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Background: Heart failure (HF) is the leading cause of mortality in adults with congenital heart disease (CHD) after transcatheter pulmonary valve replacement (TPVR), likely due to preexisting myocardial dysfunction and suboptimal reverse remodeling. Left ventricular (LV) diastolic dysfunction, unmasked by an acute increase in preload post-TPVR, may elevate left-sided filling pressures and precipitate pulmonary edema. However, the prognostic implications of elevated left-sided filling pressures prior to TPVR are currently unknown. Objective: To evaluate the prognostic value of pre-TPVR pulmonary artery wedge pressure (PAWP) and the heart failure with preserved ejection fraction – Age, Body mass index (BMI), Atrial fibrillation (HFpEF-ABA) score in patients undergoing TPVR. Methods: Adults with congenital heart disease (CHD) undergoing TPVR were stratified by pre-implant PAWP (<15 vs ≥15 mmHg) and HFpEF-ABA score (low <25%, intermediate 25–75%, high >75%). The composite endpoint was all-cause mortality, heart transplantation, heart failure (HF) hospitalization, or sustained ventricular arrhythmia. Kaplan-Meier and Cox regression analyses assessed associations with clinical outcomes. Results: Out of 150 patients, 37 (24.7%) had PAWP ≥15 mmHg. Elevated PAWP was associated with older age (36 [31;53] vs. 26 [19; 37] years, p<0.01), BMI (27.9 [24.5; 35.1] vs. 24.2 [20.6; 29.7] kg/m 2 , p<0.01), and higher HFpEF-ABA score (42.8 [9.5;63.6] vs. 6.4 [2.5;18.1]%, p<0.001) compared to normal PAWP. Over a median follow-up of 38 [13; 83] months, 26 events (17.3%) occurred. Kaplan-Meier analysis demonstrated a significant difference in event-free survival based on pre-TPVR PAWP categories (log-rank p=0.002) and HFpEF-ABA score categories (log-rank p<0.001). Elevated PAWP was associated with adverse outcomes (hazard ratio [HR] 4.27, 95% CI 1.61–11.31, p=0.003) (Figure 1), but this was no longer significant after age adjustment. HFpEF-ABA ≥25% was associated with adverse outcomes (HR 10.6, 95% CI 3.8–30.0, p<0.001) (Figure 2), independent of N-terminal prohormone of brain natriuretic peptide levels and left ventricular ejection fraction. Conclusion: Albeit confounded by demographics, pre-TPVR PAWP correlated with adverse long-term outcomes, and patients with this hemodynamic profile may require closer post-procedural surveillance. HFpEF-ABA was independently associated with incident events, representing an inexpensive, novel prognostic tool in patients undergoing TPVR.

Background: Patients with systemic right ventricle (sRV), including congenitally corrected transposition of great arteries (cc-TGA) and dextro-transposition of great arteries (d-TGA) post-atrial switch procedure are at risk of sudden cardiac death due to ventricular arrhythmias (VA). While programmed ventricular stimulation (PVS) can help with risk stratification in certain patients with congenital heart disease, its role in sRV is unknown. Objective: To study the diagnostic value of electrophysiology study (EPS) in predicting VAs in patients with sRV. Methods: EPS was performed in 53 patients with sRV at Mayo Clinic from 1994 to 2021. Patients with a history of sustained VA or cardiac arrest were excluded (n=19). The incidence of sustained VA (sudden cardiac death, sustained ventricular tachycardia [VT] or appropriate implantable cardioverter-defibrillator [ICD] therapy) was evaluated in the remaining 34 patients. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of EPS in predicting VAs is reported. Results: The mean age at EPS was 36.2±11.6 years, 21 (61.8%) were male, 21 (61.8%) had d-TGA and mean sRV ejection fraction was 31.3±10.8%. Indication for EPS was supraventricular tachycardias (n=15, 44.1%), syncope/palpitations (n=9, 26.5%) and non-sustained VT (n=6, 17.6%). 13/34 (38.2%) patients had inducible sustained VA, (5 [38.5%] with monomorphic VT and 8 [61.5%] with polymorphic VT/VF). Treatments included ICD implantation in all 13 patients and ablation in one patient. During a mean follow-up of 8±5.4 years, one patient with a positive PVS (inducible polymorphic VT) experienced sustained VT secondary to atrial flutter with 1:1 conduction. The sensitivity of PVS was 100%, specificity was 63.6%, PPV 7.7%, and NPV 100%. Conclusion: In this retrospective cohort of patients with sRV, polymorphic VT was the most commonly observed VA during PVS. The predictive value of a positive PVS was low in this cohort, and larger studies are needed to better define the role of EPS in risk stratification. Patients with negative EPS did not have future VAs recognizing that the overall event rate is low. Further multicenter research with a larger sample is required to develop predictive models to identify those at risk of VAs.

