Endocrine, cardiac and neuropsychological aspects of adult congenital adrenal hyperplasia.

OBJECTIVE: To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired synthesis of cortisol in the adrenal cortex and, if untreated compensatory hyperandrogenism. CAH is associated with an increased cardiovascular and metabolic morbidity, possibly due to overtreatment with glucocorticoids, leading to weight gain, insulin resistance, and metabolic syndrome. DESIGN, PARTICIPANTS, MEASUREMENTS: Thirty-seven individuals with CAH and 33 age- and sex-matched controls were evaluated at a single centre at Aarhus University Hospital with echocardiography, electrocardiogram, 24-h blood pressure, biochemistry, anthropometrics, and autism spectrum, anxiety, depression, personality, cognitive failures, and QoL were assessed using questionnaires. RESULTS: CAH individuals had lower height than controls (170.5 vs. 182.9 cm in males and 160.2 vs. 170.1 cm in females, p < 0.01). Compared with female controls, females with CAH had higher haemoglobin (8.8 vs. 8.2 mmol/L, p = 0.003) and BMI (29.7 vs. 25.5 kg/m2, p = 0.006), reduced insulin sensitivity (HOMA-IR): 2.7 vs. 1.9, p = 0.018), prolonged E-wave deceleration time (193 vs. 174 cm, p = 0.015), and E/é ratios (5.4 vs. 4.5, p = 0.017), and lower self-reported QoL. Males with CAH had more cognitive complaints (p = 0.034) and higher autistic scores (19.9 vs. 14.9; p = 0.068) compared with male controls. More individuals with CAH than controls reported writing problems. CONCLUSION: A sex-specific comorbidity profile is evident in CAH, with females presenting with decreased metabolic and overall self-reported health, whereas males with CAH presented with increased cognitive complaints and autistic traits.

The TGFß system and TIMP1 and 3 genotypes in Turner syndrome-Relation with aortic congenital malformations.

OBJECTIVE: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high-risk TS and reduce screening in TS participants with low cardiovascular risk. DESIGN, PATIENTS, PARTICIPANTS AND MEASUREMENTS: As part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re-examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFß), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease. RESULTS: TS participants had lower TGFß1 and TGFß2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFß1 were correlated with the aortic diameter at several measuring positions. During follow-up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFß1 and TGFß2 levels in TS. CONCLUSION: TGFß and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants.

Kawasaki disease, autoimmune disorders, and cancer: a register-based study.

Kawasaki disease has well-described cardiovascular complications. However, the association to autoimmunity and cancer in the long term is not well described. We investigated theses associations using a registry-based matched cohort follow-up study of patients diagnosed with Kawasaki disease. Patients with Kawasaki disease were included and matched 1:5 to a population control group, matched by birth year, sex and incident month of the Kawasaki disease diagnosis. A total of 820 cases < 21 years of age were identified. Median age at diagnosis was 3 years. Median follow-up time was 12 years. Patients with KD were at higher risk of being diagnosed with ischaemic heart disease at 10 years (HR 39.94 (95% CI 5.00-319.28)) and 30 years (HR 8.33 (95% CI 3.03-22.91)). The 10-, 20- and 30-year risks of developing autoimmune disorders were HR 4.23 (95% CI 3.01-5.94), HR 3.23 (95% CI 2.44-4.29) and 2.83 (95% CI, 2.17-3.68), all p < 0.001. Cancer risk was increased after 30 years (HR 2.42 (95% CI, 1.09-5.34)). All-cause mortality after 35 years was also significantly increased (HR 3.14 (95% CI, 1.03-9.60)). Children with KD have increased long-term risks of ischaemic heart disease also of autoimmune disease and cancer, as well as an increased all-cause mortality. The surprisingly increased risk of autoimmunity must be investigated further. What is known: • Kawasaki disease is characterized by acute vasculitis and inflammation that can affect the coronary arteries. • Anti-inflammatory medicine is effective in the acute stages of the disease. What is new: • Children with Kawasaki disease have an increased risk of developing autoimmune disease in the long term. • Kawasaki disease is associated with a slightly increased mortality rate driven by non-cardiovascular causes.

Clinical and pathophysiological aspects of bicuspid aortic valve disease.

A bicuspid aortic valve is not only a common congenital heart defect but also an enigmatic condition that can cause a large spectrum of diseases, such as aortic valve stenosis and severe heart failure in newborns whereas aortic dissection in adults. On the contrary, a bicuspid aortic valve can also occur with normal function throughout life and never need treatment. Numerous genetic mechanisms are involved in the abnormal cellular functions that may cause abnormal development of the aortic valve during early foetal life. As several chromosomal disorders are also associated with a bicuspid valve, there does not appear to be an apparent common trigger to the abnormal development of the aortic valve. The clinical care of the bicuspid aortic valve patient has been changed by a significant body of evidence that has improved the understanding of the natural history of the disease, including when to best intervene with valve replacement and when to provide prophylactic aortic root surgery. Moreover, as bicuspid valve disease is also part of various syndromes, we can identify high-risk patients in whom a bicuspid valve is much more unfavourable than in the normal population. This review provides an overview of all aspects of the bicuspid aortic valve condition and gives an updated perspective on issues from pathophysiology to clinical care of bicuspid aortic valve disease and associated aortic disease in asymptomatic, symptomatic, and pregnant patients, as well as our viewpoint on population screening.

Rupture of an Abdominal Aortic Aneurysm in a Young Man with Marfan Syndrome.

Abdominal aortic aneurysms (AAAs) are very rare in Marfan syndrome. We present a case with a young nonsmoking and normotensive male with Marfan syndrome, who developed an infrarenal AAA that presented with rupture to the retroperitoneal cavity causing life-threatening bleeding shock. The patient had acute aortic surgery and survived. Five months before this incident, the patient had uneventful elective aortic root replacement (ad modum David) due to an enlarged aortic root. At that time, his abdominal aorta was assessed with a routine ultrasound scan that showed a normal-sized abdominal aorta. This documents that the aneurysm had evolved very rapidly despite young age and absence of risk factors.

Osteoprotegerin in Turner syndrome - relationship to aortic diameter.

BACKGROUND: Cardiovascular disease is a cardinal trait of Turner syndrome (TS), causing half of the threefold excess mortality. As osteoprotegerin (OPG) is a potential biomarker of cardiovascular disease, this cross-sectional and prospective study aimed at elucidating OPG levels in TS and its relationship to aortic diameter as well as validated cardiovascular risk markers. METHODS: Adult women with TS (n = 99) were examined thrice (mean follow-up 4·7 ± 0·5 years), and 68 age-matched healthy female controls were examined once. Aortic diameter was assessed by cardiovascular magnetic resonance. Twenty-four-hours blood pressure monitoring and biochemical assessments were also performed. RESULTS: Osteoprotegerin levels (median with range) were lower in TS (777 [326-10 569] ng/l) compared with controls (979 [398-1987] ng/l; P < 0·05) and did not change during follow-up. The OPG concentration was higher among women with TS older than 50 years of age (996 [542-4996] vs 756 [326-10 569] ng/l; P < 0·05) with a trend towards a higher OPG in TS who were on antihypertensive medication (938 [490-2638] vs 752 [326-10 569] ng/l; P = 0·09). Contrary to controls, OPG levels correlated with BSA-indexed aortic diameter (r = 0·31-0·45; P < 0·05), age (r = 0·29; P < 0·05) and high-sensitivity C-reactive protein (r = 0·23; P = 0·02) and inversely with BSA (r = -0·20; P < 0·05), weight (r = -0·23; P < 0·05) and plasma oestradiol levels (r = -0·34; P < 0·05). CONCLUSION: Levels of OPG are lower in TS and correlate with aortic diameter, age, BSA, weight and oestradiol in TS, but not controls. Future studies are needed to assess whether OPG may serve as a biomarker of aortic or cardiovascular disease in TS.

