Thoracic aortic aneurysms involving the root and ascending aorta progressively enlarge and can lead to life-threatening acute aortic dissections, collectively termed thoracic aortic disease (TAD). Oxidative stress due to an excess of reactive oxygen species (ROS) has been implicated in TAD pathogenesis by promoting vascular inflammation, extracellular matrix degradation, and smooth muscle cell apoptosis. Cobinamide (Cbi), a potent antioxidant and vitamin B12 analog, has been reported to slow aortic aneurysm growth in TAD mouse models. We evaluated its efficacy in mice administered β-aminopropionitrile (BAPN) to induce TAD, a model in which aneurysms progress to dissections. C57BL/6J mice of both sexes were administered either BAPN alone or BAPN plus Cbi in drinking water from postnatal day 21 (P21). Survival analysis showed that 56% of mice in the BAPN group died from aortic rupture by P49, whereas mortality increased to 91% in the BAPN + Cbi group (P = 0.049). Necropsy confirmed thoracic aortic rupture as the cause of death. At P35, proximal aortic analyses showed that Cbi significantly reduced ROS abundance in the ascending aorta, based on decreased dihydroethidium staining and lower oxidative stress markers, including protein carbonylation and DNA oxidation by 8-hydroxy-deoxyguanosine staining. Cbi did not affect aortic diameters by echocardiography or elastic fiber fragmentation. Cbi was associated with reduced oxidative stress in aortic tissue; it did not prevent aortic dissection and was associated with increased rupture-related mortality in the BAPN model. These findings highlight context-dependent roles of ROS in TAD and the importance of carefully evaluating antioxidant strategies in dissection-prone settings.NEW & NOTEWORTHY Cobinamide reduced oxidative stress in aortas of mice administered BAPN but was associated with worsened fatal aortic dissections, highlighting a context-dependent role of redox signaling in aortic disease and the need for careful evaluation of antioxidant therapies intended to prevent thoracic aortic dissection.

Background : Acute Type A Aortic Dissection (ATAAD) is a severe cardiovascular emergency with complex pathogenic mechanisms. This study aims to explore the cellular heterogeneity and potential mechanisms of ATAAD, as well as evaluate the protective effects of fenofibrate on ATAAD. Methods : We established a mouse model of ATAAD and performed single-cell RNA sequencing analysis on the ascending aorta of normal control, BAPN induced ATAAD, and BAPN+fenofibrate intervention groups. Quality control, data integration, and cell clustering analyses were conducted using the Seurat package. Cell communication, pseudo-time analysis, and characteristic gene analysis were employed to investigate the pathogenesis of ATAAD and the mechanism of fenofibrate action. Results : We identified 10 major cell types, with significantly increased proportions of monocytes and macrophages in the BAPN group. Pathway analysis revealed differential expression of multiple signaling pathways in ATAAD, particularly the specific activation of the SPP1 pathway. We identified 12 macrophage subpopulations, among which the C2 subpopulation (Plekhg5+ and Timd4+) may play a role in maintaining normal aortic function, while the C5 subpopulation (Cxcl3+ and Met+) may be a potential inducer of ATAAD. Following fenofibrate intervention, inflammatory pathway activity decreased, and macrophage subpopulation distribution tended towards normal. Moreover, the expression of the Lyve1 gene in macrophages was significantly associated with favorable prognosis, suggesting its potential as a marker for assessing aortic dissection outcomes. Conclusion : This study elucidates the cellular heterogeneity and potential mechanisms of ATAAD, identifying key macrophage subpopulations and signaling pathways. Fenofibrate may ameliorate the occurrence and progression of ATAAD by modulating macrophage subpopulation distribution and function, thereby improving intimal permeability. These findings lay the foundation for developing novel therapeutic strategies for ATAAD.

