Three-dimensional cardiac magnetic resonance allows the identification of slow-conducting anatomical isthmuses in tetralogy of Fallot.

BACKGROUND AND AIMS: Patients with repaired tetralogy of Fallot remain at risk of life-threatening ventricular tachycardia related to slow-conducting anatomical isthmuses (SCAIs). Preventive ablation of SCAI identified by invasive electroanatomical mapping is increasingly performed. This study aimed to non-invasively identify SCAI using 3D late gadolinium enhancement cardiac magnetic resonance (3D-LGE-CMR). METHODS: Consecutive tetralogy of Fallot patients who underwent right ventricular electroanatomical mapping (RV-EAM) and 3D-LGE-CMR were included. High signal intensity threshold for abnormal myocardium was determined based on direct comparison of bipolar voltages and signal intensity by co-registration of RV-EAM with 3D-LGE-CMR. The diagnostic performance of 3D-LGE-CMR to non-invasively identify SCAI was determined, validated in a second cohort, and compared with the discriminative ability of proposed risk scores. RESULTS: The derivation cohort consisted of 48 (34 ± 16 years) and the validation cohort of 53 patients (36 ± 18 years). In the derivation cohort, 78 of 107 anatomical isthmuses (AIs) identified by EAM were normal-conducting AI, 22 were SCAI, and 7 blocked AI. High signal intensity threshold was 42% of the maximal signal intensity. The sensitivity and specificity of 3D-LGE-CMR for identifying SCAI or blocked AI were 100% and 90%, respectively. In the validation cohort, 85 of 124 AIs were normal-conducting AI, 36 were SCAI, and 3 blocked AI. The sensitivity and specificity of 3D-LGE-CMR were 95% and 91%, respectively. All risk scores showed an at best modest performance to identify SCAI (area under the curve ≤ .68). CONCLUSIONS: 3D late gadolinium enhancement cardiac magnetic resonance can identify SCAI with excellent accuracy and may refine non-invasive risk stratification and patient selection for invasive EAM in tetralogy of Fallot.

Decreased clinical performance in TGA-ASO patients after RVOT interventions; a multicenter European collaboration.

BACKGROUND: In patients with transposition of the great arteries and an arterial switch operation (TGA-ASO) right ventricular outflow tract (RVOT) obstruction is a common complication requiring one or more RVOT interventions. OBJECTIVES: We aimed to assess cardiopulmonary exercise capacity and right ventricular function in patients stratified for type of RVOT intervention. METHODS: TGA-ASO patients (≥16 years) were stratified by type of RVOT intervention. The following outcome parameters were included: predicted (%) peak oxygen uptake (peak VO2), tricuspid annular plane systolic excursion (TAPSE), tricuspid Lateral Annular Systolic Velocity (TV S'), right ventricle (RV)-arterial coupling (defined as TAPSE/RV systolic pressure ratio), and N-terminal proBNP (NT-proBNP). RESULTS: 447 TGA patients with a mean age of 25.0 (interquartile range (IQR) 21-29) years were included. Patients without previous RVOT intervention (n = 338, 76%) had a significantly higher predicted peak VO2 (78.0 ± 17.4%) compared to patients with single approach catheter-based RVOT intervention (73.7 ± 12.7%), single approach surgical RVOT intervention (73.8 ± 28.1%), and patients with multiple approach RVOT intervention (66.2 ± 14.0%, p = 0.021). RV-arterial coupling was found to be significantly lower in patients with prior catheter-based and/or surgical RVOT intervention compared to patients without any RVOT intervention (p = 0.029). CONCLUSIONS: TGA patients after a successful arterial switch repair have a decreased exercise capacity. A considerable amount of TGA patients with either catheter or surgical RVOT intervention perform significantly worse compared to patients without RVOT interventions.

Effect of Sodium-Glucose Cotransporter 2 Inhibitors in Adults With Congenital Heart Disease.

