Publications by authors named "Dianna M Milewicz"

183 Publications

In-hospital Outcomes and Long-term Survival of Women of Childbearing Age with Aortic Dissection: Results from a Single-Center Database.

J Vasc Surg 2021 Apr 14. Epub 2021 Apr 14.

Department of Cardiothoracic and Vascular Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA. Electronic address:

Objective: To define the outcomes and impact of pregnancy in a cohort of women of childbearing age with acute aortic dissection (AAD).

Methods: We reviewed our database of AAD to identify all eligible female patients. Women under the age of 45 were included. Data on pregnancy timing with respect to occurrence of dissection, in addition to demographic data, dissection extent, dissection treatment, dissection related outcomes, overall maternal and fetal mortality, and genetic testing results were analyzed.

Results: Sixty-two women under the age of 45 presented to us with AAD between 1999 and 2017. Of these, 37 (60%) had history of pregnancy at the time of dissection. Ten of the 37 (27%) had a peripartum aortic dissection, defined as a dissection during pregnancy or within 12 months postpartum. Five of the 10 were Type A and 5 were Type B AADs. Three presented during pregnancy (1 in 2 and 2 in 3 trimester), while 50% (5/10) developed AAD in the immediate postpartum (within 3 months) and 2 (20%) in the late postpartum period. For the immediate postpartum dissections (<3 months), 4 of the 5 patients delivered via caesarean section. Of these 10 peripartum dissections, 3 (30%) occurred in patients with known Marfan syndrome. In-hospital mortality for those with peripartum dissection was 10% (1/10). Fetal demise was 20% (2/10).

Conclusions: The frequency of aortic dissection in women of childbearing age at our institution was low. However, pregnancy may increase the risk of those young women who are genetically predisposed to dissection events. From this data, this risk appears to be highest in the immediate postpartum period, even for those who undergo caesarean section. Close clinical and radiographic surveillance is required in all women with suspected aortopathy, especially in the 3 trimester and early postpartum.
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http://dx.doi.org/10.1016/j.jvs.2021.03.028DOI Listing
April 2021

Update on the genetic risk for thoracic aortic aneurysms and acute aortic dissections: implications for clinical care.

J Cardiovasc Surg (Torino) 2021 Jun 18;62(3):203-210. Epub 2021 Mar 18.

McGovern Medical School, Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.

Genetic variation plays a significant role in predisposing individuals to thoracic aortic aneurysms and dissections. Advances in genomic research have led to the discovery of 11 genes validated to cause heritable thoracic aortic disease (HTAD). Identifying the pathogenic variants responsible for aortic disease in affected patients confers substantial clinical utility by establishing a definitive diagnosis to inform tailored treatment and management, and enables identification of at-risk relatives to prevent downstream morbidity and mortality. The availability and access to clinical genetic testing has improved dramatically such that genetic testing is considered an integral part of the clinical evaluation for patients with thoracic aortic disease. This review provides an update on our current understanding of the genetic basis of thoracic aortic disease, practical recommendations for genetic testing, and clinical implications.
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http://dx.doi.org/10.23736/S0021-9509.21.11816-6DOI Listing
June 2021

Association of De Novo Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy.

Neurology 2021 03 10;96(13):e1783-e1791. Epub 2021 Feb 10.

From the Department of Internal Medicine (A.P., A.C.C., M.A., D.G., D.M.M.), McGovern Medical School, University of Texas Health Science Center at Houston; Maritime Medical Genetics Service (A.L.R., S.P., M.A.V.), Division of Neurosurgery (M.D.J.F., P.D.M., S.W.) and Department of Pediatrics (M.A.V.), Division of Medical Genetics, Dalhousie University, IWK Health Centre Halifax, Nova Scotia Canada; Department of Pediatrics (S.C.N.), Division of Child Neurology, and Department of Genetics (A.C.E.H.), University of Alabama at Birmingham; Department of Pediatrics (M.J.B., A.M.V.), Division of Genetics Medicine and Department of Genome Sciences (M.J.B., D.A.N.), University of Washington, Seattle; and Department of Pediatrics (S.M.F.), Division of Child Neurology, University of Texas McGovern Medical School.

Objective: To test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.

Methods: Exome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.

Results: We identified 3 novel rare de novo variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114-4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.

Conclusions: These results indicate a novel syndrome associated with rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.
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http://dx.doi.org/10.1212/WNL.0000000000011653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055312PMC
March 2021

The Dynamic and Multifaceted Nature of Cardiovascular Disease and Using Genetic Testing to Inform Clinical Care: An International Perspective.

Clin Chem 2021 Jan;67(1):33-40

Department of Clinical Biochemistry, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

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http://dx.doi.org/10.1093/clinchem/hvaa251DOI Listing
January 2021

Cerebrovascular Disease Progression in Patients With Arg179 Pathogenic Variants.

Neurology 2021 01 16;96(4):e538-e552. Epub 2020 Nov 16.

