Dianna M Milewicz

Publications (79)611.73 Total impact

• Article: Smooth Muscle Hyperplasia Due To Loss of Smooth Muscle α-Actin Is Driven by Activation of Focal Adhesion Kinase, Altered p53 Localization, and Increased Levels of Platelet-Derived Growth Factor Receptor-β

  Christina L Papke, Jiumei Cao, Callie S Kwartler, Carlos Villamizar, Katerina L Byanova, Soon-Mi Lim, Harini Sreenivasappa, Grant Fischer, John Pham, Meredith Rees, Miranda Wang, Christine Chaponnier, Giulio Gabbiani, Aarif Y Khakoo, Joya Chandra, Andreea Trache, Warren Zimmer, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of α- actin (α-SMA) cause thoracic aortic aneurysms and dissections and occlusive vascular diseases, including early onset coronary artery disease and stroke. We have shown that occlusive arterial lesions in patients with heterozygous ACTA2 missense mutations show increased numbers of medial or neointimal SMCs. The contribution of SMC hyperplasia to these vascular diseases and the pathways responsible for linking disruption of α-SMA filaments to hyperplasia are unknown. Here, we show that loss of Acta2 in mice recapitulates the SMC hyperplasia observed in ACTA2 mutant SMCs and determine the cellular pathways responsible for SMC hyperplasia. Acta2(-/-) mice showed increased neointimal formation following vascular injury in vivo, and SMCs explanted from these mice demonstrated increased proliferation and migration. Loss of α-SMA induced hyperplasia through focal adhesion (FA) rearrangement, focal adhesion kinase activation, re-localization of p53 from the nucleus to the cytoplasm, and increased expression and ligand-independent activation of platelet-derived growth factor receptor beta (Pdgfr-β). Disruption of α-SMA in wild type SMCs also induced similar cellular changes. Imatinib mesylate inhibited Pdgfr-β activation and Acta2(-/-) SMC proliferation in vitro and neointimal formation with vascular injury in vivo. Loss of α-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53, and Pdgfr-β, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations.
  Human Molecular Genetics 04/2013; · 7.64 Impact Factor
• Article: Eye features in three Danish patients with multisystemic smooth muscle dysfunction syndrome.

  Hans Ulrik Moller, Hans C Fledelius, Dianna M Milewicz, Ellen S Regalado, John R Ostergaard
  [show abstract] [hide abstract]
  ABSTRACT: A de novo mutation of the ACTA2 gene encoding the smooth muscle cell α-actin has been established in patients with multisystemic smooth muscle dysfunction syndrome associated with patent ductus arteriosus and mydriasis present at birth. To describe the structural ocular findings in three Danish children with this new syndrome and evaluate the possible functional consequences for visual development of the poorer imaging condition. Unresponsive mydriatic pupils with scalloping wisps of persistent pupillary membrane from the iris collarette were an early indicator of this rare genetic disorder in all three cases. Tortuousity of retinal arterioles was the main posterior pole finding, apparent during the first year of life and with a tendency to increase with age. In one case, it progressed to an aneurysmal-like state with breakdown of the blood-retinal barrier. Congenital mydriasis is an extremely rare pupil anomaly and is the feature for the early diagnosis of this new syndrome. The ophthalmologist should act in close collaboration with other specialists owing to the risk of aortic and cerebrovascular diseases and other complications associated with this disorder.
  The British journal of ophthalmology 07/2012; 96(9):1227-31. · 2.92 Impact Factor
• Article: TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome.

  Catherine Boileau, Dong-Chuan Guo, Nadine Hanna, Ellen S Regalado, Delphine Detaint, Limin Gong, Mathilde Varret, Siddharth K Prakash, Alexander H Li, Hyacintha d'Indy, [......], Suzanne M Leal, Christine Muti, Jay Shendure, Marie-Sylvie Gross, Mark J Rieder, Alec Vahanian, Deborah A Nickerson, Jean Baptiste Michel, Guillaume Jondeau, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.
  Nature Genetics 07/2012; 44(8):916-21. · 35.53 Impact Factor
• Article: Rare, nonsynonymous variant in the smooth muscle-specific isoform of myosin heavy chain, MYH11, R247C, alters force generation in the aorta and phenotype of smooth muscle cells.

