Cardiac abnormalities in girls with Turner syndrome: ECG abnormalities, myocardial strain imaging, and karyotype-phenotype associations.

Turner syndrome (TS) is a chromosomal condition which is associated with an increased prevalence of cardiac morbidity and mortality. In this cross-sectional study, Minnesota-based electrocardiographic (ECG) abnormalities, aortic dimensions, routine- and myocardial strain echocardiographic parameters, and karyotype-cardiac phenotype associations were assessed in girls with TS. In total, 101 girls with TS (0-18 years) were included. The prevalence of major ECG abnormalities was 2% (T-wave abnormalities) and 39% had minor ECG abnormalities. Dilatation of the ascending aorta (z-score > 2) was present in 16%, but the prevalence was much lower when using TS-specific z-scores. No left ventricular hypertrophy was detected and the age-matched global longitudinal strain was reduced in only 6% of the patients. Cardiac abnormalities seemed more common in patients with a non-mosaic 45,X karyotype compared with other karyotypes, although no statistically significant association was found. Lowering the frequency of echocardiography and ECG screening might be considered in girls with TS without cardiovascular malformations and/or risk factors for aortic dissection. Nevertheless, a large prospective study is needed to confirm our results. The appropriate z-score for the assessment of aortic dilatation remains an important knowledge gap. The karyotype was not significantly associated with the presence of cardiac abnormalities, therefore cardiac screening should not depend on karyotype alone.

Coronary plaque burden in Turner syndrome a coronary computed tomography angiography study.

Turner syndrome (TS) is associated with coronary artery disease (CAD), an important cause of premature death in TS. However, the determinants of CAD in women with TS remain unknown. In a cross-sectional study design, 168 women without clinical evidence of CAD (115 with TS and 53 without TS) were assessed for the presence and volume of subclinical CAD using coronary CT angiography. Karyotype, the presence of congenital heart defects and conventional cardiovascular risk factors were also registered. Comparative analyses were performed (1) between women with and without TS and (2) in the TS group, between women with and without subclinical CAD. The prevalence of CAD, in crude and adjusted analyses, was not increased for women with TS (crude prevalence: 40 [35%] in TS vs. 25 [47%] in controls, p = 0.12). The volume of atherosclerosis was not higher in women with TS compared with controls (median and interquartile range 0 [0-92] in TS vs. 0 [0-81]mm3 in controls, p = 0.29). Among women with TS, women with subclinical CAD were older (46 ± 13 vs. 37 ± 11 years, p < 0.001), had higher blood pressure (systolic blood pressure 129 ± 16 vs. 121 ± 16 mmHg, p < 0.05) and were more frequently diagnosed with type 2 diabetes (5 [13%] vs. 2 [3%], p < 0.05). Karyotype or congenital heart defects were not associated with subclinical CAD. Some women with TS show early signs of CAD, however overall, not more than women without TS. Conventional cardiovascular risk factors were the principal determinants of CAD also in TS, and CAD prevention strategies should be observed.ClinicalTrial.gov Identifier: NCT01678261 ( https://clinicaltrials.gov/ct2/show/NCT01678261 ).

The clinical spectrum of Fontan-associated liver disease: results from a prospective multimodality screening cohort.

AIMS: Liver fibrosis and cirrhosis are a consequence of a Fontan physiology, and determine prognosis. It is unclear whether non-invasive assessment of liver pathology is helpful to provide clinically relevant information. The aims of this study were to assess the spectrum of Fontan-associated liver disease (FALD) and usefulness of non-invasive methods to assess biopsy confirmed liver fibrosis. METHODS AND RESULTS: Hepatic screening of consecutive patients consisted of a blood panel, ultrasonography, elastography, contrast-enhanced magnetic resonance imaging (MRI)/computed tomography (CT) scan, and liver biopsy (scored with Fontan specific fibrosis scores and collagen proportionate area; CPA). Fibrosis parameters, varices, ascites, and splenomegaly were measured on imaging. Thirty-eight of 49 referred patients (27 ± 6.6 years, 73.7% male) underwent the complete screening protocol. Liver fibrosis on biopsy was present in all patients, and classified as severe (Stages 3-4) in 68%. Median CPA was 22.5% (16.9-29.5) and correlated with individual fibrosis scores. ELF® and liver stiffness were elevated, but MELD-XI scores were low in all patients. Fibrosis severity neither correlated to ELF® and liver stiffness, nor to (semi-) quantitative fibrosis parameters on MRI/CT. Varices were present in 50% and hyperenhancing nodules in 25% of patients, both independent of fibrosis stage, but varices were associated with higher CPA values. CONCLUSION: The FALD spectrum includes both hepatic congestion and severe fibrosis, with signs of portal hypertension and hyperenhancing nodules as significant manifestations. Routine imaging, transient elastography, and serum biomarkers are unable to accurately assess severity of liver fibrosis in this cohort. Future research should focus on validating new diagnostic tools with biopsy as the reference standard.