From the Departments of Neurology (A.L., S.L.S., P.L.M.) and Radiology (J.B.P., J.K.-K., P.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Internal Medicine (E.R., D.M.M.), McGovern Medical School, University of Texas Health Science Center at Houston; Department of Neuroradiology (A.L., M.C.), Goethe University, Frankfurt am Main, Germany; andDepartment of Neurosurgery (E.S.), Boston Children's Hospital, Harvard Medical School, Boston, MA.

Objective: To establish progression of imaging biomarkers of stroke, arterial steno-occlusive disease, and white matter injury in patients with smooth muscle dysfunction syndrome caused by mutations in the gene, we analyzed 113 cerebral MRI scans from a retrospective cohort of 27 patients with Arg179 pathogenic variants.

Methods: Systematic quantifications of arterial ischemic strokes and white matter lesions were performed on baseline and follow-up scans using planimetric methods. Critical stenosis and arterial vessel diameters were quantified applying manual and semiautomated methods to cerebral magnetic resonance angiograms. We then assessed correlations between arterial abnormalities and parenchymal injury.

Results: We found characteristic patterns of acute white matter ischemic injury and progressive internal carotid artery stenosis during infancy. Longitudinal analysis of patients older than 1.2 years showed stable white matter hyperintensities but increased number of cystic-like lesions over time. Progressive narrowing of the terminal internal carotid artery occurred in 80% of patients and correlated with the number of critical stenoses in cerebral arteries and arterial ischemic infarctions. Arterial ischemic strokes occurred in same territories affected by critical stenosis.

Conclusions: We found characteristic, early, and progressive cerebrovascular abnormalities in patients with Arg179 pathogenic variants. Our longitudinal data suggest that while steno-occlusive disease progresses over time and is associated with arterial ischemic infarctions and cystic-like white matter lesions, white matter hyperintensities can remain stable over long periods. The evaluated metrics will enable diagnosis in early infancy and be used to monitor disease progression, guide timing of stroke preventive interventions, and assess response to current and future therapies.
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http://dx.doi.org/10.1212/WNL.0000000000011210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905785PMC
January 2021

Epac1 (Exchange Protein Directly Activated by cAMP 1) Upregulates LOX-1 (Oxidized Low-Density Lipoprotein Receptor 1) to Promote Foam Cell Formation and Atherosclerosis Development.

Arterioscler Thromb Vasc Biol 2020 12 15;40(12):e322-e335. Epub 2020 Oct 15.

Department of Integrative Biology and Pharmacology (W.G.R., F.C.M., W.Y., H.W., X.C.), McGovern Medical School, The University of Texas Health Science Center, Houston.

Objective: The cAMP second messenger system, a major stress-response pathway, plays essential roles in normal cardiovascular functions and in pathogenesis of heart diseases. Here, we test the hypothesis that the Epac1 (exchange protein directly activated by cAMP 1) acts as a major downstream effector of cAMP signaling to promote atherogenesis and represents a novel therapeutic target. Approach and Results: To ascertain Epac1's function in atherosclerosis development, a triple knockout mouse model () was generated by crossing mice with atherosclerosis-prone mice lacking both and . Deletion of Epac1 led to a significant reduction of atherosclerotic lesion formation as measured by postmortem staining, accompanied by attenuated macrophage/foam cell infiltrations within atherosclerotic plaques as determined by immunofluorescence staining in animals compared with littermates. Primary bone marrow-derived macrophages were isolated from Epac1-null and wild-type mice to investigate the role of Epac1 in lipid uptake and foam cell formation. ox-LDLs (oxidized low-density lipoproteins) stimulation of bone marrow-derived macrophages led to elevated intracellular cAMP and Epac1 levels, whereas an Epac-specific agonist, increased lipid accumulation in wild-type, but not Epac1-null, bone marrow-derived macrophages. Mechanistically, Epac1 acts through PKC (protein kinase C) to upregulate LOX-1 (ox-LDL receptor 1), a major scavenger receptor for ox-LDL uptake, exerting a feedforward mechanism with ox-LDL to increase lipid uptake and propel foam cell formation and atherogenesis.

Conclusions: Our study demonstrates a fundamental role of cAMP/Epac1 signaling in vascular remodeling by promoting ox-LDL uptake and foam cell formation during atherosclerosis lesion development. Therefore, Epac1 represents a promising, unexplored therapeutic target for atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.119.314238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831851PMC
December 2020

Cholesterol-Induced Phenotypic Modulation of Smooth Muscle Cells to Macrophage/Fibroblast-like Cells Is Driven by an Unfolded Protein Response.

Arterioscler Thromb Vasc Biol 2021 01 8;41(1):302-316. Epub 2020 Oct 8.

Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX (A.C., C.S.K., K.K., A.K., J.C., D.M.M.).