Bicuspid aortic valve (BAV) is the most common congenital heart lesion in adults and is often associated with thoracic aortic aneurysms and aortic stenosis. The genetic causes of most non-syndromic cases of BAV remain unknown. Pathogenic variants in COL1A1 or COL1A2, which encode type I collagen (COL1), cause osteogenesis imperfecta (OI), a rare disorder marked by bone fragility. Although aortic valve phenotypes, including BAV, have been described in OI, COL1 genes have not been implicated in sporadic BAV. We report rare COL1 variants in individuals with early-onset BAV (EBAV) complications. Whole-exome sequencing was performed in 272 non-syndromic BAV probands who developed valve or aortic complications before age 30 (EBAV) and 272 biological relatives. Variants were filtered by allele frequency, inheritance pattern, ClinVar classification, and in silico predictions. Participants with rare predicted damaging COL1 variants were recontacted to confirm phenotypes. Rare coding variants in COL1A1 (n = 5) and COL1A2 (n = 5) were identified in 10 (4%) EBAV probands, representing a 30-fold enrichment compared with European ancestry populations. Only two variants involved glycine substitutions in triple-helical domains. Affected probands presented with aortic regurgitation and/or thoracic aneurysms requiring repair and exhibited subtle connective tissue features such as joint hypermobility, recurrent fractures, or dental abnormalities. Predicted damaging COL1 variants are enriched in EBAV probands with features overlapping OI and Ehlers-Danlos syndrome, though involving different residues than those in OI. Genetic testing for these variants may help identify individuals who could benefit from personalized surveillance or targeted preventive strategies.

PURPOSE:Variants of uncertain significance (VUS) represent are clinical challenging. We hypothesize that bioinformatic tools can identify VUS that are "high risk." METHODS:Primary analyses were performed in the Penn Medicine Biobank, which is composed of 43,731 participants, 11,925 of whom carried at least 1 missense VUS in the 11 genes associated with heritable thoracic aortic disease. VUS rare exome variant ensemble learner, AlphaMissense, and minor allele frequency high-risk thresholds were derived using cutpointR. These cutpoints were used to test the association of high-risk VUS with prevalent thoracic aortic disease. RESULTS:In the Penn Medicine Biobank, being heterozygous for a VUS was associated with a modest increased risk of thoracic aortic aneurysm (TAA: OR = 1.14, 95% confidence interval [CI] 1.01 to 1.29, P = .034) but no increased risk of aortic dissection (OR = 1.04, 95% CI 0.55 to 2.00, P = .896). Using cutpointR, we derived are exome variant ensemble learner (>0.649), AlphaMissense (>0.2543), and minor allele frequency (<8.16 × 10-6) cutpoints that identified 435 high-risk VUS that were robustly associated with prevalent dissection (OR = 7.85, 95% CI 4.73 to 13.03, P < .001), although the association with TAA was attenuated (OR = 2.35, 95% CI 1.62 to 3.42, P < .001). Similar results were observed in 2 independent validation cohorts. CONCLUSION:High-risk VUS were strongly associated with aortic dissection, suggesting that high-risk thresholds may be applied clinically.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are associated with increased atherosclerotic cardiovascular disease (ASCVD) risk independent of plasma cholesterol levels. While T-cell activation after ICI treatment contributes to this risk, emerging data implicate vascular smooth muscle cells (SMCs) as contributors to increased ASCVD associated with ICIs. Here, we investigated the effect of the ICI nivolumab, a monoclonal antibody targeting programmed death 1 (PD-1), on cultured human SMCs and determined that it induced activation of heat shock factor 1 (HSF1), the principal transcriptional regulator of cytosolic stress. HSF1 activation led to increased activation of HMG-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis, and accumulation of cholesteryl esters. Nivolumab treatment also activated endoplasmic reticulum (ER) stress, particularly PERK signaling, and atherosclerosis-associated phenotypic modulation of SMCs. Nivolumab-induced cholesterol synthesis, PERK signaling, and SMC phenotypic modulation were reversed by neutralization and knockdown of PD-1, as well as treatment with the HMGCR inhibitor pravastatin. These results reveal that nivolumab induces HSF1-HMGCR-PERK signaling and SMC phenotypic modulation and provides a rationale for statin therapy to mitigate ICI-induced ASCVD even in normocholesterolemic patients, highlighting a potential strategy to prevent ASCVD in cancer survivors receiving ICIs.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that affects cardiovascular, musculoskeletal, and ocular tissues, with premature death often resulting from dissection of the thoracic aorta. MFS results from pathogenic variants in FBN1, which encodes fibrillin-1, a glycoprotein that promotes elastic fibre organization and stability and contributes to smooth muscle cell mechano-sensing of extracellular matrix. It has been 35 years since the discovery that FBN1 variants cause MFS, yet understanding links between a variant and thoracic aortic disease remains incomplete, and definitive treatments remain wanting. We review advances in understanding disease progression in the aorta in MFS from perspectives of genetics, histology, mechanobiology, and biomechanics, with a focus on mouse models that include further genetic modifications to assess factors contributing to disease progression as well as effects of pharmacological treatments. This monogenic disease results in hundreds of differentially expressed genes in the aorta, many cell specific, that should be delineated as protective compensations, pathologic consequences, or neutral changes, and therapies should promote beneficial compensations and prevent detrimental consequences. Given the complexity of aortic disease in MFS, data-informed and data-driven computational models promise to help integrate multimodal data and increase understanding of molecular and cellular changes that drive disease progression, with a goal of improved therapies that prevent disease progression.

