Cardiovascular Outcomes in Aortopathy: GenTAC Registry of Genetically Triggered Aortic Aneurysms and Related Conditions

1. Talha Niaz, MBBS* 2. Jonathan N. Johnson, MD*,† 3. Frank Cetta, MD*,† 4. Timothy M. Olson, MD*,† 5. Donald J. Hagler, MD*,† 1. *Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, and 2. †Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN * Abbreviations: AHA : : American Heart Association BAV : : bicuspid aortic valve TTE : : transthoracic echocardiography Bicuspid aortic valve is the most common congenital heart defect in children, adolescents, and adults. Primary care providers play an important role in screening, referral, and follow-up of these patients and should be aware of the family screening guidelines, sports participation recommendations, and periodic follow-up requirements for adequate surveillance of the complications that arise from bicuspid aortic valve. After reading this article, readers should be able to: 1. Describe the epidemiology and anatomy of bicuspid aortic valve (BAV). 2. Understand the clinical presentation and diagnosis of BAV in infants, children, and adolescents. 3. Identify the various complications of BAV disease. 4. Discuss the management and follow-up requirements for BAV. 5. Analyze the family screening and sports participation guidelines for patients with BAV. Bicuspid aortic valve (BAV) is the most common congenital heart defect in children, adolescents, and adults. (1) It is a heterogeneous disease that affects both the aortic valve and the aorta. It can lead to many complications, including aortic valve stenosis, regurgitation, or endocarditis. (2)(3) It also can lead to dilation of the aorta, predisposing individuals to a significantly higher risk of aortic aneurysm and dissection. (4) Although most individuals with BAV present with these long-term complications during adulthood, a considerable number of patients may also present during childhood and adolescence with early-onset disease; that may require interventions in up to 12% to 15% of the patients. (5)(6) Therefore, patients with BAV require lifelong follow-up and surveillance. BAV has multiple implications in terms of sports participation and family screening, making it an important subject for primary care providers. This article reviews the anatomy, genetics, presentation, diagnosis, …

The impact of genetic factors and testing on operative indications and extent of surgery for aortopathy

Update on the Diagnosis and Management of Inherited Aortopathies, Including Marfan Syndrome.

The aortic arch and its branches form during the third week of embryogenesis, which involves a complex process. Abnormalities of the arch branching pattern arise by persistence of segments of arches that normally disappear or the disappearance of segments of arches that normally remain, or both [1]. The most common human aortic arch branching pattern has the innominate artery, the left common carotid artery and the left subclavian artery all as separate branches (Fig. 1). The most common variant branching pattern involves the left common carotid artery arising in a common origin with the innominate artery (Fig. 2), and the next most common the similar left common carotid artery originating from the innominate artery itself (Fig. 3). A true bovine arch involves a single common brachiocephalic trunk arising from the arch which then splits into the right subclavian artery, a bicarotid trunk and a left subclavian artery (Fig. 4), and is actually extremely uncommon in humans [2]. Originally the variations of t...

As children, we learned that a balloon blown up to its limit of elasticity would pop. For similar aortic ballooning, we hardly know more. Furthermore, in the 21st century, with a nascent epidemic of aortic-related deaths, there have been no consequential advances in preventing the loss of aortic elasticity or in describing the etiology or injury that causes aortic disease. Nor is there an explanation as to why, in some people the aorta “pops” and in others, the aorta dissects. See p 1098 In the United States between 1999 and 2001, at least 129 533 people died from diseases of the aorta and its branches, excluding carotid and coronary disease—an average of 43 199/year, according to the Centers for Disease Control and Prevention ICD-10 codes (Table). The upper limit could potentially exceed 46 817 per year. This number is greater than the ≈40 000 people who die annually from breast cancer, homicides, pancreatic cancer, colon cancer, prostate cancer, or motor vehicle accidents.1 Despite this, little research and even less funding have been allocated to aortic disease research, possibly because disease of a supposedly utilitarian pipe that conveys blood to a pantheon of organs engenders less interest or sympathy in comparison with, for example, cancer. Furthermore, the dismal prognosis of aortic disease, a marker of systemic problems despite successful surgery, has not roused much concern, with a 5-year average survival rate of only 60% in most patients.2 This figure does not differ much from that of stage IB lung cancer. Even the aortic disease–related deaths of media figures such as Albert Einstein, Lucille Ball, Conway Twitty, and John Ritter have fomented little interest. As Western populations age, this most common cause of deaths including sudden death will become an increasing factor in long-term survival. View this table: Deaths Related to Aortic Disease …

What Is the Optimal Medical Therapy for Marfan Syndrome?