Backround: Advances in surgical and medical care of children born with congenital heart disease (CHD) has improved survival into adulthood. However, cardiac and non-cardiac morbidity and mortality remain common in adults with CHD (ACHD). We present the causes and predictors of mortality in a large cohort of ACHD patients from the USA. Methods/Approach: We conducted a retrospective review of ACHD patients followed at Mayo Clinic between 1992 - 2024. Mortality was ascertained using the Accruint national data base. Clinical characteristics and primary cause of death were identified from the electronic record. Kaplan-Meier (KM) survival analysis was performed to compare overall survival stratified by CHD severity. Cox proportional hazards regression was used to identify independent predictors of mortality. Results/Data: Amongst 9160 ACHD patients (mean age 38±16y at first visit, 51% males, 23% simple, 59% moderate and 18% severe CHD), mortality occurred in 1430(16%) patients during a mean follow-up of 11±7y. The mean age at death was 68±17 y, 58±17y, and 45±15y in mild, moderate and severe ACHD. KM analysis of survival and cause of death stratified by CHD severity are presented in Figures 2 and 3 respectively. Cause of death could not be ascertained in 33%%. Amongst those with a known cause of death, the proportion of non-cardiac death increased with decreasing severity of CHD. HF death and sudden cardiac death occurred in 11% and 19%. Infection, malignancy and chronic respiratory failure were important non-cardiac causes of death. Significant risk factors for mortality included CHD severity, ventricular arrhythmia, heart failure, declining functional capacity, diabetes and chronic kidney disease as presented in the Fig 1. Conclusion(s): Mortality in ACHD patients is associated with CHD severity, heart failure, ventricular arrhythmia and cardiovascular comorbidities. Early recognition and management of these risk factors may improve long-term survival. As patients with ACHD age, management of cardiovascular and noncardiac risk factors will require development of systems of care specific to this vulnerable population.

Background: Patients with repaired Tetralogy of Fallot (TOF) undergoing pulmonary valve replacement (PVR) are at increased risk of major adverse ventricular arrhythmias and related events (MAREs). Perioperative electrophysiological study (EPS) has been used for risk stratification and guiding future management, but these studies are limited by small sample size. Objectives: To perform a systematic review of outcomes of pre-PVR EPS in TOF patients with PVR. Methods: A comprehensive search of PubMed, Embase, Scopus and Google scholar databases was performed per PRISMA 2020 guidelines. Studies on patients with repaired TOF undergoing PVR with perioperative EPS were included. Data were extracted on study design, sample size, EPS outcomes and MAREs during follow-up. Results: A total of 1,528 patients (age: 35.5±3.8 y; 57% male; LVEF: 57.1±1.5%, RVEF: 42.6±1.5%) were included from 12 studies. EPS was performed in 1212/1528 (79.3%), with sustained VT inducibility in 404 (33.3%)-monomorphic VT in 258 (63.8%), while 808 (66.6%) were non- inducible. 8/12 studies reported the type of PVR (transcatheter-36.8%). 174/293 (59.3%) inducible patients had an ablation (9 studies), while ICD (6 studies) was implanted in 70/263 (26.6%). Follow-up EPS (6 studies) showed 35/230 (15.2%) remained inducible. Overall,113 (9.3%) patients experienced MAREs over a median follow-up ranging from 6 months to 6.7 years. Sustained VT (11/12 studies) occurred in 70/1092 (6.4%), appropriate ICD therapy (7/12 studies) in 13/622 (2.1%) and sudden cardiac death (10/12 studies) in 30/906 (3.3%). Five studies provided MARE data stratified by VT inducibility. 12/164 (7.3%) inducible patients experienced MAREs, compared to 2/318 (0.6%) non-inducible patients. Reported risk factors for MAREs included older age at initial repair and PVR, QRS duration (>180ms), LVEF <45%, RVEF <35%, history of syncope, prior palliative shunts and atrial arrhythmias. Some studies identified MRI-derived scar burden, pulmonary annulus size, and RV/LV volume ratios as additional predictors. Conclusion: TOF patients remain at high risk of VA after PVR with 1/10 patients experiencing MAREs. People with inducible VT had a 12-fold greater risk than people who were non-inducible. EPS identifies a subset of TOF patients at higher arrhythmic risk during PVR and supports tailored ablation and ICD strategies. Prospective multicentre studies are needed to optimize integration of EPS and clinical risk models.