BACKGROUND:ACTA2 pathogenic variants predispose to thoracic aortic disease, and a subset of variants lead to early onset atherosclerotic cardiovascular disease (ASCVD). The molecular pathway linking misfolded SMA (α-smooth muscle actin) monomers to augmented atherosclerosis-associated smooth muscle cell phenotypic modulation can be modeled in vitro by stably expressing the ACTA2 p.R149C variant in Acta2-/- smooth muscle cells. METHODS:The Montalcino Aortic Consortium patient registry was used to identify cases with ACTA2 pathogenic/likely pathogenic missense variants. These patients were surveyed, and medical records were reviewed, to identify cases with early onset ASCVD. The variants for these cases, as well as other recurrent ACTA2 missense variants, were individually expressed in Acta2-/- smooth muscle cells, and transcript and protein levels, HSF1 (heat shock factor 1) activation, HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) expression and activity, cholesteryl ester levels, and downstream smooth muscle cell phenotypic modulation were assessed. RESULTS:Early onset ASCVD included coronary artery disease, peripheral vascular disease, and atherosclerotic plaques identified by imaging in the arch, descending, or abdominal aorta, along with the celiac, iliac, renal, or vertebral arteries. Twelve ACTA2 variants were identified to be associated with early onset ASCVD. Early onset ASCVD was correlated with HSF1 activation (P=0.035), cellular cholesteryl ester levels (P=0.0031), and having one family member with the specific ACTA2 pathogenic variant who had early onset ASCVD (P=0.0001). CONCLUSIONS:Assays assessing the molecular mechanism that leads to early onset ASCVD can identify which ACTA2 pathogenic variants will trigger this condition. Ultimately, this information informs precision medical care for individuals with ACTA2 pathogenic variants, with the ultimate goal of preventing thoracic aortic disease and ASCVD.

BACKGROUND AND AIMS:Thoracic aortic aneurysm and dissection (TAAD) can have catastrophic health consequences. Eleven genes have strong or definitive evidence for causing heritable TAAD (HTAAD). The aim of this work was to determine the prevalence and effect of rare, pathogenic or likely pathogenic (P/LP) variants in HTAAD genes on the association of TAAD diagnoses, and whether increased polygenic risk is associated with an additive effect on monogenic risk. METHODS:This genetic association study used data from Penn Medicine Biobank (PMBB) and MyCode Biobank. P/LP HTAAD gene variants were adjudicated according to American College of Medical Genetics and Genomics standards. A polygenic risk score (PRS) was derived from a genome-wide association study of aortic diameter to assess polygenic TAAD risk. The main outcome of interest, TAAD, was identified using an algorithmic review of electronic health records. Regression analyses were performed to determine the monogenic and polygenic effects on TAAD risk. RESULTS:Across the two cohorts, .2%-.3% of participants carried a P/LP HTAAD gene variant. Individuals carrying P/LP HTAAD gene variants had a significantly higher odds of TAAD compared to non-carriers [odds ratio (OR) 13.5, 95% confidence interval (CI) 5.3-34.6, P < .001] with variable effects when stratified by gene. A one standard deviation increase in the PRS was associated with an OR for TAAD of 1.43 (95% CI 1.39-1.47, P < .001). TAAD prevalence was higher among individuals carrying a P/LP HTAAD gene variant in the highest PRS quintile compared to carriers in the lowest PRS quintile (relative risk 2.32, 95% CI 1.29-4.17, P < .01), suggesting that polygenic risk may be an important additive factor in rare variant TAAD risk. CONCLUSIONS:P/LP HTAAD gene variants confer a substantial population-level increased risk of TAAD. Polygenic risk represents an additive factor for rare variant TAAD risk, suggesting that integrating monogenic and polygenic risks has the potential to enhance patient risk stratification and treatment.

