Disease of the ascending thoracic aorta is a significant clinical problem in patients with a connective tissue disorders such as Marfan, Loeys-Dietz and Ehlers-Danlos syndromes; the congenital heart defect of bicuspid aortic valve (BAV); and familial and idiopathic TAAs. Unfortunately, TAAs are vastly asymptomatic and the only treatment to prevent aortic dissection or free rupture is elective replacement of the ascending aorta which is a major open operation requiring sternotomy, cardiopulmonary bypass and cardio-cerebral protection with deep hypothermic cooling of the patient. Conventional theory of surgical experts dictates aortic replacement should occur when aortic diameter exceeds 50-55 mm.(Ergin, Spielvogel et al. 1999) Optimal management includes early diagnosis and careful surveillance, but despite these, many patients with variable degrees of aortopathy likely incur significant risk while following the current recommended guidelines for intervention. Although surgical outcomes are often quite favorable, improved understanding of the biology could help develop more biomimetic, minimally-invasive treatment options.

  Cystic Medial Degeneration

TAAs are virtually indistinguishable from one another by histologic inspection but are distinct from aneurysms of the abdominal aorta. Most of the current understanding of TAA manifestation at the tissue level has been gleaned from study of the medial layer of the aorta. The histopathologic hallmark of TAA is cystic medial degeneration (CMD) which encompasses non-inflammatory loss of smooth muscle cells (SMCs), elastic fiber fragmentation and accumulation of proteoglycans in the tunica media as part of the final common pathway leading to TAA. A current barrier to progress is that little is known about the molecular and cellular mechanisms governing aortic wall homeostasis and what effector molecules initiate and perpetuate ascending thoracic aortic disease. This non-inflammatory phenomena is uniformly consistent with aortopathies of the ascending aorta, of which, key effector proteins inciting the phenotype have been identified for Marfan (fibrillin-1),(Dietz, Cutting et al. 1991) Loeys-Dietz (transforming growth factor beta receptor) (TGF-ŖR),(Loeys, Schwarze et al. 2006) and Ehlers-Danlos-vascular type (Type III collagen)(Narcisi, Richards et al. 1994) syndromes and familial forms of TAAs, including mutations in genes that regulate SMC contractility (a-smooth muscle actin (SMA) (ACTA2) and smooth muscle myosin heavy chain (SM-MHC)(Zhu, Vranckx et al. 2006; Pannu, Tran-Fadulu et al. 2007; Disabella, Grasso et al. 2011)). The incidence of BAV overlaps with a-SMA and TGF-ŖR mutation s at a frequency of 2.5-3%(Milewicz, Guo et al. 2008) but no gene or pathway responsible for inciting TAAs in BAV patients has been identified for these or any other proteins.

The aortopathy associated with bicuspid aortic valve is the primary focus of our research team.

Bicuspid Aortic Valve:

  Schematic BAV

Bicuspid aortic valve (BAV) is the most common cardiac malformation, occurs in 1-2% of the population and is associated with an aortopathy that manifests as a thoracic aortic aneurysm (TAA) or aortic dissection. (Ward 2000) Aortic dissection conveys mortality rates worldwide of over 23% with and 60% without surgical intervention. (Masuda, Yamada et al. 1991; Rampoldi, Trimarchi et al. 2007) The ascending aortas of BAV patients are uniformly larger in diameter compared with age- and sex-matched controls (Keane, Wiegers et al. 2000; Dore, Brochu et al. 2003) and 45% percent of patients requiring surgery to replace the ascending aorta because of TAA or dissection have BAV. Unlike the Marfan, Loeys-Dietz or Ehlers-Danlos syndromes, for which TAA-causing genes have been identified, there is no known genetic alteration responsible for causing BAV or the aortopathy. What is known, however, is that TAA formation in the setting of BAV involves degeneration of the extracellular matrix (ECM) initiated by an undefined mechanism. The overarching goal of our laboratory is to define the mechanism mediating BAV-associated aortopathy.

Clinical Importance:

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, occurring in 1-2% of the population.(Roberts 1970; Ward 2000; Nataatmadja, West et al. 2003) Presence of a BAV carries a significant risk of aortic catastrophe, often striking patients in the prime of their life. BAV is associated with ascending thoracic aortic aneurysm (TAA) formation and aortic dissection in addition to the development of valvular stenosis or insufficiency.(Edwards, Leaf et al. 1978; Fedak, Verma et al. 2002; Fedak, de Sa et al. 2003; Gleason 2005) BAV patients uniformly have larger diameter aortic roots and ascending aortas compared to age- and sex-matched controls (Keane, Wiegers et al. 2000; Dore, Brochu et al. 2003) and abnormal elasticity even in the absence of valvular stenosis or aneurysm.(Nistri, Sorbo et al. 1999; Nistri, Grande-Allen et al. 2008) Consequently, these patients have a markedly increased risk of aortic dissection and sudden death.(Fedak, Verma et al. 2002) At least 9% of aortic dissection cases occur in patients with BAV(Edwards, Leaf et al. 1978), and the 30-day mortality rate after an ascending aortic dissection is over 23% with surgical intervention and over 60% without surgical intervention. (Masuda, Yamada et al. 1991; Rampoldi, Trimarchi et al. 2007) Aortic catastrophe in the context of the BAV syndrome occurs in younger patients (<50 years) compared with patients with TAA, a tricuspid aortic valve (TAV), and no other connective tissue disorder.(Gleason 2005) Strikingly, 45% of patients undergoing replacement of the ascending aorta for aneurysm or dissection at large thoracic aortic surgical centers, including the PIís, have BAV and undergo surgical intervention at least 10 years earlier than patients with TAV.

Dr. Gleasonís clinical practice has been devoted to improving care for BAV patients and this goal will be achieved in part through his basic science research efforts toward understanding the inciting cellular and molecular mechanisms of medial degeneration and biomechanical failure of the ascending aortic wall in BAV patients.

Summary of Major Findings:

A role for oxidative stress in BAV-TAA specimens was reported by Drs Gleason and Phillippi. (Phillippi, Klyachko et al. 2009; Phillippi, Eskay et al. 2010) Components of oxidative stress pathways have been studied in non-BAV TAA patients by others as well, (Ejiri, Inoue et al. 2003; Fiorillo, Becatti et al.) but not to the extent of implicating ROS accumulation as a defining mechanism of action. In collaboration with David Vorpís group in Bioengineering, the team has uncovered some interesting differences in tensile and delamination biomechanical strengths in aneurysms with TAV and BAV. (Pasta, Phillippi et al. 2012; Pichamuthu, Phillippi et al. 2013) By incorporating the imaging expertise of Simon Watkins and his team at the Center for Biologic Imaging and unique image analysis processing of Anne Robertson and her team in Mechanical Engineering and Materials Science, distinct difference in extracellular matrix remodeling were noted in TAV vs. BAV specimens (Tsamis, Phillippi et al. 2013; Phillippi, Green et al. 2014) and provided further evidence in support of alternative effector pathways leading to the development of aneurysm in these affected patients that is related to aortic valve morphology. In collaboration with Spandan Maiti at the University of Pittsburgh, we are exploring computational models to help understand the impact of biomechanical tissue perturbations on aortic dissection propagation. (Pal, Tsamis et al. 2014) Our highly interdisciplinary and collaborative team is uniquely poised to uncover novel mechanisms causing and contributing to aortic disease and to help stratify risk for aortic catastrophe in affected patients.



Updated 15-Aug-2014