Objective: Vascular smooth muscle cells (SMCs) dedifferentiate and initiate expression of macrophage markers with cholesterol exposure. This phenotypic switching is dependent on the transcription factor Klf4 (Krüppel-like factor 4). We investigated the molecular pathway by which cholesterol induces SMC phenotypic switching. Approach and Results: With exposure to free cholesterol, SMCs decrease expression of contractile markers, activate Klf4, and upregulate a subset of macrophage and fibroblast markers characteristic of modulated SMCs that appear with atherosclerotic plaque formation. These phenotypic changes are associated with activation of all 3 pathways of the endoplasmic reticulum unfolded protein response (UPR), Perk (protein kinase RNA-like endoplasmic reticulum kinase), Ire (inositol-requiring enzyme) 1α, and Atf (activating transcription factor) 6. Blocking the movement of cholesterol from the plasma membrane to the endoplasmic reticulum prevents free cholesterol-induced UPR, Klf4 activation, and upregulation of the majority of macrophage and fibroblast markers. Cholesterol-induced phenotypic switching is also prevented by global UPR inhibition or specific inhibition of Perk signaling. Exposure to chemical UPR inducers, tunicamycin and thapsigargin, is sufficient to induce these same phenotypic transitions. Finally, analysis of published single-cell RNA sequencing data during atherosclerotic plaque formation in hyperlipidemic mice provides preliminary in vivo evidence of a role of UPR activation in modulated SMCs.

Conclusions: Our data demonstrate that UPR is necessary and sufficient to drive phenotypic switching of SMCs to cells that resemble modulated SMCs found in atherosclerotic plaques. Preventing a UPR in hyperlipidemic mice diminishes atherosclerotic burden, and our data suggest that preventing SMC transition to dedifferentiated cells expressing macrophage and fibroblast markers contributes to this decreased plaque burden.
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http://dx.doi.org/10.1161/ATVBAHA.120.315164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752246PMC
January 2021

Actin R256 Mono-methylation Is a Conserved Post-translational Modification Involved in Transcription.

Cell Rep 2020 09;32(13):108172

Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA. Electronic address:

Nuclear actin has been elusive due to the lack of knowledge about molecular mechanisms. From actin-containing chromatin remodeling complexes, we discovered an arginine mono-methylation mark on an evolutionarily conserved R256 residue of actin (R256me1). Actin R256 mutations in yeast affect nuclear functions and cause diseases in human. Interestingly, we show that an antibody specific for actin R256me1 preferentially stains nuclear actin over cytoplasmic actin in yeast, mouse, and human cells. We also show that actin R256me1 is regulated by protein arginine methyl transferase-5 (PRMT5) in HEK293 cells. A genome-wide survey of actin R256me1 mark provides a landscape for nuclear actin correlated with transcription. Further, gene expression and protein interaction studies uncover extensive correlations between actin R256me1 and active transcription. The discovery of actin R256me1 mark suggests a fundamental mechanism to distinguish nuclear actin from cytoplasmic actin through post-translational modification (PTM) and potentially implicates an actin PTM mark in transcription and human diseases.
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http://dx.doi.org/10.1016/j.celrep.2020.108172DOI Listing
September 2020

Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.

Genet Med 2021 Jan 21;23(1):103-110. Epub 2020 Aug 21.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728.

Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies.

Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2.

Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.
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http://dx.doi.org/10.1038/s41436-020-00939-4DOI Listing
January 2021

Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.

Mol Genet Genomic Med 2020 10 3;8(10):e1406. Epub 2020 Aug 3.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Bicuspid aortic valve (BAV) is the most common cardiovascular malformation in adults, with a prevalence of 0.5%-2%. The prevalence of BAV in cohorts who were ascertained due to thoracic aortic aneurysms or acute aortic dissections (TAD) is as high as 20%. However, the contribution of causal BAV genes to TAD is not known. Therefore, we evaluated rare deleterious variants of GATA4, NOTCH1, SMAD6, or ROBO4 in patients with BAV who presented with TAD.

Methods: Our cohort consisted of 487 probands with Heritable Thoracic Aortic Aneurysms or Dissections (HTAD, 12% BAV, 29% female) and 63 probands with Early onset complications of Bicuspid Aortic Valve disease (EBAV, 63% TAD, 34% female). After whole exome sequencing, we functionally annotated GATA4, NOTCH1, SMAD6, and ROBO4 variants and compared the prevalence of rare variants in these genes to controls without HTAD.

Results: We identified 11 rare deleterious variants of GATA4, SMAD6, or ROBO4 in 12 (18%) EBAV cases. The burden of rare SMAD6 and GATA4 variants was significantly enriched in EBAV but not in HTAD cases, even among HTAD cases with BAV (p < .003).

Conclusion: Rare variants of NOTCH1, ROBO4, SMAD6, or GATA4 do not significantly contribute to BAV in cohorts with HTAD. We conclude that BAV patients who present with HTAD are a genetically distinct subgroup with implications for genetic testing and prognosis.
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http://dx.doi.org/10.1002/mgg3.1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549564PMC
October 2020

TGFBR1 Rare Variant Associated With Thoracic Aortic Aneurysm, Double Chamber Left Ventricle, Coronary Anomaly, and Inducible Ventricular Tachycardia.

Circ Cardiovasc Imaging 2020 06;13(6):e010084

Division of Cardiology (K.B.-J., N.B.M., D.R., S.N., I.A.E., D.K., R.W.S., S.K.P.), Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston.