Ascending Aortic Aneurysm in an Asymptomatic Young Woman Without Risk Factors

Valve-sparing aortic root surgery in children and adults with congenital heart disease

Influence of Aortic Dilation on the Regional Aortic Stiffness of Bicuspid Aortic Valve Assessed by 4-Dimensional Flow Cardiac Magnetic Resonance: Comparison With Marfan Syndrome and Degenerative Aortic Aneurysm

Introduction: The GenTAC Registry ( G enetically Triggered T horacic A ortic Aneurysms and Cardiovascular C onditions) followed patients with aortopathies over 8 years among 8 centers with the goal of evaluating cardiovascular outcomes. Methods: Enrollment initiated in 2007, and data were collected until 2015. We included diagnoses with >100 participants: Bicuspid aortic valve with aneurysm (BAV, n=879), Marfan syndrome (MFS, n=861), Familial thoracic aortic aneurysm or dissection (FTAAD, n=378), Other thoracic aortic aneurysm at < 50 years of age (Other<50, n=524), Turner syndrome (TS, n=298), Vascular Ehlers Danlos syndrome (VEDS, n=149), and Loeys-Dietz syndrome (LDS, n=121). We identified patients who underwent elective ascending aortic replacement, total unique dissections, and time to first dissection. With MFS as a reference population and adjusted for sex, endpoints were analyzed by a Firth penalized Cox-PH regression model to account for diagnosis groups with low event numbers. Results: LDS participants at a mean age of (24.5 ± 15.0y) were youngest at elective aortic surgery followed by MFS (32.3 ±12.3y), TS (37.6 ±13.6y), VEDS (35.0 ±SD 7.4y), Other<50 (40.3 ±SD 10.3y), FTAAD (42.9 ±14.2y), and BAV(49.4 ± 13.8 y). Dissections were reported in all diagnosis groups with a total of 472 unique dissections in 3210 patients (14%). Mean age at first dissection was in the third decade for LDS, TS, MFS, VEDS and in the fourth decade for BAV, FTAD, and Other<50. Adjusted hazard ratio for time to first dissection was higher in LDS, 1.77 (95%CI 1.14- 2.77), compared to MFS and other diagnosis groups (Figure 1). Conclusions: Reported aortic dissections were prominent in the GenTAC cohort. Despite elective surgery at a younger age, LDS patients had a higher hazard risk of dissection compared to other diagnosis groups.

Aortic aneurysm and dissection is a common phenotype, accounting for 1% to 2% of all deaths in industrialized countries and ≈50 000 deaths annually in the United States.1 In contrast to abdominal aortic aneurysm, thoracic aortic aneurysm, particularly in the ascending segment, commonly occurs in young individuals in the absence of identifiable environmental risk factors. Marfan syndrome (MFS) is the most common syndromic presentation of ascending aortic aneurysm, but other syndromes such as vascular Ehlers-Danlos syndrome and Loeys-Dietz syndrome (LDS) also have ascending aortic aneurysms and the associated cardiovascular risk of aortic dissection and rupture. Familial segregation of the risk for ascending aortic aneurysm can also occur in the absence of associated systemic findings of a connective tissue abnormality in patients with familial thoracic aortic aneurysm and dissection (FTAAD) or bicuspid aortic valve with ascending aortic aneurysm (BAV/AscAA). The knowledge gained through basic and clinical research focused on MFS has improved and will continue to improve the care of patients with these related conditions. Recent paradigm-shifting discoveries about the molecular pathogenesis of MFS have highlighted the need for a focused research agenda to solidify the gains of the past 30 years and set the stage for future advances in MFS and related conditions. In April 2007, the National Heart, Lung, and Blood Institute (NHLBI) and the National Marfan Foundation convened a working group on research in MFS and related disorders to foster a multidisciplinary discussion. The working group, which included experts in cardiovascular disease, developmental biology, genetics and genomics, and proteomics, was charged with identifying opportunities and barriers to advancing the research agenda and developing recommendations to the NHLBI in the context of the Institute’s strategic plan (http://apps.nhlbi.nih.gov/strategicplan/). MFS is a systemic disorder of connective tissue caused by heterozygous mutations in the gene ( FBN1 ) that encodes the extracellular matrix …