BACKGROUND:Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS:A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS:Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes (WNT4, LEF1, STRN, and KANK2) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90-2.25; P=5.43×10-62) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS:This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

BACKGROUND:The presence of extra-aortic arterial aneurysms (AAs) is notable in Loeys-Dietz syndrome (LDS) compared with other heritable thoracic aortic diseases (HTADs). However, the characteristics of AAs in LDS are poorly characterized to date. OBJECTIVES:We sought to determine the prevalence, characteristics, and clinical outcomes of AAs in LDS. METHODS:A retrospective cohort study of LDS patients evaluated at Washington University in St Louis School of Medicine/Barnes-Jewish Hospital between 1998 and 2023 was performed. Clinical information, imaging data, and outcomes related to AAs were compiled. RESULTS:A total of 103 patients (53% female) from 60 families with LDS 1 through 5 caused by pathogenic/likely pathogenic variants in TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3 were included. The median age was 44 years, and median follow-up was 6 years. In total, 77 AAs were identified in 43 patients: 17 AAs in 9 patients with TGFBR1 variants, 33 AAs in 15 patients with TGFBR2, 15 AAs in 8 patients with SMAD3, 9 AAs in 8 patients with TGFB2, and 3 AAs in 3 patients with TGFB3. The median age at AA diagnosis was 40 years; 75% of AAs were in the arch vessels or cerebral circulation. On univariate analysis, aortic event (type A/B dissection or prophylactic aortic surgery) at baseline and prophylactic aortic surgery at baseline were associated with the presence of an AA. Hypertelorism, bifid uvula, and arterial tortuosity approached statistical significance. A multivariate model to predict AA included baseline prophylactic aortic surgery and arterial tortuosity. Of those with vs without AA on initial imaging, 61% and 35%, respectively, presented with previous aortic events. Seventeen percent of AAs enlarged over time, and 38% of AAs that enlarged led to clinical events (prophylactic surgery, dissection, or rupture). Overall, AA-related events occurred in 22% of AAs and throughout the arterial tree. AAs were repaired by open surgical and endovascular techniques. CONCLUSIONS:AAs commonly occur in patients with LDS and may occur throughout the arterial tree. Importantly, AAs may lead to clinical events including arterial dissection and rupture. Head to pelvis imaging at diagnosis and during follow-up is recommended in LDS to evaluate for AAs and their complications.

Background: Hyperhomocysteinemia (Hhcy), defined as plasma homocysteine concentrations >15μM, is an independent risk factor for early-onset atherosclerosis and ischemic strokes. We have previously demonstrated that complex phenotypic modulation of smooth muscle cells (SMCs) during atherogenesis is regulated in part by cholesterol-induced endoplasmic reticulum (ER) stress and PERK signaling. We also determined that activation of cytosolic stress and heat shock factor 1 (HSF1) leading to increased intracellular cholesterol biosynthesis from activation of HMG-CoA reductase (HMGCR) can augment PERK signaling (HSF1→HMGCR→PERK) and phenotypic modulation, which is responsible for early-onset atherosclerosis associated with missense variants in the gene ACTA2 , that codes for SMC-specific α-actin. Here, we investigated whether HSF1→HMGCR→PERK signaling drives augmented atherosclerosis associated with Hhcy. Methods: Wildtype (WT) and SMC-specific Perk -deficient ( Perk SMC-/- ) HC mice were fed a high fat diet for 12 weeks, with and without Hcy, and atherosclerotic plaque formation was characterized using en face aortic Oil Red O staining and histopathology. Single cell transcriptomics (scRNA-seq) of aortic tissue from SMC lineage-traced mice was pursued, while SMCs explanted from ascending aortas of WT and Perk SMC-/- mice were used to investigate atherosclerosis-associated SMC phenotypic modulation. Results: Hcy supplementation increased atherosclerotic plaque burden in WT mice, and both inhibition of HMGCR by pravastatin, and genetic depletion of Perk from SMCs successfully reversed the augmented plaque burden associated with Hhcy. scRNA-seq indicated that Hcy exposure disrupted protein folding, activated HSF1, and augmented PERK-mediated SMC phenotypic modulation. Cellular studies confirmed that Hcy treatment activated HSF1→HMGCR→PERK signaling, and sensitized WT SMCs to undergo atherosclerosis-associated phenotypic modulation at lower concentrations of cholesterol, and this effect was completely reversed in Perk -deficient SMCs. Conclusion: These data establish a novel mechanism by which high Hcy levels in SMCs predispose to early onset atherosclerosis. Targeting components of HSF1→HMGCR→PERK signaling in SMCs, including the use of statins – which is not currently used commonly in Hhcy patients - could prove effective against augmented atherosclerosis in these patients.

