeys B.L. Schwarze U. Holm T. Callewaert B.L. Thomas G.H. Pannu H. et al.Aneurysm syndromes caused by mutations in the TGF-beta receptor.N Engl J Med. 2006; 355: 788-798Crossref PubMed Scopus (1254) Google Scholar BAV affects approximately 1% of the population and may be familial in approximately 9% of cases.5Braverman A. Beardslee M. The bicuspid aortic valve.in: Otto C. Bonow R. Valvular heart disease: a companion to Braunwald's heart disease. 2nd ed. Saunders-Elsevier, Philadelphia2009: 169-186Crossref Google Scholar Many patients with BAV disease have associated ascending aortic aneurysm, and BAV aortopathy may be familial.5Braverman A. Beardslee M. The bicuspid aortic valve.in: Otto C. Bonow R. Valvular heart disease: a companion to Braunwald's heart disease. 2nd ed. Saunders-Elsevier, Philadelphia2009: 169-186Crossref Google Scholar Familial TAA syndromes are being more commonly recognized.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar ACTA2 gene mutations affect approximately 14% of individuals with familial TAA disease and are associated with livedo reticularis, iris flocculi, cerebral aneurysms, premature coronary and cerebrovascular disease, moyamoya, and patent ductus arteriosus.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar, 3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Because of the overlap in phenotype, in many instances where there is ambiguity in diagnosis, mutation analysis may be necessary for correct diagnosis and for the evaluation of relatives.2Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar, 3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Importantly, up to 20% of patients with a TAA will have another first-degree relative with thoracic aortic disease.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar, 3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Imaging studies may provide clues as to the underlying disorder leading to TAA. The pattern of aortic dilatation may be informative. Marfan syndrome and Loeys-Dietz syndrome lead to aneurysms of the aortic root and sinuses of Valsalva.2Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar BAV aortopathy may involve the aortic root but more commonly leads to aneurysm located in the mid–ascending aorta.5Braverman A. Beardslee M. The bicuspid aortic valve.in: Otto C. Bonow R. Valvular heart disease: a companion to Braunwald's heart disease. 2nd ed. Saunders-Elsevier, Philadelphia2009: 169-186Crossref Google Scholar Additionally, the presence of lumbosacral dural ectasia discovered in the aneurysm patient should trigger the evaluation of an underlying disease such as Marfan syndrome or Loeys-Dietz syndrome.2Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar Medical management of the patient with TAA disease involves treatment of hypertension, optimal lipid control, and smoking cessation.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Although the pathophysiology differs for the various causes of TAA (Table 1), basic treatment strategies may apply. These include medications to lessen blood pressure and reduce aortic wall stress and guidelines to modify lifestyle—such as physical activity, weight-lifting restrictions, and pregnancy recommendations.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Beta-blockers, owing to their effects on reducing the inotropic state of the heart, decreasing the impact force of ejected blood on the aorta, and lowering heart rate and blood pressure, have been a mainstay in the treatment of TAA.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Nonrandomized clinical trials suggested beta-blocker use was associated with decreased abdominal aortic aneurysm (AAA) enlargement, although 2 randomized trials did not demonstrate a reduction in AAA growth rate with propranolol.6Elefteriades J. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? PRO.Cardiol Clin. 2010; 28: 255-260Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 7Liao S. Elmariah S. van der Zee S. Sealove B. Fuster V. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? CON.Cardiol Clin. 2010; 28: 261-269Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar In 1971, Halpern theorized that beta-blocker therapy may reduce aortic dissection in patients with Marfan syndrome.8Shores J. Berger K. Murphy E. Pyeritz R. Progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in Marfan's syndrome.N Engl J Med. 1994; 330: 1335-1341Crossref PubMed Scopus (866) Google Scholar There are several lines of evidence to support this proposal. In patients with malignant hypertension, reducing blood pressure to normal—but failing to reduce the rate of rise of blood pressure—did not reduce risk of dissection.6Elefteriades J. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? PRO.Cardiol Clin. 2010; 28: 255-260Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 8Shores J. Berger K. Murphy E. Pyeritz R. Progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in Marfan's syndrome.N Engl J Med. 1994; 330: 1335-1341Crossref PubMed Scopus (866) Google Scholar Also, the contractile strength of the myocardium and the strength of pulsation are important in progression of aortic dissection.6Elefteriades J. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? PRO.Cardiol Clin. 2010; 28: 255-260Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 7Liao S. Elmariah S. van der Zee S. Sealove B. Fuster V. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? CON.Cardiol Clin. 2010; 28: 261-269Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar In early studies of hypertensive patients, beta-blockers were effective in the management of aortic dissection.6Elefteriades J. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? PRO.Cardiol Clin. 2010; 28: 255-260Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 7Liao S. Elmariah S. van der Zee S. Sealove B. Fuster V. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? CON.Cardiol Clin. 2010; 28: 261-269Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 8Shores J. Berger K. Murphy E. Pyeritz R. Progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in Marfan's syndrome.N Engl J Med. 1994; 330: 1335-1341Crossref PubMed Scopus (866) Google Scholar Additionally, research demonstrated that turkeys prone to spontaneous aortic dissection or rupture had improved survival when propranolol was added to their feed.6Elefteriades J. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? PRO.Cardiol Clin. 2010; 28: 255-260Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 8Shores J. Berger K. Murphy E. Pyeritz R. Progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in Marfan's syndrome.N Engl J Med. 1994; 330: 1335-1341Crossref PubMed Scopus (866) Google Scholar There have been several studies of beta-blockers in Marfan syndrome examining short- or long-term effects on the biomechanical properties of the aorta, both invasively and noninvasively, with mixed results.6Elefteriades J. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? PRO.Cardiol Clin. 2010; 28: 255-260Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 7Liao S. Elmariah S. van der Zee S. Sealove B. Fuster V. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? CON.Cardiol Clin. 2010; 28: 261-269Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 9Groenink M. Roos A.D. Mulder B.J.M. Spaan J.A.E. Wall E.E.V.D. Changes in aortic distensibility and beta-blocker therapy in the Marfan syndrome.Pulse. 1998; 9149: 203-208Google Scholar In a 10-year study of beta-blockers in Marfan syndrome, those treated with propranolol had a lower rate of aortic root dilatation than untreated patients.8Shores J. Berger K. Murphy E. Pyeritz R. Progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in Marfan's syndrome.N Engl J Med. 1994; 330: 1335-1341Crossref PubMed Scopus (866) Google Scholar A retrospective nonrandomized study of beta-blocker use in children with Marfan syndrome also demonstrated a slowing of aortic dilatation in patients treated with beta-blockers compared with untreated controls.10Pyeritz R.E. Loeys B.L. The 8th International Research Symposium on Marfan syndrome and related conditions.Am J Med Genet A. 2012; 158A: 42-49Crossref PubMed Scopus (17) Google Scholar The recently published thoracic aortic disease guidelines have recommended beta-blocker therapy be administered to patients with Marfan syndrome and aortic aneurysm to reduce the rate of aortic dilatation.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar With the discovery of FBN1 mutations leading to abnormalities in fibrillin-1 as the underlying defect in Marfan syndrome, the basic pathophysiology of this disease is being elucidated using mouse models.11Habashi J.P. Judge D.P. Holm T.M. Cohn R.D. Loeys B.L. Cooper T.K. et al.Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.Science. 2006; 312: 117-121Crossref PubMed Scopus (1385) Google Scholar In addition to directing elastic tissue formation and providing structural integrity to tissues, fibrillin-1 interacts with latent transforming growth factor-β (TGF-β)–binding proteins and controls TGF-β activation and signaling.11Habashi J.P. Judge D.P. Holm T.M. Cohn R.D. Loeys B.L. Cooper T.K. et al.Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.Science. 2006; 312: 117-121Crossref PubMed Scopus (1385) Google Scholar Deficiency of fibrillin-1 microfibrils results in excessive TGF-β activation and signaling in tissues altered by Marfan syndrome.11Habashi J.P. Judge D.P. Holm T.M. Cohn R.D. Loeys B.L. Cooper T.K. et al.Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.Science. 2006; 312: 117-121Crossref PubMed Scopus (1385) Google Scholar Angiotensin is also important in TGF-β signaling, and blocking TGB-β, using neutralizing antibody or the angiotensin II type 1 (AT1) receptor blocker (ARB) losartan, can prevent or attenuate aneurysm formation in Marfan mice.11Habashi J.P. Judge D.P. Holm T.M. Cohn R.D. Loeys B.L. Cooper T.K. et al.Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.Science. 2006; 312: 117-121Crossref PubMed Scopus (1385) Google Scholar ARB therapy has been demonstrated to reduce plasma levels of free TGF-β, reduce tissue expression of TGF-β–responsive genes, and reduce levels of intracellular mediators within the TGF-β signaling cascade.12Brooke B.S. Habashi J.P. Judge D.P. Patel N. Loeys B. Dietz H.C. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome.N Engl J Med. 2008; 358: 2787-2795Crossref PubMed Scopus (667) Google Scholar Thrombospondin-1 and matrix metalloproteinase levels are also reduced with ARB therapy.12Brooke B.S. Habashi J.P. Judge D.P. Patel N. Loeys B. Dietz H.C. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome.N Engl J Med. 2008; 358: 2787-2795Crossref PubMed Scopus (667) Google Scholar Underlying mechanisms of disease are being discovered with multiple signaling pathways at work in this mouse model of aneurysm disease.10Pyeritz R.E. Loeys B.L. The 8th International Research Symposium on Marfan syndrome and related conditions.Am J Med Genet A. 2012; 158A: 42-49Crossref PubMed Scopus (17) Google Scholar, 13Lindsay M. Dietz H. Lessons on the pathogenesis of aneurysm from heritable conditions.Nature. 2011; 473: 308-316Crossref PubMed Scopus (356) Google Scholar Recently, TGF-β and AT1 receptor–dependent activation of the extracellular signal-regulated kinases 1 and 2 in the aorta of fibrillin-1 deficient mice has been demonstrated to be involved in aneurysm formation. Importantly, treatment with an extracellular signal-regulated kinase inhibitor leads to attenuation of pathologic aortic growth in mouse models.13Lindsay M. Dietz H. Lessons on the pathogenesis of aneurysm from heritable conditions.Nature. 2011; 473: 308-316Crossref PubMed Scopus (356) Google Scholar This basic research may lead to effective treatments for these and many other aneurysm syndromes. In a nonrandomized study of young patients with Marfan syndrome and advanced aortic root dilatation despite beta-blocker therapy, ARB therapy led to a significant reduction in the rate of aortic dilatation.12Brooke B.S. Habashi J.P. Judge D.P. Patel N. Loeys B. Dietz H.C. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome.N Engl J Med. 2008; 358: 2787-2795Crossref PubMed Scopus (667) Google Scholar Trials of ARB therapy in Marfan syndrome are underway and will examine whether this therapy can attenuate aortic root dilatation in Marfan syndrome.10Pyeritz R.E. Loeys B.L. The 8th International Research Symposium on Marfan syndrome and related conditions.Am J Med Genet A. 2012; 158A: 42-49Crossref PubMed Scopus (17) Google Scholar Ancillary studies examining circulating TGF-β levels, pharmacogenomics, and musculoskeletal features will provide much anticipated data in this area, potentially altering the natural history of Marfan syndrome.10Pyeritz R.E. Loeys B.L. The 8th International Research Symposium on Marfan syndrome and related conditions.Am J Med Genet A. 2012; 158A: 42-49Crossref PubMed Scopus (17) Google Scholar A small, randomized trial of angiotensin-converting enzyme (ACE)–inhibitor therapy reported a reduction in aortic root and ascending aortic growth in Marfan patients.14Ahimastos A. Aggarwal A. D'Orsa K. Formosa M.F. White A.J. Saviriravan R. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial.JAMA. 2007; 298: 1539-1547Crossref PubMed Scopus (167) Google Scholar ACE-inhibitor therapy also was associated with a reduction in TGF-β, matrix metalloproteinase-2 and -3 levels, and a decrease in aortic stiffness.14Ahimastos A. Aggarwal A. D'Orsa K. Formosa M.F. White A.J. Saviriravan R. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial.JAMA. 2007; 298: 1539-1547Crossref PubMed Scopus (167) Google Scholar There are data comparing ARB with ACE inhibitors in the mouse model of Marfan syndrome, but no such data in humans. In the fibrillin-1 deficient mouse model, ARB therapy (with losartan) was superior to ACE-inhibitor therapy (with enalapril) in preventing aortic enlargement and improving aortic architecture.15Habashi J.P. Doyle J.J. Holm T.M. Aziz H. Schoenhoff F. Bedja D. et al.Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK.Science. 2011; 332: 361-365Crossref PubMed Scopus (340) Google Scholar This was demonstrated to be related to prevention of TGF-β–mediated activation of extracellular signal-regulated kinase and allowing continued signaling through angiotensin II type 2 (AT2) receptor.15Habashi J.P. Doyle J.J. Holm T.M. Aziz H. Schoenhoff F. Bedja D. et al.Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK.Science. 2011; 332: 361-365Crossref PubMed Scopus (340) Google Scholar TGF-β activation has been recognized in affected tissue in mouse models of disease or in aortic samples in human studies of other aneurysm syndromes, including those associated with Loeys-Dietz syndrome,4Loeys B.L. Schwarze U. Holm T. Callewaert B.L. Thomas G.H. Pannu H. et al.Aneurysm syndromes caused by mutations in the TGF-beta receptor.N Engl J Med. 2006; 355: 788-798Crossref PubMed Scopus (1254) Google Scholar BAV,16Gomez D. Al Haj Zen A. Borges L.F. Philippe M. Gutierrez P.S. Jondeau G. et al.Syndromic and non-syndromic aneurysms of the human ascending aorta share activation of the Smad2 pathway.J Pathol. 2009; 218: 131-142Crossref PubMed Scopus (146) Google Scholar and possibly others.13Lindsay M. Dietz H. Lessons on the pathogenesis of aneurysm from heritable conditions.Nature. 2011; 473: 308-316Crossref PubMed Scopus (356) Google Scholar The BAV Study (Beta Blockers and Angiotensin Receptor Blockers in Bicuspid Aortic Valve Disease Aortopathy [BAV Study NCT01202721]) is recruiting patients with BAV in Canada and will compare the rate of ascending aortic growth by magnetic resonance imaging in patients randomized to ARB therapy (telmisartan) versus beta-blocker (atenolol) versus placebo.17Moltzer E. Essers J. Van Esch J.H.M. Roos-Hesselink J.W. Danser A.H.J. The role of the renin-angiotensin system in thoracic aortic aneurysms: clinical implications.Pharm Ther. 2011; 131: 50-60Crossref PubMed Scopus (42) Google Scholar Whether therapy such as ARB, aimed at blocking TGF-β, or novel agents affecting other pathways will affect these aneurysm diseases is as yet unknown. Other pharmacologic therapies have been demonstrated effective in animal models of thoracic aortic disease. Doxycycline reduces matrix metalloproteinase activity and thus elastin destruction and has been demonstrated to reduce AAA in animal models.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar, 7Liao S. Elmariah S. van der Zee S. Sealove B. Fuster V. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? CON.Cardiol Clin. 2010; 28: 261-269Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Small studies of doxycycline demonstrated attenuation of AAA growth in human subjects.7Liao S. Elmariah S. van der Zee S. Sealove B. Fuster V. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? CON.Cardiol Clin. 2010; 28: 261-269Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar In fibrillin-1–deficient mice, doxycycline prevents aortic root aneurysm.18Chung A.W.Y. Yang H.H.C. Radomski M.W. Van Breemen C. Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9.Circ Res. 2008; 102: e73-e85Crossref PubMed Scopus (172) Google Scholar There are beneficial effects of statin therapy in AAA tissue and on inflammatory markers in AAA disease, mediated by inhibition of the isoprenoid pathway rather than the cholesterol biosynthetic pathway.7Liao S. Elmariah S. van der Zee S. Sealove B. Fuster V. Does medical therapy for thoracic aortic aneurysms really work? Are beta-blockers truly indicated? CON.Cardiol Clin. 2010; 28: 261-269Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Pravastatin has also demonstrated benefit in the Marfan mouse model, attenuating aortic root aneurysm formation.19McLoughlin D. McGuinness J. Byrne J. Terzo E. Huuskonen V. McAllister H. et al.Pravastatin reduces Marfan aortic dilation.Circulation. 2011; 124: S168-S173Crossref PubMed Scopus (56) Google Scholar There are no data reporting a benefit of doxycycline or statin therapy in TAA disease in humans. The patient with a TAA should have a basic understanding of the condition and should undergo routine serial imaging surveillance of the aneurysm. The patient, family, and physician should be educated about the risk of aortic dissection (and rupture) as well as the symptoms of such aortic catastrophes. The patient should be educated to seek emergency attention if any concerning symptoms develop.