A dominant-negative GFI1B mutation in the gray platelet syndrome.

The gray platelet syndrome is a hereditary, usually autosomal recessive bleeding disorder caused by a deficiency of alpha granules in platelets. We detected a nonsense mutation in the gene encoding the transcription factor GFI1B (growth factor independent 1B) that causes autosomal dominant gray platelet syndrome. Both gray platelets and megakaryocytes had abnormal marker expression. In addition, the megakaryocytes had dysplastic features, and they were abnormally distributed in the bone marrow. The GFI1B mutant protein inhibited nonmutant GFI1B transcriptional activity in a dominant-negative manner. Our studies show that GFI1B, in addition to being causally related to the gray platelet syndrome, is key to megakaryocyte and platelet development.

Adverse outcome of coarctation stenting in patients with Turner syndrome.

OBJECTIVES: This study examines the outcome and procedural outcomes of percutaneous stent angioplasty for aortic coarctation in patients with Turner syndrome (TS). BACKGROUND: TS occurs in 1 in 2,500 live-born females and is associated with aortic coarctation. METHODS: In this multicenter, retrospective cohort study, all patients with TS and a coarctation of the aorta, treated with percutaneous stent implantation were included. The procedural strategies were dictated by local protocols. Adverse events at short- and long-term follow-up and qualitative parameters concerning the stent implantation were assessed. RESULTS: In the largest study to date of TS patients receiving aortic stents, a total of 19 patients from 10 centers were included. Twelve patients were treated for native and 7 for recurrent coarctation. Age at intervention was 16.9 (7-60) years (median; min-max). The coarctation diameter increased significantly from 8.0 mm (2-12) pre-intervention to 15.0 mm (10-19) post-intervention (P < 0.001). Three (15.8%) adverse events occurred within 30 days of the procedure, including two dissections despite the use of covered stents, one resulting in death. At long-term follow-up (6.5 years, min-max: 1-16), two additional deaths occurred not known to be stent-related. CONCLUSIONS: Though percutaneous treatment of aortic coarctation in TS patients is effective, it is associated with serious morbidity and mortality. These risks suggest that alternative treatment options should be carefully weighed against percutaneous stenting strategies. © 2016 Wiley Periodicals, Inc.

[Unexpected spontaneous pregnancy in women with Turner syndrome]. / Onverwachte spontane zwangerschap bij vrouwen met het syndroom van Turner.

Most women with Turner syndrome have premature ovarian insufficiency from childhood. The chance of a spontaneous pregnancy is higher in women with a Turner mosaicism and in women who have had a spontaneous menarche. This chance is estimated at 5-8%. We discuss 2 women with Turner mosaicism who were misinformed about their chances of a spontaneous pregnancy. In both cases, puberty induction was started because of suspected gonadal dysgenesis but in retrospect only puberty was delayed, while ovarian function was still good at that time. The cases presented show that in long-term follow-up there is a pitfall in adopting incorrect assumptions. Critical re-evaluation of medical data during childhood and adolescence is therefore essential. The impact of infertility is great in women with Turner syndrome. Because pregnancy has an increased risk of complications, an unplanned pregnancy should be prevented.

Peripheral microvascular function is linked to cardiac involvement on cardiovascular magnetic resonance in systemic sclerosis-related pulmonary arterial hypertension.

AIMS: Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). METHODS AND RESULTS: Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). CONCLUSION: SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

Associations of Lifelong Exercise Characteristics With Valvular Function and Aortic Diameters in Patients With a Bicuspid Aortic Valve.

