Loeys-Dietz Research Articles

Arterial Tortuosity Syndrome: Unraveling a Rare Vascular Disorder.

Arterial tortuosity syndrome (ATS) is a rare genetic disorder characterized by abnormal twists and turns of arteries, leading to cardiovascular complications. This syndrome, first reported around 55 years ago, is inherited in an autosomal recessive manner and affects both genders. ATS manifests primarily in childhood, with arterial abnormalities disrupting blood circulation, increasing shear stress, and causing complications, such as atherosclerosis and strokes. This article reviews the genetics, etiology, pathophysiology, clinical presentation, diagnosis, associated conditions, management, and challenges of ATS. The syndrome's genetic cause is linked to mutations in the SLC2A10 gene, affecting collagen and elastin synthesis. Arterial tortuosity, a complex phenomenon, arises from factors such as vessel elongation, anatomic fixation, and vessel diameter. ATS is one of many conditions associated with arterial tortuosity, including Marfan syndrome and Loeys-Dietz syndrome. Recent studies highlight arterial tortuosity's potential as a prognostic indicator for adverse cardiovascular events. Management requires a multidisciplinary approach, and surveillance and prevention play key roles. Despite challenges, advancements in understanding ATS offer hope for targeted therapies and improved patient care.

Anesthetic management of a child with Loeys-Dietz syndrome undergoing complete aortic arch replacement.

Loeys-Dietz syndrome (LDS) is a connective tissue disease related to β-transforming growth factor mutations, which causes aneurysms formation, vascular tortuosity and skeletal manifestations. The prognosis is very poor, and mortality occurs at the age of 27 in patients without surgical treatment. Despite being diagnosed in childhood, is not usual surgical aortic replacement in children. We report a case of 12 years old child with LDS and multiple aneurysms in thoracic aorta, undergoing complete aortic arch replacement and our proposal for the anesthetic management, due to surgical complexity and implications in pediatric population.

Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier.

Background: TGFB3 variants cause Loeys-Dietz syndrome type 5, a syndromic form of thoracic aortic aneurysm and dissection. The exact disease phenotype is hard to delineate because of few identified cases and highly variable clinical representation. Methodology: We provide the results of a haplotype analysis and a medical record review of clinical features of 27 individuals from 5 different families, originating from the Campine region in Flanders, carrying the NM_003239.5(TGFB3):c.787G>C p.(Asp263His) likely pathogenic variant, dbSNP:rs796051886, ClinVar:203492. The Asp263 residue is essential for integrin binding to the Arg-Gly-Asp (RGD) motif of the TGFβ3-cytokine. Results: The haplotype analysis revealed a shared haplotype of minimum 1.92Mb and maximum 4.14Mb, suggesting a common founder originating >400years ago. Variable clinical features included connective tissue manifestations, non-aneurysmal cardiovascular problems such as hypertrophic cardiomyopathy, bicuspid aortic valve, mitral valve disease, and septal defects. Remarkably, only in 4 out of the 27 variant-harboring individuals, significant aortic involvement was observed. In one family, a 31-year-old male presented with type A dissection. In another family, the male proband (65years) underwent a Bentall procedure because of bicuspid aortic valve insufficiency combined with sinus of Valsalva of 50mm, while an 80-year-old male relative had an aortic diameter of 43mm. In a third family, the father of the proband (75years) presented with ascending aortic aneurysm (44mm). Conclusion: The low penetrance (15%) of aortic aneurysm/dissection suggests that haploinsufficiency alone by the TGFB3 variant may not result in aneurysm development but that additional factors are required to provoke the aneurysm phenotype.

David V procedure and hemiarch replacement in a patient with Loeys-Dietz-Syndrome and beta thalassemia minor: a case report

We report the case of a 36-year-old European female patient presenting with a sinus valsalva aneurysm of 47 mm with moderate aortic regurgitation. Additionally, an aneurysm of the brachiocephalic trunk and multiple aneurysms of the right internal mammary artery were identified. Previous medical history included Loeys-Dietz syndrome (LDS) Type RII due to a TGF-beta receptor mutation, and beta thalassemia minor with a baseline hemoglobin of 9,3 g/dL on admission.Reconstruction of the aortic root and hemiarch replacement was performed in circulatory arrest under moderate hypothermia. During surgery, hypothermia was required as part of the cerebral protection strategy. We aim to highlight special considerations and discuss the effects of cooling, rewarming and the use of cardiopulmonary bypass (CPB) during extensive surgery in a patient with LDS and beta thalassemia minor.

