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Familial thoracic aortic aneurysms and dissections: studies on genotype and phenotype
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Thoracic aortic aneurysms and dissections (TAAD) have a genetic component with an estimated 20-25% of the patients having a positive family history. An aneurysm often precedes a dissection. Acute aortic dissections are associated with high mortality and morbidity, even when operated on. Complications due to prophylactic surgery are considerably fewer. Therefore, patients at risk for dissection should be identified, followed-up and evaluated for prophylactic intervention.

Aims: 1. To establish reference values for ascending (AoA) and descending aortic (AoD) diameters measured by computed tomography. 2. To study the effectiveness of phenotypic cascade screening in families with an inherited form of thoracic aortic aneurysms and dissections (FTAAD) and to address questions that arise when screening for a genetic disorder is applied. 3. To study the agreement of aortic diameters obtained by TTE and MRI and to study aortic stiffness in individuals from families with FTAAD. 4. To perform exome sequencing in order to identify pathogenic sequence variants causing FTAAD, to characterize the phenotype, and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers.

Results: Paper I: The diameter of the thoracic aorta increased by 0.17 mm (0.12 – 0.20 mm) per year. The mean sex-related difference in diameter was 1.99 mm (1.28 – 2.60 mm) with men having larger aortas than women. The mean difference in aortic diameter per unit BMI was 0.27 mm (0.14 – 0.44 mm). Upper normal limits for the AoA can be calculated by the formula D (mm)=31+0.16*age and for the AoD by D (mm)=21+0.16*age.

Paper II: Of 106 individuals from families with FTAAD but without known thoracic aortic disease, 19 individuals (18%) were identified to have a dilated AoA. The expected number of individuals in this group with an autosomal dominant disease would have been 40 (p<0.0001). In first-degree relatives younger than 40, we found only one individual with a dilated aorta although the expected number of individuals with disease causing mutation would have been 10.

Paper III: Of 116 individuals investigated, 21 were identified with thoracic aortic dilatation and 95 individuals with normal thoracic aortic diameter. Aortic stiffness increased with age and diameter. The individuals with aortic dilatation were older than those without (49 vs. 37 years, p=0.001) and showed lower aortic elastic properties. The diameters measured by TTE and MRI correlated strongly (r2=0.93). The mean difference in diameters between the two methods was 0.72 mm (95% CI 0.41-1.02) with TTE giving larger diameters than MRI.

Paper IV: From exome sequencing and segregation analysis, a 2-bp deletion in the MYLK gene (c.3272_3273del) was identified to cause FTAAD. The age and the aortic diameter at dissection or rupture varied in the family members. We did not find any differences in aortic diameter, aortic stiffness, or pulse wave velocity between carriers and non-carriers.

Conclusions: Thoracic aortic diameter increases with age, and sex and body size are also associated with the diameter. In FTAAD, screening identifies family members with a previously unknown aortic dilatation. However, a normal aortic diameter does not exclude an individual from being a carrier of FTAAD. TTE can be used in follow-up for the ascending aorta. Individuals identified to have a dilated thoracic aorta have increased aortic stiffness compared to individuals with normal thoracic aortic diameter. The MYLK mutation (c.3272_3273del) causes thoracic aortic dissections with variable clinical expression. No differences in aortic stiffness were identified between MYLK mutation carriers and non-carriers.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2017. , 56 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1891
Keyword [en]
Thoracic aorta, familial aortic aneurysm, familial aortic dissection, genetics, aortic stiffness
National Category
Anesthesiology and Intensive Care Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:umu:diva-134028ISBN: 978-91-7601-695-4 (print)OAI: oai:DiVA.org:umu-134028DiVA: diva2:1090845
Public defence
2017-05-19, Sal B, Unod T, 9tr, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2017-04-28 Created: 2017-04-25 Last updated: 2017-05-05Bibliographically approved
List of papers
1. Thoracic aorta: dilated or not?
Open this publication in new window or tab >>Thoracic aorta: dilated or not?
2006 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 40, no 3, 175-178 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: Knowledge of normal aortic diameters is important in the assessment of aortic disease. The aim of this study was to determine normal thoracic aortic diameters.

Design: 77 patients undergoing computed tomography of the thorax were studied. The diameter of the thoracic aorta was measured at three levels in the ascending aorta and at three levels in the descending aorta. The diameter was studied in relation to age, sex, weight and height.

Results: We found that aortic diameter is increasing with increasing age. Even sex and BMI influence the aortic diameter but to a lesser extent than age. The upper normal limit for ascending aorta can be calculated with the formula D(mm) = 31 + 0.16*age and for descending aorta with the formula D(mm) = 21 + 0.16*age. Thus a 20-year-old person has an upper normal limit for ascending aorta of 34 mm and an 80-year-old person has a limit of 44 m.

Conclusions: The thoracic aortic diameter varies with age, sex and body weight and height. The strongest correlation can be seen with age. Age should therefore be taken into consideration when determining whether the thoracic aorta is dilated or not.