Background: Fontan circulation is characterized by the absence of a subpulmonary ventricle with resultant systemic venous hypertension. Despite exercise intolerance being nearly universal in this population, the determinants of exercise capacity in this population are still poorly understood. Research Question: We investigated the prevalence of peripheral impairment and assessed the contribution of peripheral O 2 extraction versus central hemodynamics to peak O 2 consumption (pVO 2 ) post-Fontan palliation. Methods: This single-center retrospective cross-sectional study compared 52 consecutive adults post-Fontan procedure who underwent exercise catheterization to patients with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnea (NCD) at 1:1 ratio. Several previously reported measures for peripheral O 2 extraction were evaluated in the absence of a golden standard. Correlates of pVO 2 were identified by multivariate linear regression analyses using the backward selection method. Results: Patients with Fontan circulation were younger [age 32 (24;36) years] and tended to have a lower body mass index [26 (23; 29) kg/m 2 ] compared to patients with HFpEF [70 (57; 75) years, p<0.001 and 33 (27; 39) kg/m 2 , p<0.001] and NCD [48 (38; 61) years, p<0.001 and 27 (24; 35) kg/m 2 , p=0.08]. Peak heart rate [108 (85;126) vs 108 (95;125) bpm] and indexed stroke volume [46 (39;54) vs 45 (40;53) ml/m 2 ] were similar in the Fontan and HFpEF groups but lower compared to NCD [126 (108;141) bpm, p<0.001 and 51 (45;59) ml/m 2 , p<0.001]. Peak mean pulmonary artery pressures were highest in HFpEF [45 (41;50) mmHg, p<0.001], followed by Fontan and NCD [26 (22;31) vs 23 (19;25) mmHg, p=0.03]. Median peak O 2 extraction post-Fontan was comparable to HFpEF [12 (10;14) vs 11 (10;13) ml/dl, p=0.17] but higher than in NCD [10 (9;12) ml/dl, p<0.001]. It was <14 ml/dl in 73% compared to 94% and 98% of patients with HFpEF and NCD [p<0.001]. O 2 extraction ratio was <70% in 62% compared to 60% in HFpEF and 96% in NCD [p<0.001]. Correlates of pVO 2 post-Fontan were peak O 2 extraction [β 0.5±0.1 per ml/dl; p<0.001], mean pulmonary artery pressures [β -0.2±0.05 per mmHg; p=0.002], heart rate [β 0.03±0.01 per bpm; p=0.01], and systolic arterial blood pressure [β 0.03±0.01 per mmHg; p=0.02]. Conclusion: Impaired O 2 extraction is prevalent amongst adults post-Fontan. Whether exercise can modulate this important determinant of exercise capacity post-Fontan merits further investigation.