Introduction: The natural history of aortopathy after isolated aortic valve replacement (AVR) in patients with bicuspid aortic valves (BAV) is not well characterized. Hypothesis: The incidence of dissection and thoracic aortic surgery after isolated AVR in patients with BAV is higher than in patients with tricuspid valves. Methods: From 1995-2010, 2,203 bicuspid and 1,436 rheumatic tricuspid patients undergoing isolated AVR were identified from the Statewide Planning and Research Cooperative System which captures all inpatient admissions and emergency visits to every hospital in New York State. Deaths were identified from the Social Security Death Master File. Kaplan-Meier analysis of survival and competing risk analysis of aortic dissection and thoracic aortic surgery was performed. Results: BAV patients were younger than tricuspid aortic valve (TAV) patients (52.0 vs. 64.2 years, p<0.001). Survival at 15 years after AVR was 77% versus 58%, respectively (p<0.001). During median follow up of 8.0 years (range 0-19.0 years), aortic dissection occurred in 9 BAV patients versus 4 TAV patients. The 15-year cumulative incidence of dissection after AVR in BAV patients was 0.7% versus 0.4% in TAV patients (p=0.28) (Figure 1). Thoracic aortic surgery was performed in 33 BAV patients versus 9 TAV patients. The 15-year cumulative incidence of thoracic aortic surgery was 3.1% in BAV patients versus 1.1% in TAV patients (p<0.001) (Figure 2). Conclusions: Patients undergoing isolated AVR of bicuspid valves are at greater long-term risk of aortic dissection and thoracic aortic surgery than patients with tricuspid valves, and should be considered for life-long surveillance.

Objective: Bicuspid aortic valve (BAV), the most common congenital heart condition, is frequently associated with thoracic aortic aneurysm (TAA). Aortic mRNA expression patterns in BAV patients and expression differences between BAV and tricuspid aortic valve (TAV) patients are unclear. We sought to compare mRNA expressions in TAA in patients with BAV and TAV. Methods and Results: Ascending aorta tissue was obtained from 58 aortic aneurysm repair patients (31 BAV, 27 TAV) and from 8 heart transplant donors. Illumina Human HT-12v4 microarrays were used to assess mRNA expression. After standard QC and filtering, probes were analyzed using multivariable linear regression analysis, adjusting for age, gender, medication use (beta blockers, ACE-Is, ARBs), and 10 surrogate variables. Ingenuity Pathway Analysis (IPA) was used to identify pathways and top regulator effect networks that were differentially expressed in BAV vs. TAV and BAV vs. donors. In BAV vs. TAV, MMP9, ESM1 and IL1B were downregulated 0.63, 0.74 and 0.77 fold, whereas COMP was upregulated 2.29 fold (p < 0.05 for all). In BAV vs. donors, IL1R2, MCEMP1, IL18RAP and ACAN were downregulated 0.66, 0.2, 0.2 and 0.05 fold, while ADAMTS8, CCL21 and CIDEA were upregulated 6.97, 6.24 and 4.65 fold (p < 0.0001). IPA analysis showed P53 as the top upstream regulator for both BAV vs. TAV (p = 1.9e-8) and BAV vs. donors (p = 2.3e-25). IRF7, which protects against angiotensin II-induced hypertrophy in cardiomyocytes, was also a significant upstream regulator for BAV vs. TAV (p = 3.6e-7). Additionally, miR-124-3p in BAV vs. TAV (p = 6.3e-7) and BAV vs. donors (p = 1.7e-22), as well as miR-96-5p in BAV vs. TAV (p = 4e-7) were predicted significant upstream regulators. Immune response was shown to be the top regulator effect network in BAV vs. TAV, whereas perivascular fibrosis was shown to be an important regulator effect network in BAV vs. donors. Cell stress pathways were also activated in BAV vs. donors. Conclusions: Distinct pathways and regulator effect networks exist in TAA with BAV or TAV. TAV associated TAA is more associated with inflammatory responses, while BAV aortopathy is more associated with extracellular matrix remodelling and cell stress. MiRs may also play an important role in BAV aortopathy.

