Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity.

The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directs infection of the lungs and other tissues following its binding to the angiotensin-converting enzyme 2 (ACE2) receptor. For effective infection, the S protein is cleaved at two sites: S1/S2 and S2'. The "priming" of the surface S protein at S1/S2 (PRRAR685↓) [the underlined basic amino acids refer to critical residues needed for the furin recognition] by furin has been shown to be important for SARS-CoV-2 infectivity in cells and small-animal models. In this study, for the first time we unambiguously identified by proteomics the fusion activation site S2' as KPSKR815↓ (the underlined basic amino acids refer to critical residues needed for the furin recognition) and demonstrated that this cleavage was strongly enhanced by ACE2 engagement with the S protein. Novel pharmacological furin inhibitors (BOS inhibitors) effectively blocked endogenous S protein processing at both sites in HeLa cells, and SARS-CoV-2 infection of lung-derived Calu-3 cells was completely prevented by combined inhibitors of furin (BOS) and type II transmembrane serine protease 2 (TMPRSS2) (camostat). Quantitative analyses of cell-to-cell fusion and S protein processing revealed that ACE2 shedding by TMPRSS2 was required for TMPRSS2-mediated enhancement of fusion in the absence of S1/S2 priming. We further demonstrated that the collectrin dimerization domain of ACE2 was essential for the effect of TMPRSS2 on cell-to-cell fusion. Overall, our results indicate that furin and TMPRSS2 act synergistically in viral entry and infectivity, supporting the combination of furin and TMPRSS2 inhibitors as potent antivirals against SARS-CoV-2. IMPORTANCE SARS-CoV-2, the etiological agent of COVID-19, has so far resulted in >6.1 million deaths worldwide. The spike protein (S) of the virus directs infection of the lungs and other tissues by binding the angiotensin-converting enzyme 2 (ACE2) receptor. For effective infection, the S protein is cleaved at two sites: S1/S2 and S2'. Cleavage at S1/S2 induces a conformational change favoring the S protein recognition by ACE2. The S2' cleavage is critical for triggering membrane fusion and virus entry into host cells. Our study highlights the complex dynamics of interaction between the S protein, ACE2, and the host proteases furin and TMPRSS2 during SARS-CoV-2 entry and suggests that the combination of a nontoxic furin inhibitor with a TMPRSS2 inhibitor significantly reduces viral entry in lung cells, as evidenced by an average synergistic ∼95% reduction of viral infection. This represents a powerful novel antiviral approach to reduce viral spread in individuals infected by SARS-CoV-2 or future related coronaviruses.

COVID-19 Positive Versus Negative Complete Kawasaki Disease: A Study from the International Kawasaki Disease Registry.

To determine clinical differences for children with complete Kawasaki disease (KD) with and without evidence of preceding SARS-CoV-2 infection. From January 2020, contemporaneous patients with complete KD criteria were classified as either SARS-CoV-2 positive (KDCOVID+; confirmed household exposure, positive PCR and/or serology) or SARS-CoV-2 negative (KDCOVID-; negative testing and no exposure) and compared. Of 744 patients in the International Kawasaki Disease Registry, 52 were KDCOVID- and 61 were KDCOVID+. KDCOVID+ patients were older (median 5.5 vs. 3.7 years; p < 0.001), and all additionally met diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C). They were more likely to have abdominal pain (60% vs. 35%; p = 0.008) and headache (38% vs. 10%; p < 0.001) and had significantly higher CRP, troponin, and BUN/creatinine, and lower hemoglobin, platelets, and lymphocytes. KDCOVID+ patients were more likely to have shock (41% vs. 6%; p < 0.001), ICU admission (62% vs. 10%; p < 0.001), lower left ventricular ejection fraction (mean lowest LVEF 53% vs. 60%; p < 0.001), and to have received inotropic support (60% vs. 10%; p < 0.001). Both groups received IVIG (2 doses in 22% vs. 18%; p = 0.63), but KDCOVID+ were more likely to have received steroids (85% vs. 35%; p < 0.001) and anakinra (60% vs. 10%; p = 0.002). KDCOVID- patients were more likely to have medium/large coronary artery aneurysms (CAA, 12% vs. 0%; p = 0.01). KDCOVID+ patients differ from KDCOVID-, have more severe disease, and greater evidence of myocardial involvement and cardiovascular dysfunction rather than CAA. These patients may be a distinct KD phenotype in the presence of a prevalent specific trigger.