ObjectiveWe sought to determine if hypertension in combination with a "variant of uncertain significance" that disrupts protein function, MYH11 p.Arg247Cys, would induce aortic dissections in a mouse model.Approach and ResultsAdministration of L-NAME via drinking water and a high salt diet increased blood pressure in WT and Myh11R247C/R247C mice and triggered type A dissections with cardiac tamponade in 20% of the Myh11R247C/R247C mice. Myh11R247C/R247C aortas have aberrant smooth muscle contractile unit-elastin connections by transmission electron microscopy, along with increased focal adhesion signaling at baseline, which further increases with hypertension.ConclusionGene-environment interactions trigger aortic dissections in Myh11R247C/R247C mice.

Purpose:Vascular Ehlers-Danlos syndrome (vEDS), which is caused by COL3A1 pathogenic variants, is a rare heritable aortic and arterial disorder associated with early mortality, mainly due to spontaneous vascular dissections and ruptures. Improved methods for diagnosing vEDS are needed for guideline-based management to be initiated for preventing deadly complications and differentiating vEDS from overlapping conditions, such as hypermobile EDS (hEDS). Methods:We implemented an artificial intelligence (AI) facial analysis model based on the PhenoScore framework using a support vector machine trained on facial images of 30 individuals, aged 6 to 65 years, with vEDS from the Montalcino Aortic Consortium, control images from the Chicago Face Database, and publicly available images of individuals with hEDS. Cross-validation was used to train the support vector machine, and statistical measures to evaluate the model performance were calculated. Local Interpretable Model-agnostic Explanations was used to generate facial heatmaps highlighting the features driving the model's predictions. Results:The AI classifier showed excellent performance with as few as 13 vEDS training images and distinguished vEDS from both controls and individuals with hEDS with high accuracy, achieving an area under the receiver operating characteristic curve ≥ 0.97. Local Interpretable Model-agnostic Explanations highlighted facial regions already established to characterize the facial features of vEDS patients (eg, prominent eyes). Conclusion:Our results demonstrate the potential of AI-based facial analysis for diagnosing vEDS. This method democratizes the early diagnosis of vEDS by reducing dependence on genetic testing, enabling optimal management and improved outcomes, particularly in resource-limited areas.

Spontaneous arterial aneurysms and dissections are relatively common in patients with vascular Ehlers-Danlos syndrome, and arterial rupture accounts for most deaths. Members of the Aortic and Vascular Disease Clinic at UTHealth Houston hold a monthly conference that includes cardiothoracic and vascular surgeons, cardiologists, geneticists, radiologists, and pathologists to formulate multidisciplinary approaches for the management of complex cases. In this case series, we highlight the variable presentations and clinical evolution of complex aortic and vascular disease due to vascular Ehlers-Danlos syndrome.

ACTA2 pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusions of the distal internal carotid arteries, but the mechanisms of pathogenesis are unknown and no preventive treatments exist. Here we show that Acta2R179C/+ smooth muscle cells (SMCs) fail to fully differentiate and maintain stem cell-like features, including increased migration and glycolytic flux compared to wildtype (WT) SMCs. Increasing mitochondrial respiration with nicotinamide riboside (NR) drives differentiation and decreases migration of Acta2R179C/+ SMCs. Carotid artery injury of Acta2SMC-R179C/+ mice leads to premature death, intraluminal SMC accumulation leading to MMD-like occlusive lesions, neurologic symptoms, and neuron loss, whereas injured WT mice have none of these phenotypes, and all are prevented by NR treatment in the Acta2SMC-R179C/+ mice. These data show that driving differentiation and quiescence of Acta2R179C/+ SMCs by altering cellular metabolism attenuates MMD-like disease in the Acta2SMC-R179C/+ mice, highlighting a role of immature and highly migratory SMCs in the pathogenesis of MMD.

