BACKGROUND:Pathogenic variants in TGFB3 may lead to a syndromic genetic aortopathy. Heritable thoracic aortic disease (HTAD) and arterial events may occur in TGFB3-related disease but there are limited outcomes data on vascular events in this condition. METHODS:Clinical data, phenotypical features and aortic outcomes in individuals with pathogenic/likely pathogenic (P/LP) TGFB3 variants enrolled in the Montalcino Aortic Consortium registry were reviewed. RESULTS:34 individuals (56% male, median age 42 years, IQR 17-49, range 3-74 years) with P/LP TGFB3 variants were studied. Craniofacial, cutaneous and musculoskeletal features seen in Loeys-Dietz syndrome were variably present. Extra-aortic cardiovascular features included arterial tortuosity (25%), extra-aortic arterial aneurysms (6%) and mitral valve prolapse (21%).Aortic dilation (Z-Score>2) was present in 10 individuals (29%) and aortic dissection occurred in 2 (6%). Type A aortic dissection occurred in two patients (aged between 55 years and 60 years), and one of these patients experienced a type B aortic dissection 6 years later. Seven adults (median age 62 years, range 32-69 years) with aortic root dilation (41-49 mm) are being followed. No patients have undergone prophylactic aortic surgery. Twenty-five per cent of children have aortic dilation. Sixty-eight per cent of the entire cohort remains free of aortic disease. No deaths have occurred. CONCLUSIONS:TGFB3-related HTAD is characterised by late-onset and less penetrant thoracic aortic and arterial disease compared with other transforming growth factor β HTAD. Based on our data, a larger aortic size threshold for prophylactic aortic surgery is appropriate in patients with TGFB3-related HTAD compared with HTAD due to TGFBR1 or TGFBR2 variants.

Evaluate family functioning (FF) and associations with quality of life (QOL) in a large, multicenter cohort of children and young adults with Marfan syndrome (MFS) who participated in the Pediatric Heart Network (PHN) Marfan Trial. Of the 608 patients enrolled in the PHN Marfan Trial, 359 families completed one or more of the following: the General Functioning subscale of the Family Assessment Device (FAD), the Condition Management Ability module of the Family Management Measure (FaMM), and the Pediatric Quality of Life Inventory (PedsQL) at the final trial visit at three years. The correlations between FAD and FaMM scores and patient-related factors were examined. Linear regression was used to determine the relationship between FAD, FaMM, patient-related factors, and PedsQL. 25

Rare genetic aortopathies are frequently undiagnosed due to phenotypic heterogeneity, and delayed diagnosis can lead to fatal cardiac outcomes. While genetic testing can enable early proactive interventions, it relies on primary care physicians to recognize a genetic basis for symptoms and then refer patients to clinical genetics. Broad-scale screening methods are needed to identify cases that do not fit an obvious diagnostic pattern. Clinical notes, rich in narrative details, may support the automated flagging of patients for genetic testing. Given the strength of Large Language Models (LLMs) in processing unstructured text, we developed an open-source LLM-enabled genetic testing recommendation pipeline, which leverages retrieval augmented generation (RAG) on curated genetic aortopathy-related corpora to utilize relevant clinical knowledge for identifying patients likely to benefit from genetic testing. The pipeline was validated using 22,510 patient progress notes from 500 individuals (250 cases, 250 controls) in the Penn Medicine BioBank, and successfully categorized 425 out of 499 patients, with one case requiring further clinician evaluation due to incomplete information. The pipeline achieved a patient-level recommendation accuracy of 0.852, precision of 0.889, sensitivity of 0.803, F1-score of 0.844, and F3-score of 0.811. Our LLM-enabled workflow that integrates RAG showed strong performance in recommending genetic testing for patients with rare genetic aortopathies, demonstrating its potential to support undiagnosed patient identification from free-text clinical notes, thereby automating early disease identification and improving patient outcomes.

Research participants report interest in receiving genetic research results. How best to return results remains unclear. In this randomized pilot study, we sought to assess the feasibility of returning actionable research results through a two-step process including a patient-centered digital intervention as compared to a genetic counselor (GC) in the Penn Medicine biobank. In Step 1, participants with an actionable result and procedural controls (no actionable result) were invited to digital pre-disclosure education and provided options for opting out of results. In Step 2, those with actionable results who had not opted out were randomized to receive results via a digital disclosure intervention or with a GC. Five participants (2%) opted out of results after Step 1. After both steps, 52/113 (46.0%) of eligible cases received results, 5 (4.4%) actively declined results, 34 (30.1%) passively declined and 22 (19.5%) could not be reached. Receiving results was associated with younger age (p<0.001), completing pre-disclosure education (p<0.001) and being in the GC arm (p=0.06). Being older, female, and of Black race were associated with being unable to reach. Older age and Black race were associated with passively declining. 47% of those who received results did not have personal or family history to suggest the mutation, and 55.1% completed clinical confirmation testing. The use of digital tools may be acceptable to participants and could reduce costs of returning results. Low uptake, disparities in uptake, and barriers to confirmation testing will be important to address to realize the benefit of returning actionable research results.

A 45-year-old healthy man has a myocardial infarction with no risk factors other than a grandfather with a similarly aged cardiac death and a daughter with Moyamoya disease and is found to have an aortopathy due to a pathogenic variant in the ACTA2 gene.