Short QTc interval in males with klinefelter syndrome-influence of CAG repeat length, body composition, and testosterone replacement therapy.

BACKGROUND: Klinefelter syndrome (KS) is a sex chromosomal aneuploidy (47,XXY) affecting 1/660 males. Based on findings in Turner syndrome, we hypothesized that electrocardiogram (ECG) abnormalities would be present in males with KS. OBJECTIVE: To investigate ECGs in males with KS and compare with controls. METHODS: Case control study of 62 males with KS and 62 healthy males matched on age. The primary outcome parameter was a difference in the ECG presentation between the two groups. The ECGs were analyzed by one blinded examiner (intraobserver variability 0.2-2.1%). The QT-interval was measured using "teach-the-tangent" method excluding the U-wave. QTc was calculated using Bazett's equation, Hodges' equation, and a linear regression model. Body mass index, abdominal fat, and muscle mass as well as sex hormone levels were secondary parameters. The prevalence of mutations in genes related to short QT syndrome was determined in participants with a QTc < 330 ms. RESULTS: Compared to controls, the QTc-interval was shorter (P = 0.02-0.06) in males with KS depending on the applied correction method. QTc was shortest among testosterone (T)-treated males with KS, while untreated and thus hypogonadal KS had QTc interval comparable to controls. No mutations in genes related to short QT syndrome were found. CONCLUSION: We found short QTc interval in males with KS, with further shortening of the QTc interval by T. These results suggest that genes on the X chromosome could be involved in regulation of the QTc interval and that T treatment may aggravate this mechanism.

Impact of mandatory preoperative dental screening on post-procedural risk of infective endocarditis in patients undergoing transcatheter aortic valve implantation: a nationwide retrospective observational study.

Background: Guidelines recommend preoperative dental screening (PDS) prior to cardiac valve surgery, to reduce the incidence of prosthetic valve infective endocarditis (IE). However, limited data support these recommendations, particular in patients undergoing transcatheter aortic valve implantation (TAVI). We aimed to investigate the effect of mandatory PDS on risk of IE in patients undergoing TAVI. Methods: In this observational study, a total of 1133 patients undergoing TAVI in Western-Denmark from 2020 to 2022 were included. Patients were categorized based on two implemented PDS practices: mandatory PDS (MPDS group), and no referral for PDS (NPDS group). Outcome data were retrieved from Danish registries and confirmed using medical records. The primary outcome was incidence of IE. Secondary outcomes were all-cause mortality and composite outcome of all-cause mortality and IE. Findings: Of 568 patients in the MPDS group 126 (22.2%) underwent subsequent oral dental surgery, compared to 8 (1.4%) among 565 patients in the NPDS group. During a median follow-up of 1.9 years (interquartile range 1.4-2.5 years), 31 (2.7%) developed IE. The yearly incidence IE rate was 1.4% (0.8-2.3) and 1.5% (0.8-2.4) in MPDS and NPDS, respectively, p = 0.86. All-cause mortality rates were similar between groups (estimated 2-year overall mortality of 6.7% (4.8-9.2) vs. 4.7% (3.2-6.9), MPDS and NPDS, respectively, p = 0.15). Consistent findings were found in 712 propensity score-matched patients. Interpretation: Mandatory PDS did not demonstrate reduced risk of IE or all-cause mortality compared to targeted PDS in patients undergoing TAVI. Funding: The funder had no role in the study design, data management, or writing.

A Prospective Study of Lipids in Adult Women With Turner Syndrome.