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http://dx.doi.org/10.1161/CIRCIMAGING.119.010084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285880PMC
June 2020

In Vitro Lineage-Specific Differentiation of Vascular Smooth Muscle Cells in Response to SMAD3 Deficiency: Implications for SMAD3-Related Thoracic Aortic Aneurysm.

Arterioscler Thromb Vasc Biol 2020 07 14;40(7):1651-1663. Epub 2020 May 14.

From the Department of Cardiac Surgery, North Campus Research Complex, University of Michigan, Ann Arbor (J.G., D.Z., L.J., P.Q., Y.E.C., B.Y.).

Objective: SMAD3 pathogenic variants are associated with the development of thoracic aortic aneurysms. We sought to determine the role of SMAD3 in lineage-specific vascular smooth muscle cells (VSMCs) differentiation and function. Approach and Results: c.652delA, a frameshift mutation and nonsense-mediated decay, was introduced in human-induced pluripotent stem cells using CRISPR-Cas9. The wild-type and (c.652delA) human-induced pluripotent stem cells were differentiated into cardiovascular progenitor cells or neural crest stem cells and then to lineage-specific VSMCs. Differentiation, contractility, extracellular matrix synthesis, and TGF-β (transforming growth factor-β) signaling of the differentiated VSMCs were analyzed. The homozygous frameshift mutation resulted in SMAD3 deficiency and was confirmed in human-induced pluripotent stem cells by Sanger sequencing and immunoblot analysis. In cardiovascular progenitor cell-VSMCs, SMAD3 deletion significantly disrupted canonical TGF-β signaling and decreased gene expression of VSMC markers, including SM α-actin, myosin heavy chain 11, calponin-1, SM22α, and key controlling factors, SRF and myocardin, but increased collagen expression. The loss of SMAD3 significantly decreased VSMC contractility. In neural crest stem cells-VSMCs, SMAD3 deficiency did not significantly affect the VSMC differentiation but decreased ELN (elastin) expression and increased phosphorylated SMAD2. Expression of mir-29 was increased in VSMCs, and inhibition of mir-29 partially rescued ELN expression.

Conclusions: SMAD3-dependent TGF-β signaling was essential for the differentiation of cardiovascular progenitor cell-VSMCs but not for the differentiation of neural crest stem cell-VSMCs. The lineage-specific TGF-β responses in human VSMCs may potentially contribute to the development of aortic root aneurysms in patients with mutations.
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http://dx.doi.org/10.1161/ATVBAHA.120.313033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316596PMC
July 2020

Targeting the NLRP3 Inflammasome With Inhibitor MCC950 Prevents Aortic Aneurysms and Dissections in Mice.

J Am Heart Assoc 2020 04 30;9(7):e014044. Epub 2020 Mar 30.

Division of Cardiothoracic Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston TX.

Background Aortic aneurysms and dissections are highly lethal diseases for which an effective treatment strategy is critically needed to prevent disease progression. The nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3)-caspase-1 inflammasome cascade was recently shown to play an important role in aortic destruction and disease development. In this study, we tested the effects of MCC950, a potent, selective NLRP3 inhibitor, on preventing aortic destruction and aortic aneurysm and dissection formation. Methods and Results In a model of sporadic aortic aneurysm and dissection induced by challenging wild-type mice with a high-fat, high-cholesterol diet and angiotensin II infusion, MCC950 treatment significantly inhibited challenge-induced aortic dilatation, dissection, and rupture in different thoracic and abdominal aortic segments in both male and female mice. Aortic disease reduction by MCC950 was associated with the prevention of NLRP3-caspase-1 upregulation, smooth muscle cell contractile protein degradation, aortic cell death, and extracellular matrix destruction. Further investigation revealed that preventing matrix metallopeptidase 9 (MMP-9) expression and activation in macrophages is an important mechanism underlying MCC950's protective effect. We found that caspase-1 directly activated MMP-9 by cleaving its N-terminal inhibitory domain. Moreover, the genetic knockdown of or in mice or treatment of mice with MCC950 diminished the challenge-induced N-terminal cleavage of MMP-9, MMP-9 activation, and aortic destruction. Conclusions Our findings suggest that the NLRP3-caspase-1 inflammasome directly activates MMP-9. Targeting the inflammasome with MCC950 is a promising approach for preventing aortic destruction and aortic aneurysm and dissection development.
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http://dx.doi.org/10.1161/JAHA.119.014044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428617PMC
April 2020

Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture.

Circulation 2020 01 30;141(1):42-66. Epub 2019 Dec 30.

Cardiovascular Research Institute (J.S.C., S.A.L., Y.H.S.), Baylor College of Medicine, Houston, TX.

Background: Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation.

Methods: The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in -deficient () mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro.

Results: In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development.

Conclusions: Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939474PMC
January 2020

Do Variants Predispose to Thoracic Aortic Aneurysms and Dissections?

Circ Genom Precis Med 2019 12 15;12(12):e002626. Epub 2019 Nov 15.

Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center (H.L.H., E.S.R., D.-c.G., L.X., D.M.M.).

