Computed Tomography in Infectious Endocarditis.

Imaging is one of the cornerstones in diagnosis and management of infective endocarditis, underlined by recent guidelines. Echocardiography is the first-line imaging technique, however, computed tomography (CT) has a class I recommendation in native and prosthetic valve endocarditis to detect valvular lesions in case of possible endocarditis and to detect paravalvular and periprosthetic complications in case of inconclusive echocardiography. Echocardiography has a higher diagnostic accuracy than CT in detecting valvular lesions, but not for diagnosing paravalvular lesions where CT is superior. Additionally, CT is useful and recommended by guidelines to detect extracardiac manifestations of endocarditis and in planning surgical treatment including assessment of the coronary arteries. The advent of photon-counting CT and its improved spatial resolution and spectral imaging is expected to expand the role of CT in the diagnosis of infective endocarditis. In this review, we provide an overview of the current role of CT in infective endocarditis focusing on image acquisition, image reconstruction, interpretation, and diagnostic accuracy.

ACE Inhibitor and Angiotensin Receptor Blocker Use During Pregnancy: Data from the ESC Registry Of Pregnancy and Cardiac Disease (ROPAC).

Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are not recommended during the second and third trimester because of the significant risk of congenital anomalies associated with their use. However, data are scarce, especially regarding their use in the first trimester and about the impact of stopping just before pregnancy. Our study illustrates the profile of the women who used ACE-Is or ARBs during pregnancy and evaluates the impact on perinatal outcomes. The Registry of Pregnancy and Cardiac Disease is a prospective, global registry of pregnancies in women with structural heart disease. Outcomes were compared between women who used ACE-Is or ARBs and those who did not. Multivariable regression analysis was performed to assess the effect of ACE-I or ARB use on the occurrence of congenital anomalies. ACE-Is (n = 35) and/or ARBs (n = 8) were used in 42 (0.7%) of the 5,739 Registry of Pregnancy and Cardiac Disease pregnancies. Women who used ACE-Is or ARBs more often came from a low-or-middle-income country (57% vs 40%, p = 0.021), had chronic hypertension (31% vs 6%, p <0.001), or a left ventricular ejection fraction <40% (33% vs 4%, p <0.001). In the multivariable analysis, ACE-I use during the first trimester was associated with an increased risk of congenital anomaly (odds ratio 3.2, 95% confidence interval 1.0 to 9.6). Therefore, ACE-Is should be avoided during pregnancy, also in the first trimester, because of a higher risk of congenital anomalies. However, there is no need to stop long before pregnancy. Preconception counseling is crucial to discuss the potential risks of these medications, to evaluate the clinical condition and, if possible, to change or stop the medication.

Blood Biomarkers Predict 10-Year Clinical Outcomes in Adult Patients With Congenital Heart Disease.

Background: The adult congenital heart disease (ACHD) population is growing and risk prediction is important to predict adverse outcome and consult patients during their lifecourse. Objectives: This study aims to describe the long-term prognostic value of blood biomarkers in ACHD. Methods: In this prospective observational cohort study, 602 patients with moderate or complex ACHD were included (median age 32.5 years [IQR: 24.7-41.2], 42% female, 90% New York Heart Association I). N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive-troponin T, growth differentiation factor 15, high-sensitive-C-reactive protein, suppression of tumorigenicity-2 and galectin-3, as well as full blood count, renal function, LDL, and HDL were measured. Cox models were applied to relate the selected biomarkers with the primary end point of all-cause mortality and secondary end point of mortality or heart failure. Standardized HRs adjusted for relevant prognostic factors, including age, sex, and complexity of diagnosis, were reported. Results: Abnormal biomarker levels were present in 424 (70.4%) patients. During a median follow-up of 10.1 years, 41 (6.8%) patients died and 81 (13.5%) developed heart failure. Associations were observed between the primary and secondary end point and red cell distribution width, NT-proBNP, and growth differentiation factor 15. In a multibiomarker model, only NT-proBNP remained associated with mortality (HR: 2.74; 95% CI: 2.01-3.74). NT-proBNP significantly improved the C-statistic of the clinical prediction model (0.85-0.92). Based on NT-proBNP alone, low-risk patients could be identified. Patients with NT-proBNP <76 ng/L showed a 10-year heart failure-free survival of 98.5%. Conclusions: Blood biomarkers have prognostic value in ACHD. NT-proBNP improves risk prediction and is able to identify low-risk patients. Its routine use should be implemented in ACHD.

Sex-related differences in the clinical course of aortic root and ascending aortic aneurysms: the DisSEXion Study.

BACKGROUND AND AIMS: To explore male-female differences in aneurysm growth and clinical outcomes in a two-centre retrospective Dutch cohort study of adult patients with ascending aortic aneurysm (AscAA). METHODS: Adult patients in whom imaging of an AscAA (root and/or ascending: ≥40 mm) was performed between 2007 and 2022 were included. Aneurysm growth was analysed using repeated measurements at the sinuses of Valsalva (SoV) and tubular ascending aorta. Male-female differences were explored in presentation, aneurysm characteristics, treatment strategy, survival, and clinical outcomes. RESULTS: One thousand eight hundred and fifty-eight patients were included (31.6% female). Median age at diagnosis was 65.4 years (interquartile range: 53.4-71.7) for females and 59.0 years (interquartile range: 49.3-68.0) for males (P < .001). At diagnosis, females more often had tubular ascending aortic involvement (75.5% vs. 70.2%; P = .030) while males more often had SoV involvement (42.8% vs. 21.6%; P < .001). Maximum absolute aortic diameter, at any location, at diagnosis did not differ between females (45.0 mm) and males (46.5 mm; P = .388). In females, tubular ascending growth was faster (P < .001), whereas in males, SoV growth was faster (P = .005), corrected for covariates. Unadjusted 10-year survival was 72.5% [95% confidence interval (CI) 67.8%-77.6%] for females and 78.3% (95% CI 75.3%-81.3%) for males (P = .010). Twenty-three type A dissections occurred, with an incidence rate of 8.2/1000 patient-years (95% CI 4.4-14.1) in females and 2.4/1000 patient-years (95% CI 1.2-4.5) in males [incidence rate ratio females/males: 3.4 (95% CI 1.5-8.0; P = .004)]. CONCLUSIONS: In patients having entered a diagnostic programme, involvement of aortic segments and age- and segment-related growth patterns differ between women and men with AscAA, particularly at an older age. Unravelling of these intertwined observations will provide a deeper understanding of AscAA progression and outcome in women and men and can be used as an evidence base for patient-tailored clinical guideline development.

Prognostic value of the electrocardiogram in patients with bicuspid aortic valve disease.

BACKGROUND: Identifying bicuspid aortic valve (BAV) patients at risk for cardiac events remains challenging and the role of the electrocardiogram (ECG) has not yet been described. Therefore, this study aims to describe ECG parameters in BAV patients, and investigate their prognostic value. METHODS: In this single-center prospective study patients with BAV without a prior aortic valve replacement (AVR) were included. Transthoracic echocardiogram and 12­lead resting-ECG were obtained. Associations between ECG parameters and the composite endpoint of all-cause mortality and AVR were assessed using Cox-proportional hazard analysis. RESULTS: 120 patients with BAV were included (median age 30 years, 61% male). Median aortic jet velocity was 2.4 m/s [IQR: 1.7-3.4] and 5 patients (4%) had severe aortic regurgitation. All patients were in sinus rhythm. Any ECG abnormality was present in 57 patients (48%). Median PR-interval was 156 [IQR: 138-170] msec. A deviating QRS axis was found in 17 patients (14%) and Cornell criteria for LVH were fulfilled in 20 patients (17%). Repolarization abnormalities were present in 12 patients (10%). Median follow-up duration was 7.0 [6.3-9.8] years, during which 23 patients underwent AVR and 2 patients died. After adjusting for age, a longer PR-interval was associated with worse intervention-free survival (HR 1.02, 95% CI: 1.01-1.04). CONCLUSION: Almost half of the patients with BAV had abnormalities on their ECG. Moreover, the PR-interval may be an interesting prognostic marker for intervention-free survival in BAV patients.