Context: Turner syndrome (TS) is a rare genetic syndrome with an increased mortality, mainly attributed to cardiovascular disease. Objective: This work aimed to investigate and correlate the lipid profile in adult women with TS to clinical characteristics. Methods: A 12-year prospective cohort study, including 4 study visits, was conducted at a specialist hospital. A total of 102 women with TS qualified for inclusion. Excluding missing variables and participants lost to follow-up, 86 women (mean age 38.1 years; range, 18.4-62.1 years) were included in this study. Fifty-three women completed the study. Repeated-measurement analysis was performed, using total cholesterol (Total-C), low-density lipoprotein (LDL), triglycerides (TGs), and high-density lipoprotein (HDL) as outcome variables and age, karyotype, body mass index (BMI), treatment with statins, antidiabetics, and hormone replacement therapy as explanatory variables. Principal component analysis (PCA) and partial least squares (PLS) analysis were performed at the first study visit. Results: Hyperlipidemia was present in 30% of the TS cohort. Total-C increased with age (0.12 mmol/L/y; P = .016). LDL (P = .08), TGs (P = .14), and HDL (P = .24) were not associated with age. BMI significantly increased total-C (0.19 mmol/L/kg/m2; P = .006), LDL (0.63 mmol/L/kg/m2; P < .001), and TGs (0.80 mmol/L/kg/m2; P < .001) and decreased HDL (-0.59 mmol/L/kg/m2; P < .001). PCA and PLS analysis found correlations between weight and BMI and total-C, LDL, and TGs. Conclusion: Hyperlipidemia is more prevalent in adult women with TS across adulthood compared to the background population. Total-C, LDL, TGs, and HDL were significantly associated with BMI characterizing the atherogenic profile in adult women with TS.

Comparison of international guideline recommendations for the diagnosis of pulmonary embolism.

Pulmonary embolism is one of the leading causes of death due to cardiovascular disease. Timely diagnosis is crucial, but challenging, as the clinical presentation of pulmonary embolism is unspecific and easily mistaken for other common medical emergencies. Clinical prediction rules and D-dimer measurement allow stratification of patients into groups of expected prevalence and are key elements in adequate selection of patients for diagnostic imaging; however, the strengths and weaknesses of the multiple proposed prediction rules, when to measure D-dimer, and which cutoff to apply might be elusive to a significant proportion of physicians. 13 international guidelines authored by medical societies or expert author groups provide recommendations on facets of the diagnostic investigations in suspected pulmonary embolism, some of which are hallmarked by pronounced heterogeneity. This Review summarises key recommendations of each guideline, considers the most recent evidence on the topic, compares guideline recommendations on each facet of the diagnosis of pulmonary embolism, and provides a synthesis on the most common recommendations.

Dosage of the pseudoautosomal gene SLC25A6 is implicated in QTc interval duration.

The genetic architecture of the QT interval, defined as the period from onset of depolarisation to completion of repolarisation of the ventricular myocardium, is incompletely understood. Only a minor part of the QT interval variation in the general population has been linked to autosomal variant loci. Altered X chromosome dosage in humans, as seen in sex chromosome aneuploidies such as Turner syndrome (TS) and Klinefelter syndrome (KS), is associated with altered QTc interval (heart rate corrected QT), indicating that genes, located in the pseudoautosomal region 1 of the X and Y chromosomes may contribute to QT interval variation. We investigate the dosage effect of the pseudoautosomal gene SLC25A6, encoding the membrane ADP/ATP translocase 3 in the inner mitochondrial membrane, on QTc interval duration. To this end we used human participants and in vivo zebrafish models. Analyses in humans, based on 44 patients with KS, 44 patients with TS, 59 male and 22 females, revealed a significant negative correlation between SLC25A6 expression level and QTc interval duration. Similarly, downregulation of slc25a6 in zebrafish increased QTc interval duration with pharmacological inhibition of KATP channels restoring the systolic duration, whereas overexpression of SLC25A6 shortened QTc, which was normalized by pharmacological activation of KATP channels. Our study demonstrate an inverse relationship between SLC25A6 dosage and QTc interval indicating that SLC25A6 contributes to QT interval variation.

Left ventricular hypertrophy in Turner syndrome: a prospective echocardiographic study.