BACKGROUND: The potential impact of exercise on valvular function and aortic diameters in patients with a bicuspid aortic valve remains unclear. Therefore, we assessed the association between lifelong exercise characteristics, valvular dysfunction, and aortic dilatation in patients with a bicuspid aortic valve. METHODS AND RESULTS: In this cross-sectional study, exercise volume (metabolic equivalent of task minutes per week), exercise intensity, and sport type were determined from the age of 12 years to participation using a validated questionnaire. Echocardiography was used to assess aortic stenosis or aortic regurgitation and to measure diameters at the sinuses of Valsalva and ascending aorta. Aortic dilatation was defined as a Z-score ≥2. Four hundred and seven patients (42±17 years, 60% men) were included, of which 133 were sedentary (<500 metabolic equivalent of task minutes per week), 94 active (500-1000 metabolic equivalent of task minutes per week), and 180 highly active (≥1000 metabolic equivalent of task minutes per week). Moderate-to-severe aortic stenosis or aortic regurgitation was present in 23.7% and 20.0%, respectively. Sinuses of Valsalva and ascending aorta diameters were 34.8±6.6 and 36.5±8.1 mm, whereas aortic dilatation was found in 21.6% and 53.4%, respectively. Exercise volume was not associated with valve dysfunction or aortic dilatation. Vigorous intensity and mixed sports were associated with a lower prevalence of aortic stenosis (adjusted odds ratios, 0.43 [0.20-0.94] and adjusted odds ratios, 0.47 [0.23-0.95]). Exercise intensity and sport type were not associated with aortic regurgitation and aortic dilatation. CONCLUSIONS: We found no deleterious associations between lifelong exercise characteristics, valvular dysfunction, and aortic dilatation in patients with a bicuspid aortic valve. Vigorous intensity and exercise in mixed sports were associated with a lower prevalence of moderate-to-severe aortic stenosis. These observations suggest that lifelong exercise does not appear to induce adverse cardiovascular effects in patients with a bicuspid aortic valve.

Blood and Imaging Biomarkers in the Long-term Follow-up of Bicuspid Aortic Valve Patients.

Background: Bicuspid aortic valve (BAV) is a common congenital heart defect. Patients with BAV are at risk for long-term complications such as valve stenosis and regurgitation. This study aimed to investigate sex differences in blood and imaging biomarkers and to describe the long-term prognostic value of blood and echocardiographic biomarkers. Methods: Patients were included from 2 prospective observational cohort studies; they underwent venous blood sampling and transthoracic echocardiography including speckle tracking. Analyzed blood biomarkers were red-cell distribution width (RDW), creatinine, C-reactive protein (CRP), troponin T, N-terminal pro B-type natriuretic peptide (NT-proBNP), and transforming growth factor-beta (TGF-ß). Sex differences were analyzed at baseline. Associations between biomarkers and arrhythmia-free and intervention-free survival were determined by Cox regression, adjusted for age and sex. Results: A total of 182 patients with BAV were included: median age 34; interquartile range [IQR]: 23-46 years; 55.5% male. CRP, NT-proBNP, and RDW were higher in women, whereas creatinine, troponin T and TGF-ß were higher among men. After a median follow-up time of 6.9 (IQR: 6.5-9.9) years, arrhythmia-free and intervention-free survival was, 81.0% and 73.1%, respectively. NT-proBNP was associated with both arrhythmia-free and intervention-free survival (hazard ratio [HR], 1.94, P = 0.005 and HR, 2.06, P = 0.002, respectively). On echocardiography higher left atrial (LA) size, left ventricular end-diastolic diameter (LVEDD), left ventricular (LV) mass index and E/e' ratio were associated with lower arrhythmia-free survival, whereas higher LA size, LV mass index, aortic valve peak velocity, and aortic regurgitation were associated with lower intervention-free survival. Conclusions: Differences were observed in blood biomarkers between men and women with BAV. Besides LV systolic parameters, diastolic LV function and NT-proBNP should have a more prominent role as prognostic markers in clinical care.