  Shao-Qing Kuang, Callie S Kwartler, Katerina L Byanova, John Pham, Limin Gong, Siddharth K Prakash, Jian Huang, Kristine E Kamm, James T Stull, H Lee Sweeney, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: Mutations in myosin heavy chain (MYH11) cause autosomal dominant inheritance of thoracic aortic aneurysms and dissections. At the same time, rare, nonsynonymous variants in MYH11 that are predicted to disrupt protein function but do not cause inherited aortic disease are common in the general population and the vascular disease risk associated with these variants is unknown. To determine the consequences of the recurrent MYH11 rare variant, R247C, through functional studies in vitro and analysis of a knock-in mouse model with this specific variant, including assessment of aortic contraction, response to vascular injury, and phenotype of primary aortic smooth muscle cells (SMCs). The steady state ATPase activity (actin-activated) and the rates of phosphate and ADP release were lower for the R247C mutant myosin than for the wild-type, as was the rate of actin filament sliding in an in vitro motility assay. Myh11(R247C/R247C) mice exhibited normal growth, reproduction, and aortic histology but decreased aortic contraction. In response to vascular injury, Myh11(R247C/R247C) mice showed significantly increased neointimal formation due to increased SMC proliferation when compared with the wild-type mice. Primary aortic SMCs explanted from the Myh11(R247C/R247C) mice were dedifferentiated compared with wild-type SMCs based on increased proliferation and reduced expression of SMC contractile proteins. The mutant SMCs also displayed altered focal adhesions and decreased Rho activation, associated with decreased nuclear localization of myocardin-related transcription factor-A. Exposure of the Myh11(R247C/R247C) SMCs to a Rho activator rescued the dedifferentiated phenotype of the SMCs. These results indicate that a rare variant in MYH11, R247C, alters myosin contractile function and SMC phenotype, leading to increased proliferation in vitro and in response to vascular injury.
  Circulation Research 04/2012; 110(11):1411-22. · 9.49 Impact Factor
• Article: Diabetes and reduced risk for thoracic aortic aneurysms and dissections: a nationwide case-control study.

  Siddharth K Prakash, Claudia Pedroza, Yameen A Khalil, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: Vascular diseases are the principal causes of death and disability in people with diabetes. At the same time, studies suggest a protective role of diabetes in the development of abdominal aortic aneurysms. We sought to determine whether diabetes is associated with decreased hospitalization due to thoracic aortic aneurysms and dissections (TAAD). We used the 2006 and 2007 Nationwide Inpatient Sample (NIS) to determine TAAD discharge rates. Control subjects were randomly selected to achieve three controls per case. Predictor variables in multilevel logistic regression included age, race, median income, diabetes, and hypertension. We estimated that the average rate of hospital discharge for TAAD among individuals diagnosed with diabetes was 9.7 per 10 000, compared to 15.6 per 10 000 among all discharges. The prevalence of diabetes was substantially lower in TAAD (13%) than in control (22%) records. After adjustment for demographic characteristics, the negative association between diabetes and TAAD remained highly significant in both NIS datasets. Compared to discharges without diabetes, those with chronic complications of diabetes were least likely to be diagnosed with TAAD (OR [odds ratio] 0.17, 95% CI, 0.12-0.23). A significant association remained between uncomplicated diabetes and TAAD. We replicated these findings in an independent group of patients who were hospitalized with acute thoracic aortic dissections. The principal implication of our findings is that diabetes is independently associated with a decreased rate of hospitalization due to TAAD in proportion to the severity of diabetic complications. Future studies should consider diabetes in predictive models of aneurysm expansion or dissection. (J Am Heart Assoc. 2012;1:jah3-e000323 doi: 10.1161/JAHA.111.000323.).
  Journal of the American Heart Association. 04/2012; 1(2).
• Article: Long-term implications of emergency versus elective proximal aortic surgery in patients with Marfan syndrome in the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Consortium Registry.