BACKGROUND: Cardiovascular risk stratification in Turner syndrome (TS) is difficult. Increased left ventricular mass associates with an adverse prognosis in several settings, and this study aimed to elucidate this risk marker in relation to metabolic and cardiovascular status in TS. METHODS: An echocardiographic follow-up study (4.8 years) of 82 adult females with TS. Left ventricular mass was the primary outcome parameter. Metabolic status (glucose, Hemoglobin A1c, lipids), aortic valve function and morphology, and 24-hour ambulatory blood pressure were secondary outcome parameters. Healthy age-matched females served as baseline controls (n = 55). RESULTS: Left ventricular mass was increased in TS (TS vs. controls: 88 ± 21 g/m(2) vs. 77 ± 12 g/m(2), P < 0.05). More participants were treated for hypertension at follow-up (32% at baseline vs. 55% at follow-up). This coincided with a reduction of left ventricular mass in TS (84 ± 20 g/m(2) at follow up, P < 0.05) and favorable remodeling with a contrasting increase in left atrial size. In a baseline multiple regression model, left ventricular mass (r(2) = 0.28, P < 0.05) increased with body surface area, age and the presence of a bicuspid aortic valve. In another model, left ventricular mass increased with blood pressure, ongoing estrogen treatment and body surface area (r(2) = 0.26, P < 0.05). No single factor reached statistically significant levels for prediction of prospective left ventricular mass changes. CONCLUSION: The increased left ventricular mass in TS was associated with aortic valve disease, age, hypertension, physical stature and metabolic status. During follow-up left ventricular mass was only slightly reduced along with blood pressure, whereas the diastolic dysfunction did not seem to improve.

[Diagnostic accuracy of fibrin D-dimer].

Dyspnoea and chest pain are common causes of referral to emergency departments. Both symptoms are non-specific and may be caused by ST elevation myocardial infarction, aortic dissection, pulmonary embolism, or infection. Fibrin D-dimer is often used for ruling out suspicion of acute diseases, but the clinical utility is limited by a modest specificity which lowers with age to approximately ten per cent at the age of 80 years. This review summarises the recommended approaches and highlights potential pitfalls when utilizing and interpreting fibrin D-dimer in the diagnostic work-up of commonly suspected medical conditions.

Percutaneous left atrial appendage occlusion discrepancy between randomised trials and clinical practice.

In patients with atrial fibrillation and previous episodes of bleeding on oral anticoagulant treatment, left atrial appendage occlusion (LAAO) has emerged as an alternative way to decrease the risk of stroke.The use of the procedure has been on the rise, and the news coverage has been dominated by an uncritical acceptance of the benefit of this procedure, which probably have contributed to the increasing number of procedures.This commentary is a presentation and critical appraisal of the available evidence on the efficacy and safety of left atrial appendage closure as stroke prophylaxis.We illustrate that LAAO is supported by limited randomised data risk of serious complications, which we do not believe supports the current widespread use.

The association between Takotsubo cardiomyopathy and thyrotoxicosis: A systematic review.

PURPOSE: This study aims to review all published cases on the association between thyrotoxicosis and Takutsubo Syndrome by describing clinical characteristics, diagnostic work-up, treatment, and outcome. METHODS: We searched PubMed and Embase databases from inception to the 17th of February 2022 for case reports or series reporting the above-mentioned association. We extracted data on demographic characteristics, clinical features, diagnostic work-up, treatment, and clinical outcomes. Cases were stratified into groups based on the presumed cause of the thyrotoxicosis (iatrogenic vs non-iatrogenic and Graves' diseases vs non-Graves' disease, respectively). RESULTS: We identified 25 cases from 24 articles. The mean age was 61.7 years (+/- SD 14.5). Most patients were women (88%). Graves' disease (52%) was the leading cause of thyrotoxicosis. Previous cancer was significantly more common in patients with iatrogenic thyrotoxicosis (P = 0.03). The most common symptoms were respiratory symptoms (68%), chest pain (56%), and palpitations (40%). The most common ECG characteristics were T-wave abnormalities (48%) and ST-elevations (36%). Elevated troponin levels were found in 92% of the cases. Patients with Graves's disease and Takutsubo Syndrome had higher plasma levels of serum thyroxine (P = 0.03) and were more often treated with beta-blockers (P = 0.01) compared to patients with thyrotoxicosis of other origins. Notably, 40% of cases experienced in-hospital complications. No deaths were reported. All patients had improved cardiac function within a median follow-up of 42 days. CONCLUSION: Evidence-based on current case reports suggests an increased risk of Takutsubo Syndrome and subsequently increased risk of in-hospital complications in patients with thyrotoxicosis.