Genetic Basis, New Diagnostic Approaches, and Updated Therapeutic Strategies of the Syndromic Aortic Diseases: Marfan, Loeys-Dietz, and Vascular Ehlers-Danlos Syndrome.

Syndromic aortic diseases (SADs) encompass various pathological manifestations affecting the aorta caused by known genetic factors, such as aneurysms, dissections, and ruptures. However, the genetic mutation underlying aortic pathology also gives rise to clinical manifestations affecting other vessels and systems. As a consequence, the main syndromes currently identified as Marfan, Loeys-Dietz, and vascular Ehlers-Danlos are characterized by a complex clinical picture. In this contribution, we provide an overview of the genetic mutations currently identified in order to have a better understanding of the pathogenic mechanisms. Moreover, an update is presented on the basis of the most recent diagnostic criteria, which enable an early diagnosis. Finally, therapeutic strategies are proposed with the goal of improving the rates of patient survival and the quality of life of those affected by these SADs.

Mitral annular disjunction on cardiac MRI: Prevalence and association with disease severity in Loeys-Dietz syndrome

BackgroundThe purpose of this study was to evaluate mitral annular disjunction (MAD) on cardiac magnetic resonance imaging (MRI) in Loeys-Dietz Syndrome (LDS) and to explore its association with adverse outcomes. MethodsIn this retrospective cohort study, adult patients with LDS who underwent cardiac MRI were evaluated for MAD, aortic dimensions, and ventricular volumetry. Aortic events were defined as aortic surgery and/or dissection and severe arrhythmic events as cardiac arrest or sustained ventricular tachycardia (VT). ResultsAmong 46 LDS patients (52% female, 37.2 ± 14.3 years), 17 had MAD (37%). MAD and no MAD groups were similar in age, sex, aortic dimensions and left ventricular parameters. After a clinical follow-up of 4.3 years (IQR 1.5–8.4), 3 in MAD and 4 in no MAD groups required aortic valve sparing root replacement (VSRR) and 1 in MAD developed type A dissection. Over a similar imaging follow-up period [4.1 years (IQR 2.7–9.1) vs. 3.2 years (IQR 1.0–9.0), p = 0.65], compared to baseline, increase in native aortic root size was significant only in MAD (39.4 ± 4.6 mm vs. 38.1 ± 5.3 mm, p = 0.02, 19.3 ± 2.4 mm/m2 vs. 18.7 ± 2.4 mm/m2, p = 0.01) compared to those without MAD. Patients with MAD were younger at first aortic event compared to those without (26.7 ± 11.5 years vs. 45.0 ± 14.9 years, p = 0.03). MAD distance correlated with need for VSRR, r = 0.57, p = 0.02. Two patients in the MAD group developed sustained VT. No cardiac arrest or death was observed. ConclusionMAD is highly prevalent in LDS, associated with progressive aortic dilatation, and aortic events at younger age. MAD may be a marker of disease severity necessitating close surveillance.

Early clinical outcomes and molecular smooth muscle cell phenotyping using a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome

ObjectivesPatients with Loeys-Dietz syndrome demonstrate a heightened risk of distal thoracic aortic events after valve-sparing aortic root replacement. This study assesses the clinical risks and hemodynamic consequences of a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome and characterizes smooth muscle cell phenotype in Loeys-Dietz syndrome aneurysmal and normal-sized downstream aorta. MethodsPatients with genetically confirmed Loeys-Dietz syndrome (n = 8) underwent prophylactic aortic arch replacement during valve-sparing aortic root replacement. Four-dimensional flow magnetic resonance imaging studies were performed in 4 patients with Loeys-Dietz syndrome (valve-sparing aortic root replacement + arch) and compared with patients with contemporary Marfan syndrome (valve-sparing aortic root replacement only, n = 5) and control patients (without aortopathy, n = 5). Aortic tissues from 4 patients with Loeys-Dietz syndrome and 2 organ donors were processed for anatomically segmented single-cell RNA sequencing and histologic assessment. ResultsPatients with Loeys-Dietz syndrome valve-sparing aortic root replacement + arch had no deaths, major morbidity, or aortic events in a median of 2 years follow-up. Four-dimensional magnetic resonance imaging demonstrated altered flow parameters in patients with postoperative aortopathy relative to controls, but no clear deleterious changes due to arch replacement. Integrated analysis of aortic single-cell RNA sequencing data (>49,000 cells) identified a continuum of abnormal smooth muscle cell phenotypic modulation in Loeys-Dietz syndrome defined by reduced contractility and enriched extracellular matrix synthesis, adhesion receptors, and transforming growth factor-beta signaling. These modulated smooth muscle cells populated the Loeys-Dietz syndrome tunica media with gradually reduced density from the overtly aneurysmal root to the nondilated arch. ConclusionsPatients with Loeys-Dietz syndrome demonstrated excellent surgical outcomes without overt downstream flow or shear stress disturbances after concomitant valve-sparing aortic root replacement + arch operations. Abnormal smooth muscle cell–mediated aortic remodeling occurs within the normal diameter, clinically at-risk Loeys-Dietz syndrome arch segment. These initial clinical and pathophysiologic findings support concomitant arch replacement in Loeys-Dietz syndrome.

Aggressive Aortic Disease with Marfan-like Phenotype in Malaysian Patients with Loeys-Dietz Syndrome

Loeys- Dietz Syndrome (LDS, pronounced LOH-eez-DEETS) is a connective tissue disorder that was first described in 2005. In the past, many patients were misdiagnosed clinically as Marfan Syndrome (MFS) due to their overlapping phenotype. Distinguishing craniofacial features of LDS include hypertelorism, bifid uvula, cleft palate and absence of lens dislocation. Unlike MFS, aortic root dilatation with or without arterial tortuosity elsewhere are almost always present. Patient 1 was a 7-year- old boy, diagnosed with MFS at 4 years of age. Echocardiogram showed aortic root dilatation with no lens dislocation on eye assessment. He was initially started on β-blocker by the cardiologist, losartan was added on subsequently due to the increasing size of his aortic root diameter. Patient 2 was a 14-year-old boy, followed up for severe aortic root dilatation. He had a stormy neonatal period; diagnosed with tracheobronchomalacia, multiple joint dislocation, feeding intolerance, scoliosis and squint. He was followed up for many years as possible MFS. Genetic testing performed showed mutation at TGFBR2 gene, confirming a diagnosis of LDS in both patients. In addition to these families, another 6 families under our aortopathy clinic follow up have had their diagnosis of LDS confirmed molecularly. LDS is increasingly being described in patients with a more severe aortic disease and Marfan-like phenotype. The difference in disease severity highlights the importance of genetic testing in patients with suspected aortopathy, enabling timely implementation of therapeutic strategies.

Aortic Dissection in a Young Patient With Unsuspected Aortopathy.

Aortic dissection is often a fatal condition if not recognized and treated emergently. Fortunately, it is extremely rare in children and adolescents. We report a case of an adolescent boy who survived an aortic dissection due to severe aortic root dilation. A comprehensive history and physical examination, including family history, can facilitate an early diagnosis of connective tissue diseases, such as Loeys-Dietz syndrome (LDS).

Marfan Syndrome: Enhanced Diagnostic Tools and Follow-up Management Strategies

Marfan syndrome (MFS) is a rare inherited autosomic disorder, which encompasses a variety of systemic manifestations caused by mutations in the Fibrillin-1 encoding gene (FBN1). Cardinal clinical phenotypes of MFS are highly variable in terms of severity, and commonly involve cardiovascular, ocular, and musculoskeletal systems with a wide range of manifestations, such as ascending aorta aneurysms and dissection, mitral valve prolapse, ectopia lentis and long bone overgrowth, respectively. Of note, an accurate and prompt diagnosis is pivotal in order to provide the best treatment to the patients as early as possible. To date, the diagnosis of the syndrome has relied upon a systemic score calculation as well as DNA mutation identification. The aim of this review is to summarize the latest MFS evidence regarding the definition, differences and similarities with other connective tissue pathologies with severe systemic phenotypes (e.g., Autosomal dominant Weill–Marchesani syndrome, Loeys–Dietz syndrome, Ehlers–Danlos syndrome) and clinical assessment. In this regard, the management of MFS requires a multidisciplinary team in order to accurately control the evolution of the most severe and potentially life-threatening complications. Based on recent findings in the literature and our clinical experience, we propose a multidisciplinary approach involving specialists in different clinical fields (i.e., cardiologists, surgeons, ophthalmologists, orthopedics, pneumologists, neurologists, endocrinologists, geneticists, and psychologists) to comprehensively characterize, treat, and manage MFS patients with a personalized medicine approach.