Regional aortic wall shear stress increases over time in patients with a bicuspid aortic valve.

BACKGROUND: Aortic wall shear stress (WSS) is a known predictor of ascending aortic growth in patients with a bicuspid aortic valve (BAV). The aim of this study was to study regional WSS and changes over time in BAV patients. METHODS: BAV patients and age-matched healthy controls underwent four-dimensional (4D) flow cardiovascular magnetic resonance (CMR). Regional, peak systolic ascending aortic WSS, aortic valve function, aortic stiffness measures, and aortic dimensions were assessed. In BAV patients, 4D flow CMR was repeated after 3 years of follow-up and both at baseline and follow-up computed tomography angiography (CTA) were acquired. Aortic growth (volume increase of ≥5%) was measured on CTA. Regional WSS differences within patients' aorta and WSS changes over time were analyzed using linear mixed-effect models and were associated with clinical parameters. RESULTS: Thirty BAV patients (aged 34 years [interquartile range (IQR) 25-41]) were included in the follow-up analysis. Additionally, another 16 BAV patients and 32 healthy controls (aged 33 years [IQR 28-48]) were included for other regional analyses. Magnitude, axial, and circumferential WSS increased over time (all p < 0.001) irrespective of aortic growth. The percentage of regions exposed to a magnitude WSS >95th percentile of healthy controls increased from 21% (baseline 506/2400 regions) to 31% (follow-up 734/2400 regions) (p < 0.001). WSS angle, a measure of helicity near the aortic wall, decreased during follow-up. Magnitude WSS changes over time were associated with systolic blood pressure, peak aortic valve velocity, aortic valve regurgitation fraction, aortic stiffness indexes, and normalized flow displacement (all p < 0.05). CONCLUSION: An increase in regional WSS over time was observed in BAV patients, irrespective of aortic growth. The increasing WSSs, comprising a larger area of the aorta, warrant further research to investigate the possible predictive value for aortic dissection.

Left ventricular strain-volume loops in bicuspid aortic valve disease: new insights in cardiomechanics.

Aims: By combining temporal changes in left ventricular (LV) global longitudinal strain (GLS) with LV volume, LV strain-volume loops can assess cardiac function across the cardiac cycle. This study compared LV strain-volume loops between bicuspid aortic valve (BAV) patients and controls, and investigated the loop's prognostic value for clinical events. Methods and results: From a prospective cohort of congenital heart disease patients, BAV patients were selected and compared with healthy volunteers, who were matched for age and sex at group level. GLS analysis from apical views was used to construct strain-volume loops. Associations with clinical events, i.e. a composite of all-cause mortality, heart failure, arrhythmias, and aortic valve replacement, were assessed by Cox regression. A total of 113 BAV patients were included (median age 32 years, 40% female). BAV patients demonstrated lower Sslope (0.21%/mL, [Q1-Q3: 0.17-0.28] vs. 0.27%/mL [0.24-0.34], P < 0.001) and ESslope (0.19%/mL [0.12-0.25] vs. 0.29%/mL [0.21-0.43], P < 0.001) compared with controls, but also greater uncoupling during early (0.48 ± 1.29 vs. 0.05 ± 1.21, P = 0.04) and late diastole (0.66 ± 1.02 vs. -0.07 ± 1.07, P < 0.001). Median follow-up duration was 9.9 [9.3-10.4] years. Peak aortic jet velocity (HR 1.22, P = 0.03), enlarged left atrium (HR 3.16, P = 0.003), E/e' ratio (HR 1.17, P = 0.002), GLS (HR 1.16, P = 0.008), and ESslope (HR 0.66, P = 0.04) were associated with the occurrence of clinical events. Conclusion: Greater uncoupling and lower systolic and diastolic slopes were observed in BAV patients compared with healthy controls, suggesting presence of altered LV cardiomechanics. Moreover, lower ESslope was associated with clinical events, highlighting the strain-volume loop's potential as prognostic marker.

Diuretics in pregnancy: Data from the ESC Registry of Pregnancy and Cardiac disease (ROPAC).

