Arterial tortuosity is emerging as a common feature in genetically mediated thoracic aortic disease that may be prognostic. This review will summarize recent literature on arterial tortuosity in the ...setting of genetic arteriopathies.
Although arterial tortuosity has been primarily described in Loeys-Dietz syndrome due to TGFBR1 and TGFBR2 mutations and in arterial tortuosity syndrome due to SLC210A mutations, recent studies that use quantitative measures of tortuosity suggest that tortuosity is present in many other genetic conditions associated with aortic dilation and dissection. The mechanisms of the development of tortuosity in these disorders are not fully understood, but are founded in the concept that there is abnormal, pathologic arterial lengthening in a fixed space, resulting in more tortuous vessels. Further studies suggest that patients with increased arterial tortuosity are at increased risk of adverse cardiovascular events, including aortic surgery, aortic dissection, and death.
Arterial tortuosity is commonly present in genetically mediated aortic disease. Given the suboptimal performance of aortic dimension alone in predicting aortic dissection, quantification of tortuosity may augment the current algorithms for determining risk in patients with aortic disease.
Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, ...including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10(-7)), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91-178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57-99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.
Arterial tortuosity is described as a common and distinctive feature of Loeys-Dietz syndrome (LDS), yet reports on arterial tortuosity are based on qualitative observations and none have investigated ...an association between tortuosity and cardiovascular outcomes in LDS or other connective tissue disorders.
We performed a retrospective analysis of 90 patients ≤50 years of age with Marfan syndrome, LDS, Ehlers-Danlos syndrome, or nonspecific connective tissue disorder who underwent thoracic contrast-enhanced magnetic resonance angiography. Controls (n=30) underwent magnetic resonance imaging to exclude arrhythmogenic right ventricular dysplasia. Using a volume-rendered angiogram, vertebral arteries were measured along the curvature of the vessel (actual length) and linearly (straight length), and distance factor was calculated: (actual/straight length-1)×100. Each subject's maximum distance factor was designated the Vertebral Tortuosity Index (VTI). The VTI was compared among diagnostic groups and among patients with cardiac surgery, dissection, and death. Median age at magnetic resonance imaging was 19.6 years (range 0.2 to 50.1). VTI interrater reliability was excellent (intraclass correlation coefficient =0.987). The VTI was higher in Marfan syndrome (n=57, median 26; interquartile range 10 to 49) and LDS (n=13, median 58; interquartile range 18 to 92) compared with controls (median 4.5; interquartile range 3 to 6; P<0.001 for both). Higher VTI was associated with younger age at surgery even when controlling for root size (adjusted P=0.002). Vertebral tortuosity index ≥50 was associated with earlier age at dissection and death compared with VTI <50 (P=0.001 versus P<0.001). We found no difference in age at surgery, dissection, or death in Marfan syndrome compared with LDS.
Arterial tortuosity measured by magnetic resonance angiography is a reproducible marker of adverse cardiovascular outcomes in connective tissue disorders.
Obstetric Management of Loeys-Dietz Syndrome Russo, Melissa L; Sukhavasi, Neelima; Mathur, Veena ...
Obstetrics and gynecology (New York. 1953),
06/2018, Volume:
131, Issue:
6
Journal Article
Peer reviewed
Open access
Loeys-Dietz syndrome is associated with arterial tortuosity and aortic dissection. Pregnancy may be a period of increased risk for aortic dissection.
A 16-year-old primigravid girl was referred to ...our center with a family history of aortic dissection. Loeys-Dietz syndrome was suspected, and genetic testing confirmed the TGFβ2 (c.988C>T) mutation. A cesarean delivery was performed at 36 weeks of gestation, with no cardiovascular complications. In this case, the uterine vessels were significantly tortuous; this may be an additional finding in Loeys-Dietz syndrome.
Women with Loeys-Dietz syndrome warrant special consideration in obstetric management secondary to the risk for aortic dissection. It is recommended that a multidisciplinary team with knowledge about connective tissue disorders and expertise in aortic surgery coordinate maternal obstetric and cardiovascular care.
Objectives
A subset of hypoplastic‐left‐heart‐syndrome (HLHS) fetuses have a complex cor‐triatriatum sinister that we named “labyrinthine‐cor (L‐cor)”. We sought to determine the prevalence of L‐cor ...in HLHS fetuses and hypothesized that it is associated with increased mortality.
Methods
This single‐center retrospective cohort study included all HLHS fetuses from January 2010‐December 2020. Fetuses with other hypoplastic‐left‐heart variants, inadequate images, lack of follow‐up and fetal atrial‐septal interventions were excluded. RAS was defined as the ratio of pulmonary‐vein forward‐to‐reverse velocity‐time‐integral (VTI) ≤ 5 and severe‐RAS defined as VTI‐ratio <3. Kaplan‐Meier survival‐analysis was performed for the primary outcome of transplant‐free survival for 62 weeks after gestational‐age of 30 weeks (∼1 year).
Results
Of the 156 consecutive fetuses with HLHS, 11 (7.7%) had L‐cor and 8/11 (72.7%) of these had RAS. When compared to HLHS‐RAS without L‐cor, fetuses with HLHS‐RAS and L‐cor were less likely to survive to 28 days (87% vs. 62.5%, p = 0.017) and to 1 year (69.6% vs. 25%, p = 0.029). When comparing by survival analysis, fetuses with severe‐RAS with L‐cor had lower survival compared severe‐RAS without L‐cor (p = 0.020).
Conclusion
L‐cor in fetal HLHS is associated with increased mortality. Recognition of this finding is important for prognostication and atrial‐septal‐intervention planning.
Key points
What is already known about this topic?
Fetuses with HLHS with restrictive atrial septum have the worst mortality among all HLHS patients.