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Because shear stresses on the aorta may play a role in acute aortic dissection, patients with TAA (as well as genetic disorders predisposing to them) are restricted from participating in most competitive athletics as well as heavy weight lifting.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar, 20Maron B. Ackerman M. Nishimura R. Pyeritz R.E. Towbin J.A. Udelson J.E. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome.J Am Coll Cardiol. 2005; 45: 1340-1345Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar Athletes with TAAs such as in Marfan syndrome, BAV with aneurysm, and familial TAA syndromes with a dilated aorta (>40 mm or Z-score > 2 in children) may only participate in low static/low dynamic sports (IA, such as golf and bowling) and should not participate in any sports with potential for bodily collision.20Maron B. Ackerman M. Nishimura R. Pyeritz R.E. Towbin J.A. Udelson J.E. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome.J Am Coll Cardiol. 2005; 45: 1340-1345Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar During physical activity, especially isometric activity, blood pressure may rise markedly. In studies of bodybuilders, direct arterial blood pressure measurements of over 300 mm Hg have been reported.21Mayerick C. Carré F. Elefteriades J. Aortic dissection and sport: physiologic and clinical understanding provide an opportunity to save young lives.J Cardiovasc Surg. 2010; 51: 669-681PubMed Google Scholar In elite strength-trained athletes, the aortic root and ascending aorta have larger diameters compared with controls. The longer the period of intense weight training, the larger the aortic diameters in these athletes.22Babae Biqi M. Aslani A. Aortic root size and prevalence of aortic regurgitation in elite strength trained athletes.Am J Cardiol. 2007; 100: 528-530Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar A series of 31 acute aortic dissections were reported by Hatzaras and associates23Hatzaras I. Tranquilli M. Coady M. Barrett P.M. Bible J. Elefteriades J.A. Weight lifting and aortic dissection: more evidence for a connection.Cardiology. 2007; 107: 103-106Crossref PubMed Scopus (136) Google Scholar in the setting of weight lifting, heavy lifting, or strenuous activity. The mean age of this group was 47 years, and 10% had a family history of aortic disease. The vast majority (87%) were ascending aortic dissections, and in 26 of 31 cases, the aortic diameter was available by premortem imaging. In 85% of these cases, the aorta was dilated with an average diameter of 4.6 cm (range, 3-7.8 cm).23Hatzaras I. Tranquilli M. Coady M. Barrett P.M. Bible J. Elefteriades J.A. Weight lifting and aortic dissection: more evidence for a connection.Cardiology. 2007; 107: 103-106Crossref PubMed Scopus (136) Google Scholar This highlights the importance of recognizing the patient with underlying TAA disease and prohibiting activities associated with increased aortic stress.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar, 20Maron B. Ackerman M. Nishimura R. Pyeritz R.E. Towbin J.A. Udelson J.E. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome.J Am Coll Cardiol. 2005; 45: 1340-1345Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar Pregnancy is an important consideration in the management of women with TAA disease.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar, 3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar, 24Goland S. Elkayam U. Cardiovascular problems in pregnant women with Marfan syndrome.Circulation. 2009; 119: 619-623Crossref PubMed Scopus (63) Google Scholar One should discuss birth control methods and the risks of aortic dissection before conception in women at risk. It is difficult to quantify the exact risk of aortic dissection for the individual woman with TAA disease, and much of the information is derived from series of patients with Marfan syndrome.24Goland S. Elkayam U. Cardiovascular problems in pregnant women with Marfan syndrome.Circulation. 2009; 119: 619-623Crossref PubMed Scopus (63) Google Scholar Although all women with Marfan syndrome are considered at increased risk of aortic dissection during pregnancy or early postpartum, the greatest threat occurs when there is an aortic aneurysm larger than 40 mm or prior aortic dissection.24Goland S. Elkayam U. Cardiovascular problems in pregnant women with Marfan syndrome.Circulation. 