Contexte: La bicuspide valvulaire aortique (BVA) est une anomalie cardiaque congénitale fréquente. Les patients atteints d'une BVA présentent des risques de complications à long terme, comme la sténose valvulaire ou la régurgitation valvulaire. Cette étude visait 1) à évaluer les différences entre les sexes en ce qui concerne les biomarqueurs sanguins et les biomarqueurs à l'imagerie; et 2) à décrire la valeur pronostique à long terme des biomarqueurs sanguins et échocardiographiques. Méthodologie: Des patients de 2 études de cohortes observationnelles prospectives ont été inclus dans l'analyse. Des échantillons de sang veineux ont été prélevés, et des échocardiographies transthoraciques, y compris le suivi des marqueurs acoustiques, ont été effectuées. Les biomarqueurs sanguins analysés étaient les suivants : indice de distribution des globules rouges (IDR), créatinine, protéine C-réactive (CRP), troponine T, propeptide natriurétique de type B N-terminal (NT-proBNP) et facteur de croissance transformant ß (TGF-ß). Les différences entre les sexes ont été analysées au départ. Les liens entre les biomarqueurs et la survie sans arythmie et sans intervention ont été déterminés par la régression de Cox, avec correction en fonction de l'âge et du sexe. Résultats: Cent quatre-vingt-deux patients présentant une BVA étaient inclus (âge médian de 34 [écart interquartile : 23-46] ans, 55,5 % hommes). La CRP, la NT-proBNP et l'IDR étaient plus élevées chez les femmes, alors que la créatinine, la troponine T et le TGF-ß étaient plus élevés chez les hommes. Après une période de suivi médiane de 6,9 (écart interquartile : 6,5-9,9) ans, les taux de survie sans arythmie et sans intervention étaient respectivement de 81,0 % et de 73,1 %. La NT-proBNP a été associée à la survie sans arythmie (rapport des risques instantanés [RRI] : 1,94, p = 0,005) et à la survie sans intervention (RRI : 2,06, p = 0,002). À l'échocardiographie, des valeurs élevées pour la taille de l'oreillette gauche, le diamètre télédiastolique du ventricule gauche (VG), l'indice de masse du VG et le rapport E/e' étaient associées à un faible taux de survie sans arythmie, alors que des valeurs élevées pour la taille de l'oreillette gauche, l'indice de masse du VG, la vitesse maximale aortique et la régurgitation aortique étaient associées à un faible taux de survie sans intervention. Conclusions: Les biomarqueurs sanguins variaient en fonction du sexe des personnes présentant une BVA. Outre les paramètres systoliques du VG, la fonction VG diastolique et la NT-proBNP devraient être davantage utilisées comme marqueurs pronostiques en soins cliniques.

Aortic dilation and growth in women with Turner syndrome.

OBJECTIVE: Women with Turner syndrome (TS) are at increased risk of aortic dissection, which is a life-threatening event associated with aortic dilation. Knowledge on the development of aortic dilation over time remains limited. This study aims to describe the prevalence of aortic dilation, to find associated factors and to study aortic growth in women with TS. METHODS: In this prospective multicentre cohort study, consecutive adult women with genetically proven TS included between 2014 and 2016 underwent ECG-triggered multiphase CT angiography at baseline and after 3 years. Aortic diameters were measured at seven levels of the thoracic aorta using double oblique reconstruction and indexed for body surface area. Ascending aortic dilation was defined as an aortic size index >20 mm/m2. Aorta-related and cardiovascular events were collected. Statistical analysis included linear and logistic regression and linear mixed effects models. RESULTS: The cohort consisted of 89 women with a median age of 34 years (IQR: 24-44). Ascending aortic dilation was found in 38.2% at baseline. At baseline, age (OR: 1.08 (95% CI 1.03 to 1.13), p<0.001), presence of bicuspid aortic valve (BAV) (OR: 7.09 (95% CI 2.22 to 25.9), p=0.002) and systolic blood pressure (OR: 1.06 (95% CI 1.02 to 1.11), p=0.004) were independently associated with ascending aortic dilation. During a median follow-up of 3.0 (2.4-3.6) years (n=77), significant aortic growth was found only at the sinotubular junction (0.20±1.92 mm, p=0.021). No aortic dissection occurred, one patient underwent aortic surgery and one woman died. CONCLUSIONS: In women with TS, ascending aortic dilation is common and associated with age, BAV and systolic blood pressure. Aortic diameters were stable during a 3-year follow-up, apart from a significant yet not clinically relevant increase at the sinotubular junction, which may suggest a more benign course of progression than previously reported.

Medication in adults after atrial switch for transposition of the great arteries: clinical practice and recommendations.