Cor triatriatum sinister in HLHS may have a complex appearance and has been mislabeled as total anomalous pulmonary venous return in prior case reports.
Cor‐triatriatum has been known to be associated with increased mortality in single ventricle heart disease.
What are the clinical implications of this work?
This is the first study to evaluate the prevalence of cor‐triatriatum sinister in fetal HLHS and we have named it “labyrinthine‐cor (L‐cor)” due to its complex appearance.
The prognostic implications of cor triatriatum in HLHS fetuses are not known. This study evaluated the outcomes of fetuses with HLHS with L‐cor and varying degrees of atrial septal restriction.
Labyrinthine‐cor in fetal HLHS is associated with increased mortality.
Our goal is to bring attention to this lesion and hope that this study encourages fetal cardiologists to recognize this finding and use our data as guidance for prognostication counseling.
BACKGROUNDPathogenic 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. OBJECTIVESThis 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. METHODSA 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. RESULTSSignificant differences in aortic event risk were identified among the smooth muscle contraction genes (ACTA2, MYLK, and PRKG1; P = 0.002) and among the genes for Loeys-Dietz syndrome, which encode proteins in the transforming growth factor (TGF)-β pathway (SMAD3, TGFB2, TGFBR1, and TGFBR2;P < 0.0001). Cumulative incidence of type A aortic dissection was higher than elective aneurysm surgery in patients with variants in ACTA2, MYLK, PRKG1, and SMAD3; in contrast, patients with TGFBR2 variants had lower cumulative incidence of type A aortic dissection than elective aneurysm surgery. Cumulative incidence of type B aortic dissection was higher for ACTA2, PRKG1, and TGFBR2 than other genes. After adjusting for proband status, sex, and recruitment location, specific variants in ACTA2 and TGFBR2 were associated with substantially higher risk of aortic event with childhood onset. CONCLUSIONSGene- and variant-specific data on aortic events in individuals with HTAD support personalized aortic surveillance and clinical management.
Cardiomyopathy is a complication in adults with Marfan syndrome (MFS). Early recognition of MFS patients at high risk of cardiomyopathy could impact monitoring and treatment. Abnormal ventricular ...strain has been associated with impaired ventricular function among adults with MFS but remains understudied in children. We retrospectively analyzed a cohort of patients with MFS undergoing cardiac magnetic resonance imaging (CMR) performed in 2003–2018 at age < 19 years. Correlations were evaluated between initial global circumferential strain (GCS) and global longitudinal strain (GLS) and the outcomes of left ventricular ejection fraction (LVEF), aortic root
z
-score, and vertebral artery tortuosity index corrected for height (VTI-h), all measured from CMR, using Spearman correlation. In those with serial CMR, the ability of ventricular strain to predict development of abnormal LVEF within a 5-year period was assessed. A total of 31 subjects were included (median age at initial CMR 13.5 years, Q1Q3 10.7–16.2 years), with 48% (
n
= 15) having LVEF < 55%. Worse GCS and worse GLS were associated with lower LVEF (
ρ
= − 0.629,
p
< 0.001 and
ρ
= − 0.411,
p
= 0.030, respectively). A clinical cutoff of GCS = − 34% predicted LVEF < 55% with sensitivity = 80% and specificity = 50%. Neither GCS nor GLS was associated with aortic root
z
-score (GCS:
p
= 0.524; GLS:
p
= 0.624) nor VTI-h (GCS:
p
= 0.949; GLS:
p
= 0.593). Of those with LVEF ≥ 55%, initial GCS and GLS did not differ between those with later normal versus abnormal LVEF (GCS:
p
= 0.505; GLS:
p
= 0.232). In this cohort, abnormal LV strain was associated with abnormal LVEF, but not with aortic dilation or low LVEF within the 5 years post-CMR.
Turner syndrome (TS) is associated with aortic coarctation, dissection and dilation/aneurysm. Predictors of dissection are not well delineated, making decisions regarding prophylactic root ...replacement challenging. In other disorders, arterial tortuosity is an imaging biomarker associated with increased risk for aortic dissection and adverse cardiovascular events. We aimed to determine if, in TS, arterial tortuosity was associated with aortic dilation or aortic events. We performed a retrospective cohort analysis of unselected women and children with TS who underwent cardiovascular magnetic resonance angiography (MRA) for a prior prospective study. We calculated tortuosity indices including vertebral artery tortuosity index, aortic arch tortuosity index, thoracic aortic tortuosity index (ATI-D), and aortic tortuosity index to the celiac artery (ATI-C). We compared tortuosity in TS patients against age and gender matched controls. We evaluated univariable and multivariable associations between the tortuosity indices and aortic root and ascending aorta size as defined by z-scores, which give a sense of how far a measurement deviates from the mean. We also studied associations between tortuosity and need for aortic root replacement or aortic dissection. Of 184 subjects, with median age 34 years, mean general aortic root z-score was 0.1 ± 1.2 and mean general ascending aortic z-score was 0.4 ± 1.5. Three patients had aortic dissection, and one had prophylactic root replacement, which all occurred prior to first MRA. Vertebral tortuosity index, ATI-D, and ATI-C all increased with age (p < 0.0001) for all. ATI-C was associated with larger general ascending z-score. In multivariable analysis, ATI-C remained independently associated with larger ascending aortic z-scores. The relationship between aortic indices and surgery/dissection could not be evaluated since all were collected post-surgery/dissection. Thoracic aortic tortuosity as measured by ATI-C is independently associated with larger ascending aortic dimensions. In this population with only three aortic dissections occurring prior to imaging assessment, we could not assess for associations between aortic tortuosity and dissection. Studies including more patients with aortic dissection are needed to draw further conclusions.
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