Ten-year follow-up study of a young woman with loeys-dietz syndrome: a case report

We herein report the 10-year surgical course of a 27-year-old woman who underwent two surgeries after being diagnosed with Loeys-Dietz syndrome. As described in previous cases, this patient developed ectopic arterial enlargement. We followed her temporal changes over a 10-year period, including the changes in computed tomography, pathology, and surgery.

Fluid dynamics by 4D flow CMR in Marfan and Loeys-Dietz patients before and after valve sparing aortic root replacement

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III (Spain), Sociedad Española de Cardiología Introduction Patients with Marfan or Loeys-Dietz syndrome present abnormal aortic flow patterns in the arch and the proximal descending aorta that may contribute to aortic dilation (1,2). Valve sparing aortic root replacement, which is effective in reducing the risk of aortic dissection in case of severe dilation, may also normalize flow patterns beyond the replaced aorta and potentially slow its progressive aortic dilation. Purpose To assess aortic flow dynamics in these patients with Marfan or Loeys-Dietz by 4D flow cardiovascular magnetic resonance (CMR) before and after valve sparing aortic root replacement (David surgery), and to compare the results with those of healthy volunteers (HV). Methods Patients with Marfan or Loeys-Dietz syndrome underwent two non-contrast enhanced 4D flow CMR, one before and another after undergoing David surgery. Healthy volunteers matched for age, sex and BSA were also included for comparison. Maximum velocity, in-plane rotational flow (IRF), systolic flow reversal ratio (SFRR) and wall shear stress (WSS) magnitude and its axial and circumferential components were obtained at 24 planes covering the thoracic aorta from the sinotubular junction to the descending aorta at the diaphragmatic level (3–5). Results Sixteen patients and 21 healthy volunteers were included. Demographic and clinical data is presented in Table. The mean time between the CMR prior and posterior to surgery was 15 months. Compared to HV, patients with CTD before intervention presented lower maximum velocity at the proximal ascending aorta (Figure 1A), lower IRF and circumferential WSS at the arch and the proximal descending aorta (Figure 1B and F), lower magnitude and axial WSS at the proximal ascending and descending aorta (Figure 1E and D), and increased SFRR at the proximal descending aorta (Figure 1C). The intervention completely restored maximum velocity and partially-restored physiological helical flow and circumferential WSS, but barely improved axial WSS and SFRR. Conclusion Valve sparing aortic root replacement in patients with Marfan or Loeys-Dietz syndrome partially restore to physiological level both in-plane rotational flow and circumferential wall shear stress in the descending aorta.

Outcomes After Endovascular Aortic Intervention in Patients With Connective Tissue Disease