  Howard K Song, Mark Kindem, Joseph E Bavaria, Harry C Dietz, Dianna M Milewicz, Richard B Devereux, Kim A Eagle, Cheryl L Maslen, Barbara L Kroner, Reed E Pyeritz, Kathryn W Holmes, Jonathan W Weinsaft, Victor Menashe, William Ravekes, Scott A LeMaire
  [show abstract] [hide abstract]
  ABSTRACT: Patients with Marfan syndrome with aortic root aneurysms undergo elective aortic root replacement to avoid the life-threatening outcomes of aortic dissection and emergency repair. The long-term implications of failed aortic surveillance leading to acute dissection and emergency repair are poorly defined. We compared the long-term clinical courses of patients with Marfan syndrome who survive emergency versus elective proximal aortic surgery. The Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Registry is a National Institutes of Health-funded multicenter database and biorepository that enrolls patients with genetically triggered thoracic aortic aneurysms. Of the 635 patients with Marfan syndrome enrolled as of March 2011, 194 had undergone proximal aortic replacement. Patients were grouped according to emergency (n = 47) or elective (n = 147) status at the time of surgery. Patients in the emergency group were more likely to have incomplete proximal aortic resection; 83% of emergency procedures included aortic root replacement, compared with 95% of elective procedures. At long-term follow-up (mean, >6 years), the emergency group had a higher incidence of chronic dissection of the distal aorta and significantly larger diameters in distal aortic segments than elective patients. Patients in the emergency group had undergone more operations (1.31 vs 1.11 procedures/patient; P = .01) and had lower activity scores on a health-related quality of life survey. For patients with Marfan syndrome, failed aortic surveillance and consequent emergency dissection repair have important long-term implications with regard to the status of the distal aorta, need for multiple procedures, and quality of life. These findings emphasize the importance of aortic surveillance and timely elective aortic root aneurysm repair for patients with Marfan syndrome.
  The Journal of thoracic and cardiovascular surgery 11/2011; 143(2):282-6. · 3.41 Impact Factor
• Article: Stopping a killer: improving the diagnosis, treatment, and prevention of acute ascending aortic dissections.

  Dianna M Milewicz
  Circulation 11/2011; 124(18):1902-4. · 14.74 Impact Factor
• Article: The National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC): results from phase I and scientific opportunities in phase II.

  Barbara L Kroner, H Eser Tolunay, Craig T Basson, Reed E Pyeritz, Kathryn W Holmes, Cheryl L Maslen, Dianna M Milewicz, Scott A LeMaire, Tabitha Hendershot, Patrice Desvigne-Nickens, Richard B Devereux, Harry C Dietz, Howard K Song, Danny Ringer, Megan Mitchell, Jonathan W Weinsaft, William Ravekes, Victor Menashe, Kim A Eagle
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: Genetically triggered thoracic aortic conditions (GenTACs) represent an important problem for patients and their families. Accordingly, the National Heart, Lung, and Blood Institute established the first phase of its national GenTAC Registry in 2006. ENROLLMENT AND DIAGNOSES: Between 2007 and 2010, 6 enrolling centers established the GenTAC I Registry consisting of 2,046 patients (Marfan syndrome 576 [28.2%], bicuspid aortic valve disease 504 [24.6%], aneurysm or dissection age <50 years 369 [18%], and others). Biologic samples for DNA analyses (white blood cells or saliva) are available in 97%, and stored plasma is available in 60% of enrollees. RESULTS: Initial scientific inquiry using the GenTAC Registry has included validation studies of genetic causes for aortic syndromes, potential usefulness of transforming growth factor beta (TGFB) blood levels in Marfan subjects, and current surgical approaches to ascending aortic conditions. FUTURE OPPORTUNITY: The second phase of GenTAC will allow biannual follow-up of GenTAC I enrollees for up to 9 years, enrollment of an additional 1,500 subjects, further integration of imaging findings with clinical and genetic data through utilization of an imaging core laboratory, important validation of phenotype-genotype correlations through a phenotyping core laboratory, and integration of a scientific advisory committee to help define the full range and depth of the Registry's scientific capabilities. The registry resources are available to the external scientific community through an application process accessible at https://gentac.rti.org.
  American heart journal 10/2011; 162(4):627-632.e1. · 4.65 Impact Factor
• Article: The genetics of colored sequence synesthesia: suggestive evidence of linkage to 16q and genetic heterogeneity for the condition.