AIMS: Heart failure is the main threat to long-term health in adults with transposition of the great arteries (TGA) corrected by an atrial switch operation (AtrSO). Current guidelines refrain from recommending heart failure medication in TGA-AtrSO, as there is insufficient data to support the hypothesis that it is beneficial. Medication is therefore prescribed based on personal judgements. We aimed to evaluate medication use in TGA-AtrSO patients and examine the association of use of renin-angiotensin-aldosterone system (RAAS) inhibitors and ß-blockers with long-term survival. METHODS AND RESULTS: We identified 150 TGA-AtrSO patients [median age 30 years (interquartile range 25-35), 63% male] included in the CONCOR registry from five tertiary medical centres with subsequent linkage to the Dutch Dispensed Drug Register for the years 2006-2014. Use of RAAS inhibitors, ß-blockers, and diuretics increased with age, from, respectively, 21% [95% confidence interval (CI) 14-40], 12% (95% CI 7-21), and 3% (95% CI 2-7) at age 25, to 49% (95% CI 38-60), 51% (95% CI 38-63), and 41% (95% CI 29-54) at age 45. Time-varying Cox marginal structural models that adjusted for confounding medication showed a lower mortality risk with use of RAAS inhibitors and ß-blockers in symptomatic patients [hazard ratio (HR) = 0.13 (95% CI 0.03-0.73); P = 0.020 and HR = 0.12 (95% CI 0.02-0.17); P = 0.019, respectively]. However, in the overall cohort, no benefit of RAAS inhibitors and ß-blockers was seen [HR = 0.93 (95% CI 0.24-3.63); P = 0.92 and HR = 0.98 (0.23-4.17); P = 0.98, respectively]. CONCLUSION: The use of heart failure medication is high in TGA-AtrSO patients, although evidence of its benefit is limited. This study showed lower risk of mortality with use of RAAS inhibitors and ß-blockers in symptomatic patients only. These findings can direct future guidelines, supporting use of RAAS inhibitors and ß-blockers in symptomatic, but not asymptomatic patients.

Influence of Pregnancy on Aortic Diameter in Women With the Turner Syndrome.

Women with Turner syndrome (TS) have high prevalence of cardiovascular anomalies. Literature suggests pregnancy is associated with a higher dissection risk, presumably preceded by aortic dilatation. Whether the aortic diameter truly changes during pregnancy in TS is not well investigated. This study aims to evaluate ascending aortic diameter change during pregnancy and reports on cardiac events during and directly after pregnancy. This tertiary hospital retrospective study investigated all TS women pregnancies (2009 to 2018). Outcome parameters included aortic diameter growth and aortic complications, specifically dissection. Thirty-five pregnancies in 30 TS women, 57% assisted by oocyte donation. Mean age at delivery 32 ± 5 years. In 27 pregnancies of 22 women imaging was available. From over 350 childless TS women a comparison group of 27 was individually matched. The median ascending aortic diameter growth between pre- and postpregnancy imaging was 1.0 mm (IQR -1.0; 2.0), no significant change (p = 0.077). Whether the patient had a bicuspid aortic valve (p = 0.571), monosomy X or mosaic karyotype (p = 0.071) or spontaneous pregnancy or resulting from oocyte donation (p = 0.686) had no significant influence on diameter change. Aortic growth between pregnancy and matched childless group (0.23 vs 0.32 mm/year, p = 0.788) was not significant over 3.3 ± 2 versus 4.4 ± 1 years. During pregnancy or the first 6 months after delivery no aortic complications were observed. In conclusion, this study suggests pregnancy in TS women does not induce faster ascending aortic diameter increase. Also not in presence of a bicuspid aortic valve, monosomy X karyotype, and oocyte donation. No aortic complications occurred. Based on current study pregnancy in TS women seems safe.

No QTc Prolongation in Girls and Women with Turner Syndrome.

