DISCLOSURES CURRENT UNDERSTANDING: INDIVIDUAL None & PHYSIOLOGY TYPE B AORTIC DISSECTION INSTITUTIONAL Cook, Inc Not discussing off-label use of anything Medial degeneration characterized by Smooth muscle cell loss Fragmentation and depletion of elastic fibers Accumulation of proteoglycans and glycosaminoglycans in cell depleted areas of the aortic wall 1
Progression results from interplay of Hemodynamic stress Aortic injury Chronic inflammation Genetic propensity Epidemiologic risk factors Media consists of elastic fibers and vascular smooth muscle cells, interconnected by collagen fibers, proteoglycans, glycosaminoglycans and various adhesive proteins When functioning normally, these ECM components Impart elasticity & tensile strength Sequester growth factors Form structural interactions All aortic media components show defects Elastin fibers, microfibrils, associated proteins & interface proteins Collagen increased expression, disordered deposition Smooth muscle cells Apoptosis Phenotype change PG / GAG content, function All the usual inflammatory markers are present (T-cells, macrophages, cytokines) Hypoxia and increased oxidative stress An excess of proteases (including MMPs) Pathologic signalling TGFβ Angiotensin II 2
Percentage 60% 10-15% 25-30% Golledge et al, Lancet, 2008 Type DeBakey I DeBakey II DeBakey III Stanford A Stanford B Proximal Distal Svensson et al, Circulation, 1999 INTIMAL TEAR Location Outer curve less likelihood of retrograde extension possibly less likelihood of late enlargement Inner curve greater likelihood of retrograde extension (only 15% with NO arch or ascending aortic involvement) 3
INTIMAL TEAR Size / Number Less likelihood of late enlargement small entry tear (<10 mm) multiple tears More likelihood of late enlargement large entry tear single / few tears no distal tear INTIMAL TEAR Caution How imaged How measured Modeling vs in vivo AORTIC DIAMETER More likelihood of late enlargement Overall initial aortic diameter 40 mm Proximal descending thoracic aortic false lumen 22 mm Initial diameter of the mid-thoracic aorta LUMEN LOCATION, SHAPE & FLOW Increased Risk True lumen Elliptical shape False lumen Patent Partially thrombosed Saccular Inner curve Decreased Risk True lumen Circular lumen False lumen Thrombosed Outer curve 4
PHYSIOLOGY PHYSIOLOGY HEMODYNAMICS HEMODYNAMICS Importance of false lumen pressure Importance of false lumen pressure BP control HR control Onitsuka et al, J Thor Surg, 2003 Kodama et al, Circulation, 2008 PHYSIOLOGY PHYSIOLOGY HEMODYNAMICS HEMODYNAMICS Static Obstruction Static Obstruction aortic stent-graft branch stent thrombectomy Dynamic Obstruction Dynamic Obstruction aortic stent-graft fenestration 5
50 year old man, with Type B dissection, mild (onedrug) antecedent hypertension, no abnormal morphometrics, a cousin who had an aortic aneurysm (not dissection). He probably has A. Hypertension-related sporadic TAD B. Some form of Marfan s C. Some other genetic abnormality D. Bad luck H y p e r t e n s i o n - r e l a t e d s p... 51% S o m e f o r m o f M a r f a n s 3% S o m e o t h e r g e n e t i c a b... 31% 14% B a d l u c k Syndromic DeBacker et al, Ann Cardiothor Surg, 2013 Syndromic SYNDROME GENE LOCATION Marfans Fibrillin 1 Mostly ascending aorta, aortic root; few descending aorta Loeys-Dietz 1 TGFBR1/2 Aortic root Ehlers-Danlos IV COL3A1 Mostly thoracic aorta and abdominal aorta Aneurysm-Osteoarthritis SMAD3 Mostly ascending aorta Turners syndrome 46X 15% are Type B enos 4a/b polymorphism 90% Type A Non-Syndromic genes related to smooth muscle contractile function Isolated / sporadic DeBacker et al, Ann Cardiothor Surg, 2013 6
Non-Syndromic Estimated that 20% of TAAD have a genetic component Autosomal dominant Interfamilial variability Variable penetrance Variable severity ACTA2 (12-21%) About 50% have aortic events Thoracic dissection 25% mortality Type A > Type B Age of Type B < age at Type A Arterial occlusive disease Livedo reticularis Dissect at diameter of 4.5-5.0 cm TGFβ2 (4%) MYH11 (1-2%) Patent ductus Dissect at diameter of 4.0-4.5 cm MLYK dissect with no enlargement FTAAD5 causes proteoglycan deposition TGFβ Arteriopathies Marfan s abnormal fibrillin-1 failed sequestration of TGFβ complex, resulting in increased active TGFβ & TGFβ signalling Loeys-Dietz TGFBR1 & 2 increased active TGFβ Aneurysm/ SMAD gene abnormalities in the TGFβ2 ligand Osteoarthritis ACTA2 MYH11 FTAAD5 increased TGFβ signalling increased TGFβ signalling increased PG deposition,? caused by TGFβ signalling 7
TGFβ Arteriopathies Marfan s abnormal fibrillin-1 failed sequestration of TGFβ complex, resulting in increased active TGFβ & TGFβ signalling Loeys-Dietz TGFBR1 & 2 increased active TGFβ Aneurysm/ SMAD gene abnormalities in the TGFβ2 ligand Osteoarthritis ACTA2 MYH11 FTAAD5 increased TGFβ signalling increased TGFβ signalling increased PG deposition,? caused by TGFβ signalling DeBacker et al, Ann Cardiothor Surg, 2013 Hiratzka et al, Circulation, 2010 Hiratzka et al, Circulation, 2010 8
Hiratzka et al, Circulation, 2010 Hiratzka et al, Circulation, 2010 9