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http://dx.doi.org/10.1161/CIRCGEN.119.002626DOI Listing
December 2019

Grange syndrome due to homozygous YY1AP1 missense rare variants.

Am J Med Genet A 2019 12 21;179(12):2500-2505. Epub 2019 Oct 21.

Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houstan, Texas.

Grange syndrome (OMIM 602531) is an autosomal recessive condition characterized by severe early onset vascular occlusive disease and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Grange syndrome is caused by homozygous or compound heterozygous loss-of-function variants in the YYA1P1 gene. We report on the case of a 53-year old female with novel homozygous missense variants in YYA1P1 (c.1079C>T, p.Pro360Leu), presenting with a history of brachysyndactyly, hypertension, and ischemic stroke. Imaging studies revealed stenosis of the bilateral internal carotid with extensive collateralization of cerebral vessels in a moyamoya-like pattern, along with stenosis in the splenic, common hepatic, celiac, left renal, and superior mesenteric arteries. Functional studies conducted with the patient's dermal fibroblasts suggest that the p.Pro360Leu variant decreases the stability of the YY1AP1 protein. This is the first report of a missense variant associated with Grange syndrome characterized by later onset of vascular disease and a lack of developmental delay and bone fragility.
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http://dx.doi.org/10.1002/ajmg.a.61379DOI Listing
December 2019

Open Thoracoabdominal Aortic Repair in Patients With Heritable Aortic Disease in the GenTAC Registry.

Ann Thorac Surg 2020 05 27;109(5):1378-1384. Epub 2019 Sep 27.

Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, Texas. Electronic address:

Background: Although patients with various types of heritable aortopathy often require distal aortic repair, data are limited regarding the most extensive operations-open thoracoabdominal aortic aneurysm (TAAA) repairs. The objective of this multicenter registry study was to characterize TAAA repairs in a large cohort of patients with different heritable aortic diseases.

Methods: From the 3699 patients enrolled at 8 participating centers in the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Registry, we identified 155 open TAAA repairs in 142 unique patients. We examined data related to clinical characteristics, surgical techniques, and outcomes.

Results: The primary diagnoses included Marfan syndrome (n = 76; 54%), familial thoracic aortic aneurysm and dissections (n = 31; 22%), and Loeys-Dietz syndrome (n = 10; 7%). Most repairs were performed for aneurysms associated with aortic dissection (n = 110; 71%). The most common repairs involved the entire descending thoracic aorta with distal extension (21% Crawford extent I and 36% extent II). Adjuncts used during repair varied substantially. The operative mortality rate was 1.3%. Other complications included paraplegia (4%), acute renal failure (5%), and vocal cord paralysis (21%). Reoperation after TAAA repair was required in a subset of cases for early bleeding (n = 15; 10%) and late repair failure (n = 7; 5%).

Conclusions: Open TAAA repairs are necessary in a variety of heritable aortic diseases. These patients often require extensive surgical repair, and a variety of adjunctive techniques are utilized. The risk of repair failure and the need for reoperation in a subset of patients support the need for vigilant long-term surveillance after repair.
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http://dx.doi.org/10.1016/j.athoracsur.2019.08.047DOI Listing
May 2020

The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.

Genet Med 2020 02 2;22(2):427-431. Epub 2019 Sep 2.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Purpose: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

Methods: Exome sequencing from 39 trios were analyzed.

Results: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.

Conclusion: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
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http://dx.doi.org/10.1038/s41436-019-0639-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673309PMC
February 2020

Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B analog.

Nat Commun 2019 08 6;10(1):3533. Epub 2019 Aug 6.

Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.

People heterozygous for an activating mutation in protein kinase G1 (PRKG1, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation. Prkg1 aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)-to increase wall stress in the ascending aorta-induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome.
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http://dx.doi.org/10.1038/s41467-019-11389-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684604PMC
August 2019

Type B Aortic Dissection in Young Individuals With Confirmed and Presumed Heritable Thoracic Aortic Disease.

Ann Thorac Surg 2020 02 31;109(2):534-540. Epub 2019 Jul 31.

Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas.

Background: To investigate clinical course of patients with type B aortic dissection (TBAD) occurring at a young age with confirmed or suspected heritable thoracic aortic disease.

Methods: Individuals with TBAD occurring at an age <50 years enrolled in the National Registry of the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Consortium were selected for analysis. Three cohorts were compared: Marfan syndrome (MFS TBAD), nonsyndromic familial TBAD (FTBAD), and sporadic TBAD. Demographics, comorbidities, aortic dissection details, and repair were compared.