Endovascular treatment is not recommended for aortic pathologies in patients with connective tissue diseases (CTDs) other than in redo operations and as bridging procedures in emergencies. However, recent developments in endovascular technology may challenge this dogma. To assess the midterm outcomes of endovascular aortic repair in patients with CTD. For this descriptive retrospective study, data on demographics, interventions, and short-term and midterm outcomes were collected from 18 aortic centers in Europe, Asia, North America, and New Zealand. Patients with CTD who had undergone endovascular aortic repair from 2005 to 2020 were included. Data were analyzed from December 2021 to November 2022. All principal endovascular aortic repairs, including redo surgery and complex repairs of the aortic arch and visceral aorta. Short-term and midterm survival, rates of secondary procedures, and conversion to open repair. In total, 171 patients were included: 142 with Marfan syndrome, 17 with Loeys-Dietz syndrome, and 12 with vascular Ehlers-Danlos syndrome (vEDS). Median (IQR) age was 49.9 years (37.9-59.0), and 107 patients (62.6%) were male. One hundred fifty-two (88.9%) were treated for aortic dissections and 19 (11.1%) for degenerative aneurysms. One hundred thirty-six patients (79.5%) had undergone open aortic surgery before the index endovascular repair. In 74 patients (43.3%), arch and/or visceral branches were included in the repair. Primary technical success was achieved in 168 patients (98.2%), and 30-day mortality was 2.9% (5 patients). Survival at 1 and 5 years was 96.2% and 80.6% for Marfan syndrome, 93.8% and 85.2% for Loeys-Dietz syndrome, and 75.0% and 43.8% for vEDS, respectively. After a median (IQR) follow-up of 4.7 years (1.9-9.2), 91 patients (53.2%) had undergone secondary procedures, of which 14 (8.2%) were open conversions. This study found that endovascular aortic interventions, including redo procedures and complex repairs of the aortic arch and visceral aorta, in patients with CTD had a high rate of early technical success, low perioperative mortality, and a midterm survival rate comparable with reports of open aortic surgery in patients with CTD. The rate of secondary procedures was high, but few patients required conversion to open repair. Improvements in devices and techniques, as well as ongoing follow-up, may result in endovascular treatment for patients with CTD being included in guideline recommendations.

Aortopathies: From Etiology to the Role of Arterial Stiffness.

The aorta and aortic wall have a complex biological system of structural, biochemical, biomolecular, and hemodynamic elements. Arterial stiffness could be considered a manifestation of wall structural and functional variations, and it has been revealed to have a strong connection with aortopathies and be a predictor of cardiovascular risk, especially in patients affected by hypertension, diabetes mellitus, and nephropathy. Stiffness affects the function of different organs, especially the brain, kidneys, and heart, promoting remodeling of small arteries and endothelial dysfunction. This parameter could be easily evaluated using different methods, but pulse-wave velocity (PWV), the speed of transmission of arterial pressure waves, is considered the gold standard for a good and precise assessment. An increased PWV value indicates an elevated level of aortic stiffness because of the decline in elastin synthesis and activation of proteolysis and the increase in fibrosis that contributes to parietal rigidity. Higher values of PWV could also be found in some genetic diseases, such as Marfan syndrome (MFS) or Loeys-Dietz syndrome (LDS). Aortic stiffness has emerged as a major new cardiovascular disease (CVD) risk factor, and its evaluation using PWV could be very useful to identify patients with a high cardiovascular risk, giving some important prognostic information but also being used to value the benefits of therapeutic strategies.

Comparison of Genes Associated with Thoracic and Abdominal Aortic Aneurysms.

Aneurysms impacting the ascending thoracic aorta and the abdominal aorta affect patient populations with distinct clinical characteristics. Through a literature review, this paper compares the genetic associations of ascending thoracic aortic aneurysm (ATAA) with abdominal aortic aneurysms (AAA). Genes related to atherosclerosis, lipid metabolism, and tumor development are associated specifically with sporadic AAA, while genes controlling extracellular matrix (ECM) structure, ECM remodeling, and tumor growth factor β function are associated with both AAA and ATAA. Contractile element genes uniquely predispose to ATAA. Aside from known syndromic connective tissue disease and poly-aneurysmal syndromes (Marfan disease, Loeys-Dietz syndrome, and Ehlers-Danlos syndrome), there is only limited genetic overlap between AAA and ATAA. The rapid advances in genotyping and bioinformatics will elucidate further the various pathways associated with the development of aneurysms affecting various parts of the aorta.

Long-term durability of valve-sparing root replacement in patients with and without connective tissue disease

