Multifocal disease progression and subsequent intervention in patients with actin alpha-2 variants: A single-center experience.

OBJECTIVES: To describe patient characteristics and indications for surgical intervention, reoperation, and outcomes in patients with actin alpha-2 (ACTA2) variants. METHODS: A single-center retrospective cohort study with prospective follow-up was performed for 38 patients with an ACTA2 variant. RESULTS: From 1999 to 2020, 26 (70%) patients underwent surgery; 11 remain under surveillance (mean follow-up, 7.5 ± 5 years). Median age at index operation was 42 (range, 10-69) years, with 4 pediatric cases. Thoracic aortic aneurysm was present in 19 (73%) patients (mean adult max diameter, 5.2 ± 0.8 cm; pediatric z score, 10.7 ± 5.4). Aortic dissection was present in 13 (50%) patients, with 4 (15%) having type A dissection. Operations included replacement of the aortic root in 16 (17%), ascending aorta in 20 (77%), and aortic arch in 14 (54%) patients. Four (15%) patients had coronary artery disease, and 2 (7.7%) underwent concomitant coronary artery bypass grafting. There was no operative mortality, stroke, reoperation for bleeding, or dialysis-dependent renal failure; One (3.8%) patient developed acute on chronic kidney injury. Three patients (12%) required prolonged ventilation. Eleven (42%) patients underwent 26 reoperations, median time 45 (range, 4-147) months, including 5 open thoracoabdominal aneurysm repairs. CONCLUSIONS: Patients with ACTA2 variants frequently develop aortic aneurysm and are at risk of aortic dissection and coronary artery disease. However, age at diagnosis and symptoms at presentation are highly variable. Multiple operations are often required for disease management, particularly after dissection. Close monitoring and timely intervention are important in mitigating disease progression and improving outcomes.

Loeys-Dietz syndrome: Intermediate-term outcomes of medically and surgically managed patients.

OBJECTIVES: Loeys-Dietz syndrome (LDS) is an aggressive connective tissue disorder associated with increased risk of aortic dissection and aneurysm rupture at an early age and smaller aortic diameters. We report our experience with LDS to better understand its natural history and treatment outcomes and help establish treatment guidelines. METHODS: We retrospectively reviewed all patients with LDS who underwent medical or surgical treatment at Cleveland Clinic before April 27, 2017. Primary endpoints were postoperative in-hospital morbidity and mortality. Secondary endpoints were aorta-related reoperations and short- and long-term mortality. RESULTS: We identified 53 patients with LDS. Of these, 33 (62%) underwent aortic surgery. Mean age was 39 ± 14 years, and mean maximum aortic diameter was 4.3 cm. There were 2 (6%) deaths after urgent or emergency surgery. Twenty-two patients (67%) required no aortic reoperation; 20 of these had prophylactic surgery. Multiple aortic operations were performed on 11 (33%) patients, 9 of whom experienced aortic dissections. Six patients (18%) required total aortic replacement. Among 19 patients with modified root reimplantation, no aorta- or valve-related complications occurred. Overall, 33 patients underwent 58 aortic and 81 cardiovascular operations, with 1 late death. Kaplan-Meier survival of the aortic-surgery cohort was 89% at 10 years (median follow-up 5.2 years). There were no late deaths in the non-aortic surgery group (20/53; 38%). CONCLUSIONS: Prophylactic aortic surgical outcomes in LDS are excellent. Surgical reintervention remains high, particularly after aortic dissections. Close surveillance of medically managed and postoperative patients and early prophylactic surgery are crucial to avoid aortic catastrophe and achieve a good long-term prognosis.

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.

The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs∗25 and p.Glu750∗) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-ß binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3-/- mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.

Assessment of clinical workload for general and specialty genetic counsellors at an academic medical center: a tool for evaluating genetic counselling practices.

With genomics influencing clinical decisions, genetics professionals are exponentially called upon as part of multidisciplinary care. Increasing demand for genetic counselling, a limited workforce, necessitates practices improve efficiency. We hypothesised that distinct differences in clinical workload exist between various disciplines of genetic counselling, complicating practice standardisation and patient volume expectations. We thus sought to objectively define and assess workload among various specialties of genetic counselling. Twelve genetic counsellors (GCs), representing 9.3 clinical FTE, in general or specialty (cancer, cardiovascular or prenatal) services at an academic health system developed a data collection tool for assessing time and complexity. Over a 6-week period, the data were recorded for 583 patient visits (136 general and 447 specialty) and analysed comparing general versus specialty GCs. Variables were compared with hierarchical linear models for ordinal or continuous data and hierarchical logistic models for binary data. General GCs completed more pre- and post-visit activities (P=0.011) and spent more time (P=0.009) per case. General GCs reported greater case discussion with other providers (P<0.001), literature review (P=0.026), exploring testing options (P=0.041), electronic medical record review (P=0.040), insurance preauthorization (P=0.05) and fielding patient inquiries (P=0.003). Lesser redundancy in referral indication was observed by general GCs. GCs in general practice carry a higher pre- and post-visit workload compared with GCs in specialty practices. General GCs may require lower patient volumes than specialty GCs to allow time for additional pre- and post-visit activities. Non-clinical activities should be transferred to support staff.

Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal vascular structures that may present as epistaxis, telangiectasias, and/or arteriovenous malformations. The genes associated with HHT (ACVRL1, ENG, and SMAD4) are members of the TGFß pathway. Other syndromes associated with abnormalities in TGFß signaling include Marfan syndrome, Loeys-Dietz syndrome and related disorders. These disorders have aortic disease as a prominent finding. While there are case reports of patients with HHT and aortopathy (dilatation/aneurysm, dissection, and rupture), this has not been systematically investigated. We conducted a retrospective chart review to determine the prevalence of aortopathy in an HHT cohort. Patients from a single institution were identified who met the Curacao Criteria for a clinical diagnosis of HHT and/or had a mutation in ACVRL1, ENG, or SMAD4 and underwent echocardiogram. Two-dimensional echocardiograms were reviewed by a single pediatric cardiologist, and data were collected on demographics, genotype, HHT features, aortic root measurements, past medical history, and family history. Z scores and nomograms were utilized to identify abnormal results. Twenty-six patients from 15 families (one ACVRL1, four ENG, eight SMAD4, and two clinical diagnoses) were included in the analysis. Aortopathy was found in 6/26 (23%) patients; all had SMAD4 mutations. In our cohort, 6/16 (38%) SMAD4 mutation carriers had evidence of aortopathy. These data suggest that aortopathy could be part of the spectrum of SMAD4-induced HHT manifestations. Routine aortic imaging, including measurements of the aorta, should be considered in patients with SMAD4 mutations to allow for appropriate medical and surgical recommendations.

Family history of aortic disease predicts disease patterns and progression and is a significant influence on management strategies for patients and their relatives.

BACKGROUND: While a positive family history (FH) is a known risk factor for developing an aneurysm, its association with the extent of disease has not been established. We evaluated the influence of a FH of aortic disease with respect to the pattern and distribution of aortic aneurysms in a given patient. METHODS AND RESULTS: From November 1999 to November 2011, 1263 patients were enrolled in physician-sponsored endovascular device trials to treat aortic aneurysms. Of the 555 patients who were alive and returning for follow-up, we obtained 426 (77%) family histories. Three-dimensional imaging studies were used to identify the presence of aneurysms; 36% (155/426) of patients had a FH of aortic aneurysms and 5% (21/155) had isolated intracranial aneurysms. A logistic regression model was used to compare aortic morphology between patients with a positive or negative FH for aneurysms. Patients with a positive FH of aortic aneurysms were younger at their initial aneurysm (63 vs 70 years; P < .0001), more frequently had proximal aortic involvement (root: odds ratio [OR], 5.4; P < .0001; ascending: OR, 2.9; P < .001; thoracic: OR, 2.2; P = .01) with over 50% of FH patients ultimately developing suprarenal aortic involvement (P = .0001) and had a greater incidence of bilateral iliac artery aneurysm (OR, 1.8; P = .03). CONCLUSIONS: FH is an important tool that provides insight into the expected behavior of the untreated aorta and has significant implications for the development of treatment strategies. These findings should be used to guide patient's management with regard to treatment, follow-up paradigms, genetic testing, and screening of other family members.

Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia.

Patients with fibromuscular dysplasia (FMD) may have clinical features consistent with Mendelian vascular connective tissue disorders. The yield of genetic testing for these disorders among patients with FMD has not been determined. A total of 216 consecutive patients with FMD were identified. Clinical characteristics were collected and genetic test results reviewed for abnormalities in the following genes: transforming growth factor-ß receptor 1 and 2 (TGFßR1 and TGFßR2), collagen 3A1, fibrillin-1, smooth muscle α-actin 2, and SMAD3. A total of 63 patients (63/216; 29.2%) were referred for genetic counseling with testing performed in 35 (35/63; 55.6%). The percentage of patients with a history of arterial or aortic dissection, history of aortic aneurysm, systemic features of a connective tissue disorder, and a family history of sudden death was significantly larger in the group that underwent genetic testing (62.9% vs 18.2%, p < 0.001; 8.6% vs 1.7%, p = 0.02; 51.4% vs 17.1%, p < 0.001; and 42.9% vs 22.7%, p = 0.04, respectively). Two patients were found to have distinct variants in the TGFßR1 gene (c.611 C>T, p.Thr204lle and c.1285 T>C, p.Tyr429His). The yield of genetic testing for vascular connective tissue disorders was low in a high-risk subset of FMD patients. However, two patients with a similar phenotype had novel and distinct variants in the TGFßR1 gene, a finding which merits further investigation.