BACKGROUND: Heart failure (HF) is the principal cause of morbidity and mortality in adults with congenital heart disease (ACHD). Robust evidence-based treatment options are lacking. OBJECTIVES: This study aims to evaluate the safety, tolerability, and short-term HF-related effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in a real-world ACHD population. METHODS: All patients with ACHD treated with SGLT2i in 4 European ACHD centers were included in this retrospective study. Data were collected from 1 year before starting SGLT2i to the most recent follow-up. Data on side effects, discontinuation, mortality, and hospitalizations were collected. RESULTS: In total, 174 patients with ACHD were treated with SGLT2i from April 2016 to July 2023. The mean age was 48.7 ± 15.3 years, 72 (41.4%) were female, and 29 (16.7%) had type 2 diabetes mellitus. Ten (5.7%) patients had mild, 75 (43.1%) moderate, and 89 (51.1%) severe congenital heart disease. HF was the most frequent starting indication (n = 162, 93.1%), followed by type 2 diabetes (n = 11, 6.3%) and chronic kidney disease (n = 1, 0.6%). At median follow-up of 7.7 months (Q1-Q3: 3.9-13.2 months), 18 patients (10.3%) reported side effects, 12 (6.9%) permanently discontinued SGLT2i, and 4 (2.3%) died of SGLT2i-unrelated causes. A significant reduction in the HF hospitalization rate was observed from 6 months before to 6 months after starting SGLT2i (relative rate = 0.30; 95% CI: 0.14-0.62; P = 0.001). CONCLUSIONS: SGLT2i generally seem safe, well-tolerated, and potentially beneficial in patients with ACHD. SGLT2i was associated with a 3-fold reduction in the 6-month HF hospitalization rate. These results warrant prospective randomized investigation of the potential benefits of SGLT2i for patients with ACHD.

The relevance of the superior cervical ganglion for cardiac autonomic innervation in health and disease: a systematic review.

PURPOSE: The heart receives cervical and thoracic sympathetic contributions. Although the stellate ganglion is considered the main contributor to cardiac sympathetic innervation, the superior cervical ganglia (SCG) is used in many experimental studies. The clinical relevance of the SCG to cardiac innervation is controversial. We investigated current morphological and functional evidence as well as controversies on the contribution of the SCG to cardiac innervation. METHODS: A systematic literature review was conducted in PubMed, Embase, Web of Science, and COCHRANE Library. Included studies received a full/text review and quality appraisal. RESULTS: Seventy-six eligible studies performed between 1976 and 2023 were identified. In all species studied, morphological evidence of direct or indirect SCG contribution to cardiac innervation was found, but its contribution was limited. Morphologically, SCG sidedness may be relevant. There is indirect functional evidence that the SCG contributes to cardiac innervation as shown by its involvement in sympathetic overdrive reactions in cardiac disease states. A direct functional contribution was not found. Functional data on SCG sidedness was largely unavailable. Information about sex differences and pre- and postnatal differences was lacking. CONCLUSION: Current literature mainly supports an indirect involvement of the SCG in cardiac innervation, via other structures and plexuses or via sympathetic overdrive in response to cardiac diseases. Morphological evidence of a direct involvement was found, but its contribution seems limited. The relevance of SCG sidedness, sex, and developmental stage in health and disease remains unclear and warrants further exploration.

Noninvasive Advanced Cardiovascular Magnetic Resonance-Derived Fontan Hemodynamics Are Associated With Reduced Kidney Function But Not Albuminuria.

BACKGROUND: Kidney disease is the most important predictor of death in patients with a Fontan circulation, yet its clinical and hemodynamic correlates have not been well established. METHODS AND RESULTS: A total of 53 ambulatory patients with a Fontan circulation (median age, 16.2 years, 52.8% male patients) underwent advanced cardiovascular magnetic resonance assessment, including 4-dimensional flow imaging and computational fluid dynamics. Estimated glomerular filtration rate (eGFR) <90 mL/min per 1.73 m2 was observed in 20.8% and albumin-to-creatinine ratio >3 mg/mmol in 39.6%. The average eGFR decline rate was -1.83 mL/min per 1.73 m2 per year (95% CI, -2.67 to -0.99; P<0.001). Lower eGFR was associated with older age, larger body surface area at examination, longer time since Fontan procedure, and lower systemic ventricular ejection fraction. Higher albumin-to-creatinine ratio was associated with absence of fenestration at the Fontan operation, and older age and lower systemic ventricular ejection fraction at the assessment. Lower cross-sectional area of the Fontan conduit indexed to flow (r=0.32, P=0.038), higher inferior vena cava-conduit velocity mismatch factor (r=-0.35, P=0.022), higher kinetic energy indexed to flow in the total cavopulmonary connection (r=-0.59, P=0.005), and higher total cavopulmonary connection resistance (r=-0.42, P=0.005 at rest; r=-0.43, P=0.004 during exercise) were all associated with lower eGFR but not with albuminuria. CONCLUSIONS: Kidney dysfunction and albuminuria are common among clinically well adolescents and young adults with a Fontan circulation. Advanced cardiovascular magnetic resonance-derived metrics indicative of declining Fontan hemodynamics are associated with eGFR and might serve as targets to improve kidney health. Albuminuria might be driven by other factors that need further investigation.

Quantification of the intrinsic neural plexus of the heart - The missing link in histological tissue analysis.

BACKGROUND AND OBJECTIVE: The heart is under strict regulation of the autonomic nervous system, during which, in a healthy state, the effects of sympathetic and parasympathetic branches are balanced. In recent years, there has been increasing interest in pathological remodeling and outgrowth of cardiac autonomic nerves in relation to arrhythmogenesis. However, the small size of the cardiac nerves in relatively large tissues renders research using histological quantification of these nerves extremely challenging and usually relies on quantification of the nerve density in selected regions of interest only. Our aim was to develop a method to be able to quantify the histological nerve density in transmural tissue sections. METHODS: Here we describe a novel workflow that enables visualization and quantification of variable innervation types and their heterogeneity within transmural myocardial tissue sections. A custom semiautomatic workflow for the quantification of cardiac nerves involving Python, MATLAB and ImageJ is provided and described in this protocol in a stepwise and detailed manner. REPRESENTATIVE RESULTS: The results of two example tissue sections are represented in this paper. An example tissue section taken from the infarction core with a high heterogeneity value of 0.20, 63.3% normal innervation, 12.2% hyperinnervation, 3.6% hypoinnervation and 21.0% denervation. The second example tissue section taken from an area of the left ventricle remote from the infarction showed a low heterogeneity value of 0.02, 95.3% normal innervation, 3.8% hyperinnervation, 0.5% hypoinnervation and 0.5% denervation. CONCLUSIONS: This approach has the potential to be broadly applied to any research involving high-resolution imaging of nerves in large tissues.

Cardiac sympathetic hyperinnervation after myocardial infarction: a systematic review and qualitative analysis.

BACKGROUND: Cardiac sympathetic hyperinnervation after myocardial infarction (MI) is associated with arrhythmogenesis and sudden cardiac death. The characteristics of cardiac sympathetic hyperinnervation remain underexposed. OBJECTIVE: To provide a systematic review on cardiac sympathetic hyperinnervation after MI, taking into account: (1) definition, experimental model and quantification method and (2) location, amount and timing, in order to obtain an overview of current knowledge and to expose gaps in literature. METHODS: References on cardiac sympathetic hyperinnervation were screened for inclusion. The included studies received a full-text review and quality appraisal. Relevant data on hyperinnervation were collected and qualitatively analysed. RESULTS: Our literature search identified 60 eligible studies performed between 2000 and 2022. Cardiac hyperinnervation is generally defined as an increased sympathetic nerve density or increased number of nerves compared to another control group (100%). Studies were performed in a multitude of experimental models, but most commonly in male rats with permanent left anterior descending (LAD) artery ligation (male: 63%, rat: 68%, permanent ligation: 93%, LAD: 97%). Hyperinnervation seems to occur mainly in the borderzone. Quantification after MI was performed in regions of interest in µm2/mm2 (41%) or in percentage of nerve fibres (46%) and the reported amount showed a great variation ranging from 439 to 126,718 µm2/mm2. Hyperinnervation seems to start from three days onwards to >3 months without an evident peak, although studies on structural evaluation over time and in the chronic phase were scarce. CONCLUSIONS: Cardiac sympathetic hyperinnervation after MI occurs mainly in the borderzone from three days onwards and remains present at later timepoints, for at least 3 months. It is most commonly studied in male rats with permanent LAD ligation. The amount of hyperinnervation differs greatly between studies, possibly due to differential quantification methods. Further studies are required that evaluate cardiac sympathetic hyperinnervation over time and in the chronic phase, in transmural sections, in the female sex, and in MI with reperfusion.

KEY MESSAGESCardiac sympathetic hyperinnervation occurs three days after MI mainly in the borderzone and remains present at all timepoints.It is most commonly studied in male rats with permanent LAD ligation.The amount of hyperinnervation differs greatly between studies, possibly due to the differential quantification methods.

Anomalous Aortic Origin of the Right Coronary Artery: Invasive Haemodynamic Assessment in Adult Patients With High-Risk Anatomic Features.

