Background Adults with congenital heart disease (CHD) experience earlier and higher cardiovascular morbidity and mortality than the general population. Serious illness conversations (SICs) can help align care with patients’ values and preferences but are underused, partly because clinicians lack guidance on when to initiate them. Objectives This study aimed to develop consensus-based clinical criteria that should prompt SICs in adults with CHD, incorporating perspectives from clinical experts, people with lived experience (PWLE), and advocacy group representatives. Methods In a modified Delphi study, an international panel of 39 health care professionals rated 67 potential SIC trigger criteria over 3 rounds. Consensus was predefined as ≥70% agreement. A second panel of 4 PWLEs and 4 advocacy group representatives rated the Round 1 consensus triggers for appropriateness. Triggers deemed sufficient on their own were labeled as “major,” those requiring at least one additional criterion were labeled as “minor.” Results Forty-one clinical experts were invited, of which 39 agreed to participate. Response rates were 94.9% in Rounds 1 and 2, and 92.3% in Round 3. Fifty of 67 criteria (74.6%) reached consensus in Round 1, and all were judged appropriate by PWLE and advocacy group representatives. Eighteen criteria were classified as major, spanning “patient needs,” “CHD-defect characteristics,” “lifetime events,” “preintervention” triggers, “disease progression,” and the surprise question. Conclusions This international consensus identified 18 major trigger criteria to support timely SIC initiation in adults with CHD. These criteria span diverse clinical scenarios and provide a practical framework for integrating SICs into routine care for adults with CHD.

Purpose: Vascular Ehlers-Danlos syndrome (vEDS) is a rare and aggressive heritable aortic disease caused by pathogenic variants in COL3A1 gene, characterized by spontaneous arterial dissection and organ rupture. The purpose of this study is to evaluate ventricular size and function and to explore their associations with complications in vEDS. Methods: Adults with genetically confirmed vEDS who underwent clinical cardiac MRI were retrospectively compared with controls matched for age and sex. Cardiac MRI analysis included assessment of ventricular volumetry and arterial vasculature. vEDS-related complications were evaluated including dissection, aneurysm, and pneumothorax. Multivariable logistic regression was performed. Results: We studied 26 individuals with vEDS (38.6 ± 15.6 years, 50.0% female) and 26 healthy controls. Median clinical follow-up was 2.4 (1.1-3.6) years. Left and right ventricular ejection fractions were lower in vEDS compared with controls (LVEF 58 ± 6% vs 61 ± 4%, P = .03; RVEF 54 ± 5% vs 58 ± 4%, P = .03). After controlling for age, sex, and antihypertensive medication, LV end-diastolic volume indexed to body surface area (LVEDVi) predicted dissections (OR 1.1, 95% CI 1.01-1.2, P = .04) and aneurysms (OR 1.1, 95% CI 1.01-1.3, P = .03). Indexed LV end systolic volume (LVESVi) also predicted aneurysms (OR 1.2, 95% CI 1.03-1.5, P = .02). LVEF predicted the presence of any complication (OR 0.71, 95% CI 0.52-0.99, P = .04). Pneumothorax occurred exclusively in vEDS group among those with LVEF <58% (below the mean), 50.0% versus 0.0%, P = .02. Those with LVEF <58% had more frequent dissection and/or aneurysm (75.0% vs 12.5%, P = .04). Conclusion: Lower LVEF and larger cardiac size are associated with complications in vEDS.

Background This study aimed to ascertain socioeconomic factors affecting successful transfer to adult congenital cardiology and cardiac surgical services in Ontario. Methods Patients with congenital heart disease (CHD) referred from a pediatric CHD program to an adult CHD (ACHD) center between January 1, 2004, and December 31, 2015, were identified. The prevalence of (1) failed transfer (FT), (2) lost to follow-up (LTFU), and (3) cardiac surgery (CS) during the extended study period of 2004-2018 was investigated. Socioeconomic variables associated with FT, LTFU, and CS were explored using Environics data associated with postal code at the time of transfer. Results A total of 2196 patients were referred from the pediatric to ACHD center between 2004 and 2015. Within this cohort, 11% had FT and 25% had LTFU; there was a 2% overlap between the FT and LTFU groups. A total of 106 patients (4.8%) underwent CS. Age at referral (odds ratio [OR]: 0.591, P < 0.001) and being unable to travel to work by car (OR: 0.986, P < 0.001) were both associated with FT, though the latter is not clinically relevant. Residential addresses with lower income (OR: 0.976, P = 0.016) were associated with LTFU. Factors associated with CS were higher household income (P < 0.001), access to a car for travel to work (P < 0.001), Canadian citizenship (P = 0.041), and French or English as the primary language in the home (P = 0.038). Conclusions Socioeconomic factors are associated with access to specialized ACHD services among young adults. Strategies to ensure equity in care should be explored.