ObjectiveThe goal of this study was to evaluate the long-term outcomes of valve-sparing root replacement in patients with connective tissue disease (CTD) and compare them with patients without CTD who underwent valve-sparing root replacement for root aneurysm. MethodsOf 487 patients, 380 (78%) did not have CTD and 107 (22%) had CTD; 97 (91%) with Marfan syndrome, 8 (7%) with Loeys-Dietz syndrome, and 2 (2%) with Vascular Ehlers-Danlos syndrome. Operative and long-term outcomes were compared. ResultsThe CTD group was younger (36 ± 14 years vs 53 ± 12 years; P < .001), had more women (41% vs 10%; P < .001) and had less hypertension (28% vs 78%; P < .001) and bicuspid aortic valve (8% vs 28%; P < .001). Other baseline characteristics did not differ between the groups. Overall operative mortality was nil (P = 1.000); the incidence of major postoperative complications was 1.2% (0.9% vs 1.3%; P = 1.000) and did not differ between groups. Residual mild aortic insufficiency (AI) was more frequent in the CTD group (9.3% vs 1.3%, P < .001) with no difference in moderate or greater AI. Ten-year survival was 97.3% (97.2% vs 97.4%; log-rank P = .801). Of the 15 patients with residual AI, 1 had none, 11 remained mild, 2 had moderate, and 1 had severe AI on follow-up. Ten-year freedom from moderate/severe AI was 89.6% (hazard ratio, 1.05; 95% CI, 0.8-1.37; P = .750) and 10-year freedom from valve reoperation was 94.9% (hazard ratio, 1.21; 95% CI, 0.43-3.39; P = .717). ConclusionsThe operative outcomes as well as long-term durability of valve-sparing root replacement is excellent in patients with or without CTD. Valve function and durability are not influenced by CTD.

Abstract 284: Pro-Inflammatory Adventitial Fibroblast Contribute To Aortic Aneurysms In Loeys Dietz Syndrome

Introduction: Vascular smooth muscle cell (SMC) phenotype modulation is implicated in thoracic aneurysm formation, however, the role of adventitial fibroblasts (AdvFib) in aneurysm formation remains poorly characterized. Loeys-Dietz Syndrome (LDS), caused by a spectrum of mutations in the TGF-β signaling cascade, leads to aggressive thoracic aneurysms. Given the ubiquitous nature of TGF-β signaling machinery, the exact cell type(s) responsible for initiation of LDS pathogenesis is poorly understood. Methods: We performed single cell transcriptomic characterization of aortic root and ascending aortic samples from LDS patients ((n=6 LDS (harboring TGFB2 , TGFBR1 , TGFBR2 , or SMAD3 mutation); n=2 Donor control)) as well as root/ascending aorta from a murine model of LDS ( Tgfbr2 G357W/+ ) to understand cell-state transitions and transcriptomic alterations in LDS. Results: Single cell RNA sequencing (scRNAseq) of human and mice LDS samples (in total &gt;40,000 cells) revealed a secondary pattern of cellular activation in LDS as compared to Marfan Syndrome. Instead of SMC phenotypic modulation as seen in MFS, LDS appears to preferentially modulate adventitial fibroblasts (AdvFib) phenotype in the Tgfbr2 G357W/+ mouse model. Human LDS patient’s AdvFib turn on high levels of macrophage-recruiting pro-inflammatory cytokines CCL2 and HLA-B, with a corresponding 1.8-fold increase in LDS aortic wall macrophages compared to Donor. A more extreme pattern was observed in the Tgfbr2 G357W/+ LDS mouse model. While Tgfbr2 G357W/+ SMC are transcriptomically similar to wild type counterparts, AdvFib were activated into a pro-inflammatory state associated with increased aortic macrophage recruitment ( Ccl2 , Il6 , Vcam1, and Cxcl2 ) and fibrotic response ( Col1a1 , Col1a2 , Col3a1, and Fn1 ). A 6-fold increase in the number of aortic wall macrophages was identified in Tgfbr2 G357W/+ compared to WT. Conclusions: LDS mouse and human AdvFib undergo phenotypic alterations into a pro-inflammatory state evidenced by increased expression of numerous cytokines, macrophage recruitment, and ECM deposition. AdvFib, in addition to SMCs, are potentially another important pathological cell population in LDS aneurysm formation.

Abstract 564: Genetic Basis Of Thoracic Aortic Aneurysms In A Large Unselected Clinical Population