Background Thoracic aortic aneurysm (TAA) is a pathological widening of the aorta, due to degeneration of extracellular matrix (ECM) and loss of smooth muscle cells (SMCs). Bicuspid aortic valve (BAV) is a congenital disorder present in 1-2 % of the population which makes TAA associated with BAV a common complication. Previously we showed that aortas isolated from BAV and normal tricuspid aortic valve (TAV) patients are different both at gene and protein levels. Particularly, differences in the TGFβ pathway seem to be crucial players in aneurysm development, affecting matrix remodeling and wound healing. Since SMCs and myofibroblasts are the critical cells responsible for these activities, we evaluated different properties of the cells focusing on fibronectin (FN) and its spliced versions, a target gene of TGFβ. Interestingly, extra domain A of FN (EDA) was previously described for its roles in vascular morphogenesis, as well as in processes like migration and proliferation. Methods and results Biopsies from the thoracic aorta and Aortic valves were collected during Elective Aortic Valve Replacement Surgery. mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=46) and BAV (n=77). Expression of EDA was found increased only in dilated aortas from TAV patients but not in BAV patients. Primary SMCs were isolated with the explant outgrowth technique from aortas of BAV and TAV patients (n=15). Myofibroblasts were isolated by collagenase digestion from BAV and TAV valves (n=30). Cells were cultured and treated with TGFβ at a concentration of 20 ng/ml for 6h. TGFβ treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in SMCs from TAV patients but not in cells derived from BAV patients. We have not observed clear differences in SMC proliferation and migration. Myofibrolasts analysis is ongoing. Conclusions So far, our results suggest that despite a decreased EDA-fibronectin expression in BAV cells, the phenotype of SMCs isolated from BAV and TAV patients in culture does not differ. However, impaired TGFβ signaling that may result in the increased susceptibility of BAV patients to develop TAA could be due to effects on other cell types.

Aortic aneurysm and aortic dissection can have a major impact on the life expectancy of Marfan syndrome (MFS) or Loeys-Dietz syndrome (LDS) patients. Although obesity can influence the development of aortic complications, evidence on whether obesity influences the development of aortic aneurysm or dissection in MFS and LDS is limited. The aim of the present study was to elucidate the relationship between aortic size and body composition, assessed by modern bioelectrical impedance analysis (BIA) in MFS/LDS-patients. In this exploratory cross-sectional study in MFS or LDS patients, enrolled between June 2020 and May 2022, 34 patients received modern BIA and magnetic resonance imaging (MRI) (n=32) or computed tomography (CT) imaging (n=2) of the entire aorta. A P value of <0.05 was considered significant. Fifty-one patients (66% female; mean age: 37.7±11.7; range, 17-68 years) with MFS or LDS were enrolled; 34 patients, 27 with MFS and 7 with LDS, underwent aortic MRI or CT scanning. The mean aortic length was 503.7±58.7 mm, and the mean thoracic aortic length and abdominal aortic length were 351.5±52.4 and 152.2±27.4 mm, respectively. The aortic bulb and the ascending aorta were measured only in the non-surgically repaired patients. Fifteen MFS (88.2%) and two LDS (40.0%) patients had an aortic aneurysm. In these, the aortic bulb tended to be larger in MFS than in LDS patients [42.6×41.9×41.2 vs. 37.8×37.4×36.8 mm; P=0.07 (-1.1; 9.1); P=0.07 (-1.2; 8.4); P=0.07 (-1.5; 7.9)]. BIA revealed mean body fat levels of 31.6%±8.7% (range, 9.5-53.5%), indicating that 18 patients (52.9%) were obese. There was a significant correlation between body fat content and thoracic aortic length (R=-0.377; P=0.02), muscle mass and total aortic length (R=0.359; P=0.03), thoracic aortic length (R=0.399; P=0.02), extracellular mass (ECM), and total aortic length (R=0.354; P=0.04), and connective tissue and aortic diameters at the aortic arch (R=0.511; P=0.002), aortic isthmus (R=0.565; P<0.001), and abdominal aorta (R=0.486; P=0.004). Older age was correlated with wider aortic arch, isthmus, and abdominal aorta. Male patients had a longer aorta. While a slender habitus is commonly known for MFS and LDS patients, our data show that many MFS and LDS patients (especially female) do not fit this phenotypic characteristic and are obese, which is associated with a more severe aortic phenotype. This topic should be included in the clinical assessment of affected MFS and LDS patients, in addition to measurement of the aortic diameters. Physicians should systematically screen MFS and LDS patients for obesity, educate them about the potential risk of resulting aortic complications, and encourage them to adopt a healthy lifestyle, that includes (mild) exercise and a balanced diet.