  Steffie N Tomson, Nili Avidan, Kwanghyuk Lee, Anand K Sarma, Rejnal Tushe, Dianna M Milewicz, Molly Bray, Suzanne M Leal, David M Eagleman
  [show abstract] [hide abstract]
  ABSTRACT: Synesthesia is a perceptual condition in which sensory stimulation triggers anomalous sensory experiences. In colored sequence synesthesia (CSS), color experiences are triggered by sequences such as letters or numbers. We performed a family based linkage analysis to identify genetic loci responsible for the increased neural crosstalk underlying CSS. Our results implicate a 23 MB region at 16q12.2-23.1, providing the first step in understanding the molecular basis of CSS.
  Behavioural brain research 09/2011; 223(1):48-52. · 3.22 Impact Factor
• Article: Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1.

  Scott A Lemaire, Merry-Lynn N McDonald, Dong-Chuan Guo, Ludivine Russell, Charles C Miller, Ralph J Johnson, Mir Reza Bekheirnia, Luis M Franco, Mary Nguyen, Reed E Pyeritz, [......], Christine Seidman, J G Seidman, Eric M Isselbacher, Molly Bray, Joseph S Coselli, Anthony L Estrera, Hazim J Safi, John W Belmont, Suzanne M Leal, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10(-5) in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.
  Nature Genetics 09/2011; 43(10):996-1000. · 35.53 Impact Factor
• Article: Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1

  Scott A LeMaire, Merry-Lynn N McDonald, Dong-chuan Guo, Ludivine Russell, Charles C Miller III, Ralph J Johnson, Mir Reza Bekheirnia, Luis M Franco, Mary Nguyen, Reed E Pyeritz, [......], Christine Seidman, J G Seidman, Eric M Isselbacher, Molly Bray, Joseph S Coselli, Anthony L Estrera, Hazim J Safi, John W Belmont, Suzanne M Leal, Dianna M Milewicz
  Nature Genetics 09/2011; 43(10):996-1000. · 35.53 Impact Factor
• Article: Susceptibility to acute thoracic aortic dissections in patients dying outside the hospital: an autopsy study.

  Siddharth K Prakash, Kathryn Haden-Pinneri, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: The objectives of this study were to identify the incidence and predictors of death from acute thoracic aortic dissections (AoDs) and to describe their associated clinical findings. We analyzed the clinical and pathologic data from 141 consecutive autopsies of individuals with sudden death due to AoDs in Harris County, TX, from 2003 to 2010, which represented 20% (107/534) of all deaths attributed to AoDs during this period by the Texas Department of Health. Multivariate Cox regression was used to identify predictors of survival adjusting for differences in demographic and clinical characteristics. During the study period, 141 of 145 fatal victims of acute thoracic dissections underwent a full autopsy and were included in the analysis. In 84% of cases, death was caused by pericardial tamponade from ascending AoD. The frequency of deaths showed seasonal variation with peak incidence in the winter months. Compared with patients presenting to hospitals with AoD, individuals dying outside the hospital were more likely to be female, African American, younger than 50 years and to have had prior aortic disease. One third of subjects with AoD had seen a physician within 1 week of sudden death. The most consistent pathologic abnormality was marked ventricular hypertrophy (257 g/m(2) on average) out of proportion to expected values for age, gender, and body size. Hispanic patients and patients with congenital disorders, such as bicuspid aortic valve and Marfan syndrome, were significantly more likely to die of AoD at a younger age (38% vs 13%, P < .002). Our findings identify differences between patients hospitalized for AoD versus those who died without being hospitalized. Previously unreported vulnerabilities to sudden death from AoD in minority populations, specifically Hispanics, were also identified that merit follow-up in prospective studies.
  American heart journal 09/2011; 162(3):474-9. · 4.65 Impact Factor
• Article: Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms.

  Ellen Regalado, Sarah Medrek, Van Tran-Fadulu, Dong-Chuan Guo, Hariyadarshi Pannu, Hossein Golabbakhsh, Suzanne Smart, Julia H Chen, Sanjay Shete, Dong H Kim, Ralph Stern, Alan C Braverman, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (P < 0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty-nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable. In these families, routine cerebral and aortic imaging for at risk members could prevent cerebral hemorrhages and aortic dissections.
  American Journal of Medical Genetics Part A 09/2011; 155A(9):2125-30. · 2.39 Impact Factor
• Article: Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.