CONTEXT: Turner syndrome (TS) is a genetic condition that is reported to be associated with a prolonged rate-corrected QT (QTc) interval. OBJECTIVES: To evaluate the prevalence of QTc prolongation in patients with TS, to compare their QTc intervals with healthy controls, and to investigate whether QTc prolongation is associated with a monosomy 45,X karyotype. METHOD: Girls (n = 101) and women (n = 251) with TS visiting our center from 2004-2018 were included in this cross-sectional study. QT intervals of 12-leaded electrocardiograms were measured manually, using Bazett's and Hodges formulas to correct for heart rate. A QTc interval of >450 ms for girls and >460 ms for women was considered prolonged. Corrected QT (QTc) intervals of patients with TS were compared to the QTc intervals of healthy girls and women from the same age groups derived from the literature. RESULTS: In total, 5% of the population with TS had a prolonged QTc interval using Bazett's formula and 0% using Hodges formula. Mean QTc intervals of these patients were not prolonged compared with the QTc interval of healthy individuals from the literature. Girls showed shorter mean QTc intervals compared with women. We found no association between monosomy 45,X and prolongation of the QTc interval. CONCLUSIONS: This study shows that the QTc interval in girls and women with TS is not prolonged compared with the general population derived from the literature, using both Bazett's and Hodges formulas. Furthermore, girls show shorter QTc intervals compared with women, and a monosomy 45,X karyotype is not associated with QTc prolongation.

Atrial fibrillation in patients with an atrial septal defect in a single centre cohort during a long clinical follow-up: its association with closure and outcome of therapy.

OBJECTIVE: Currently, consensus is lacking on the relation between closure of atrial septal defect (ASD) and the incidence of atrial fibrillation (AF), which is a known complication in ASD patients. More importantly, studies reporting on the treatment applied for AF in ASD patients are scarce. The aims of this study were (1) to assess the incidence of AF in ASD patients, (2) to study the relation between closure and AF and (3) to evaluate applied treatment strategies. METHODS: A single-centre retrospective study in 173 patients with an ASD was performed. We analysed the incidence of AF, the relation of AF with closure, method of closure and the treatment success of therapies applied. RESULTS: Almost 20% of patients with an ASD developed AF, with a mean age of 59 (±14) years at first presentation of AF during a median clinical follow-up of 43 (29-59) years. Older age (OR 1.072; p<0.001) and a dilated left atrium (OR 3.727; p=0.009) were independently associated with new-onset AF. Closure itself was not independently associated with AF. First applied treatment strategy was rhythm control in 77%. Of the 18 patients treated with antiarrhythmic drugs 50% had at least 1 recurrence of AF. CONCLUSION: No clear relation between closure of the ASD and AF could be assessed. This is the first study describing applied therapy for AF in ASD patients of which medical rhythm control was the most applied strategy with a disappointing efficacy.

Left ventricular global longitudinal strain in bicupsid aortic valve patients: head-to-head comparison between computed tomography, 4D flow cardiovascular magnetic resonance and speckle-tracking echocardiography.

Left ventricular global longitudinal strain (LVGLS) analysis is a sensitive measurement of myocardial deformation most often done using speckle-tracking transthoracic echocardiography (TTE). We propose a novel approach to measure LVGLS using feature-tracking software on the magnitude dataset of 4D flow cardiovascular magnetic resonance (CMR) and compare it to dynamic computed tomography (CT) and speckle tracking TTE derived measurements. In this prospective cohort study 59 consecutive adult patients with a bicuspid aortic valve (BAV) were included. The study protocol consisted of TTE, CT, and CMR on the same day. Image analysis was done using dedicated feature-tracking (4D flow CMR and CT) and speckle-tracking (TTE) software, on apical 2-, 3-, and 4-chamber long-axis multiplanar reconstructions (4D flow CMR and CT) or standard apical 2-, 3-, and 4-chamber acquisitions (TTE). CMR and CT GLS analysis was feasible in all patients. Good correlations were observed for GLS measured by CMR (- 21 ± 3%) and CT (- 20 ± 3%) versus TTE (- 20 ± 3%, Pearson's r: 0.67 and 0.65, p < 0.001). CMR also correlated well with CT (Pearson's r 0.62, p < 0.001). The inter-observer analysis showed moderate to good reproducibility of GLS measurement by CMR, CT and TTE (Pearsons's r: 0.51, 0.77, 0.70 respectively; p < 0.05). Additionally, ejection fraction (EF), end-diastolic and end-systolic volume measurements (EDV and ESV) correlated well between all modalities (Pearson's r > 0.61, p < 0.001). Feature-tracking GLS analysis is feasible using the magnitude images acquired with 4D flow CMR. GLS measurement by CMR correlates well with CT and speckle-tracking 2D TTE. GLS analysis on 4D flow CMR allows for an integrative approach, integrating flow and functional data in a single sequence. Not applicable, observational study.

