| 1. |
- Hannuksela, Matias, et al.
(author)
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A novel variant in MYLK causes thoracic aortic dissections : genotypic and phenotypic description
- 2016
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In: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 17
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Journal article (peer-reviewed)abstract
- 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.
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| 2. |
- Hannuksela, Matias, et al.
(author)
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Aortic stiffness in families with inherited non-syndromic thoracic aortic disease
- 2018
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In: Scandinavian Cardiovascular Journal. - : Taylor & Francis. - 1401-7431 .- 1651-2006. ; 52:6, s. 301-307
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Journal article (peer-reviewed)abstract
- 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.Conclusions. 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.
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| 3. |
- Hannuksela, Matias, 1969-
(author)
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Familial thoracic aortic aneurysms and dissections : studies on genotype and phenotype
- 2017
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 4. |
- Hannuksela, Matias, et al.
(author)
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Familära torakala aortaaneurysm och dissektioner : flera former finns
- 2014
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In: Läkartidningen. - Stockholm : Sveriges läkarförbund. - 0023-7205 .- 1652-7518. ; 111:9-10, s. 399-403
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Journal article (peer-reviewed)abstract
- Thoracic aortic aneurysms and dissections (TAAD) can be divided into three different main categories. 1. Inherited syndromes predisposing to TAAD such as Marfan syndrome, Ehlers-Danlos syndrome type IV and Loeys-Dietz syndrome (less than 5% of all TAAD). 2. Familial TAAD (FTAAD) with more than one affected family member (20 % of all TAAD). Inheritance shows an autosomal dominant pattern and there are no features of known syndromes. 3. Sporadic forms of TAAD with no family history or features of syndromic forms. FTAAD present earlier in life and dissections occur in smaller diameter than in sporadic cases. The underlying genetic cause can be found in about 20 % of the inherited cases. The pathogenesis seems to be an involvement of the transforming growth factor β (TGFβ) signaling pathway or a dysfunction of the smooth muscle cell contraction. The role of β-blockers for aneurysm prevention is uncertain and there are on-going studies comparing angiotensin receptor blockers and β-blockers.
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| 5. |
- Hannuksela, Matias, et al.
(author)
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Screening for familial thoracic aortic aneurysms with aortic imaging does not detect all potential aarriers of the disease
- 2015
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In: Aorta. - : Georg Thieme Verlag KG. - 2325-4637. ; 3:1, s. 1-8
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Journal article (peer-reviewed)abstract
- 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.
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| 6. |
- Hannuksela, Matias, et al.
(author)
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Thoracic aorta : dilated or not?
- 2006
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In: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 40:3, s. 175-178
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Journal article (peer-reviewed)abstract
- 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.
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| 7. |
- Karlsson, Mattias, et al.
(author)
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Cardiopulmonary bypass and dual antiplatelet therapy : a strategy to minimise transfusions and blood loss
- 2020
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In: Perfusion. - : Sage Publications. - 0267-6591 .- 1477-111X. ; 35:3, s. 236-245
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Journal article (peer-reviewed)abstract
- Background: Patients with preoperative dual antiplatelet therapy prior to coronary artery bypass surgery are at risk of bleeding and blood component transfusion. We hypothesise that an optimised cardiopulmonary bypass strategy reduces postoperative blood loss and transfusions.Methods: In total, 60 patients admitted for coronary artery bypass grafting with ticagrelor and aspirin medication withdrawn <96 hours before surgery were prospectively randomised into two equal sized groups. Cardiopulmonary bypass combined a closed Cortiva (R) heparin-coated circuit with low systemic heparinisation (activated clotting time < 250 seconds) and intraoperative cell salvage in the study group, whereas the control group used a Balance (R) coated open circuit, full systemic heparinisation (activated clotting time > 480 seconds) and conventional cardiotomy suction. This perfusion strategy was evaluated by the chest drain volume after 24 hours, perioperative haemoglobin and platelet loss accompanied by global coagulation assessments.Results: Patients in the study group demonstrated significantly better outcomes signified by lower blood loss 554 +/- 224 versus 1,100 +/- 989 mL (p < 0.001), reduced packed red cell transfusion 7% versus 53% (p < 0.001), reduced haemoglobin -28 +/- 15 versus -40 +/- 14 g/L (p = 0.004) and platelet loss -35 +/- 36 versus -82 +/- 67 x 10(9)/L (p = 0.001). Indices of rotational thromboelastometry indicated shorter clotting times within the internal and external pathways. Adenosine diphosphate activated platelet function was within normal range based on Multiplate (R) aggregometry, while ROTEM (R) platelet analyses indicated inhibited function both preoperatively and post-bypass. Platelet inhibition by aspirin was verified throughout the perioperative period. Platelet function showed no intergroup differences.Conclusion: A stringent perfusion strategy reduced blood loss and transfusions in dual antiplatelet therapy patients requiring urgent surgery.
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| 8. |
- Svenmarker, Staffan, et al.
(author)
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A retrospective analysis of the mixed venous oxygen saturation as the target for systemic blood flow control during cardiopulmonary bypass
- 2018
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In: Perfusion. - : Sage Publications. - 0267-6591 .- 1477-111X. ; 33:6, s. 453-462
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Journal article (peer-reviewed)abstract
- Objectives: The patient's body surface area serves as the traditional reference for the determination of systemic blood flow during cardiopulmonary bypass (CPB). New strategies refer to different algorithms of oxygen delivery. This study reports on the mixed venous oxygen saturation (SvO2) as the target for systemic blood flow control. We hypothesise that an SvO2>75% (S(v)O(2)75) is associated with better preservation of renal function and improved short-term survival.Methods: This retrospective, 10-year, observational study analysed 6945 consecutive cardiac surgical cases requiring CPB. Endpoints included rates of acute kidney injury (AKI) and short-term survival, also the estimated glomerular filtration rate ((e)GFR), lactate levels and blood transfusions.Results: Seventy-seven percent of the patients attained the S(v)O(2)75 target. For this group, the median SvO2 was 78.1 (5.8) %, with a mean oxygen delivery of 331 (78) ml/min per m(2) body surface area. Overall incidence of AKI levels (I-III): 7.5% - 2.6% - 0.6%. Incidence of (e)GFR (<50%): 3.9%, increasing to 6% for haemoglobin levels <80 g/L (p<0.001). Red cell transfusion was more frequent (p<0.001) within this group (30.6%) compared to levels >100 g/L (0.3%). Further, women (52.8%) were transfused more often than men (14.6%). Lactate level at weaning from CPB was 1.3 (0.7) mmol/L. The S(v)O(2)75 target demonstrated a relative risk reduction of 22.5% (p=0.032) for AKI (I), increasing to 32.3% (p=0.026) for procedures extending >90 minutes. In addition, the risk for death 90-days postop was lower (p=0.039).Conclusion: The S(v)O(2)75 target showed a decreased risk for postoperative AKI and prolonged short-term survival. Good clinical outcomes were also linked to measures of lactate and the (e)GFR. However, anaemia remains a risk factor for AKI.
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| 9. |
- Wallace, Stephanie E., et al.
(author)
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MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants
- 2019
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In: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 21:1, s. 144-151
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Journal article (peer-reviewed)abstract
- Purpose: Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLKmissense variants are pathogenic and information to guide aortic disease management are limited.Methods: Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed.Results: Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK.Conclusion: These data further define the aortic phenotype associated with MYLKpathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.
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