  Ellen S Regalado, Dong-Chuan Guo, Carlos Villamizar, Nili Avidan, Dawna Gilchrist, Barbara McGillivray, Lorne Clarke, Francois Bernier, Regie L Santos-Cortez, Suzanne M Leal, Aida M Bertoli-Avella, Jay Shendure, Mark J Rieder, Deborah A Nickerson, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner. To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants. A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers. SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.
  Circulation Research 08/2011; 109(6):680-6. · 9.49 Impact Factor
• Chapter: Familial Thoracic Aortic Aneurysms and Dissections

  Sumera N. Hasham, Dianna M. Milewicz, Peter N. Robinson, Maurice Godfrey
  [show abstract] [hide abstract]
  ABSTRACT: Ascending aortic aneurysms leading to type A aortic dissections are the major cardiovascular complication of the Marfan syndrome (MFS). MFS is a major genetic syndrome predisposing individuals to these aortic conditions but other genetic syndromes also have similar aortic problems. In addition, ascending thoracic aortic aneurysms and dissections can be inherited in an autosomal dominant manner with decreased penetrance and variable expression, and the locations of the genes contributing to familial thoracic aortic aneurysms and dissections are beginning to be mapped in the human genome.
  07/2011: pages 113-122;
• Article: Impact of image analysis methodology on diagnostic and surgical classification of patients with thoracic aortic aneurysms.

  Dorinna D Mendoza, Minisha Kochar, Richard B Devereux, Craig T Basson, James K Min, Kathryn Holmes, Harry C Dietz, Dianna M Milewicz, Scott A LeMaire, Reed E Pyeritz, Joseph E Bavaria, Cheryl L Maslen, Howard Song, Barbara L Kroner, Kim A Eagle, Jonathan W Weinsaft
  [show abstract] [hide abstract]
  ABSTRACT: For patients with thoracic aortic aneurysms (TAA), aortic size on imaging is widely used to guide clinical decision making. This study examined the impact of methodological variance on aortic quantification. We studied enrollees in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions. Aortic size on computed tomography was quantified by 2 linear methods; cross-sectional dimensions in axial (AX) and double oblique (DO) plane. Calculated area was compared to planimetry. Established cutoffs (area/height>10 cm2/m, diameter≥5 cm) for prophylactic TAA repair were used to compare surgical eligibility by each method. Fifty subjects were studied. Aortic size differed between AX and DO at all locations (p≤0.001), with magnitude greatest at the sinotubular junction (4.8±1.1 vs 4.0±1.0 cm, p<0.001). The difference between AX and DO correlated with aortic angular displacement (r=0.37, p<0.01), which was threefold larger at the sinotubular junction (37±12 degrees) than the ascending aorta (12±5 degrees; p<0.001). At all locations, aortic area calculated using DO yielded smaller differences with planimetry than AX (p<0.05). DO and planimetry yielded equal prevalence (24%) of subjects eligible for prophylactic TAA repair based on area-height cutoff, whereas AX prevalence was higher (44%; p=0.006). Using a linear cutoff, AX yielded over a twofold greater prevalence of surgically eligible subjects (56%) than did DO (24%; p<0.001). Established linear methods for aortic measurement yield different results that impact surgical eligibility. DO yielded improved agreement with planimetry and differed with AX in proportion to aortic geometric obliquity. Findings support DO measurements for imaging evaluation of subjects with TAA.
  The Annals of thoracic surgery 07/2011; 92(3):904-12. · 3.74 Impact Factor
• Source

  Available from: PubMed Central

  Article: Recurrent chromosome 16p13.1 duplications are a risk factor for aortic dissections.

  Shao-Qing Kuang, Dong-Chuan Guo, Siddharth K Prakash, Merry-Lynn N McDonald, Ralph J Johnson, Min Wang, Ellen S Regalado, Ludivine Russell, Jiu-Mei Cao, Callie Kwartler, Kurt Fraivillig, Joseph S Coselli, Hazim J Safi, Anthony L Estrera, Suzanne M Leal, Scott A Lemaire, John W Belmont, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0 × 10⁻⁵, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes.
  PLoS Genetics 06/2011; 7(6):e1002118. · 8.69 Impact Factor
• Article: Familial thoracic aortic aneurysms and dissections: identification of a novel locus for stable aneurysms with a low risk for progression to aortic dissection.