Blood biomarkers in patients with bicuspid aortic valve disease.

BACKGROUND: Patients with a bicuspid aortic valve (BAV) are at risk of developing valve deterioration and aortic dilatation. We aimed to investigate whether blood biomarkers are associated with disease stage in patients with BAV. METHODS: Serum levels of high sensitivity C-reactive protein (hsCRP), high sensitivity troponin T (hsTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and total transforming growth factor-beta 1 (TGF-ß1) were measured in adult BAV patients with valve dysfunction or aortic pathology. Age-matched general population controls were included for TGFß-1 measurements. Correlation analyses and multivariable linear regression were used to determine the association between (2log-transformed) biomarker levels and aortic valve regurgitation, aortic valve stenosis, aortic dilatation, or left ventricular function. RESULTS: hsCRP and hsTnT were measured in the total group of 183 patients (median age 34 years, 25th-75th percentile 23-46), NT-proBNP in 162 patients, and TGF-ß1 beta in 108 patients. Elevated levels of NT-proBNP were found in 20% of the BAV patients, elevated hsTnT in 6%, and elevated hsCRP in 7%. Higher hsTnT levels were independently associated with aortic regurgitation [odds ratio per doubling (OR2log) 1.34, 95% CI 1.01;1.76] and higher NT-proBNP levels with aortic valve maximal velocity (ß2log 0.17, 95%CI 0.07;0.28) and aortic regurgitation (OR2log 1.41, 95%CI 1.11;1.79). Both BAV patients with (9.9 ± 2.7 ng/mL) and without aortic dilatation (10.4 ± 2.9 ng/mL) showed lower TGF-ß1 levels compared to general population controls (n = 85, 11.8 ± 3.2 ng/mL). CONCLUSIONS: Higher NT-proBNP and hsTNT levels were associated with aortic valve disease in BAV patients. TGF-ß1 levels were lower in BAV patients than in the general population, and not related to aortic dilatation. Longitudinal data are needed to further investigate the prognostic value of biomarkers in these patients.

Abnormal Aortic Wall Properties in Women with Turner Syndrome.

BACKGROUND: Turner syndrome (TS) is associated with aortic dilatation and dissection, but the underlying process is unclear. The aim of this study was to investigate the elastic properties and composition of the aortic wall in women with TS. METHODS: In this cross-sectional study, 52 women with TS aged 35 ± 13 years (50% monosomy, 12 with bicuspid aortic valve [BAV] and 4 with coarctation) were investigated using carotid-femoral pulse wave velocity (CF-PWV) by echocardiography and ascending aortic distensibility (AAD) and aortic arch pulse wave velocity (AA-PWV) by magnetic resonance imaging (MRI). As control group, 13 women with BAV without TS and 48 healthy patients were included. RESULTS: Women with TS showed a higher AA-PWV (ß = 1.08, confidence interval [CI]: 0.54-1.62) after correcting for age and comorbidities compared with controls. We found no significant difference in AAD and CF-PWV. In women with TS, the presence of BAV, coarctation of the aorta, or monosomy (45, X) was not associated with aortic stiffness. In addition, aortic tissue samples were investigated with routine and immunohistochemical stains in five additional women with TS who were operated. The tissue showed more compact smooth muscle cell layers with abnormal deposition and structure of elastin and diminished or absent expression of contractile proteins desmin, actin, and caldesmon, as well as the progesterone receptor. CONCLUSION: Both aortic arch stiffness measurements on MRI and histomorphological changes point toward an inherent abnormal thoracic aortic wall in women with TS.

Aortic dissection and prophylactic surgery in congenital heart disease.