Background:Adults with congenital heart disease (CHD) face increased risks of premature morbidity and mortality. Advance care planning (ACP) facilitates longitudinal, patient-centered care but remains underused in this population, partly due to the lack of validated trigger criteria to initiate ACP. This study aimed to systematically review the literature to identify proposed triggers to initiate ACP conversations in adults with CHD. Methods:We conducted a systematic search of MEDLINE, Embase, PsycInfo, CINAHL, Web of Science, Scopus, and the Cochrane Library from database inception to July 26, 2024. The search focused on 2 core concepts: CHD and adults, and ACP or palliative care. Two reviewers independently screened articles for inclusion and extracted potential trigger criteria for ACP initiation. Results:Of 4257 articles screened, 21 were included for data extraction. Nearly half (48%) were published between 2020 and 2024, with most (81%) appearing in cardiology journals. ACP was most often recommended during routine follow-up (15 articles, 71%), independent of defect complexity or functional status. Specific interventions (10 articles, 48%) and signs of disease progression (10 articles, 48%) were the second most frequently cited trigger criteria, followed by defect-specific triggers (7 articles, 33%). Symptom- and patient-based triggers were less frequently reported. Conclusions:This review highlights a wide range of proposed triggers and a lack of consensus on when to initiate ACP in adults with CHD. The identified triggers can inform clinical practice and serve as a foundation for developing standardized criteria. However, findings are limited by the heterogeneity among the included studies. Registration:PROSPERO CRD42024597771.

BACKGROUND:Pregnancy in women with a Fontan circulation carries increased risk. Given the relative evidence void, pregnancy counseling requires considerable nuance and experience. OBJECTIVES:This study aimed to identify risk factors for maternal and fetal complications and to contrast risk estimates obtained from existing risk stratification tools, including the modified WHO, CARPREG II, and ZAHARA risk scores. METHODS:Pregnant women (>20 weeks of gestation) with a Fontan circulation were retrospectively included from 13 international centers. Univariate and multivariable analyses identified predictors of complications, and the performance of risk stratification tools was assessed. RESULTS:From 2006 to 2018, 84 women with Fontan physiology had 108 pregnancies, and form the basis of this investigation. Maternal cardiovascular complications occurred in 32 (30%) of all pregnancies including Fontan circulatory failure (17%), supraventricular tachycardia (7.4%), and thromboembolic events (3.7%). No maternal deaths occurred. Premature birth constituted 68% of neonatal complications, with a fetal and neonatal mortality of 13%. Multivariable analysis linked adverse maternal outcomes to pre-pregnancy oxygen saturation (adjusted OR 0.77; 95%CI 0.61-0.96; p=0.02). None of the risk models showed good discriminative ability. The modified WHO classification was the only risk model significantly associated with adverse fetal outcomes. CONCLUSIONS:Pregnancy in women with Fontan circulation poses a significant cardiovascular risk for the mother and a high burden of fetal and neonatal complications. The existing predictive risk stratification models do not discriminate hazard between well-functioning patients with Fontan from those with additional hemodynamic burden. This underscores the necessity for large-scale studies to refine risk stratification.