Keyword
Aortic diameter, aortic dilatation, thoracic aorta, ascending aorta, descending aorta
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-6824 (URN)10.1080/14017430600565999 (DOI)000238562500008 ()16798665 (PubMedID)
Available from: 2007-12-18 Created: 2007-12-18 Last updated: 2017-04-27Bibliographically approved
2. Screening for familial thoracic aortic aneurysms with aortic imaging does not detect all potential aarriers of the disease
Open this publication in new window or tab >>Screening for familial thoracic aortic aneurysms with aortic imaging does not detect all potential aarriers of the disease
2015 (English)In: Aorta, ISSN 2325-4637, Vol. 3, no 1, 1-8 p.Article in journal (Refereed) Published
Abstract [en]

Background: About 20% of patients with thoracic aortic aneurysm or dissection (TAAD) have a first-degree relative with a similar disease. The familial form (FTAAD) of the disease is inherited in an autosomal-dominant pattern. Current guidelines for thoracic aortic disease recommend screening of first-degree relatives of TAAD patients. In known familial disease, screening of both first- and second-degree relatives is recommended. However, the outcomes of such a screening program are unknown.

Methods: We screened all first- and second-degree relatives in seven families with known FTAAD with echo- cardiography. No underlying gene defect had been detected in these families.

Results: Of 119 persons investigated, 13 had known thoracic aortic disease. In the remaining 106 cases, we diagnosed 19 additional individuals with a dilated ascending thoracic aorta; for an autosomal-dominant disease, the expected number of individuals in this group would have been 40 (p<0.0001). Further, only one of the 20 first-degree relatives younger than 40 years had a dilated aorta, although the expected number of individuals with a disease-causing mutation would have been 10.

Conclusions: In most families with TAAD, a diagnosis still relies on measuring the diameter of the thoracic aorta. We show that a substantial number of previously unknown cases of aortic dilatation can be identified by screening family members. It is, however, not possible to consider anyone free of the condition, even if the aortic diameter is normal, especially at a younger age.

Keyword
Aorta, Aortic aneurysm, Aortic dissection
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-107257 (URN)10.12945/j.aorta.2015.14-052 (DOI)
Available from: 2015-08-20 Created: 2015-08-20 Last updated: 2017-04-27Bibliographically approved
3. Aortic stiffness in families with inherited non-syndromic thoracic aortic disease
Open this publication in new window or tab >>Aortic stiffness in families with inherited non-syndromic thoracic aortic disease
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: In families with an inherited form of non-syndromic thoracic aortic disease (TAAD), aortic diameter alone is not a reliable marker for disease occurrence or progression. To identify other parameters of aortic function, we studied aortic stiffness in families with TAAD. We also compared diameter measurements obtained by transthoracic echocardiography (TTE) and magnetic resonance imaging (MRI).

Methods: Seven families, including 116 individuals, with non-syndromic TAAD were studied. The aortic diameter was measured by TTE and MRI. Aortic stiffness was assessed as local distensibility in the ascending aorta and as regional and global pulse wave velocity (PWV). Individuals with a dilated thoracic aorta (n=21) were compared with those without aortic dilatation (n=95).

Results: Ascending aortic diameter measured by TTE strongly correlated with the diameter measured by MRI (r2=0.93). The individuals with dilated aortas were older than those without dilatation (49 vs. 37 years old). Ascending aortic diameter increased and distensibility decreased with increasing age; while, PWV increased with age and diameter. Some young subjects without aortic dilatation showed increased aortic stiffness. Individuals with a dilated thoracic aorta had significantly higher PWV and lower distensibility, measured by MRI, than individuals without dilatation.

Conclusion: Diameters measured with TTE agree with those measured by MRI. Aortic stiffness might be a complementary marker for aortic disease and progression when used with aortic diameter, especially in young individuals.

Keyword
thoracic aortic aneurysm, thoracic aortic dissection, aortic stiffness
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-134022 (URN)
Available from: 2017-04-25 Created: 2017-04-25 Last updated: 2017-04-27
4. A novel variant in MYLK causes thoracic aortic dissections: genotypic and phenotypic description
Open this publication in new window or tab >>A novel variant in MYLK causes thoracic aortic dissections: genotypic and phenotypic description
Show others...
2016 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 17, 61Article in journal (Refereed) Published
Abstract [en]

Background: Mutations in MYLK cause non- syndromic familial thoracic aortic aneurysms and dissections (FTAAD). Very little is known about the phenotype of affected families. We sought to characterize the aortic disease and the presence of other vascular abnormalities in FTAAD caused by a deletion in MYLK and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers.

Methods: We studied FTAAD in a 5-generation family that included 19 living members. Exome sequencing was performed to identify the underlying gene defect. Aortic elastic properties measured by TTE, MRI and pulse wave velocity were then compared between mutation carriers and non-carriers.

Results: Exome sequencing led to the identification of a 2-bp deletion in MYLK (c3272_ 3273del, p. Ser1091*) that led to a premature stop codon and nonsense-mediated decay. Eleven people were mutation carriers and eight people were non-carriers. Five aortic ruptures or dissections occurred in this family, with two survivors. There were no differences in aortic diameter or stiffness between carriers and non-carriers of the mutation.

Conclusions: Individuals carrying this deletion in MYLK have a high risk of presenting with an acute aortic dissection or rupture. Aortic events occur over a wide range of ages and are not always preceded by obvious aortic dilatation. Aortic elastic properties do not differ between carriers and non-carriers of this mutation, rendering it uncertain whether and when carriers should undergo elective prophylactic surgery.

Keyword
Thoracic aorta, Aortic dissection, Gene mutation, MYLK
National Category
Genetics
Identifiers
urn:nbn:se:umu:diva-126499 (URN)10.1186/s12881-016-0326-y (DOI)000383335100001 ()27586135 (PubMedID)
Available from: 2016-10-27 Created: 2016-10-10 Last updated: 2017-04-27Bibliographically approved

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