Objectives: Thoracic aortic aneurysms (TAAs) are associated with protein coding variants in genes associated with Loeys-Dietz Syndrome (LDS), vascular Ehlers-Danlos Syndrome (VEDS) and ACTA2 . The purpose of this study was to estimate the prevalence of these variants, along with potential novel variants, in a large unselected clinical population. Methods: We analyzed exome sequence data from 174,452 participants. Rare variants (frequency &lt;0.001) were annotated by functional consequence and classification as pathogenic or likely pathogenic (P/LP) in the ClinVar database. TAA diagnoses were determined by ICD-10 codes. Results: 2,670 (1.5%) individuals had a TAA diagnosis; mean age was 66.1 years, compared to 56.7 for the study population (p=0.014). 69% of TAA cases were male and 71% were smokers. There were 20 carriers of ClinVar P/LP variants in LDS genes (8 variants in 10 carriers for SMAD3 , 3 variants in 3 carriers for TGFB2 , 2 variants in 2 carriers for TGFBR1 , 3 variants in 5 carriers for TGFBR2); 5 had a diagnosis of TAA (2 for SMAD 3, 1 each for the others; ORs =16-65); the age of diagnosis was significantly lower than for non-carriers (p&lt;0.0001). 11 P/LP carriers without a TAA diagnosis were &lt;55 years old and could be at risk for TAA. There was 1 TAA case in 21 COL3A1 P/LP carriers and 0 cases in 10 COL1A1 P/LP carriers. We also identified LDS and VEDS variants that are classified as uncertain significance that could be reclassified as P/LP based on their association with early TAA (Table 1). ACTA2 P/LP variants were also strongly associated with TAA (OR=26; p&lt;0.001). The prevalence of P/LP variants in these genes is 1/3,300 (1/1,350 if potential novel pathogenic variants are included). Conclusions: Our results provide estimates of the prevalence and penetrance of variants associated with TAA in a large unselected clinical population, reveal potential novel pathogenic variants, and support the use of genetic data to identify individuals with high disease risk.

Reimplantation of the aortic valve in patients with tricuspid aortic valve: the Toronto General Hospital experience.

Aortic valve sparing operations were introduced three decades ago but controversy remains regarding its appropriateness, reproducibility and durability. This article describes the long-term outcomes of patients who had reimplantation of the aortic valve. All patients who had reimplantation of a tricuspid aortic valve at Toronto General Hospital from 1989 through 2019 were selected for this study. Patients were followed prospectively with periodical clinical assessments and imaging of the heart and aorta. Four hundred and four patients were identified. The median age was 48.0 [interquartile range (IQR), 35.0-59.0] years and 310 (76.7%) were men. There were 150 patients with Marfan syndrome, 20 with Loeys-Dietz syndrome and 33 with acute or chronic aortic dissections. The median follow-up was 11.7 (IQR, 6.8-17.1) years. There were 55 patients alive and without reoperation at 20 years. The cumulative mortality at 20 years was 26.7% [95% confidence interval (CI): 20.6-34.2%], the cumulative incidence of reoperation on the aortic valve was 7.0% (95% CI: 4.0-12.2%) and the development of moderate or severe aortic insufficiency was 11.8% (95% CI: 8.5-16.5%). We could not identify variables associated with reoperation on the aortic valve or with the development of aortic insufficiency. New distal aortic dissections were common in patients with associated genetic syndromes. Reimplantation of the aortic valve in patients with tricuspid aortic valve provides excellent aortic valve function during the first two decades of follow-up. Distal aortic dissections are relatively common in patients with associated genetic syndromes.

Aortic valve-sparing procedure in the pediatric population.

Aortic valve-sparing procedures have been established as a mainstream treatment option for adult patients with aortic root aneurysms. However, data regarding their use in the pediatric population is limited. This study reports on our experience with aortic valve-sparing procedures in children. A retrospective review was conducted of all patients who underwent an aortic valve-sparing procedure at the Royal Children's Hospital, Melbourne, Australia between April 2006 and April 2016. Clinical and echocardiographic data were analyzed. The study included 17 patients, with a median age of 15.7 years and a majority of patients being male (82.4%). The most common diagnosis was transposition of great arteries after arterial switch operation, followed by Loeys-Dietz syndrome and Marfan syndrome. Preoperative echocardiography showed more than moderate aortic regurgitation in 94.1% of the patients. The David procedure was performed in all 17 patients, with no mortality during follow-up. Reoperation was required in 29.4% of patients, and 23.5% required aortic valve replacement. Freedom from reoperation for aortic valve replacement at 1, 5, and 10 years was 93.8%, 93.8% and 68.2% respectively. Aortic valve-sparing surgery can be successfully performed in the pediatric population. However, it requires a highly skilled surgeon due to the often dysplastic or distorted nature of these valves and the need for additional procedures on the aortic valve leaflets.