  Dong-Chuan Guo, Ellen S Regalado, Charles Minn, Van Tran-Fadulu, Joshua Coney, Jiumei Cao, Min Wang, Robert K Yu, Anthony L Estrera, Hazim J Safi, Sanjay S Shete, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: Thoracic aortic aneurysms leading to acute aortic dissections are the major diseases that affect the thoracic aorta. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of TAAD, and these patients present younger with more rapidly enlarging aneurysms than patients without a family history of aortic disease. A large family with multiple members with TAAD inherited in an autosomal-dominant manner was identified. The ascending aortic aneurysms were associated with slow enlargement, a low risk of dissection, and decreased penetrance in women. Genome-wide linkage analysis was performed, and a novel locus on chromosome 12 was identified for the mutant gene causing disease in this family. Of the 12 male members who carry the disease-linked microsatellite haplotype, 9 had ascending aortic aneurysms with an average diameter of 4.7 cm at an average age of 52.4 years (range, 32 to 76 years) at the time of diagnosis; only 1 individual had progressed to acute aortic dissection, and no other members with aortic dissections were identified. Women harboring the disease-linked haplotype did not have thoracic aortic disease, including 1 aged 84 years. Sequencing of 9 genes within the critical interval at the chromosome 12 locus did not identify the mutant gene. Mapping a locus for ascending thoracic aortic aneurysms associated with a low risk of aortic dissection supports our hypothesis that genes leading to familial disease can be associated with less-aggressive thoracic aortic disease.
  Circulation Cardiovascular Genetics 02/2011; 4(1):36-42. · 6.11 Impact Factor
• Article: Treatment guidelines for thoracic aortic aneurysms and dissections based on the underlying causative gene.

  Dianna M Milewicz, Ellen S Regalado, Dong-Chuan Guo
  The Journal of thoracic and cardiovascular surgery 12/2010; 140(6 Suppl):S2-4; discussion S45-51. · 3.41 Impact Factor
• Article: TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections.

  Sakiko Inamoto, Callie S Kwartler, Andrea L Lafont, Yao Yun Liang, Van Tran Fadulu, Senthil Duraisamy, Marcia Willing, Anthony Estrera, Hazim Safi, Mark C Hannibal, John Carey, John Wiktorowicz, Filemon K Tan, Xin-Hua Feng, Hariyadarshi Pannu, Dianna M Milewicz
  [show abstract] [hide abstract]
  ABSTRACT: Transforming growth factor-β (TGF-β) signaling is critical for the differentiation of smooth muscle cells (SMCs) into quiescent cells expressing a full repertoire of contractile proteins. Heterozygous mutations in TGF-β receptor type II (TGFBR2) disrupt TGF-β signaling and lead to genetic conditions that predispose to thoracic aortic aneurysms and dissections (TAADs). The aim of this study is to determine the molecular mechanism by which TGFBR2 mutations cause TAADs. Using aortic SMCs explanted from patients with TGFBR2 mutations, we show decreased expression of SMC contractile proteins compared with controls. Exposure to TGF-β1 fails to increase expression of contractile genes in mutant SMCs, whereas control cells further increase expression of these genes. Analysis of fixed and frozen aortas from patients with TGFBR2 mutations confirms decreased in vivo expression of contractile proteins relative to unaffected aortas. Fibroblasts explanted from patients with TGFBR2 mutations fail to transform into mature myofibroblasts with TGF-β1 stimulation as assessed by expression of contractile proteins. These data support the conclusion that heterozygous TGFBR2 mutations lead to decreased expression of SMC contractile protein in both SMCs and myofibroblasts. The failure of TGFBR2-mutant SMCs to fully express SMC contractile proteins predicts defective contractile function in these cells and aligns with a hypothesis that defective SMC contractile function contributes to the pathogenesis of TAAD.
  Cardiovascular research 12/2010; 88(3):520-9. · 5.80 Impact Factor