2009; 119: 619-623Crossref PubMed Scopus (63) Google Scholar We25Braverman A. Harris K. Pyeritz R. Hutchison S. Pitler L. Evangelista A. et al.Aortic dissection during pregnancy: results from the International Registry of Acute Aortic Dissection (IRAD).J Am Coll Cardiol. 2012; 59A: A467Google Scholar reported data on 15 women with acute aortic dissection during pregnancy or early postpartum from the International Registry of Acute Aortic Dissection database. Most women had a recognized underlying connective tissue disorder or aortopathy. Of the 8 type A dissections, the average aortic root diameter at dissection was 53 mm (range, 41-76 mm). Importantly, the type B dissections related to pregnancy often occurred in nondilated or only mildly dilated aortas (average size of descending aorta, 32 mm; range, 24-57 mm).25Braverman A. Harris K. Pyeritz R. Hutchison S. Pitler L. Evangelista A. et al.Aortic dissection during pregnancy: results from the International Registry of Acute Aortic Dissection (IRAD).J Am Coll Cardiol. 2012; 59A: A467Google Scholar Multidisciplinary evaluation with maternal fetal medicine or high-risk obstetrics and consultations with anesthesia, cardiology and cardiac surgery and genetics are important in managing these patients. Once the diagnosis of TAA is established, it is imperative that long-term imaging surveillance of the aorta at regular intervals be performed.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar, 3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar It is also important to consider body size when evaluating the significance of aortic root dimensions.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar, 2Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar, 3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar When an aortic root or ascending aortic aneurysm is present, an echocardiogram should be performed to evaluate for the presence of a BAV, one of the most common causes of a dilated aorta.5Braverman A. Beardslee M. The bicuspid aortic valve.in: Otto C. Bonow R. Valvular heart disease: a companion to Braunwald's heart disease. 2nd ed. Saunders-Elsevier, Philadelphia2009: 169-186Crossref Google Scholar One generally recommends repeat imaging of the TAA 6 months after initial diagnosis to ensure stability in aortic dimension.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar If stable, then reevaluating the TAA with at least yearly computed tomographic or magnetic resonance imaging is recommended. For the degenerative TAA of 3.5 to 4.4 cm, annual imaging is suggested.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar For the degenerative aneurysm of 4.5 to 5.4 cm, semiannual computed tomography or magnetic resonance imaging is suggested.3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar If the aorta demonstrates more rapid growth or is approaching the threshold for surgery or endovascular repair, imaging every 3 to 6 months is recommended.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar For genetic syndromes, the aortic dimension at which prophylactic repair is recommended is smaller than for degenerative aneurysms and depends on the specific condition, the rate of growth, the family history, and other factors.1Braverman A. Thompson R. Sanchez L. Diseases of the aorta.in: Bonow R. Mann D. Zipes D. Libby P. Braunwald's heart disease. 9th ed. Elsevier Inc, Philadelphia2011: 1309-1337Google Scholar, 2Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar, 3Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.N. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.J Am Coll Cardiol. 2010; 55: e27-e129Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar After surgery or endovascular repair, long-term imaging of the thoracic aorta by computed tomography or magnetic resonance imaging remains important to evaluate for any complications or subsequent aneurysm formation. Patients with TAA disease require multidisciplinary management, including evaluation for an underlying genetic condition and screening of family members for TAA disease. Once the diagnosis is established, patients require long-term imaging for progressive aneurysm enlargement and instructions on lifestyle modifications to lessen stress on the aorta. Although only limited data are available on pharmacologic therapy in TAA disease, research involving animal models has identified multiple pathways underlying the pathogenesis of aneurysm syndromes. This research holds great promise for translation into effective therapy in humans.