Results: A total of 150 individuals met inclusion criteria (mean age at TBAD, 36.9 ± 9 years): 73 MFS TBAD, 42 FTBAD, and 35 sporadic TBAD. The cohort of sporadic TBAD had more male patients (71.4%) and fewer individuals of European descent (51.4%) compared with MFS TBAD (57.5% male, 84.9% European descent) and FTBAD (59.5% male, 90.5% European descent). There was a stepwise increase in hypertension prevalence across the cohorts (28.8% MFS, 59.5% FTBAD, 71.4% sporadic TBAD, P < .001). Repair of the descending thoracic aorta was performed in 92 cases (67.1% in MFS, 61.9% in FTBAD, and 48.6% sporadic TBAD, P = .18) at a mean of 3.4 ± 5.4 years from TBAD. The repair extent varied. The largest extent of repair was in MFS TBAD, in which thoracoabdominal aortic aneurysm repair was performed in 56.2% compared with 35.7% FTBAD and 17.1% sporadic TBAD (P < .001).

Conclusions: Control of hypertension is an essential component of care to decrease the risk of TBAD. Over half of the young individuals with TBAD require aortic repair, and individuals with MFS undergo a larger anatomical extent of repair after TBAD.
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http://dx.doi.org/10.1016/j.athoracsur.2019.07.004DOI Listing
February 2020

A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis.

J Vasc Surg 2020 01 26;71(1):149-157. Epub 2019 Jul 26.

Division of Vascular Surgery, University of California Los Angeles, Los Angeles, Calif.

Objective: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015.

Methods: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation.

Results: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts.

Conclusions: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.
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http://dx.doi.org/10.1016/j.jvs.2019.04.487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245161PMC
January 2020

Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection.

Circ Genom Precis Med 2019 06 18;12(6):e002476. Epub 2019 Jun 18.

University of Michigan (B.N.W., W.E.H., L.F., J.M., A.D., X.W., M.R.M., S.K.G., N.J.D., C.M.B., J.K., Y.E.C., K.K., G.M.D., H.P., K.A.E., C.J.W., B.Y.), Michigan Medicine, University of Michigan, Ann Arbor.

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members.

Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.

Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6-19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4-22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4-22.3, siblings: OR, 5.1; 95% CI, 1.1-23.9, children: OR, 6.0; 95% CI, 1.4-26.7).

Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.
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http://dx.doi.org/10.1161/CIRCGEN.118.002476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582991PMC
June 2019

A multi-institutional experience in the aortic and arterial pathology in individuals with genetically confirmed vascular Ehlers-Danlos syndrome.

J Vasc Surg 2019 11 21;70(5):1543-1554. Epub 2019 May 21.

Division of Vascular Surgery, University of California Los Angeles, Los Angeles, Calif.

Objective: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder owing to pathogenic variants in COL3A1 that lead to impaired type III collagen production. We aim to describe the contemporary multi-institutional experience of aortic and arterial pathology in individuals with vEDS, to evaluate disease patterns and refine management recommendations.

Methods: This cross-sectional, retrospective study of individuals with genetically confirmed vEDS was conducted between 2000 and 2015 at multiple institutions participating in the Vascular Low Frequency Disease Consortium. Aortic and arterial events including aneurysms, pseudoaneurysms, dissections, fistulae, or ruptures were studied. Demographics, COL3A1 variants, management, and outcomes data were collected and analyzed. Individuals with and without arterial events were compared.

Results: Eleven institutions identified 86 individuals with pathogenic variants in COL3A1 (47.7% male, 86% Caucasian; median age, 41 years; interquartile range [IQR], 31.0-49.5 years; 65.1% missense COL3A1 variants). The median follow-up from the time of vEDS diagnosis was 7.5 years (IQR, 3.5-12.0 years). A total of 139 aortic/arterial pathologies were diagnosed in 53 individuals (61.6%; 50.9% male; 88.5% Caucasian; median age, 33 years; IQR, 25.0-42.3 years). The aortic/arterial events presented as an emergency in 52 cases (37.4%). The most commonly affected arteries were the mesenteric arteries (31.7%), followed by cerebrovascular (16.5%), iliac (16.5%), and renal arteries (12.2%). The most common management was medical management. When undertaken, the predominant endovascular interventions were arterial embolization of medium sized arteries (13.4%), followed by stenting (2.5%). Aortic pathology was noted in 17 individuals (32%; 58.8% male; 94.1% Caucasian; median age, 38.5 years; IQR, 30.8-44.7 years). Most notably, four individuals underwent successful abdominal aortic aneurysm repair with excellent results on follow-up. Individuals with missense mutations, in which glycine was substituted with a large amino acid, had an earlier onset of aortic/arterial pathology (median age, 30 years; IQR, 23.5-37 years) compared with the other pathogenic COL3A1 variants (median age, 36 years; IQR, 29.5-44.8 years; P = .065). There were 12 deaths (22.6%) at a median age of 36 years (IQR, 28-51 years).

Conclusions: Most of the vEDS arterial manifestations were managed medically in this cohort. When intervention is required for an enlarging aneurysm or rupture, embolization, and less frequently stenting, seem to be well-tolerated. Open repair of abdominal aortic aneurysm seems to be as well-tolerated as in those without vEDS; vEDS should not be a deterrent to offering an operation. Future work to elucidate the role of surgical interventions and refine management recommendations in the context of patient centered outcomes is warranted.
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http://dx.doi.org/10.1016/j.jvs.2019.01.069DOI Listing
November 2019

Update on Clinical Trials of Losartan With and Without β-Blockers to Block Aneurysm Growth in Patients With Marfan Syndrome: A Review.