Background Patients with complex congenital heart disease unfit for biventricular repair are often palliated with Fontan circulation (FC), which obviates the need for a subpulmonary ventricle. This approach has led to high survival rates, with over 80% of patients expected to live beyond 30 years. Despite increasing patient numbers and existing guidelines, there are no standardized hemodynamic parameters defining Fontan failure, resulting in considerable variability in management practices. This pilot project aimed to assess real-world practices in FC patient management, particularly in surveillance, defining Fontan circulatory failure, and determining treatment thresholds. Methods A cross-sectional survey with 10 multiple-choice questions and optional free-form responses was distributed globally to congenital heart disease cardiologists through 2 academic centers. Conducted from January to December 2021, the survey targeted clinicians managing adult FC patients. Results Of 310 invited cardiologists, 170 (55%) participated, including 27% from the United States, 22% from Canada, and 20% from the United Kingdom. Respondents included pediatric (37%), adult congenital (47%), and dual trained adult/pediatric cardiologists (14%), mostly in academic settings (94%). Variability existed in defining FC failure, with markers such as protein-losing enteropathy (74%), fatigue/dyspnea (62%), and elevated Fontan pressure (58%) commonly cited. Responses differed on defining elevated Fontan pressure, with 53% selecting >15 mm Hg, 33% >18 mm Hg, and 14% >20 mm Hg. Ninety-one percent prescribed pulmonary vasodilators, though indications and thresholds varied. Conclusion Substantial heterogeneity in FC patient management currently exists, underscoring the need for standardized hemodynamic parameters.

ObjectiveMachine learning (ML) can facilitate prediction of major adverse cardiovascular events (MACEs) in repaired tetralogy of Fallot (rTOF). We sought to determine the incremental value of ML above expert clinical judgement for risk prediction in rTOF.MethodsAdult congenital heart disease (ACHD) clinicians (≥10 years of experience) participated (one cardiac surgeon and four cardiologists (two paediatric and two adult cardiology trained) with expertise in heart failure (HF), electrophysiology, imaging and intervention). Clinicians identified 10 high-yield variables for 5-year MACE prediction (defined as a composite of mortality, resuscitated sudden death, sustained ventricular tachycardia and HF). Risk for MACE (low, moderate or high) was assigned by clinicians blinded to outcome for adults with rTOF identified from an institutional database (n=25 patient reviews conducted by five independent observers). A validated ML model identified 10 variables for risk prediction in the same population.ResultsPrediction by ML was similar to the aggregate score of all experts (area under the curve (AUC) 0.85 (95% CI 0.58 to 0.96) vs 0.92 (0.72 to 0.98), p=0.315). Experts with ≥20 years of experience had superior discriminative capacity compared with <20 years (AUC 0.98 (95% CI 0.86 to 0.99) vs 0.80 (0.56 to 0.93), p=0.027). In those with <20 years of experience, ML provided incremental value such that the combined (clinical+ML) AUC approached ≥20 years (AUC 0.85 (95% CI 0.61 to 0.95), p=0.055).ConclusionsRobust prediction of 5-year MACE in rTOF was achieved using either ML or a multidisciplinary team of ACHD experts. Risk prediction of some clinicians was enhanced by incorporation of ML suggesting that there may be incremental value for ML in select circumstances.

Background:Successful catheter ablation of ventricular tachycardia (VT) in repaired tetralogy of Fallot (TOF) can be achieved by targeting 1 or more anatomical isthmuses. However, significant interindividual variability in the size and location of surgical patches means careful mapping is required to design ablation lines to block the isthmus. Intracardiac echocardiography (ICE) may assist ablation by accurate identification of individual TOF anatomy. Objectives:The authors hypothesized ICE-guided VT ablation improved isthmus recognition, ablation, and procedural outcomes. Methods:Retrospective study of adults with repaired TOF undergoing VT ablation between January 1, 2017 and December 31, 2022. ICE integration was compared to a strategy using electroanatomical mapping only to identify anatomic boundaries. All cases underwent ablation and had proven isthmus block as the procedural endpoint. Results:Twenty-three patients (age 47 ± 14 years; 61% male) underwent 27 VT ablations (ICE: 16/27 [59%]; no ICE: 11/27 [41%]). ICE improved the ability to localize and ablate the anatomical isthmus (ICE: 13/15 [87%] vs no ICE: 4/11 [36%]; P = 0.014); however, there was no difference in long-term freedom from VT (ICE: 9/12 [75%] vs no ICE: 8/11 [73%]; P = 0.901). ICE had no impact on procedural times (ICE: 173 ± 48 minutes vs no ICE: 157 ± 47 minutes; P = 0.399), fluoroscopy time (ICE: 30 ± 16 minutes vs no ICE: 29 ± 10 minutes; P = 0.864), or major complications (ICE: 1/16 [6%] vs no ICE 0/11; P = 1.000). Conclusions:ICE improves ablation of the anatomical isthmus for sustaining VT in patients with repaired TOF by demonstrating the individual anatomy but does not improve long-term outcomes.