Background: Anomalous aortic origin of a right coronary artery (AAORCA) with an interarterial course merits further evaluation; however, robust risk assessment strategies for myocardial ischemia and sudden cardiac death are currently lacking. The aim of this study is to explore the potential role of fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), and intravascular ultrasound (IVUS) in patients with AAORCA. Methods: Consecutive adult patients with AAORCA with an interarterial course were included. Computed tomography angiography, noninvasive ischemia detection, and FFR, iFR, and IVUS were performed at baseline and during adrenaline-induced stress. External compression was evaluated with IVUS. Results: Eight patients (63% female, mean age: 53 ± 9.5 years) were included. Five patients (63%) were symptomatic, and computed tomography angiography revealed high-risk anatomy of the AAORCA in all patients. Only in 1 (12.5%) patient FFR and iFR were positive; however, this was attributed at large to concomitant diffuse atherosclerosis. In 2 of 8 (25%), IVUS revealed external compression; however, the ostial coronary surface area remained unchanged. In all patients, a conservative treatment strategy was pursued. During a mean follow-up of 29.3 months (standard deviation ±2.6 months), symptoms spontaneously disappeared in 4 of 5 (80%) and no adverse cardiac events occurred in any of the patients. Conclusions: Despite the presence of high-risk anatomy in all patients, none had proven ischemia prompting a conservative treatment strategy. No adverse cardiac events occurred during follow-up, and in the majority of patients, symptoms spontaneously disappeared. Therefore, FFR, iFR, and IVUS with pharmacologic stress merit further investigation and might contribute to ischemia-based risk stratification and management strategies in adult patients with AAORCA.

Contexte: L'anomalie de naissance de l'artère coronaire droite à partir de l'aorte (AAORCA, anomalous aortic origin of a right coronary artery) combinée à un trajet interartériel mérite un examen plus approfondi. Cependant, on observe à l'heure actuelle des lacunes en ce qui a trait à l'emploi de stratégies fiables d'évaluation du risque d'ischémie myocardique et de mort subite d'origine cardiaque. L'objectif de cette étude est d'examiner le rôle potentiel de la mesure de la réserve coronarienne (MRC), de l'évaluation du rapport instantané sans onde (iFR, instantaneous wave-free ratio) et de l'échographie intravasculaire chez des patients présentant une AAORCA. Méthodologie: Des cas de patients adultes consécutifs présentant une AAORCA combinée à un trajet interartériel ont été inclus à l'étude. Une angiographie par tomodensitométrie (TDM), une détection non invasive de la présence d'une ischémie, la MRC, l'évaluation de l'iFR et l'échographie intravasculaire ont été effectuées au début de l'étude ainsi que lors d'un stress induit par l'adrénaline. La compression externe a également été évaluée au moyen d'une échographie intravasculaire. Résultats: Huit patients (63 % de sexe féminin; âge moyen de 53 ans ± 9,5 ans) ont participé à l'étude. Cinq patients (63 %) présentaient des symptômes, et l'angiographie par TDM a révélé une AAORCA à risque élevé chez tous les patients. Les résultats de la MRC et de l'évaluation de l'iFR étaient positifs chez seulement un patient (12,5 %), ce qui est attribuable en majeure partie à une athérosclérose diffuse concomitante. Chez deux patients (25 %), l'échographie intravasculaire a montré une compression externe de l'artère coronaire droite même si l'aire de l'ostium de l'artère n'avait pas changé. Une stratégie thérapeutique prudente a été employée pour tous les patients. Pendant la période de suivi qui a duré en moyenne 29,3 mois (écart-type : ± 2,6 mois), les symptômes se sont résorbés de manière spontanée chez quatre des cinq patients (80 %), et aucun événement cardiaque indésirable n'est survenu. Conclusion: Malgré une anatomie à risque élevé chez tous les patients, aucun d'entre eux ne présentait une ischémie connue, ce qui justifiait une stratégie thérapeutique prudente. Aucun événement cardiaque indésirable n'est survenu durant la période de suivi, et les symptômes se sont résorbés de manière spontanée chez la majorité des patients. À la lumière de ces renseignements, la MRC, l'évaluation de l'iFR et l'échographie intravasculaire lors d'un stress pharmacologique devraient faire l'objet d'autres études et pourraient éventuellement être utiles dans la stratification du risque d'ischémie et dans le choix des stratégies de prise en charge des patients adultes présentant une AAORCA.

Catheter-Based Techniques for Addressing Atrioventricular Valve Regurgitation in Adult Congenital Heart Disease Patients: A Descriptive Cohort.

INTRODUCTION: Increasing survival of adult congenital heart disease (ACHD) patients comes at the price of a range of late complications-arrhythmias, heart failure, and valvular dysfunction. Transcatheter valve interventions have become a legitimate alternative to conventional surgical treatment in selected acquired heart disease patients. However, literature on technical aspects, hemodynamic effects, and clinical outcomes of percutaneous atrioventricular (AV) valve interventions in ACHD patients is scarce. METHOD: This is a descriptive cohort from CAHAL (Center of Congenital Heart Disease Amsterdam-Leiden). ACHD patients with severe AV valve regurgitation who underwent a transcatheter intervention in the period 2020-2022 were included. Demographic, clinical, procedural, and follow-up data were collected from patient records. RESULTS: Five ACHD patients with severe or torrential AV valve regurgitation are described. Two patients underwent a transcatheter edge-to-edge repair (TEER), one patient underwent a valve-in-valve procedure, one patient received a Cardioband system, and one patient received both a Cardioband system and TEER. No periprocedural complications occurred. Post-procedural AV valve regurgitation as well as NYHA functional class improved in all patients. The median post-procedural NYHA functional class improved from 3.0 (IQR [2.5-4.0]) to 2.0 (IQR [1.5-2.5]). One patient died 9 months after the procedure due to advanced heart failure with multiorgan dysfunction. CONCLUSION: Transcatheter valve repair is feasible and safe in selected complex ACHD patients. A dedicated heart team is essential for determining an individualized treatment strategy as well as pre- and periprocedural imaging to address the underlying mechanism(s) of AV regurgitation and guide the transcatheter intervention. Long-term follow-up is essential to evaluate the clinical outcomes of transcatheter AV valve repair in ACHD patients.

Virtual surgery to predict optimized conduit size for adult Fontan patients with 16-mm conduits.

OBJECTIVES: Recent evidence suggests that conduits implanted in Fontan patients at the age of 2-4 years become undersized for adulthood. The objective of this study is to use computational fluid dynamic models to evaluate the effect of virtual expansion of the Fontan conduit on haemodynamics and energetics of the total cavopulmonary connection (TCPC) under resting conditions and increased flow conditions. METHODS: Patient-specific, magnetic resonance imaging-based simulation models of the TCPC were performed during resting and increased flow conditions. The original 16-mm conduits were virtually enlarged to 3 new sizes. The proposed conduit sizes were defined based on magnetic resonance imaging-derived conduit flow in each patient. Flow efficiency was evaluated based on power loss, pressure drop and resistance and thrombosis risk was based on flow stagnation volume and relative residence time (RRT). RESULTS: Models of 5 adult patients with a 16-mm extracardiac Fontan connection were simulated and subsequently virtually expanded to 24-32 mm depending on patient-specific conduit flow. Virtual expansion led to a 40-65% decrease in pressure gradient across the TCPC depending on virtual conduit size. Despite improved energetics of the entire TCPC, the pulmonary arteries remained a significant contributor to energy loss (60-73% of total loss) even after virtual surgery. Flow stagnation volume inside the virtual conduit and surface area in case of elevated RRT (>20/Pa) increased after conduit enlargement but remained negligible (flow stagnation <2% of conduit volume in rest, <0.5% with exercise and elevated RRT <3% in rest, <1% with exercise). CONCLUSIONS: Virtual expansion of 16-mm conduits to 24-32 mm, depending on patient-specific conduit flow, in Fontan patients significantly improves TCPC efficiency while thrombosis risk presumably remains low.

Quantification of Large Transmural Biopsies Reveals Heterogeneity in Innervation Patterns in Chronic Myocardial Infarction.