AIMS: Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can be used safely. Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure. METHODS AND RESULTS: The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (86%). Age >35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0), other cardiac medication use (OR 5.4, 95% CI 4.2-6.9), signs of heart failure (OR 1.7, 95% CI 1.2-2.2), estimated left ventricular ejection fraction <40% (OR 2.9, 95% CI 2.0-4.2), New York Heart Association class >II (OR 3.4, 95% CI 2.3-5.1), valvular heart disease (OR 6.3, 95% CI 4.7-8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6-5.7) were associated with diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7-2.6), and diuretic use during pregnancy was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0-1.9). CONCLUSIONS: Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal outcomes. Given these findings, it is essential to assess the risk-benefit ratio on an individual basis to guide clinical decisions.

Clinical Course of TGA After Arterial Switch Operation in the Current Era.

Background: The number of patients with an arterial switch operation (ASO) for transposition of the great arteries (TGA) is steadily growing; limited information is available regarding the clinical course in the current era. Objectives: The purpose was to describe clinical outcome late after ASO in a national cohort, including survival, rates of (re-)interventions, and clinical events. Methods: A total of 1,061 TGA-ASO patients (median age 10.7 years [IQR: 2.0-18.2 years]) from a nationwide prospective registry with a median follow-up of 8.0 years (IQR: 5.4-8.8 years) were included. Using an analysis with age as the primary time scale, cumulative incidence of survival, (re)interventions, and clinical events were determined. Results: At the age of 35 years, late survival was 93% (95% CI: 88%-98%). The cumulative re-intervention rate at the right ventricular outflow tract and pulmonary branches was 36% (95% CI: 31%-41%). Other cumulative re-intervention rates at 35 years were on the left ventricular outflow tract (neo-aortic root and valve) 16% (95% CI: 10%-22%), aortic arch 9% (95% CI: 5%-13%), and coronary arteries 3% (95% CI: 1%-6%). Furthermore, 11% (95% CI: 6%-16%) of the patients required electrophysiological interventions. Clinical events, including heart failure, endocarditis, and myocardial infarction occurred in 8% (95% CI: 5%-11%). Independent risk factors for any (re-)intervention were TGA morphological subtype (Taussig-Bing double outlet right ventricle [HR: 4.9, 95% CI: 2.9-8.1]) and previous pulmonary artery banding (HR: 1.6, 95% CI: 1.0-2.2). Conclusions: TGA-ASO patients have an excellent survival. However, their clinical course is characterized by an ongoing need for (re-)interventions, especially on the right ventricular outflow tract and the left ventricular outflow tract indicating a strict lifelong surveillance, also in adulthood.

Perinatal outcomes after in-utero exposure to beta-blockers in women with heart disease: Data from the ESC EORP registry of pregnancy and cardiac disease (ROPAC).

BACKGROUND: Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied. METHODS: In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders). RESULTS: Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p < 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was -177 g (-5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3-2.1) and for nCHD 2.3 (1.6-3.5). With metoprolol as reference, labetalol (0.2, 0.1-0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1-4.9) the most. CONCLUSIONS: In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided.

Aortic geometry and long-term outcome in patients with a repaired coarctation.