Five-Year Outcomes After Coronary Computed Tomography Angiography (From 110,599 Patients in a Danish Nationwide Register-Based Follow-Up Study).

The long-term cardiovascular risk for patients examined with coronary computed tomography angiography (CCTA) to rule out coronary heart disease compared with population controls remains unexplored. A nationwide register-based study including first-time CCTA-examined patients between 2007 and 2017 in Denmark alive 180 days post-CCTA was conducted. We evaluated 5-year outcomes of myocardial infarction (MI) or revascularization and all-cause mortality in 3 distinct CCTA-groups: (1) no post-CCTA preventive pharmacotherapy use (cholesterol-lowering drugs, antiplatelets, or anticoagulants); (2) post-CCTA preventive pharmacotherapy use; and (3) revascularization or MI within 180 days post-CCTA. For each patient group, population controls were matched on age, gender, and calendar year. Absolute risks standardized to the age, gender, selected co-morbidity, and anti-anginal pharmacotherapy distributions of the specific CCTA-examined patients and respective controls were obtained from multivariable Cox regression. Of 110,599 CCTA-examined patients, (1) 48,231 patients were not prescribed preventive pharmacotherapy 180 days post-CCTA; (2) 42,798 patients were prescribed preventive pharmacotherapy within 180 days post-CCTA; and (3) 19,570 patients were diagnosed with MI or revascularized within 180 days post-CCTA. For patient groups 1 to 3 versus respective controls, 5-year MI or revascularization risks were <0.1% versus 2.0%, <0.1% versus 3.8%, and 19.0% versus 2.5%, all p<0.001. Five-year all-cause mortality were 2.8% versus 4.2%, 5.5% versus 8.8%, and 6.7% versus 8.5%, all p <0.001. In conclusion, the 5-year MI or revascularization risk can be considered very low for CCTA-examined patients without ischemic events within 180 days post-CCTA. Conversely, CCTA-examined patients with MI or revascularization events within 180 days post-CCTA have significantly elevated 5-year MI or revascularization risk.

Global longitudinal strain by speckle tracking for infarct size estimation.

AIMS: To assess the utility of speckle tracking global longitudinal systolic strain (GLS) compared with traditional echocardiographic indices including left ventricular ejection fraction (LVEF), wall motion score index (WMSI), and end-systolic volume index (ESVI), in estimating the infarct size (IS) following a ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: The study includes 227 patients with STEMI and day 1 and day 30 echocardiograms, and myocardial perfusion imaging (MPI) only at day 30 to assess IS. IS was modelled by linear regression with echocardiographic parameters using MPI as reference. Resulting echocardiographic IS estimates were compared by ratios of standard deviations of model residuals (RSD). To estimate the resultant day 30 IS 1 day after a STEMI, GLS was more precise than LVEF (RSD: 0.91, P = 0.014) and ESVI (RSD: 0.88, P = 0.002), and comparable with WMSI (RSD 0.99, P = 0.86). To estimate IS from a day 30 echocardiogram, GLS was comparable with LVEF (RSD: 0.98, P = 0.68) and ESVI (RSD: 1.04, P = 0.40), but WMSI was more precise (RSD: 0.89, P = 0.006). Multiple linear regression revealed that on day 1 after STEMI, GLS significantly complemented the standard parameters separately (P-values all models <0.001) or combined [multivariable model: GLS (P = 0.001), WMSI (P = 0.03), LVEF (P = 0.40)]. On day 30, GLS significantly complemented LVEF and ESVI, but when WMSI was in the model, GLS's association with IS was not significant. CONCLUSION: On day 1 after revascularization for STEMI, GLS contains additional information about final IS compared with standard echocardiographic systolic function indices. Studies are needed to clarify whether this has prognostic implications.