Introduction: Complex congenital heart disease (CHD) patients with atrial arrhythmias have higher rates of morbidity and mortality compared to less complex CHD patients. This study aims to identify echocardiographic predictors of thromboembolism (TE) and major bleeding in patients with Tetralogy of Fallot (ToF) or Pulmonary Atresia with Intact Ventricular Septum (PA-IVS) and atrial fibrillation or flutter (AF). Methods: This cohort study included patients with ToF or PA-IVS who had a diagnosis of AF who underwent a TTE across three sites. Outcomes were incidence rate of major bleeding or TE, calculated using univariable and multivariable cox regression with interaction for anticoagulant choice and fractional area change (FAC). The HAS-BLED score was augmented with major predictors of bleeding, and receiver operator curves compared. Results: We included 300 patients (287 ToF [95.7%], 13 PA-IVS [4.3%]), mean age 45.6 years. Most received warfarin (227 [79.4%]), 40 (13%) used DOACs, and 5 (1.6%) used enoxaparin. TTE predictors of TE included large LVOT diameter ≥3cm (HR 8.92, p=0.002), small LVOT VTI (p=0.014), FAC <30% (HR 7.08, p=0.026) and moderate RV dysfunction (HR 10.75, p=0.026). Predictors of major bleeding included moderate tricuspid regurgitation (HR 2.40, p=0.022), right atrial pressure (1.12, p<0.001), severe RA enlargement (HR 2.30, p=0.048), RV mid diameter (HR 1.06, p=0.005), RV end diastolic area (HR 1.04, p=0.021), RV end systolic area (HR 1.05, p=0.016) elevated RVSP and FAC ≤45% (HR 0.37, p=0.016). Among warfarin users, impaired RV function (FAC ≤45%) was linked to reduced major bleeding events (HR 0.27, p=0.025). There was a nonsignificant trend towards higher bleeding in DOAC users with FAC >45% (HR 3.87, p=0.284), but significantly higher bleeding in DOAC users with FAC ≤45% (HR 12.41, p=0.008) vs. warfarin users with normal RV function (table 1). We developed an augmented HAS-BLED score: the standard score plus one point for moderate-to-severe pulmonic or tricuspid regurgitation and one for FAC ≤45%. This outperformed the standard HAS-BLED in predicting major bleeding (AUC 0.67 augmented vs. 0.57 un-augmented, p=0.008) (figure 1). Conclusion: Echocardiographic evidence of right heart disease is a strong predictor of major bleeding in patients with ToF or PA-IVS. FAC is a useful tool to determine excess major bleeding risk, particularly in DOAC users. Augmenting HAS-BLED with right heart parameters improves diagnostic accuracy.

BACKGROUND: The current study aims to describe outcomes after transcatheter valve replacement in adults with congenital heart disease. METHODS: Retrospective study of adults with congenital heart disease who underwent transcatheter valve replacement and had a 1-year follow-up postintervention at Mayo Clinic (2010–2024). The study period was divided into early (2010–2014), mid (2015–2019), and late (2020–2024) eras. The primary outcome was valve reintervention. The secondary outcomes were all-cause mortality and temporal change in prosthetic valve gradient and clinical indices of disease severity. RESULTS: Overall, 341 patients (age 38±17 years; 175 [51%] men) received 346 prostheses (pulmonary [N=236, 68%], tricuspid [N=75, 22%], aortic [N=22, 8%], and mitral [N=7, 2%]). The prostheses were Sapien (N=181, 52%), Melody (N=142, 41%), and Harmony prostheses (N=23, 7%). The number of transcatheter valve implantations increased from the early era (N=75), mid era (N=109), to the late era (N=162). The 10-year incidence of valve reintervention was 35%, and was similar between Sapien versus Melody prosthesis (41% versus 33%; P =0.11). The 10-year incidence of all-cause mortality was 13%. There was a temporal increase in prosthetic valve Doppler mean gradient (baseline versus 10 years) for pulmonary (12±5 versus 28±11 mmHg; P <0.001), tricuspid (3±1 versus 8±3 mmHg; P <0.001), and aortic prosthesis (13±5 versus 26±12 mmHg; P <0.001). There was a temporal increase in predicted peak oxygen consumption (absolute ∆, 9% [95% CI, 4–13]; P =0.006) and a decrease in NT-proBNP (N-terminal pro-B-type natriuretic peptide) level (absolute ∆, −138 pg/mL [95% CI, −209 to −64]; P <0.001) at 1-year postintervention. CONCLUSIONS: There has been a temporal increase in the number of transcatheter valve implantations over time. Transcatheter valve replacement was associated with clinical improvement across multiple domains. However, there was a significant increase in prosthetic valve gradient within 10 years of follow-up, suggesting limited prosthesis longevity. There is a need for strategies to improve prosthetic valve longevity, which in turn may improve outcomes in this population.

BACKGROUND: Fontan conversion (FC) is associated with a lower risk of atrial arrhythmias and thromboembolism, but it is unknown whether FC improves long-term survival. The purpose of this study was to assess the impact of FC on transplant-free survival. METHOD: Adults with Fontan palliation were divided into 3 groups: (1) atriopulmonary Fontan connection; (2) atriopulmonary Fontan and subsequent FC to total cavopulmonary connection (TCPC); (3) TCPC at initial Fontan operation. The risk of death/transplant was compared between the 3 groups using Cox regression analysis. RESULTS: We studied 534 patients (age 27±9 years; males [N=298; 56%]). Patients were divided into atriopulmonary Fontan group (N=199, 37%); FC-TCPC (N=138, 26%); and TCPC (N=197, 37%). The FC-TCPC and TCPC groups have similar 15-year incidence of death/transplant (42% versus 47%; P =0.8), even after excluding the 8% operative mortality in the FC-TCPC group (38% versus 47%; P =0.3). On multivariable analyses, neither FC nor the type of Fontan connection was associated with death/transplant. Rather, the risk factors for death/transplant were older age, hepatorenal dysfunction, heart failure, and higher Fontan pressures. The prevalence and severity of these comorbidities increased with age, suggesting that these factors reflect the duration of Fontan physiology, rather than the type of Fontan connection. CONCLUSIONS: These findings, in addition to the high operative mortality associated with FC, suggest that this may not be the optimal treatment option for most adults with atriopulmonary Fontan presenting with Fontan failure. Duration of Fontan physiology rather than the type of Fontan connection may be the main determinant of outcomes.

Introduction/Background: Despite numerous medical advances, 30% of patients with Fontan circulation require heart transplantation by 21. Current risk stratification relies on clinical metrics that lack strong correlations to patient outcomes, leading to a high waitlist mortality. Hypothesis: Integration of physics-based hemodynamic modeling with interpretable machine learning will improve prediction of patient outcomes (listing for heart transplant and/or cardiac death) by quantifying physiologic mechanisms inaccessible through clinical measures alone. Goals/Aims: 1. Develop a lumped-parameter mechanistic model (LPMM) of Fontan circulation 2. Identify patient clusters and predictors of patient outcomes 3. Validate model-informed classifiers against clinical-only approaches Methods/Approach: A LPMM incorporating ventricular sarcomere mechanics, atrial hemodynamics, and vascular viscoelastic effects was optimized to cardiac catheterization and echocardiography data from 51 patients (age 25±8 years). Thirty-eight parameters (ventricular inotropy, atrial stiffness, pulmonary elastance, etc.) were calibrated via surrogate optimization, minimizing least-squares error versus 11 clinical targets. Partial least-squares regression with leave-one-out cross-validation compared clinical-only versus model-informed classifiers of outcomes. Results/Data: The LPMM achieved 2% mean error across hemodynamic targets, with CVP and pulmonary pressures matching clinical measurements within 1%. Model-derived minimum atrial pressure (4.46±1.78 vs 2.68±0.87 mmHg, p<0.05) outperformed all clinical variables in discriminating patient outcomes. Integration of LPMM parameters increased AUROC from 0.67 to 0.78 for patient outcome prediction. Conclusions: Physics-based modeling identifies ventricular passive stiffness, atrial end-diastolic volume, and minimum atrial pressure, along with patient age (a clinical value) as critical determinants of Fontan failure. Combined mechanistic-machine learning approaches enable phenotype-specific risk stratification, supporting earlier referral for advanced therapies. This methodology establishes a framework for precision management of complex congenital circulations.