BACKGROUND: Over the past 25 years, diagnosis and therapy for acute aortic dissection (AAD) have evolved. We aimed to study the effects of these iterative changes in care. METHODS: Patients with nontraumatic AAD enrolled in the International Registry of Acute Aortic Dissection (61 centers; 15 countries) were divided into time-based tertiles (groups) from 1996 to 2022. The impact of changes in diagnostics, therapeutic care, and in-hospital and 3-year mortality was assessed. Cochran-Armitage trend and Jonckheere-Terpstra tests were conducted to test for any temporal trend. RESULTS: Each group consisted of 3785 patients (mean age, ≈62 years old; ≈65.5% males); nearly two-thirds had type A AAD. Over time, the rates of hypertension increased from 77.8% to 80.4% ( P =0.002), while smoking (34.1% to 30.6%, P =0.033) and atherosclerosis decreased (25.6%–16.6%; P <0.001). Across groups, the percentage of surgical repair of type A AAD increased from 89.1% to 92.5% ( P <0.001) and was associated with decreased hospital mortality (from 24.1% in group 1 to 16.7% in group 3; P <0.001). There was no difference in 3-year survival ( P =0.296). For type B AAD, stent graft therapy (thoracic endovascular aortic repair) was used more frequently (22.3%–35.9%; P <0.001), with a corresponding decrease in open surgery. Endovascular in-hospital mortality decreased from 9.9% to 6.2% ( P =0.003). As seen with the type A AAD cohort, overall 3-year mortality for patients with type B AAD was consistent over time ( P =0.084). CONCLUSIONS: Over 25 years, substantial improvements in-hospital survival were associated with a more aggressive surgical approach for patients with type A AAD. Open surgery has been partially supplanted by thoracic endovascular aortic repair for complicated type B AAD, and in-hospital mortality has decreased over the time period studied. Postdischarge survival for up to 3 years was similar over time.

Autoimmunity is a breakdown of the normal mechanisms that maintain immunologic homeostasis in the immune system response to specific antigens. The pathogenesis of autoimmune disease is multifactorial, including both genetic and environmental factors affecting the onset, maintenance, and progression of diseases. Autoimmune disorders result from the recognition of self-antigen(s) and the subsequent attack on self-tissues, usually by the adaptive immune response. Autoimmune pathology can be caused by T lymphocytes, natural killer cell, and/or antibodies and can be modulated by hormonal effects. One of the unifying themes of many autoimmune disorders is that they are associated with specific alleles and genotypes of the highly polymorphic major histocompatibility complex where, in humans, the human leukocyte antigen loci reside. In addition, a host of other genes can contribute to the onset, course, management, and response to therapy of specific diseases.

BACKGROUND: Arterial tortuosity is associated with adverse events in Marfan and Loeys-Dietz syndromes but remains understudied in Vascular Ehlers-Danlos syndrome. METHODS AND RESULTS: Subjects with a pathogenic COL3A1 variant diagnosed at age <50 years were included from 2 institutions and the GenTAC Registry (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions). Height-adjusted vertebral artery tortuosity index (VTI-h) using magnetic resonance or computed tomography angiography was calculated. Associations between VTI-h and outcomes of (1) cardiovascular events (arterial dissection/rupture, aneurysm requiring intervention, stroke), or (2) hollow organ collapse/rupture at age <50 years were evaluated using receiver operator curve analysis (using outcome by age 30 years) and mixed-effects Poisson regression for incidence rate ratios. Of 65 subjects (54% male), median VTI-h was 12 (interquartile range, 8-16). Variants were missense in 46%, splice site in 31%, and null/gene deletion in 14%. Thirty-two subjects (49%) had 59 events, including 28 dissections, 5 arterial ruptures, 4 aneurysms requiring intervention, 4 strokes, 11 hollow organ ruptures, and 7 pneumothoraces. Receiver operator curve analysis suggested optimal discrimination at VTI-h >= 15.5 for cardiovascular events (sensitivity 70%, specificity 76%) and no association with noncardiovascular events (area under the curve, 0.49 [95% CI, 0.22-0.78]). By multivariable analysis, older age was associated with increased cardiovascular event rate while VTI-h >= 15.5 was not (incidence rate ratios, 1.79 [95% CI, 0.76-4.24], P=0.185). However, VTI-h >= 15.5 was associated with events among those with high-risk variants <40 years (incidence rate ratios, 4.14 [95% CI, 1.13-15.10], P= 0.032), suggesting effect modification by genotype and age. CONCLUSIONS: Increased arterial tortuosity is associated with a higher incidence rate of cardiovascular events in Vascular Ehlers-Danlos syndrome. Vertebral tortuosity index may be a useful biomarker for prognosis when evaluated in conjunction with genotype and age.

Over the past 2 decades, understanding the genetics underlying a wide spectrum of arteriopathies, and especially aortopathies, has advanced markedly. In part, this has been due to describing the clinical and inheritance of syndromes, and then finding their genetic bases. From the opposite direction, discovery of genes involved in arterial structure and function has enabled “new” human phenotypes to be defined. Over four dozen Mendelian conditions affect the arterial system, and the underlying genetic bases are known for many. These genes encode a variety of proteins that serve diverse functions in arterial structure and function. Principal among them are components of the extracellular matrix, vascular smooth muscle, and signaling pathways such as for TGF-β. Knowing the genetic variant underlying disease in a particular patient enables predicting the course of their condition and the detection of disease, often undetected, in relatives. Understanding the basic pathophysiology of genetic variants has already produced novel therapeutics, a perfect example of precision medicine.