BACKGROUND:Cardiomyopathy is a clinically and genetically heterogeneous heart condition that can lead to heart failure and sudden cardiac death in childhood. While it has a strong genetic basis, the genetic aetiology for over 50% of cardiomyopathy cases remains unknown. METHODS:In this study, we analyse the characteristics of tandem repeats from genome sequence data of unrelated individuals diagnosed with cardiomyopathy from Canada and the United Kingdom (n = 1216) and compare them to those found in the general population. We perform burden analysis to identify genomic and epigenomic features that are impacted by rare tandem repeat expansions (TREs), and enrichment analysis to identify functional pathways that are involved in the TRE-associated genes in cardiomyopathy. We use Oxford Nanopore targeted long-read sequencing to validate repeat size and methylation status of one of the most recurrent TREs. We also compare the TRE-associated genes to those that are dysregulated in the heart tissues of individuals with cardiomyopathy. FINDINGS:We demonstrate that tandem repeats that are rarely expanded in the general population are predominantly expanded in cardiomyopathy. We find that rare TREs are disproportionately present in constrained genes near transcriptional start sites, have high GC content, and frequently overlap active enhancer H3K27ac marks, where expansion-related DNA methylation may reduce gene expression. We demonstrate the gene silencing effect of expanded CGG tandem repeats in DIP2B through promoter hypermethylation. We show that the enhancer-associated loci are found in genes that are highly expressed in human cardiomyocytes and are differentially expressed in the left ventricle of the heart in individuals with cardiomyopathy. INTERPRETATION:Our findings highlight the underrecognized contribution of rare tandem repeat expansions to the risk of cardiomyopathy and suggest that rare TREs contribute to ∼4% of cardiomyopathy risk. FUNDING:Government of Ontario (RKCY), The Canadian Institutes of Health Research PJT 175329 (RKCY), The Azrieli Foundation (RKCY), SickKids Catalyst Scholar in Genetics (RKCY), The University of Toronto McLaughlin Centre (RKCY, SM), Ted Rogers Centre for Heart Research (SM), Data Sciences Institute at the University of Toronto (SM), The Canadian Institutes of Health Research PJT 175034 (SM), The Canadian Institutes of Health Research ENP 161429 under the frame of ERA PerMed (SM, RL), Heart and Stroke Foundation of Ontario & Robert M Freedom Chair in Cardiovascular Science (SM), Bitove Family Professorship of Adult Congenital Heart Disease (EO), Canada Foundation for Innovation (SWS, JR), Canada Research Chair (PS), Genome Canada (PS, JR), The Canadian Institutes of Health Research (PS).

OBJECTIVE:There is a high burden of reintervention after repair of tetralogy of Fallot (TOF). We compare procedural burden and late outcomes in valve-sparing repair (VSR) and transannular patch (TAP) cohorts over 30 years. METHODS:Patients undergoing TOF repair (1990-2021, excluding complex TOF) were included in this study (n = 1239) with subsequent comparisons between TAP (n = 550) and VSR (n = 648) cohorts. Descriptive statistics, cumulative incidence frequencies, survival analysis, and propensity matching (n = 425) were used to analyze reintervention burden and survival. RESULTS:Overall survival of the cohort was 96.7% at 15 years and 95.6% at 25 years, with similar survival between TAP and VSR cohorts (P = .22). The TAP cohort had increased incidence of procedural burden at 25 years (TAP 69.8% vs VSR 37.2%; P < .001), with 34.6% undergoing ≥2 reinterventions. The TAP cohort had higher incidence of surgical pulmonary valve replacement at 15 years (TAP 20.7% vs VSR 7.6%; P < .001) and placement of pulmonary artery stents (TAP 20.2% vs VSR 4.9%; P < .001). By contrast, VSR had higher incidence of right ventricular outflow tract (RVOT) reoperation at 15 years (VSR 7.3% vs TAP 3.6%; P = .047). After propensity score matching there was no survival advantage between the VSR and TAP cohorts (Era 2), whereas the need for RVOT reoperation was not different between the 2 cohorts (P = .060). CONCLUSIONS:The procedural burden remains high following TOF repair. TAP is associated with higher procedural burden in matched and nonmatched cohorts. VSR has increased risk of reoperation for RVOT obstruction only in nonmatched comparisons. Anatomical complexity and surgical repair strategy influence procedural burden following TOF repair.

Objective This study aimed to ascertain socioeconomic factors affecting access to young adult congenital heart disease (ACHD) cardiac surgical services in Ontario. Design and method The ACHD center identified 468 congenital cardiac surgery patients were 18-33 years between 2004- 2019. Of the 468, 259 had their 18th birthday between January 1st 1986 and December 31st 1998.Of the 259, 119 were part a referral cohort of patients with complex congenital heart disease (CHD) referred specifically to the reference ACHD center from 2004-2016, from the adjacent pediatric congenital cardiac surgery program that included an electronic transfer of pediatric records with a 3 year follow up to assess successful transfer to adult care. Of the 259, The remaining 140 patients were initially from the adjacent pediatric institution and were referred elsewhere at 18 years (N=53, 20.4%) for follow up or were lost to follow prior to the age of 18 years (N=6, 23%) , were from another pediatric program elsewhere in Canada(N=22, 8.5%) or had pediatric care elsewhere in the world and were new Canadians (n=24, 9.3%) , or newly diagnosed as an adult with CHD (N=39, 151%).The 259 patients with their 18th birthday between January 1st 1986 and December 31st 1998 were analyzed on socioeconomic variables associated with their home address. Clinical characteristics were summarized using descriptive statistics. Continuous variables were characterized using median and interquartile range; dichotomous or polytomous variables were characterized using frequencies.Adverse outcomes between pediatric graduates specifically referred to the reference ACHD center and non-referred patients aged 18-33 over the time period 2004-2019 were compared with McNemar testing after propensity score matching. Outcome Analysis was focused on the composite adverse outcome (COA) of prolonged ventilation >7days, acute kidney injury requiring dialysis, and in-hospital mortality as well as ventilation time. Results and conclusions Overall, 89.8% of the cases were elective, 10.2% emergent and 5.4% active endocarditis with no significant difference between groups.Pediatric-referred graduates were much more likely to have had 2+ previous sternotomies (p<.001), be of the male sex (p=.028), least of all groups to experience a lost to follow up gap in care of 5 or more years (p= .008), live at addresses associated with higher education including college diploma or trade certificate or university degrees (p=.005, p=.042), and more likely to be Canadian Citizens and speak either English or French in the home (p=.018, p=.041)Patients lost to follow up prior to the age of 18 compared with the referral group lived at addresses associate with a lower median household income (53,898vs. 91,692), were more likely to be female (57.1% vs. 33.6%), and have cognitive impairment (28.6% vs. 8.5%)Propensity matching of pediatric graduates and non-referrals from elsewhere showed no difference in composite adverse outcome of prolonged ICU stay, ventilation time or In Hospital mortality. Conclusions There are socioeconomic differences in the referral pathways to ACHD cardiac surgical care. However, once they have negotiated a pathway to care, they have no increase in adverse surgical outcomes.

Background: Rastelli surgery is used for the correction of several CHDs. Although late-onset cardiac arrhythmias have emerged as a major complication after corrective surgeries, there is a paucity of data on arrhythmias after Rastelli surgery.Methods: This retrospective cohort study was conducted on patients who had undergone Rastelli surgery and have been followed at the adult CHD clinic at our hospital.Results: A total of 55 patients (36.4% female, age 22.2 +/- 6.4 years) were followed for a median period of 24.2 (20.6-31.0) years. Tachyarrhythmias occurred in 21 (38.4 %) patients (n = 15 for atrial tachycardia, 5 for ventricular tachycardia, and 1 for both atrial and ventricular tachycardia). Older age at surgery was significantly associated with the risk of tachyarrhythmias (P = 0.022). Bradyarrhythmia occurred in 12 (21.8%) patients and consisted of perioperative AV block (n = 5), late AV block (n = 1), and sinus node dysfunction (n = 6). Nine (16.4%) patients underwent catheter ablation. The mechanisms of atrial arrhythmias include cavotricuspid isthmus-dependent and surgical scar-dependent intra-atrial reentrant tachycardias. Among the three patients who underwent ablation for ventricular tachycardia, all circuits were dependent on the scar at the base of the right ventricle to pulmonary artery conduit. Median survival free from any event (arrhythmia, death, or heart failure) was 31.6 (28.1-35.1) years after Rastelli surgery.Conclusions: The prevalence of arrhythmias late after Rastelli surgery is substantial and increases in the second decade after surgery. Older age at surgery is associated with a higher prevalence of arrhythmias.

BACKGROUND A comprehensive understanding of adult congenital heart disease outcomes must include psychological functioning. Our multisite study offered the opportunity to explore depression and anxiety symptoms within a global sample. OBJECTIVES In this substudy of the APPROACH-IS (Assessment of Patterns of Patient-Reported Outcomes in Adults With Congenital Heart Disease-International Study), the authors we investigated the prevalence of elevated depression and anxiety symptoms, explored associated sociodemographic and medical factors, and examined how quality of life (QOL) and health status (HS) differ according to the degree of psychological symptoms. METHODS Participants completed the Hospital Anxiety and Depression Scale, which includes subscales for symptoms of anxiety (HADS-A) and depression (HADS-D). Subscale scores of 8 or higher indicate clinically elevated symptoms and can be further categorized as mild, moderate, or severe. Participants also completed analogue scales on a scale of 0 to 100 for QOL and HS. Analysis of variance was performed to investigate whether QOL and HS differed by symptom category. RESULTS Of 3,815 participants from 15 countries (age 34.8 +/- 12.9 years; 52.7% female), 1,148 (30.1%) had elevated symptoms in one or both subscales: elevated HADS-A only (18.3%), elevated HADS-D only (2.9%), or elevations on both subscales (8.9%). Percentages varied among countries. Both QOL and HS decreased in accordance with increasing HADS-A and HADS-D symptom categories (P < 0.001). CONCLUSIONS In this global sample of adults with congenital heart disease, almost one-third reported elevated symptoms of depression and/or anxiety, which in turn were associated with lower QOL and HS. We strongly advocate for the implementation of strategies to recognize and manage psychological distress in clinical settings.

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.

Abstract Background Congenital heart disease (CHD) is the most common congenital anomaly. Almost 90% of isolated cases have an unexplained genetic etiology after clinical testing. Non-canonical splice variants that disrupt mRNA splicing through the loss or creation of exon boundaries are not routinely captured and/or evaluated by standard clinical genetic tests. Recent computational algorithms such as SpliceAI have shown an ability to predict such variants, but are not specific to cardiac-expressed genes and transcriptional isoforms. Methods We used genome sequencing (GS) (n = 1101 CHD probands) and myocardial RNA-Sequencing (RNA-Seq) (n = 154 CHD and n = 43 cardiomyopathy probands) to identify and validate splice disrupting variants, and to develop a heart-specific model for canonical and non-canonical splice variants that can be applied to patients with CHD and cardiomyopathy. Two thousand five hundred seventy GS samples from the Medical Genome Reference Bank were analyzed as healthy controls. Results Of 8583 rare DNA splice-disrupting variants initially identified using SpliceAI, 100 were associated with altered splice junctions in the corresponding patient myocardium affecting 95 genes. Using strength of myocardial gene expression and genome-wide DNA variant features that were confirmed to affect splicing in myocardial RNA, we trained a machine learning model for predicting cardiac-specific splice-disrupting variants (AUC 0.86 on internal validation). In a validation set of 48 CHD probands, the cardiac-specific model outperformed a SpliceAI model alone (AUC 0.94 vs 0.67 respectively). Application of this model to an additional 947 CHD probands with only GS data identified 1% patients with canonical and 11% patients with non-canonical splice-disrupting variants in CHD genes. Forty-nine percent of predicted splice-disrupting variants were intronic and > 10 bp from existing splice junctions. The burden of high-confidence splice-disrupting variants in CHD genes was 1.28-fold higher in CHD cases compared with healthy controls. Conclusions A new cardiac-specific in silico model was developed using complementary GS and RNA-Seq data that improved genetic yield by identifying a significant burden of non-canonical splice variants associated with CHD that would not be detectable through panel or exome sequencing.

Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), with variant enrichment in constrained coding regions. Pediatric patients had a higher burden of sarcomere and lower burden of channelopathy gene variants compared to adults. Specifically, pediatric patients had more MYH7 and MYL3 variants in hypertrophic cardiomyopathy, and fewer TTN truncating variants in dilated cardiomyopathy. MYH7 variants clustered in the myosin head and neck domains in children. OBSCN was a top mutated gene in adults, enriched for protein-truncating variants. In dilated cardiomyopathy, female patients had a higher burden of z-disc gene variants compared to males. Genetic differences may explain age and sex-related variability in cardiomyopathy penetrance. Genotype-guided predictions of age of onset can inform pre-test genetic counseling. Graphical Abstract Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in MYH7, MYL3, TNNT2, VCL . Adults had a higher burden of OBSCN and TTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.

The natural history of an unrepaired isolated partial anomalous pulmonary venous con-nection(s) (PAPVC) and the absence of other congenital anomalies remains unclear. This study aimed to expand the understanding of the clinical outcomes in this population. Iso-lated PAPVC with an intact atrial septum is a relatively uncommon condition. There is the perception that patients with isolated PAPVC are usually asymptomatic, that the lesion generally has a limited hemodynamic impact, and that surgical repair is rarely justi-fied. For this retrospective study, we reviewed our institutional database to identify patients with either 1 or 2 anomalous pulmonary veins that drain a portion of but not the complete ipsilateral lung. Patients with previous surgical cardiac repair, coexistence of other congenital cardiac anomalies that would result in either pretricuspid or post-tricus-pid loading of the right ventricle (RV), or scimitar syndrome were excluded. We reviewed their clinical course over the follow-up period. We identified 53 patients; 41 with a single and 12 with 2 anomalous PAPVC. A total of 30 patients (57%) were men, with a mean age at the latest clinic visit of 47 & PLUSMN; 19 years (18 to 84 years). Turner syndrome (6 of 53, 11.3%), bicuspid aortic valve (6 of 53, 11.3%), and coarctation of the aorta (5 of 53, 9.4%) were commonly associated anomalies. A single anomalous left upper lobe vein was the most commonly identified variation. More than half of the patients were asymptomatic. Cardiopulmonary exercise test demonstrated a maximal oxygen consumption of 73 & PLUSMN; 20% expected (36 to 120). Transthoracic echocardiography demonstrated a mean RV basal diameter of 4.4 & PLUSMN; 0.8 cm, RV systolic pressure of 38 & PLUSMN; 13 (16 to 84) mm Hg. A total of 8 patients (14.8%) had & GE;moderate tricuspid regurgitation. Cardiac magnetic resonance in 42 patients demonstrated a mean RV end-diastolic volume index of 122 & PLUSMN;3 0 ml/m2 (66 to 188 ml/m2), of which in 8 (14.8%), it was >150 ml/m2. Magnetic resonance imaging-based Qp:Qs was 1.6 & PLUSMN; 0.3. A total of 5 patients (9.3%) had established pulmonary hyper-tension (mean pulmonary artery pressure & GE;25 mm Hg). In conclusion, isolated single or dual anomalous pulmonary venous connection is not necessarily a benign congenital anomaly because a proportion of patients develop pulmonary hypertension and/or RV dilation. Regular follow-up and on-going patient surveillance with cardiac imaging is advised. & COPY; 2023 Published by Elsevier Inc. (Am J Cardiol 2023;201:232-238)

Genetic changes affect embryogenesis, cardiac and extracardiac phenotype, development, later onset conditions, and both short- and long-term outcomes and comorbidities in the increasing population of individuals with tetralogy of Fallot (TOF). In this review, we focus on current knowledge about clinically relevant genetics for patients with TOF across the lifespan. The latest findings for TOF genetics that are pertinent to day-to-day practice and lifelong management are highlighted: morbidity/mortality, cardiac/extracardiac features, including neurodevelopmental expression, and recent changes to prenatal screening and diagnostics. Genome-wide microarray is the first-line clinical genetic test for TOF across the lifespan, detecting relevant structural changes including the most common for TOF, the 22q11.2 microdeletion. Accumulating evidence illustrates opportunities for advances in understanding and care that may arise from genetic diagnosis at any age. We also glimpse into the near future when the multigenic nature of TOF will be more fully revealed, further enhancing possibilities for preventive care. Precision medicine is nigh.