Comparative Risks of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease

Pathogenic variant; Precision medicine; Thoracic aortic aneurysmVariante patógena; Medicina de precisión; Aneurisma de la aorta torácicaVariant patògena; Medicina de precisió; Aneurisma de l'aorta toràcicaBackground Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes. Objectives This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene. Methods A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, and location of recruitment. Results Significant differences in aortic event risk were identified among the smooth muscle contraction genes (ACTA2, MYLK, and PRKG1; P = 0.002) and among the genes for Loeys-Dietz syndrome, which encode proteins in the transforming growth factor (TGF)-β pathway (SMAD3, TGFB2, TGFBR1, and TGFBR2; P < 0.0001). Cumulative incidence of type A aortic dissection was higher than elective aneurysm surgery in patients with variants in ACTA2, MYLK, PRKG1, and SMAD3; in contrast, patients with TGFBR2 variants had lower cumulative incidence of type A aortic dissection than elective aneurysm surgery. Cumulative incidence of type B aortic dissection was higher for ACTA2, PRKG1, and TGFBR2 than other genes. After adjusting for proband status, sex, and recruitment location, specific variants in ACTA2 and TGFBR2 were associated with substantially higher risk of aortic event with childhood onset. Conclusions Gene- and variant-specific data on aortic events in individuals with HTAD support personalized aortic surveillance and clinical management.These studies were funded by the National Institutes of Health (NIH) (NIH R01HL109942 to Dr Milewicz DMM and K23HL127266 to Dr Morris), Genetic Aortic Disorders Association Canada, Temerty Family Foundation, and the John Ritter Foundation. Dr LeMaire serves as a consultant for Terumo Aortic and Cerus; and serves as a principal investigator for clinical studies sponsored by Terumo Aortic and CytoSorbents. Dr Morris is on the scientific advisory board for vascular Ehlers Danlos syndrome clinical trial for Aytu Biopharma. Dr Regalado is an employee and shareholder of Invitae. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose

Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials

Background: Angiotensin receptor blockers (ARBs) and β blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments. Methods: In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus β blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus β blocker; and indirectly, β blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. Findings: We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference –0·07 [95% CI –0·12 to –0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with β-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with β blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase –0·08 [SE 0·03] in ARB groups vs –0·11 [SE 0·02] in β-blocker groups; absolute difference 0·03 [95% CI –0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between β blockers and control was –0·09 (95% CI –0·18 to 0·00; p=0·042). Interpretation In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a β blocker. The effects of β blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and β blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery. Funding: Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council

False lumen flow patterns and their relation with morphological and biomechanical characteristics of chronic aortic dissections: Computational model compared with magnetic resonance imaging measurements

Aortic wall stiffness, tear size and location and the presence of abdominal side branches arising from the false lumen (FL) are key properties potentially involved in FL enlargement in chronic aortic dissections (ADs). We hypothesize that temporal variations on FL flow patterns, as measured in a cross-section by phase-contrast magnetic resonance imaging (PC-MRI), could be used to infer integrated information on these features. In 33 patients with chronic descending AD, instantaneous flow profiles were quantified in the FL at diaphragm level by PC-MRI. We used a lumped-parameter model to assess the changes in flow profiles induced by wall stiffness, tear size/location, and the presence of abdominal side branches arising from the FL. Four characteristic FL flow patterns were identified in 31/33 patients (94%) based on the direction of flow in systole and diastole: BA = systolic biphasic flow and primarily diastolic antegrade flow (n = 6); BR = systolic biphasic flow and primarily diastolic retrograde flow (n = 14); MA = systolic monophasic flow and primarily diastolic antegrade flow (n = 9); MR = systolic monophasic flow and primarily diastolic retrograde flow (n = 2). In the computational model, the temporal variation of flow directions within the FL was highly dependent on the position of assessment along the aorta. FL flow patterns (especially at the level of the diaphragm) showed their characteristic patterns due to variations in the cumulative size and the spatial distribution of the communicating tears, and the incidence of visceral side branches originating from the FL. Changes in wall stiffness did not change the temporal variation of the flows whereas it importantly determined intraluminal pressures. FL flow patterns implicitly codify morphological information on key determinants of aortic expansion in ADs. This data might be taken into consideration in the imaging protocol to define the predictive value of FL flows.The research leading to these results has received funding from the Subprograma de Proyectos de Investigación en Salud (FIS), Instituto de Salud Carlos III, Spain (ref. PI108/0608, PI11/01709); the Programa de ayudas destinadas a universidades, centros de investigación y fundaciones hospitalarias para la contratación de personal investigador novel (FI-DGR 2011), Spain; and the EU FP7 for research, technological development and demonstration under grant agreement VP2HF (no 611823). All authors have reported that they have no relationships relevant to the contents of this paper to disclose. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript