Vertebral Tortuosity Is Associated With Increased Rate of Cardiovascular Events in Vascular Ehlers-Danlos Syndrome.

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

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

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes. OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene. METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, and location of recruitment. RESULTS: Significant differences in aortic event risk were identified among the smooth muscle contraction genes (ACTA2, MYLK, and PRKG1; P = 0.002) and among the genes for Loeys-Dietz syndrome, which encode proteins in the transforming growth factor (TGF)-ß pathway (SMAD3, TGFB2, TGFBR1, and TGFBR2;P < 0.0001). Cumulative incidence of type A aortic dissection was higher than elective aneurysm surgery in patients with variants in ACTA2, MYLK, PRKG1, and SMAD3; in contrast, patients with TGFBR2 variants had lower cumulative incidence of type A aortic dissection than elective aneurysm surgery. Cumulative incidence of type B aortic dissection was higher for ACTA2, PRKG1, and TGFBR2 than other genes. After adjusting for proband status, sex, and recruitment location, specific variants in ACTA2 and TGFBR2 were associated with substantially higher risk of aortic event with childhood onset. CONCLUSIONS: Gene- and variant-specific data on aortic events in individuals with HTAD support personalized aortic surveillance and clinical management.

Location of Aortic Enlargement and Risk of Type A Dissection at Smaller Diameters.

BACKGROUND: Previous work has demonstrated that more than one-half of acute type A aortic dissections (ATADs) occur at a maximal aortic diameter (MAD) of <5.5 cm. However, no analysis has investigated whether ATAD risk at smaller MADs is more common with modest dilation of the aortic root (AR) or supracoronary ascending aorta (AA) in patients without genetically triggered aortopathy. OBJECTIVES: This study sought to determine if the segment of modest aortic dilation affects risk of ATAD. METHODS: Using the International Registry of Acute Aortic Dissection (IRAD) database from May 1996 to October 2016, we identified 667 ATAD patients with MAD <5.5 cm. Patients were stratified by location of the largest proximal aortic segment (AR or AA). Patients with known genetically triggered aortopathy were excluded. MADs at time of dissection were compared between AR and AA groups. Secondary outcomes included operation, postoperative outcomes, and long-term survival. RESULTS: Of patients with ATAD at an MAD <5.5 cm, 79.5% (n = 530) were in the AA group and 20.5% (n = 137) in the AR group. Modestly dilated ARs (median MAD 4.6 cm [IQR: 4.1-5.0 cm]) dissected at a significantly smaller diameter than modestly dilated AAs (median MAD 4.8 cm [IQR: 4.4-5.1 cm]) (P < 0.01). AR patients were significantly younger than AA patients (58.5 ± 13.0 years vs 63.2 ± 13.3 years; P < 0.01) and more commonly male (78% vs 65%; P < 0.01). Postoperative and long-term outcomes did not differ between groups. CONCLUSIONS: ATAD appears to occur at smaller diameters in patients with modest dilation in the AR vs the AA (4.6 vs 4.8 cm). These findings may have implications for future consensus guidelines regarding the management of patients with aortic disease.

Cardiovascular Outcomes in Aortopathy: GenTAC Registry of Genetically Triggered Aortic Aneurysms and Related Conditions.

BACKGROUND: The GenTAC (Genetically Triggered Thoracic Aortic Aneurysm and Cardiovascular Conditions) Registry enrolled patients with genetic aortopathies between 2007 and 2016. OBJECTIVES: The purpose of this study was to compare age distribution and probability of elective surgery for proximal aortic aneurysm, any dissection surgery, and cardiovascular mortality among aortopathy etiologies. METHODS: The GenTAC study had a retrospective/prospective design. Participants with bicuspid aortic valve (BAV) with aneurysm (n = 879), Marfan syndrome (MFS) (n = 861), nonsyndromic heritable thoracic aortic disease (nsHTAD) (n = 378), Turner syndrome (TS) (n = 298), vascular Ehlers-Danlos syndrome (vEDS) (n = 149), and Loeys-Dietz syndrome (LDS) (n = 121) were analyzed. RESULTS: The 25% probability of elective proximal aortic aneurysm surgery was 30 years for LDS (95% CI: 18-37 years), followed by MFS (34 years; 95% CI: 32-36 years), nsHTAD (52 years; 95% CI: 48-56 years), and BAV (55 years; 95% CI: 53-58 years). Any dissection surgery 25% probability was highest in LDS (38 years; 95% CI: 33-53 years) followed by MFS (51 years; 95% CI: 46-57 years) and nsHTAD (54 years; 95% CI: 51-61 years). BAV experienced the largest relative frequency of elective surgery to any dissection surgery (254/33 = 7.7), compared with MFS (273/112 = 2.4), LDS (35/16 = 2.2), or nsHTAD (82/76 = 1.1). With MFS as the reference population, risk of any dissection surgery or cardiovascular mortality was lowest in BAV patients (HR: 0.13; 95% CI: 0.08-0.18; HR: 0.13; 95%: CI: 0.06-0.27, respectively). The greatest risk of mortality was seen in patients with vEDS. CONCLUSIONS: Marfan and LDS cohorts demonstrate age and event profiles congruent with the current understanding of syndromic aortopathies. BAV events weigh toward elective replacement with relatively few dissection surgeries. Nonsyndromic HTAD patients experience near equal probability of dissection vs prophylactic surgery, possibly because of failure of early diagnosis.

Digital vascular lesions detected by transillumination.

Abnormalities of the capillaries of the digits in hereditary hemorrhagic telangiectasia can be detected by shining through a narrow beam of light through the dorsal side and visualizing the vasculature on the palmar side, a procedure termed transillumination. This study was performed to determine if this method can detect digital vascular abnormalities in aortopathies and arteriopathies. Transillumination was performed in patients with Marfan syndrome (MFS), thoracic aortic aneurysm and dissection (TAAD), vascular Ehlers-Danlos syndrome (vEDS), bicuspid aortic valve with aortopathy, and arteriopathies without aortopathy. Subjects with no known vascular disorders were controls. Digital vascular abnormalities were present in some patients with all of the disorders and were especially frequent in MFS, TAAD, and vEDS. All patients had significantly more digital vascular abnormalities than control subjects. Transillumination can detect vascular abnormalities in digits of patients with a variety of conditions with aortopathy or arteriopathy.

Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant, age-related but highly penetrant condition with substantial intrafamilial and interfamilial variability. MFS is caused by pathogenetic variants in FBN1, which encodes fibrillin-1, a major structural component of the extracellular matrix that provides support to connective tissues, particularly in arteries, the pericondrium and structures in the eye. Up to 25% of individuals with MFS have de novo variants. The most prominent manifestations of MFS are asymptomatic aortic root aneurysms, aortic dissections, dislocation of the ocular lens (ectopia lentis) and skeletal abnormalities that are characterized by overgrowth of the long bones. MFS is diagnosed based on the Ghent II nosology; genetic testing confirming the presence of a FBN1 pathogenetic variant is not always required for diagnosis but can help distinguish MFS from other heritable thoracic aortic disease syndromes that can present with skeletal features similar to those in MFS. Untreated aortic root aneurysms can progress to life-threatening acute aortic dissections. Management of MFS requires medical therapy to slow the rate of growth of aneurysms and decrease the risk of dissection. Routine surveillance with imaging techniques such as transthoracic echocardiography, CT or MRI is necessary to monitor aneurysm growth and determine when to perform prophylactic repair surgery to prevent an acute aortic dissection.

Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

Arachnodactyly represented in art.

Arachnodactyly, a term used since 1902 to describe abnormally long (spider-like) fingers, is a pathologic feature of several heritable conditions, notably the Marfan syndrome and congenital contractural arachnodactyly. A number of prominent artists, dating from the 16th to the 20th centuries, have depicted subjects with unusually long fingers, sometime associated with elongation of the body, neck and head. El Greco incorporated this style in many paintings. Little evidence supports any subject in any of these paintings as having a congenital deformity.

Uncertainty in Genomics Impacts Precision Medicine.

As exacting as genetic and genomic testing have become, health professionals continue to encounter uncertainty in their applications to medical practice. As examining the human genome at more refined levels increases, so is the likelihood of encountering uncertainty about the meaning of the information. The history of this concept informs how we might confront and deal with uncertainty, and what the future might hold. Precision medicine holds great promise for establishing more accurate diagnoses, directing specific therapy to patients who will most benefit from it, and avoiding treatments in patients who are most likely to suffer adverse consequences, or at best not benefit. But its application depends importantly on the proper interpretation of a person's genotype.

Clinical Features and Outcomes of Pregnancy-Related Acute Aortic Dissection.

Importance: Women with aortopathy conditions are at risk for pregnancy-related aortic dissection, and these conditions may not be recognized until after the aortic dissection occurs. Objective: To examine the clinical characteristics, imaging features, and outcomes in women with pregnancy-related acute aortic dissection. Design, Setting, and Participants: A cohort study, comprising data from the International Registry of Acute Aortic Dissection (IRAD) (February 1, 1998, to February 28, 2018). The multicenter referral center study included 29 women with aortic dissection during pregnancy or less than 12 weeks post partum in IRAD from 1998 to 2018. Main Outcomes and Measures: Clinical features of pregnancy-related aortic dissection to be studied included underlying aortopathy, aortic size, type of aortic dissection, timing of dissection, hypertension, and previous aortic surgery. Results: A total of 29 women (mean [SD] age, 32 [6] years) had pregnancy-related aortic dissection, representing 0.3% of all aortic dissections and 1% of aortic dissection in women in the IRAD. Among women younger than 35 years, aortic dissection was related to pregnancy in 20 of 105 women (19%). Thirteen women (45%) had type A aortic dissection, and 16 women (55%) had type B. Aortic dissection onset was known in 27 women (93%): 15 during pregnancy, 4 in the first trimester, and 11 in the third trimester; 12 were post partum, occurring a mean (SD) of 12.5 (14) days post partum. At type A aortic dissection diagnosis, the mean (SD) aortic diameters were sinus of Valsalva, 54.5 (5) mm and ascending aorta, 54.7 (6) mm. At type B aortic dissection diagnosis, the mean (SD) descending aortic diameter was 32.5 (5) mm. Twenty women (69%) had an aortopathy condition or a positive family history: 13 women (65%) with Marfan syndrome, 2 women (10%) with Loeys-Dietz syndrome, 2 women (10%) with bicuspid aortic valves, 2 women (10%) with a family history of aortic disease, and 1 woman (5%) with familial thoracic aortic aneurysm. Aortopathy was not recognized until after aortic dissection in 47% of the women. Twenty-eight women (97%) survived aortic dissection hospitalization. Conclusions and Relevance: Aortic dissection complicating pregnancy is rare. Most pregnancy-related aortic dissection is due to an aortopathy often not diagnosed until after aortic dissection. In this study, type A aortic dissections were associated with a dilated aorta, and type B aortic dissections often were not. Recognition of underlying conditions and risks for aortic dissection may improve management of pregnancy in women with aortopathy.

Cerebrovascular Malformations in a Pediatric Hereditary Hemorrhagic Telangiectasia Cohort.

BACKGROUND: We determined the frequency of cerebrovascular malformations in a pediatric cohort with hereditary hemorrhagic telangiectasia. METHODS: Retrospective cohort study of 54 children diagnosed with hereditary hemorrhagic telangiectasia at a tertiary care center. All neuroimaging was reviewed to assess for number and types of cerebrovascular malformations and for intracerebral hemorrhage and arterial ischemic stroke. Clinical charts were reviewed for clinical manifestations, genetic mutation, and clinically evident intracerebral hemorrhages and arterial ischemic strokes. RESULTS: Among 54 children with hereditary hemorrhagic telangiectasia with a median age of 3.5 years (interquartile range 0.4 to 7.9 years) at diagnosis, neuroimaging was performed in 52 (96.3%) at a median age of 5.2 years (interquartile range 1.8 to 9 years). Fourteen of 52 imaged children (26.9%) had cerebrovascular malformations. Cerebrovascular malformations included arteriovenous malformations, arteriovenous fistulas, vein of Galen malformations, and developmental venous anomalies. Six of the 14 children with cerebrovascular malformations (42.9%) had multiple malformations. Three children developed new cerebral arteriovenous malformations over time. Six children (11.1%) had clinically evident intracerebral hemorrhage, arterial ischemic stroke, or transient ischemic attack. The three children with intracerebral hemorrhage presented at young ages (4.3 to 7.7 years). CONCLUSIONS: More than a quarter of children with hereditary hemorrhagic telangiectasia who were imaged had cerebrovascular malformations, and overt stroke occurred in more than 10%. Intracerebral hemorrhages can occur in pediatric hereditary hemorrhagic telangiectasia patients at young ages, and new cerebral arteriovenous malformations may develop over time. Early screening with neuroimaging including neurovascular imaging as well as repeat neuroimaging may be warranted in children with hereditary hemorrhagic telangiectasia.

Postembolotherapy Pulmonary Arteriovenous Malformation Follow-Up: A Role for Graded Transthoracic Contrast Echocardiography Prior to High-Resolution Chest CT Scan.

BACKGROUND: High-resolution chest CT (HRCT) scan is recommended after pulmonary arteriovenous malformation (PAVM) embolotherapy to assess for PAVM persistence and untreated PAVM growth. Graded transthoracic contrast echocardiography (TTCE) predicts the need for embolotherapy in PAVM screening. This study sought to determine whether postembolotherapy graded TTCE can similarly predict the need for repeat embolotherapy. METHODS: Thirty-two patients (8 men and 24 women; mean age, 51.1 ± 12.6 years) with prior PAVM embolotherapy and follow-up HRCT scan were prospectively enrolled. Patients underwent graded TTCE using a validated three-point quantitative grading scale. TTCE grade and HRCT findings were compared. RESULTS: Median time between most recent HRCT scan and TTCE was 7 days (interquartile range, 0-272 days). Thirty patients (94%) had no PAVMs requiring repeat embolotherapy on HRCT scan. Two patients (6%) had PAVMs requiring repeat embolotherapy (feeding artery [FA] ≥ 3 mm), one with untreated PAVM growth and one with treated PAVM persistence. TTCE was positive in 88% of patients (n = 28). All patients (n = 4, 12%) with negative TTCE had no visible PAVMs on HRCT scan. Nine patients (32%) had grade 1 shunt, 10 (35%) had grade 2 shunt, and nine (32%) had grade 3 shunt. No patients with grade 1 shunt had PAVMs amenable to repeat embolotherapy on HRCT scan. All patients (n = 2) with PAVMs requiring repeat embolotherapy (FA ≥ 3 mm) had grade 3 shunt. TTCE grade was significantly associated with PAVM FA diameter (P < .001). CONCLUSIONS: Postembolotherapy graded TTCE can predict the need for repeat embolotherapy on HRCT scan. Patients with negative TTCE and grade 1 shunt may not require HRCT follow-up and can potentially be followed with serial graded TTCE. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02936349; URL: www.clinicaltrials.gov.

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

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.

Health-Related Quality of Life in Children and Young Adults with Marfan Syndrome.

OBJECTIVE: To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial. STUDY DESIGN: The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with Marfan syndrome (5-25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol vs losartan), severity of clinical features, and number of patient-reported symptoms on HRQOL was assessed by general linear models. RESULTS: Mean PedsQL scores in children (5-18 years) with Marfan syndrome were lower than healthy population norms for physical (P ≤ .003) and psychosocial (P < .001) domains; mean psychosocial scores for adults (19-25 years) were greater than healthy norms (P < .001). HRQOL across multiple domains correlated inversely with frequency of patient-reported symptoms (r = 0.30-0.38, P < .0001). Those <18 years of age with neurodevelopmental disorders (mainly learning disability, attention-deficit/hyperactivity disorder) had lower mean PedsQL scores (5.5-7.4 lower, P < .04). A multivariable model found age, sex, patient-reported symptoms, and neurodevelopmental disorder to be independent predictors of HRQOL. There were no differences in HRQOL scores by treatment arm, aortic root z score, number of skeletal features, or presence of ectopia lentis. CONCLUSIONS: Children and adolescents with Marfan syndrome were at high risk for impaired HRQOL. Patient-reported symptoms and neurodevelopmental disorder, but not treatment arm or severity of Marfan syndrome-related physical findings, were associated with lower HRQOL.