BACKGROUND: Proximal aortic dilatation in certain congenital heart diseases (CHD) prompts concerns about dissection and consideration of prophylactic surgery. To evaluate contemporary prophylactic practice, we determined incidence of aortic dissection and prophylactic surgery in aortopathy-associated CHD, compared to Marfan syndrom (MFS) and controls. METHODS AND RESULTS: We followed patients from the CONCOR adult CHD registry (2002-2015), with a native proximal aorta and aortopathy-associated CHD, comprising bicuspid aortic valve/aortic stenosis ('BAV/AS'; n = 2239) and aortic coarctation/conotruncal defects/univentricular heart/ventricular septal defect ('At-risk CHD'; n = 5439). As reference, we selected MFS (n = 356) and 'Control' (atrial septal defect, pulmonary stenosis; n = 2940) patients. Cumulative incidences of dissection and prophylactic proximal aortic replacement - considered competing events - were determined, and compared corrected for age and sex. Median follow-up was 6.7 years. Ten-year dissection-incidence was 0.3% (95%CI: 0.0-0.7) in BAV/AS and 0.2% (0.0-0.3) in At-risk CHD, both significantly lower than in MFS (4.1%; 1.8-6.4) and similar to Controls (0.1%; 0.0-0.3). Ten-year prophylactic-surgery incidence was 9.3% (7.6-11.0) in BAV/AS and 0.7% (0.5-1.0) in At-risk CHD, both significantly lower than in MFS (21.3%; 16.3-26.3) and higher than in Controls (0.1%; 0.0-0.3). CONCLUSIONS: In contemporary practice, aortic-dissection incidence is low in adults with aortopathy-associated CHDs, while prophylactic-surgery incidence is high in BAV/AS. To reduce surgical burden, BAV/AS patients could benefit from more individualised prophylactic-surgery algorithms.

Dysrhythmias in patients with a complete atrioventricular septal defect: From surgery to early adulthood.

OBJECTIVE: Outcomes after surgical repair of complete atrioventricular septal defect (cAVSD) have improved. With advancing age, the risk of development of dysrhythmias may increase. The aims of this study were to (1) examine development of sinus node dysfunction (SND), atrial and ventricular tachyarrhythmias, and (2) study progression of atrioventricular conduction abnormalities in young adult patients with repaired cAVSD. STUDY DESIGN: In this retrospective multicenter study, 74 patients (68% female) with a cAVSD repaired in childhood were included. Patients' medical files were evaluated for occurrence of SND, atrioventricular conduction block (AVB), atrial and ventricular tachyarrhythmias. RESULTS: Median age at repair was 6 months (interquartile range 3-10) and median age at last follow-up was 24 years (interquartile range 21-28). SND occurred after a median of 17 years (interquartile range 11-19) after repair in 23% of patients, requiring pacemaker implantation in two patients (12%). Regular supraventricular tachycardia was observed in three patients (4%). Atrial fibrillation and ventricular tachyarrhythmias were not observed. Twenty-seven patients (36%) had first-degree AVB, which was self-limiting in 16 (59%) and persistent in 10 (37%) patients. One patient developed third-degree AVB 7 days after left atrioventricular valve replacement. Spontaneous type II second-degree AVB occurred in a 28-year-old patient. Both patients underwent pacemaker implantation. CONCLUSIONS: Clinically significant dysrhythmias were uncommon in young adult patients after cAVSD repair. However, three patients required pacemaker implantation for either progression of SND or spontaneous type II second-degree AVB. Longer follow-up should point out whether dysrhythmias will progress or become more prevalent with increasing age.

Concomitant pulmonary vein isolation and percutaneous closure of atrial septal defects: A pilot project.

BACKGROUND: Patients with an atrial septal defect (ASD) are at increased risk of developing atrial fibrillation (AF). Currently percutaneous ASD closure is the preferred therapeutic strategy and although pulmonary vein isolation (PVI) for AF is feasible after ASD closure, the transseptal puncture can be technically challenging and probably increases the perioperative risk. A staged approach, with PVI several months before ASD closure, has been recommended for patients already scheduled for closure, but no data are available on combined procedures. PURPOSE: This pilot study evaluates the feasibility of a combined procedure of PVI and ASD closure in patients with a hemodynamic important ASD and documented AF. METHODS: In one procedure, PVI was performed prior to placement of the ASD closure device. Transseptal access for PVI was obtained via wire passage through the ASD in all patients. Patients were followed with 5-day-holter monitoring at 3, 6, and 12 months. Recurrence of AF was defined as a documented, symptomatic episode of AF. RESULTS: The study population consisted of five patients (four females, mean age: 58 (±3) years). Acute PVI was achieved in all patients. Only one patient had a small residual ASD after closure. Besides a small groin hematoma in two patients, no complications occurred. After 12-month follow-up, three patients were free of AF recurrence (60%). CONCLUSION: This study shows that a combined PVI with ASD closure is feasible with an acceptable success rate of AF free survival. These preliminary results in a small patient group warrants a larger trial.