OBJECTIVE: This study aims to compare aortic morphology between repaired coarctation patients and controls, and to identify aortic morphological risk factors for hypertension and cardiovascular events (CVEs) in coarctation patients. METHODS: Repaired coarctation patients with computed tomography angiography (CTA) or magnetic resonance angiography (MRA) were included, followed-up and compared with sex-matched and age-matched controls. Three-dimensional aortic shape was reconstructed using patients' CTA or MRA, or four-dimensional flow cardiovascular magnetic resonance in controls, and advanced geometrical characteristics were calculated and visualised using statistical shape modelling. In patients, we examined the association of geometrical characteristics with (1) baseline hypertension, using multivariable logistic regression; and (2) cardiovascular events (CVE, composite of aortic complications, coronary artery disease, ventricular arrhythmias, heart failure hospitalisation, stroke, transient ischaemic attacks and cardiovascular death), using multivariable Cox regression. The least absolute shrinkage and selection operator (LASSO) method selected the most informative multivariable model. RESULTS: Sixty-five repaired coarctation patients (23 years (IQR 19-38)) were included, of which 44 (68%) patients were hypertensive at baseline. After a median follow-up of 8.7 years (IQR 4.8-15.4), 27 CVEs occurred in 20 patients. Aortic arch dimensions were smaller in patients compared with controls (diameter p<0.001, wall surface area p=0.026, volume p=0.007). Patients had more aortic arch torsion (p<0.001) and a higher curvature (p<0.001). No geometrical characteristics were associated with hypertension. LASSO selected left ventricular mass, male sex, tortuosity and age for the multivariable model. Left ventricular mass (p=0.014) was independently associated with CVE, and aortic tortuosity showed a trend towards significance (p=0.070). CONCLUSION: Repaired coarctation patients have a smaller aortic arch and a more tortuous course of the aorta compared with controls. Besides left ventricular mass index, geometrical features might be of importance in long-term risk assessment in coarctation patients.

Pregnancy in patients with the Fontan operation.

Improved survival rates for patients with a Fontan circulation has allowed more women with this complex cardiac physiology to contemplate pregnancy. However, pregnancy in women with a Fontan circulation is associated with a high risk of adverse maternal and foetal outcomes, high rates of miscarriage, and preterm delivery. Factors associated with a successful pregnancy outcome are younger age, normal body weight, absence of significant functional limitation, no Fontan-related complications, and well-functioning single ventricle physiology. Appropriate care with timely preconception counselling and regular, frequent clinical reviews by a multidisciplinary team based at a tertiary centre improves the chance of a successful pregnancy. Empowerment of patients with education on their specific congenital cardiac condition and its projected trajectory helps them make informed choices regarding their health, reproductive choices, and assists them to achieve their life goals.

Pregnancy in women with Fontan is feasible but associated with a high risk of adverse maternal/foetal outcomes. Younger age, normal body weight, absence of significant functional limitation, and no Fontan-related complications are favourable factors. Timely preconception counselling and regular clinical reviews in a tertiary centre with an MDT improves pregnancy outcomes. Empowerment of patients with education helps them make informed choices on health, family planning, and the future.

Surveillance of adults with congenital heart disease: Current guidelines and actual clinical practice.

BACKGROUND AND AIM: Congenital heart disease (CHD) is the most common birth defect with prevalence of 0.8%. Thanks to tremendous progress in medical and surgical practice, nowadays, >90% of children survive into adulthood. Recently European Society of Cardiology (ESC), American College of Cardiology (ACC)/ American Heart Association (AHA) issued guidelines which offer diagnostic and therapeutic recommendations for the different defect categories. However, the type of technical exams and their frequency of follow-up may vary largely between clinicians and centres. We aimed to present an overview of available diagnostic modalities and describe current surveillance practices by cardiologists taking care of adults with CHD (ACHD). METHODS AND RESULTS: A questionnaire was used to assess the frequency cardiologists treating ACHD for at least one year administrated the most common diagnostic tests for ACHD. The most frequently employed diagnostic modalities were ECG and echocardiography for both mild and moderate/severe CHD. Sixty-seven percent of respondents reported that they routinely address psychosocial well-being. CONCLUSION: Differences exist between reported current clinical practice and published guidelines. This is particularly true for the care of patients with mild lesions. In addition, some differences exist between ESC and American guidelines, with more frequent surveillance suggested by the Americans.

Long-Term Health-Related Quality of Life following Acute Type A Aortic Dissection with a Focus on Male-Female Differences: A Cross Sectional Study.