BACKGROUND:Thoracic aortic dissection is a life-threatening condition that often occurs in the presence of aortic dilation. However, currently there are limited clinical risk factors beyond aortic diameter (AoD) used to determine individual-level dissection risk. OBJECTIVES:The purpose of this study was to determine whether common variant genetics can be used to improve identification of individuals most at risk for dissection. METHODS:A genome-wide association study (GWAS)-by-subtraction was performed to characterize the diameter-independent genetics of thoracic aortic dissection by subtracting a GWAS of AoD from a GWAS of thoracic aortic aneurysm and dissection. A polygenic risk score (PRS) was calculated using the PRS-Continuous Shrinkage statistical package and applied to Penn Medicine BioBank participants. Statistical analysis was performed in R version 4.3.2. RESULTS:We identified 43 genetic risk loci associated with dissection and derived a "Dissection-PRS" from our GWAS-by-subtraction. In the Penn Medicine BioBank, the Dissection-PRS associated with prevalent dissection (OR: 2.13 per 1 SD increase in Dissection-PRS; 95% CI: 1.91-2.39; P < 0.001). When adjusting for risk factors including AoD, the association of the Dissection-PRS with prevalent dissection was attenuated but remained statistically robust (OR: 1.62 per 1 SD increase in PRS; 95% CI: 1.36-1.94; P < 0.001). The addition of the PRS to a model containing age, sex, and clinical risk factors substantially improved model discrimination (base model area under the receiver operator characteristic curve = 0.676; 95% CI: 0.651-0.702; with addition of PRS area under the receiver operator characteristic curve = 0.723; 95% CI: 0.702-0.744). CONCLUSIONS:A common-variant PRS can predict aortic dissection in a diverse population.

Smooth muscle cell-specific myosin heavy chain, encoded by MYH11, is selectively expressed in smooth muscle cells (SMCs). Pathogenic variants in MYH11 predispose to a number of disorders, including heritable thoracic aortic disease associated with patent ductus arteriosus, visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Rare variants of uncertain significance occur throughout the gene, including MYH11 p.Glu1892Asp, and we sought to determine if this variant causes thoracic aortic disease in mice. Genomic editing was used to generate Myh11E1892D/E1892D mice. Wild-type (WT) and mutant mice underwent cardiovascular phenotyping with and without transverse aortic constriction (TAC). Myh11E1892D/E1892D and WT mice displayed similar growth, blood pressure, root and ascending aortic diameters, and cardiac function up to 13 months of age, along with similar contraction and relaxation on myographic testing. The hypertension induced by TAC was similarly in Myh11E1892D/E1892D and WT mice, but mutant mice showed augmented ascending aortic enlargement and increased elastic fiber fragmentation on histology. Unexpectedly, male Myh11E1892D/E1892D mice undergoing TAC had decreased ejection fraction, stroke volume, fractional shortening, and cardiac output compared to similarly treated male WT mice. Importantly, left ventricular mass increased significantly due to primarily posterior wall thickening, and cardiac histology confirmed cardiomyocyte hypertrophy and increased collagen deposition in the myocardium and surrounding arteries. These results further highlight the phenotypic heterogeneity associated with MYH11 rare variants. Given that MYH11 is selectively expressed in SMCs, these results implicate a role of SMCs in the arteries of the heart contributing to cardiac hypertrophy and failure with pressure overload.

A 25-year-old patient with dysmorphic facies presented with tingling in both hands and a speech disorder that occurred for a few hours approximately once a month since the age of 12 years. A magnetic resonance angiography of the brain showed signs of a bilateral moyamoya phenomenon with distal carotid artery occlusions with significant collateral vessel formation and bilateral posterior cerebral artery occlusions. In addition, there was an extracranial, nonatherosclerotic carotid artery stenosis. Genetic testing identified a heterozygous de novo , loss-of-function variant in SETD5 , which was classified pathogenic according to the American College of Medical Genetics and Genomics criteria. This case report describes a newfound SETD5 pathogenic variant in a patient with moyamoya syndrome, but surprisingly without intellectual disability. Furthermore, our patient suffered from nonarteriosclerotic extracranial carotid artery stenosis, which is distinctly unusual in patients with moyamoya angiopathy. This raises the possibility that the occlusive vascular disease in patients with SETD5 variants may extend beyond the cerebrovascular circulation. In summary, this case presents a moyamoya patient with an unusual vascular feature which can be explained with the newfound SETD5 mutation variant.