Cardiac Biomarkers Aid in Differentiation of Kawasaki Disease from Multisystem Inflammatory Syndrome in Children Associated with COVID-19.

Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 show clinical overlap and both lack definitive diagnostic testing, making differentiation challenging. We sought to determine how cardiac biomarkers might differentiate KD from MIS-C. The International Kawasaki Disease Registry enrolled contemporaneous KD and MIS-C pediatric patients from 42 sites from January 2020 through June 2022. The study population included 118 KD patients who met American Heart Association KD criteria and compared them to 946 MIS-C patients who met 2020 Centers for Disease Control and Prevention case definition. All included patients had at least one measurement of amino-terminal prohormone brain natriuretic peptide (NTproBNP) or cardiac troponin I (TnI), and echocardiography. Regression analyses were used to determine associations between cardiac biomarker levels, diagnosis, and cardiac involvement. Higher NTproBNP (≥ 1500 ng/L) and TnI (≥ 20 ng/L) at presentation were associated with MIS-C versus KD with specificity of 77 and 89%, respectively. Higher biomarker levels were associated with shock and intensive care unit admission; higher NTproBNP was associated with longer hospital length of stay. Lower left ventricular ejection fraction, more pronounced for MIS-C, was also associated with higher biomarker levels. Coronary artery involvement was not associated with either biomarker. Higher NTproBNP and TnI levels are suggestive of MIS-C versus KD and may be clinically useful in their differentiation. Consideration might be given to their inclusion in the routine evaluation of both conditions.

Prevalence of prostate cancer in PI-RADS version 2.1 T2-weighted transition zone 'nodule in nodule' and 'homogeneous mildly hypointense area between nodules' criteria: MRI-radical prostatectomy histopathological evaluation.

OBJECTIVES: To evaluate the prevalence of prostate cancer (PCa) of two PI-RADS version (v) 2.1 transition zone (TZ) features (PI-RADS 1 ['nodule in nodule'] and 2 ['homogeneous mildly hypointense area between nodules']). METHODS: With an institutional review board approval, from a 5-year cohort between 2012 and 2017, we retrospectively identified 53 consecutive men with radical prostatectomy (RP) confirmed TZ tumors and MRI. Three blinded radiologists (R1/2/3) independently evaluated T2-weighted and diffusion-weighted imaging (DWI) using PI-RADS v2.1 for the presence of (1) 'nodule in nodule' (recording 'cystic change', inner nodule encapsulation, size, and DWI score) and (2) 'homogeneous mildly hypointense area between nodules' (also recording size and DWI score). MRI-RP maps established ground truth. Primary tumor was evaluated assessing PI-RADS v2.1 category, size, and presence of imaging variants. RESULTS: R1/2/3 identified 26/18/22 'nodule in nodule' respectively with 7.7% (2/26; 95% confidence interval [95% CI]: 0.1-17.9%), 5.6% (1/18; 95% CI: 0.01-16.1%), and 4.5% (1/22; 95% CI: 0.01-13.3%) PCa (both Gleason score 3 + 4 = 7). Agreement was fair-to-substantial, kappa = 0.222-0.696. 'Cystic change', inner nodule absent/incomplete encapsulation and DWI score ≥ 4 for R1/R2/R2 were present in 80.8% (21/26), 46.2% (12/26), 7.7% (2/26); 94.4% (17/18), 33.3% (6/18), 5.6% (1/18); and 59.1% (13/22), 63.6% (14/22), 9.1% (2/22). Both PCa had inner nodule absent/incomplete encapsulation and DWI score ≥ 4. No other TZ tumors demonstrated 'nodule in nodule', nodule 'cystic change', or 'homogeneous mildly hypointense area between nodules'. R1/2/3 identified 5/6/13 'homogeneous mildly hypointense area between nodules' with zero PCa for any reader (upper bound 95% CI: 24.7-52.2%). Interobserver agreement was fair-to-substantial, kappa = 0.104-0.779. CONCLUSION: The proportion of cancers in PI-RADS v2.1 'nodule in nodule' was low (~5-8%) with zero cancers detected in 'homogeneous mildly hypointense area between nodules'. When 'nodule in nodule' inner nodule shows absent or incomplete encapsulation with marked restricted diffusion, PCa may be considered; however, this warrants further studies. KEY POINTS: • The prevalence of clinically significant prostate cancers in PI-RADS v2.1 'nodule in nodule' was low (5-8%, 95% CI: 0.1-17.9%). • Clinically significant prostate cancer was only detected in the 'nodule in nodule' variant when the inner nodule showed absent or incomplete encapsulation ('atypical nodule') with marked restricted diffusion. • 'Homogeneous mildly hypointense area between nodules' is likely benign with no cancers identified in the current study, however, with a wide 95% CI due to low prevalence.

Identification of cell-free DNA methylation patterns unique to the human left ventricle as a potential indicator of acute cellular rejection.

Increased levels of donor-derived cell-free DNA (dd-cfDNA) in recipient plasma have been associated with rejection after transplantation. DNA sequence differences have been used to distinguish between donor and recipient, but epigenetic differences could also potentially identify dd-cfDNA. This pilot study aimed to identify ventricle-specific differentially methylated regions of DNA (DMRs) that could be detected in cfDNA. We identified 24 ventricle-specific DMRs and chose two for further study, one on chromosome 9 and one on chromosome 12. The specificity of both DMRs for the left ventricle was confirmed using genomic DNA from multiple human tissues. Serial matched samples of myocardium (n = 33) and plasma (n = 24) were collected from stable adult heart transplant recipients undergoing routine endomyocardial biopsy for rejection surveillance. Plasma DMR levels increased with biopsy-proven rejection grade for individual patients. Mean cellular apoptosis in biopsy samples increased significantly with rejection severity (2.4%, 4.4% and 10.0% for ACR 0R, 1R, and 2R, respectively) but did not show a consistent relationship with DMR levels. We identified multiple DNA methylation patterns unique to the human ventricle and conclude that epigenetic differences in cfDNA populations represent a promising alternative strategy for the non-invasive detection of rejection.

Comparison Between Currently Recommended Long-Term Medical Management of Coronary Artery Aneurysms After Kawasaki Disease and Actual Reported Management in the Last Two Decades.

In the 2017 American Heart Association (AHA) Kawasaki disease (KD) guidelines, risk levels (RLs) for long-term management are defined by both maximal and current coronary artery (CA) dimensions normalized as z-scores. We sought to determine the degree to which current recommended practice differs from past actual practice, highlighting areas for knowledge translation efforts. The International KD Registry (IKDR) included 1651 patients with CA aneurysms (z-score > 2.5) from 1999 to 2016. Patients were classified by AHA RL using maximum CA z-score (RL 3 = small, RL 4 = medium, RL 5 = large/giant) and subcategorized based on decreases over time. Medical management provided was compared to recommendations. Low-dose acetylsalicylic acid (ASA) use ranged from 86 (RL 3.1) to 95% (RL 5.1) for RLs where use was "indicated." Dual antiplatelet therapy (ASA + clopidogrel) use ranged from 16% for RL 5.2 to 9% for RL 5.4. Recommended anticoagulation (warfarin or low molecular weight heparin) use was 65% for RL 5.1, while 12% were on triple therapy (anticoagulation + dual antiplatelet). Optional statin use ranged from 2 to 8% depending on RL. Optional beta-blocker use was 2-25% for RL 5, and 0-5% for RLs 3 and 4 where it is not recommended. Generally, past practice was consistent with the latest AHA guidelines, taking into account the flexible wording of recommendations based on the limited evidence, as well as unmeasured patient-specific factors. In addition to strengthening the overall evidence base, knowledge translation efforts may be needed to address variation in thromboprophylaxis management.

Rationale and Design of the FREQUENCY Study: The Fetal Cardiac Registry of Québec to Improve Resource Utilization in Fetal Cardiology.

OBJECTIVE: Prenatal detection of congenital heart diseases (CHD) decreases morbidity and cost. To improve detections rates, most physicians refer pregnant women with high-risk pregnancies to fetal cardiologists even when there is no suspicion of CHD at the second trimester screening. This paper presents the rationale and detailed method of the Fetal Cardiac Registry of Québec to Improve Resource Utilization in Fetal Cardiology (FREQUENCY) study. The overall objective is to assess the impact of second trimester ultrasound screening (U/S) and referral pattern in fetal cardiology on detection rates, health care costs, and resource utilization, as well as perinatal morbidity and mortality. METHODS: This multicentre retrospective population-based cohort study will link fetal echocardiography data from all centres performing fetal echocardiography in Québec with administrative health care data. This data linking will allow the determination of a true denominator (all women in Québec who underwent second trimester U/S) with complete follow-up of up to 2 years for offspring. This protocol meets Canadian Task Force Classification II-2. RESULTS: The study investigators have collected and cleaned fetal echocardiography data for 24 259 eligible pregnancies referred to fetal cardiology. These data will be matched to approximately 860 000 pregnancies between 2007 and 2015. CONCLUSION: The results of the FREQUENCY study will shed light on the impact of the current prenatal CHD screening strategy in Canada.

Determination of peak cardiorespiratory fitness parameters in children: which averaging method should we use?

The purpose of this study was to identify which averaging methods most accurately measures peak cardiorespiratory fitness (CRF) parameters [peak O2 uptake (VO2), peak O2pulse and peak respiratory exchange ratio (RER)] in a sample of healthy children and adolescents. In this cross-sectional multicenter study, we recruited 278 healthy children aged 12-17 years. We compared the mean peak value of three CRF parameters using the recommended averaging methods (30-second block average) with alternative averaging methods such as moving averages or shorter smoothing periods. We also assessed averaging methods for accuracy by individually reviewing breath-by-breath scatter plots. The 30-second block average method resulted in a lower mean peak VO2 and in an increased proportion of underestimated peak values. Using a 30-second moving average significantly increased mean peak values which increased accuracy. Similar results were found for peak RER and peak O2pulse. In conclusion, the currently recommended averaging method (30-second block average) increased the risk of misinterpretation of peak CRF values in children. Using a moving average approach decreased misinterpretation and increased accuracy.

Growth of Cardiovascular Structures from the Fetus to the Young Adult.

The size, hemodynamics, and function of cardiovascular structures change dramatically from the early fetal life to late adolescence. The principal determinants of cardiovascular dimensions are related to the blood flow needed to meet metabolic demands. This demand is in turn tightly related to body size and body composition, keeping in mind that various tissues may have different metabolic rates. There is no simple model that links cardiac dimensions with a single body size measurement. Consequently, despite abundant scientific literature, few studies have proposed pediatric reference values that efficiently and completely account for the effect of body size. Other factors influence cardiovascular size and function in children, including sex. The influence of sex is multifactorial and not fully understood, but differences in body size and body composition play an important role. We will first review the determinants of cardiovascular size and function in children. We then explore the evaluation and normalization of cardiovascular size and function in pediatric cardiology in relation to the growth of cardiovascular structures during childhood, with a particular focus on sex differences.

The Role of Cardiopulmonary Exercise Testing for Decision Making in Patients with Repaired Tetralogy of Fallot.

Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. As a result of the surgical strategies employed at the time of initial repair, chronic pulmonary regurgitation (PR) is prevalent in this population. Despite sustained research efforts, patient selection and timing of pulmonary valve replacement (PVR) to address PR in young asymptomatic patients with repaired tetralogy of Fallot (rToF) remain a fundamental but as yet unanswered question in the field of congenital heart disease. The ability of the heart to compensate for the chronic volume overload imposed by PR is critical in the evaluation of the risks and benefits of PVR. The difficulty in clarifying the functional impact of PR on the cardiovascular capacity may be in part responsible for the uncertainty surrounding the timing of PVR. Cardiopulmonary exercise testing (CPET) may be used to assess abnormal cardiovascular response to increased physiologic demands. However, its use as a tool for risk stratification in asymptomatic adolescents and young adults with rToF is still ill-defined. In this paper, we review the role of CPET as a potentially valuable adjunct to current risk stratification strategies with a focus on asymptomatic rToF adolescents and young adults being considered for PVR. The role of maximal and submaximal exercise measurements to identify young patients with a decreased or borderline low peak VO2 resulting from impaired ventricular function is explored. Current knowledge gaps and research perspectives are highlighted.

Aortic dilatation in patients with Turner's syndrome without structural cardiac anomaly.

INTRODUCTION: Dilatation of the ascending aorta is described in Turner's syndrome with variable prevalence (6.8-32%). Reported series typically include patients with associated cardiac anomalies. OBJECTIVE: To characterise the prevalence, age of onset, and the progress of dilatation of the ascending aorta in Turner's syndrome patients free of structural cardiac anomalies. Potential risk factors such as karyotype and growth hormone therapy were analysed for correlation with aortic dilatation. METHODS: We carried out a retrospective study with data collected from medical records and echocardiography studies. Patients with Tuner's syndrome followed-up between 1992 and 2010 with at least two echocardiography studies were eligible. Patients with previous cardiac surgery or under anti-hypertensive medication were excluded. Ascending aorta diameter measurements were adjusted for body surface area, and dilatation was defined as Z-score>2. RESULTS: The study population consisted of 44 patients, aged 11.9±7.4 years at the first echocardiogram and 17.9±7.3 years at the last follow-up, with a follow-up duration of 6.0±3.7 years. A total of 13 (29.5%) patients exhibited aortic dilatation during follow-up, suggesting an actuarial estimate of the freedom from aortic dilatation dropping from 86 to 70% and then to 37% at 10, 20, and 30 years of age, respectively. There was no statistically significant impact of karyotype or growth hormone therapy on aortic Z-score progression. CONCLUSION: The prevalence of dilatation of the ascending aorta in Turner's syndrome patients free of structural aortic anomalies is comparable with published data with associated lesions. Growth hormone therapy and karyotype had no significant impact; however, longitudinal follow-up is warranted.

Bias related to body mass index in pediatric echocardiographic Z scores.

In pediatric echocardiography, cardiac dimensions are often normalized for weight, height, or body surface area (BSA). The combined influence of height and weight on cardiac size is complex and likely varies with age. We hypothesized that increasing weight for height, as represented by body mass index (BMI) adjusted for age, is poorly accounted for in Z scores normalized for weight, height, or BSA. We aimed to evaluate whether a bias related to BMI was introduced when proximal aorta diameter Z scores are derived from bivariate models (only one normalizing variable), and whether such a bias was reduced when multivariable models are used. We analyzed 1,422 echocardiograms read as normal in children ≤18 years. We computed Z scores of the proximal aorta using allometric, polynomial, and multivariable models with four body size variables. We then assessed the level of residual association of Z scores and BMI adjusted for age and sex. In children ≥6 years, we found a significant residual linear association with BMI-for-age and Z scores for most regression models. Only a multivariable model including weight and height as independent predictors produced a Z score free of linear association with BMI. We concluded that a bias related to BMI was present in Z scores of proximal aorta diameter when normalization was done using bivariate models, regardless of the regression model or the normalizing variable. The use of multivariable models with weight and height as independent predictors should be explored to reduce this potential pitfall when pediatric echocardiography reference values are evaluated.

A Systematic Review of Reference Values in Pediatric Cardiopulmonary Exercise Testing.

Cardiopulmonary exercise testing (CPET) is used for the diagnosis and prognosis of cardiovascular and pulmonary conditions in children and adolescents. Several authors have published reference values for pediatric CPET, but evaluation of their validity is lacking. The aim of this study was to review pediatric CPET references values published between 1980 and 2014. We specifically assessed the adequacy of the normalization methods used to adjust for body size. Articles that proposed references values were reviewed. We abstracted information on exercise protocols, CPET measurements and normalization methods. We then evaluated the studies' methodological quality and assessed them for potential biases. Thirty-four studies were included. We found important heterogeneity in the choice of exercise protocols and in the approach to adjustment for body size or other relevant confounding factors. Adjustment for body size was principally done using linear regression for age or weight. Assessment of potential biases (residual association, heteroscedasticity and departure from the normal distribution) was mentioned in only a minority of studies. Our study shows that contemporary pediatric reference values for CPET have been developed based on heterogeneous exercise protocols and variable normalization strategies. Furthermore, assessment of potential bias has been inconsistent and insufficiently described. High-quality reference values with adequate adjustment for confounding variables are needed in order to optimize CPET's specificity and sensitivity to detect abnormal cardiopulmonary response to exercise.