Objectives: Acute type A aortic dissection (ATAAD) is a life-threatening cardiovascular emergency, of which the long-term impact on health-related quality of life (HRQoL) and male-female-specific insights remain inadequately clarified. Methods: Consecutive adult ATAAD patients who underwent surgery were retrospectively included between 2007 and 2017 in four referral centers in the Netherlands, and baseline data were collected. The 36-Item Short-Form (SF-36) Health Survey was sent to all survivors between 2019 and 2021 and compared to validated SF-36 scores of the Dutch general population stratified by age group and sex. Results: In total, 324/555 surviving patients returned the SF-36 questionnaire (response rate 58%), of which 40.0% were female; the median follow-up was 6.5 years (range: 1.7-13.9, IQR: 4.0-9.4) after surgery for ATAAD. In comparison to the general population, ATAAD patients scored significantly lower on 6/8 SF-36 subdomains and higher on bodily pain. Differences in HRQoL domains compared to the sex-matched data were largely comparable between sexes, apart from bodily pain. In the age-matched subgroups impaired HRQoL was most pronounced in younger patients aged 41-60 (5/8 impaired domains). Female ATAAD patients scored significantly worse on 5/8 SF-36 subdomains and the physical component summary (PCS) scores than male patients. Age at ATAAD, female sex, hypertension, COPD, and prior thoracic aortic aneurysm were associated with worse PCS scores. Conclusions: Long-term HRQoL was impaired in both male and female ATAAD patients when compared to the general population. Further studies on the nature of this impairment and on interventions to improve HRQoL after ATAAD are clearly warranted, with special attention to females and younger patients.

The proprotein convertase FURIN is a novel aneurysm predisposition gene impairing TGF-ß signaling.

AIM: Aortic aneurysms (AA) frequently involve dysregulation of transforming growth factor ß (TGF-ß)-signaling in the aorta. Here, FURIN was tested as aneurysm predisposition gene given its role as proprotein convertase in pro-TGF-ß maturation. METHODS AND RESULTS: Rare FURIN variants were detected by whole-exome sequencing of 781 unrelated aortic aneurysm patients and affected relatives. Thirteen rare heterozygous FURIN variants occurred in 3.7% (29) unrelated index AA patients, of which 72% had multiple aneurysms or a dissection.FURIN maturation and activity of these variants were decreased in vitro. Patient-derived fibroblasts showed decreased pro-TGF-ß processing, phosphorylation of downstream effector SMAD2 and kinases ERK1/2, and steady-state mRNA levels of the TGF-ß-responsive ACTA2 gene. In aortic tissue, collagen and fibrillin fibers were affected. One variant (R745Q), observed in 10 unrelated cases, affected TGF-ß signaling variably, indicating effect modification by individual genetic backgrounds. CONCLUSION: FURIN is a novel, frequent genetic predisposition for abdominal-, thoracic-, and multiple aortic or middle sized artery aneurysms in older patients, by affecting intracellular TGF-ß signaling, depending on individual genetic backgrounds.

Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation.

RATIONALE: Pathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis. OBJECTIVES: Investigate the impact of P/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants. METHODS: A retrospective analysis on clinical data from individuals with a P/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts. RESULTS: Individuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P = 0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0 years [IQR 29.0-47.0] in individuals with DN variants in MH2, compared to 46.0 years [IQR 40.0-54.0] in those with HI variants (P = 0.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines. CONCLUSION: Distinguishing between P/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs.

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.

Effects of antiplatelet therapy on menstrual blood loss in reproductive-aged women: a systematic review.

Background: The effects of antiplatelet therapy on menstrual bleeding have not been well characterized. Objectives: To systematically review the effects of antiplatelet therapy on menstrual bleeding. Methods: A literature search was performed for studies of reproductive-aged women who received antiplatelet therapy. Characteristics of menstrual bleeding both before and after initiation of antiplatelet therapy and from comparison groups were collected. Two reviewers independently assessed the risk of bias in individual studies. Results: Thirteen studies with a total of 611 women who received antiplatelet therapy were included. Types of antiplatelet drugs used were aspirin (n = 8), aspirin and/or clopidogrel (n = 2), prasugrel (n = 1), and not specified (n = 2). Risk of bias was assessed at moderate (n = 1), serious (n = 8), critical (n = 2), and no information (n = 2). Three studies reported changes in menstrual blood loss volume. One of these showed no increase during antiplatelet therapy; the other 2 studies suggested that aspirin may increase menstrual blood loss volume. In 3 studies that assessed the duration of menstrual bleeding, up to 13% of women reported an increased duration of menstruation. In 5 studies that reported the intensity of menstrual flow, 13% to 38% of women experienced an increase in the intensity of flow. Five studies reported the prevalence of heavy menstrual bleeding in women who received antiplatelet therapy, with estimates ranging from 7% to 38%. Conclusion: There is lack of high-quality data on the effects of antiplatelet therapy on menstrual bleeding. Aspirin may increase menstrual blood loss, at least in a minority of women, whereas the effects of P2Y12 inhibitors are unknown.