JAMA Cardiol 2019 07;4(7):702-707

McGovern Medical School, University of Texas Health Science Center at Houston.

Importance: Thoracic aortic aneurysms leading to acute aortic dissections are a major cause of morbidity and mortality despite significant advances in surgical treatment, which remains the main intervention to prevent type A dissections. In the past 2 decades progress has been made toward a better understanding of molecular mechanisms that lead to aneurysm formation and dissections of the thoracic aorta. This focused review emphasizes the results of clinical trials using β-blocker, losartan potassium, and irbesartan in patients with Marfan syndrome and comments briefly on mechanisms of aortic remodeling, including fibrosis and transforming growth factor β signaling.

Observation: The major risk factors for the disease are increased hemodynamic forces, typically owing to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease have been shown or are predicted to decrease vascular smooth muscle cell contraction, decrease transforming growth factor β signaling, or alter the extracellular matrix. Preclinical models of Marfan syndrome showed promising results for losartan as a potential therapy to attenuate aortic dilation in mice. However, several clinical trials did not conclusively confirm that losartan attenuated aortic aneurysm expansion better than β-blockers. Most importantly, clinical trials assessing whether losartan therapy not only reduces aortic growth but also improves adverse aortic outcomes, including dissection, need for surgery, and death, have not been conducted. The largest trial to date to our knowledge, the Pediatric Heart Network trial, sponsored by the National Heart, Lung, and Blood Institute, showed a nonsignificant increase in adverse aortic outcomes, with almost a doubling of adverse events in patients randomized to losartan treatment compared with β-blockers, suggesting that this study was underpowered to assess adverse aortic outcomes. On the other hand, the evidence for β-blocker therapy to reduce morbidity and mortality in Marfan syndrome is limited to a single small, prospective randomized and nonblinded clinical trial.

Conclusions And Relevance: Taken together, these data emphasize the need for clinical trials adequately powered to assess both aortic aneurysm growth and adverse aortic outcomes to identify effective medical therapies for Marfan syndrome and other aortopathies.
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http://dx.doi.org/10.1001/jamacardio.2019.1176DOI Listing
July 2019

The natural history of type B aortic dissection in patients with PRKG1 mutation c.530G>A (p.Arg177Gln).

J Vasc Surg 2019 09 11;70(3):718-723. Epub 2019 Mar 11.

Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Tex.

Objective: The c.530G>A (p.Arg177Gln) mutation in PRKG1 has been shown to be associated with thoracic aortic aneurysms and dissections. This rare mutation accounts for an estimated 1% of nonsyndromic heritable thoracic aortic disease. We sought to describe the clinical presentation of type B aortic dissection (TBAD), management, and outcomes in patients with this mutation.

Methods: This is a descriptive multi-institutional retrospective study of patients from six families with the PRKG1 mutation. Patients with TBAD were selected for analysis. Demographics, family histories, TBAD management, and outcomes were reviewed.

Results: Of the 29 individuals diagnosed with the PRKG1 mutation, 12 (41.3%) had TBAD (50% male, TBAD median age: 31 years [range, 16-58 years], median follow-up: 6 years [range, 3-15 years] after TBAD). All had a family history of aortic dissections and none had features of Marfan syndrome. The median size of the descending thoracic aorta (DTA) at TBAD was 4.1 cm (range, 3.8-5 cm). Most cases (9 acute TBAD, 1 incidental TBAD diagnosis during screening) were managed medically. One case had open DTA repair the acute phase. Repair for dissection-related aneurysmal degeneration was performed in seven cases (58.3%) in the chronic phase at a median of 2 years (range, 1-8 years) after TBAD. In four cases (33.3%), the DTA remained stable in size over a range of 1 to 7 years after TBAD. Type A aortic dissection subsequent to TBAD occurred in three cases (25%). There were four (33.3%) deaths in the series, all aortic related at a median age of 24 years (range, 19-43 years).

Conclusions: The PRKG1 (p.Arg177Gln) mutation although rare is associated with nonsyndromic TBAD in young and middle-aged patients. Workup for this gene mutation should be included as part of the workup for TBAD etiology in relatively young patients and those with familial history of aortic dissections. Once diagnosed, testing of first-degree family members is warranted. In all individuals with a PRKG1 mutation, close follow-up for aortic root dilatation and hypertension control is essential to reduce the risk of type A or type B aortic dissection, and in cases of TBAD, to decrease the risk of dissection-related aneurysmal degeneration.
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http://dx.doi.org/10.1016/j.jvs.2018.12.032DOI Listing
September 2019

Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation.

FASEB J 2019 06 27;33(6):6713-6725. Epub 2019 Feb 27.

Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Very little is known about how lipid signaling regulates intima hyperplasia after vascular injury. Herein, we report that deletion and pharmacological inhibition of phospholipase D (PLD)2, which generates the signaling lipid phosphatidic acid (PA), reduced neointimal formation in the mouse carotid artery ligation model. PLD2 deficiency inhibits migration of vascular smooth muscle cells (VSMCs) into the intima in mice as well as migration and formation of membrane ruffles in primary VSMCs. PA specifically binds to the IQ motif-containing guanosine triphosphatase-activating protein 1 (IQGAP1) scaffold protein. The binding between PA and IQGAP is required for the plasma membrane recruitment of IQGAP1. Similar to PLD2 inhibition, knockdown of IQGAP1 blocks ruffle formation and migration in VSMCs, which are rescued by expression of the exogenous IQGAP1 but not the PA binding-deficient mutant. These data reveal that the PLD2-PA-IQGAP1 pathway plays an important role in VSMC migration and injury-induced vascular remodeling, and implicate PLD2 as a candidate target for therapeutic interventions.-Wang, Z., Cai, M., Tay, L. W. R., Zhang, F., Wu, P., Huynh, A., Cao, X., Di Paolo, G., Peng, J., Milewicz, D. M., Du, G. Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation.
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http://dx.doi.org/10.1096/fj.201800390RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529346PMC
June 2019

SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections.

Eur J Hum Genet 2019 07 26;27(7):1054-1060. Epub 2019 Feb 26.

Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA.

SMAD4 pathogenic variants cause juvenile polyposis (JPS) and hereditary hemorrhagic telangiectasia (HHT), and 40% of affected individuals also have thoracic aortic disease. At the same time, SMAD4 pathogenic variants have not been reported in thoracic aortic disease families without JPS-HHT. A SMAD4 heterozygous variant, c.290G>T, p.(Arg97Leu), not present in population databases and predicted to be damaging to protein function, was identified in a family with thoracic aortic disease and no evidence of HHT or JPS. Cellular studies revealed that the SMAD4 p.(Arg97Leu) alteration increased SMAD4 ubiquitination and 26S proteasome-mediated protein degradation. Smooth muscle cells (SMCs) infected with lentivirus expressing the SMAD4 p.(Arg97Leu) variant demonstrated reduced contractile protein gene expression when compared to that of wild-type SMAD4. In addition, two rare variants were identified in individuals with early age of onset of thoracic aortic dissection. These results suggest that SMAD4 rare missense variants can lead to thoracic aortic disease in individuals who do not have JPS or HHT.
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http://dx.doi.org/10.1038/s41431-019-0357-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777456PMC
July 2019

Spontaneous pneumothorax and hemothorax frequently precede the arterial and intestinal complications of vascular Ehlers-Danlos syndrome.

Am J Med Genet A 2019 05 22;179(5):797-802. Epub 2019 Feb 22.

Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas.

Vascular Ehlers-Danlos syndrome (vEDS) is a connective tissue disorder due to defective type III collagen production and is associated with arterial rupture, spontaneous intestinal perforation, and gravid uterine rupture. Spontaneous pneumothorax and/or hemothorax (P/HTX) also occurs in vEDS patients. The temporal relation of pulmonary manifestations to arterial and intestinal complications in vEDS has not been well described. This was investigated in a multi-institutional retrospective case series of vEDS patients with confirmatory testing for COL3A1 mutation between 2000 and 2012. Data abstracted included demographics, family histories, presentation, and management of associated complications. Ninety-six cases (39% males, mean age 38.6 ± 15.5 years, range 8-79) had confirmatory testing for vEDS. P/HTX was documented in 17 (17.7%) cases. Most P/HTX preceded the diagnosis of vEDS (81%). Diagnosis of vEDS was made after arterial or intestinal complications at a mean of 7 years (range 0-26) post the initial P/HTX. In conclusion, spontaneous P/HTX is an early manifestation of vEDS frequently preceding an arterial complication or intestinal perforation. Thus, a spontaneous P/HTX in a young patient should trigger a differential diagnosis that includes vEDS. This should lead to an investigation of other vEDS features and subsequent genetic testing if vEDS features are present.
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http://dx.doi.org/10.1002/ajmg.a.61094DOI Listing
May 2019

Genetics of Thoracic and Abdominal Aortic Diseases.

Circ Res 2019 02;124(4):588-606

From the Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School; University of Texas Health Science Center at Houston (A.P., D.M.M.).

Dissections or ruptures of aortic aneurysms remain a leading cause of death in the developed world, with the majority of deaths being preventable if individuals at risk are identified and properly managed. Genetic variants predispose individuals to these aortic diseases. In the case of thoracic aortic aneurysm and dissections (thoracic aortic disease), genetic data can be used to identify some at-risk individuals and dictate management of the associated vascular disease. For abdominal aortic aneurysms, genetic associations have been identified, which provide insight on the molecular pathogenesis but cannot be used clinically yet to identify individuals at risk for abdominal aortic aneurysms. This compendium will discuss our current understanding of the genetic basis of thoracic aortic disease and abdominal aortic aneurysm disease. Although both diseases share several pathogenic similarities, including proteolytic elastic tissue degeneration and smooth muscle dysfunction, they also have several distinct differences, including population prevalence and modes of inheritance.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428422PMC
February 2019