Cardiovascular Response to Exercise Testing in Children and Adolescents Late After Kawasaki Disease According to Coronary Condition Upon Onset.

Multiple cardiovascular sequelae have been reported late after Kawasaki disease (KD), especially in patients with coronary artery lesions. In this perspective, we hypothesized that exercise response was altered after KD in patients with coronary aneurysms (CAA-KD) compared to those without history of coronary aneurysms (NS-KD). This study is a post hoc analysis of exercise data from an international multicenter trial. A group of 133 CAA-KD subjects was compared to a group of 117 NS-KD subjects. Subjects underwent a Bruce treadmill test followed to maximal exertion. Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were assessed at each stage of the test including recovery. Myocardial perfusion was evaluated by stress and rest Tc-99m sestamibi SPECT imaging. Endurance time was similar between NS-KD and CAA-KD (11.3 ± 2.6 vs. 11.0 ± 2.6 min; p = 0.343). HR, SBP, and DBP responses to exercise were similar between groups (p = 0.075-0.942). Myocardial perfusion defects were present in 16.5 % CAA-KD versus 22.2 % NS-KD (p = 0.255). Analysis based on myocardial perfusion status identified a lower heart rate at 1 min into recovery as well as lower DBP at 1 and 5 min into recovery in patients with abnormal SPECT imaging (p = 0.017-0.042). Compared to patients without CA involvement, the presence of coronary aneurysms at the subacute phase of KD does not induce a differential effect on exercise parameters. In contrast, exercise-induced myocardial perfusion defect late after the onset of KD correlates with abnormal recovery parameters.

Aggresome formation by the adenoviral protein E1B55K is not conserved among adenovirus species and is not required for efficient degradation of nuclear substrates.

Much of the work on the basic molecular biology of human adenoviruses has been carried out on a very limited number of the more than 60 serotypes, primarily the highly related species C viruses adenovirus type 5 (Ad5) and Ad2 and, to some extent, Ad12 of species A. Until recently, it has been widely assumed that insights obtained with these model viruses were representative of all human adenoviruses. Recent studies on the E3 ubiquitin ligase formed by the viral E1B55K and E4orf6 proteins with a cellular Cullin-based complex indicated that although all species form such a functional complex, significant variations exist in terms of complex composition and the substrates that are degraded. In the present report we conducted a comprehensive analysis of the localization of E1B55K products from representatives of six of the seven adenovirus species in the presence and the absence of the corresponding E4orf6 protein. We found that although in some species E1B55K localized in aggresomes, such was not always the case, suggesting that these structures are not necessary for the efficient degradation of substrates. In addition, differences were evident in the localization of E1B55K, although all forms readily associated with PML. Finally, Ad5 E1B55K was seen to localize in close proximity to Rab11, a marker for the endosomal recycling compartment, and both focused at the microtubule organizing center. These findings suggest that E1B55K from some species may employ the transport system utilized by the membrane recycling pathway to assemble aggresomes and the possibility that this structure might then affect recycling of cell surface components.

Determinants and Clinical Outcomes of Patients With Tetralogy of Fallot Lost to Cardiology Follow-up.

BACKGROUND: Various rates of loss to follow-up (LTFU) have been reported in patients with congenital heart disease, but return to follow-up is rarely considered in those analyses. Outcomes of LTFU patients are difficult to assess because the patients no longer attend cardiac care. We leveraged data from the TRIVIA cohort, which combines more than 30 years of clinical and administrative data, allowing us to study outcomes even after LTFU. METHODS: This population-based cohort included 904 patients with tetralogy of Fallot (TOF) born from 1982 to 2015 in Québec, Canada. Risk factors for LTFU and outcomes were calculated by Cox models and marginal means/rates models. Outcomes of LTFU patients were compared with propensity score-matched non-LTFU patients. RESULTS: The cumulative risk of experiencing 1 episode of LTFU was 50.3% at 30 years. However, return to follow-up was frequent and the proportion of patients actively followed was 85.9% at 10 years, 76.4% at 20 years, and 70.6% at 30 years. Factors associated with a reduced risk of LTFU were primary repair with conduit (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.15-0.58) and transannular patch (HR 0.60, 95% CI 0.46-0.79). LTFU patients had lower rates of cardiac hospitalisations (HR 0.49, 95% CI 0.42-0.56) and cardiac interventions (HR 0.32, 95% CI 0.25-0.42), but similar rates of cardiac mortality (HR 0.95, 95% CI 0.24-3.80). CONCLUSIONS: There was a lower proportion of LTFU patients compared with previous studies. Factors associated with lower rates of LTFU were conduits and non-valve-sparing surgery. LTFU patients had lower rates of cardiac procedures and cardiac hospitalisations.

Outcomes After Pediatric Pulmonary Valve Replacement in Patients With Tetralogy of Fallot.

BACKGROUND: People with tetralogy of Fallot might require a transannular patch during primary repair, which leads to pulmonary valve regurgitation. Pulmonary valve replacement (PVR) is performed to prevent complications of chronic pulmonary regurgitation, but the optimal timing of PVR remains a matter of debate. In this study we aimed to assess the association of PVR performed in children younger than 18 years of age with the rate of hospitalizations, interventions, and mortality. METHODS: This was a retrospective observational cohort of people with tetralogy of Fallot born in Québec between 1982 and 2015, using a combination of clinical and administrative data. Marginal means and rates models and survival curves were used to compare outcomes of patients with pediatric PVR (younger than 18 years) and those without. Outcomes of interest were rates of cardiac hospitalizations, all-cause hospitalizations, cardiac interventions, and mortality. Groups were balanced using models weighed on the inverse probability of receiving pediatric PVR. RESULTS: Of the 316 eligible patients, 58 (18.4%) received a pediatric PVR. Compared with patients who did not receive pediatric PVR, they were at increased risk of cardiac hospitalizations, although the rates of cardiac hospitalization were low: 0.50 vs 0.09 hospitalizations per 20 years (hazard ratio [HR] = 4.71 [95% confidence interval (CI), 2.22-9.96]). Patients who received a pediatric PVR had a comparable risk of all-cause hospitalizations (HR = 0.95 [95% CI, 0.71-1.26]) and of cardiac interventions (HR = 1.13 [95% CI, 0.72-1.77]). CONCLUSIONS: Patients who underwent pediatric PVR had higher rates of cardiac hospitalizations, but similar rates of all-cause hospitalizations, cardiac procedures, and mortality. In this observational cohort, pediatric PVR was not associated with an improved outcome.

Meta-Analysis of Risk Factors for Congenital Heart Disease: Part 2, Maternal Medication, Reproductive Technologies, and Familial and Fetal Factors.

BACKGROUND: The quantitative effects of congenital heart disease (CHD) risk factors are not fully understood. We conducted a meta-analysis of all CHD risk factors. This report explores maternal medication, assisted reproductive technologies (ART), and familial and fetal factors. METHODS: Relevant studies were identified using a search strategy encompassing the concepts of CHD and prenatal risk factors with the following inclusion criteria: (1) peer-reviewed articles, (2) quantifying the effects of CHD risk factors, and (3) between 1989 and 2022. Pooled odds ratios (OR) and 95% confidence intervals (CIs) were calculated using a random effect model. RESULTS: There were 131 articles that met the inclusion criteria. Associations were found between CHDs and extracardiac anomalies (OR, 3.41; 95% CI, 1.72-6.77), increased nuchal translucency (OR, 6.87; 95% CI, 2.42-19.53), family history of CHD (OR, 2.90; 95% CI, 2.25-3.75), maternal antidepressants (OR, 1.23; 95% CI, 1.09-1.38), and antihypertensives (OR, 2.07; 95% CI, 1.80-2.38). A positive association was observed between severe CHDs and lithium, but with a very wide CI encompassing the null effect. A positive association was observed between severe CHDs and ARTs (OR, 1.98; 95% CI, 1.30-3.02). The data were insufficient for anomalies of the umbilical cord, anticonvulsants, and retinoid medication. CONCLUSIONS: There were strong associations among CHDs and increased nuchal translucency, extracardiac anomalies, and family history of CHD. Effect sizes were modest for maternal medication and ART. Data were scarce and sometimes inconclusive for some risk factors commonly cited as being associated with CHD such as lithium, anomalies of the umbilical cord, anticonvulsants, and retinoid medication.