Long-term surgical outcomes of congenital supravalvular aortic stenosis: a systematic review, meta-analysis and microsimulation study.

OBJECTIVES: Congenital supravalvular aortic stenosis (SVAS) is a rare form of congenital outflow tract obstruction and long-term outcomes are scarcely reported. This study aims to provide an overview of outcomes after surgical repair for congenital SVAS. METHODS: A systematic review of published literature was conducted, including observational studies reporting long-term clinical outcome (>2 years) after SVAS repair in children or adults considering >20 patients. Early risks, late event rates and time-to-event data were pooled and entered into a microsimulation model to estimate 30-year outcomes. Life expectancy was compared to the age-, sex- and origin-matched general population. RESULTS: Twenty-three publications were included, encompassing a total of 1472 patients (13 125 patient-years; pooled mean follow-up: 9.0 (6.2) years; median follow-up: 6.3 years). Pooled mean age at surgical repair was 4.7 (5.8) years and the most commonly used surgical technique was the single-patch repair (43.6%). Pooled early mortality was 4.2% (95% confidence interval: 3.2-5.5%) and late mortality was 0.61% (95% CI: 0.45-0.83) per patient-year. Based on microsimulation, over a 30-year time horizon, it was estimated that an average patient with SVAS repair (mean age: 4.7 years) had an observed life expectancy that was 90.7% (95% credible interval: 90.0-91.6%) of expected life expectancy in the matched general population. The microsimulation-based 30-year risk of myocardial infarction was 8.1% (95% credible interval: 7.3-9.9%) and reintervention 31.3% (95% credible interval: 29.6-33.4%), of which 27.2% (95% credible interval: 25.8-29.1) due to repair dysfunction. CONCLUSIONS: After surgical repair for SVAS, 30-year survival is lower than the matched-general-population survival and the lifetime risk of reintervention is considerable. Therefore, lifelong monitoring of the cardiovascular system and in particular residual stenosis and coronary obstruction is recommended.

Heart rate: an accessible risk indicator in adult congenital heart disease.

BACKGROUND: Higher resting heart rate has been described as a risk factor for adverse outcome in healthy individuals and cardiovascular patients. The aim of this study was to evaluate resting heart rate as risk factor in adult congenital heart disease (ACHD). METHODS: In this prospective observational cohort study, patients with moderate or complex ACHD were included at routine outpatient visit. Standard 12-lead ECGs were obtained in rest. Heart rate was obtained from the ECG automatically by the Modular ECG Analysis System (MEANS). The primary endpoint was all-cause mortality and the secondary endpoint was a composite of all-cause mortality and heart failure. Survival was derived using the Kaplan-Meier estimator. Subgroups based on heart rate tertiles were compared by the log-rank test. Cox proportional hazards models were adjusted for clinical factors including age, sex and diagnosis (moderate vs complex ACHD). RESULTS: A total of 556 patients were included (median age 32 years (IQR 24-41), 57.6% male). Mean heart rate was 69±13 bpm. Negative chronotropic medication was used by 74 (13.3%) patients. During a median follow-up of 10.1 (IQR 9.6-10.5) years, 36 patients (6.5%) died and 83 (14.9%) reached the secondary endpoint. Patients with higher heart rates had significantly lower survival and heart failure-free survival. After adjusting for clinical factors, heart rate remained associated with mortality (HR 1.57 per 10 bpm, 95% CI 1.26 to 1.96) and mortality or heart failure (HR 1.33 per 10 bpm, 95% CI 1.13 to 1.57). CONCLUSION: Higher heart rate is associated with lower survival and heart failure-free survival in ACHD.