BACKGROUND: Abnormal cardiac innervation plays an important role in arrhythmogenicity after myocardial infarction (MI). Data regarding reperfusion models and innervation abnormalities in the medium to long term after MI are sparse. Histologic quantification of the small-sized cardiac nerves is challenging, and transmural analysis has not been performed. OBJECTIVES: This study sought to assess cardiac innervation patterns in transmural biopsy sections in a porcine reperfusion model of MI (MI-R) using a novel method for nerve quantification. METHODS: Transmural biopsy sections from 4 swine (n = 83) at 3 months after MI-R and 3 controls (n = 38) were stained with picrosirius red (fibrosis) and beta-III-tubulin (autonomic nerves). Biopsy sections were classified as infarct core, border zone, or remote zone. Each biopsy section was analyzed with a custom software pipeline, allowing calculation of nerve density and classification into innervation types at the 1 × 1-mm resolution level. Relocation of the classified squares to the original biopsy position enabled transmural quantification and innervation heterogeneity assessment. RESULTS: Coexisting hyperinnervation, hypoinnervation, and denervation were present in all transmural MI-R biopsy sections. The innervation heterogeneity was greatest in the infarct core (median: 0.14; IQR: 0.12-0.15), followed by the border zone (median: 0.05; IQR: 0.04-0.07; P = 0.02) and remote zone (median: 0.02; IQR: 0.02-0.03; P < 0.0001). Only in the border zone was a positive linear relation between fibrosis and innervation heterogeneity observed (R = 0.79; P < 0.0001). CONCLUSIONS: This novel method allows quantification of nerve density and heterogeneity in large transmural biopsy sections. In the chronic phase after MI-R, alternating innervation patterns were identified within the same biopsy section. Persistent innervation heterogeneity, in particular in the border zone biopsy sections, may contribute to late arrhythmogenicity.

The potential of sodium-glucose cotransporter 2 inhibitors for the treatment of systemic right ventricular failure in adults with congenital heart disease.

Aims: Given the compelling evidence on the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the conventional heart failure population, SGLT2i deserve exploration in systemic right ventricular (sRV) failure. The initial experience with dapagliflozin in sRV failure patients is described, with a focus on tolerability and short-term effects on clinical outcomes. Methods and results: Ten patients (70% female, median age 50 years [46.5-52]) with symptomatic sRV failure who received dapagliflozin 10 mg per day on top of optimal medical therapy between 04-2021 and 01-2023 were included. Within 4 weeks, no significant changes in blood pressure, electrolytes, or serum glucose occurred. Creatinine and estimated glomerular filtration rate (eGFR) showed a slight decline (88 ± 17 to 97 ± 23 µmol/L, p = 0.036, and 72 ± 14 vs. 66 ± 16 ml/min/1.73m2, p = 0.020, respectively). At 6 months follow-up (n = 8), median NT-proBNP decreased significantly from 736.6 [589.3-1193.3] to 531.6 [400.8-1018] ng/L (p = 0.012). Creatinine and eGFR recovered to baseline levels. There were no significant changes in echocardiographic systolic sRV or left ventricular function. New York Heart Association class improved significantly in 4 out of 8 patients (p = 0.046), who also showed an improvement in the 6-minute walk test or bicycle exercise test performance. One female patient developed an uncomplicated urinary tract infection. No patients discontinued treatment. Conclusion: Dapagliflozin was well-tolerated in this small cohort of sRV failure patients. While the early results on the reduction of NT-proBNP and clinical outcome parameters are encouraging, large-scale prospective studies are warranted to thoroughly evaluate the effects of SGLT2i in the growing sRV failure population.

The R″ wave in V1 and the negative terminal QRS vector in aVF combine to a novel 12-lead ECG algorithm to identify slow conducting anatomical isthmus 3 in patients with tetralogy of Fallot.

AIMS: Patients with repaired tetralogy of Fallot (rTOF) have an increased risk of ventricular tachycardia (VT), with slow conducting anatomical isthmus (SCAI) 3 as dominant VT substrate. In patients with right bundle branch block (RBBB), SCAI 3 leads to local activation delay with a shift of terminal RV activation towards the lateral RV outflow tract which may be detected by terminal QRS vector changes on sinus rhythm electrocardiogram (ECG). METHODS AND RESULTS: Consecutive rTOF patients aged ≥16 years with RBBB who underwent electroanatomical mapping at our institution between 2017-2022 and 2010-2016 comprised the derivation and validation cohort, respectively. Forty-six patients were included in the derivation cohort (aged 40±15 years, QRS duration 165±23 ms). Among patients with SCAI 3 (n = 31, 67%), 17 (55%) had an R″ in V1, 18 (58%) had a negative terminal QRS portion (NTP) ≥80 ms in aVF, and 12 (39%) had both ECG characteristics, compared to only 1 (7%), 1 (7%), and 0 patient without SCAI, respectively.Combining R″ in V1 and/or NTP ≥80 ms in aVF into a diagnostic algorithm resulted in a sensitivity of 74% and specificity of 87% in detecting SCAI 3. The inter-observer agreement for the diagnostic algorithm was 0.875. In the validation cohort [n = 33, 18 (55%) with SCAI 3], the diagnostic algorithm had a sensitivity of 83% and specificity of 80% for identifying SCAI 3. CONCLUSION: A sinus rhythm ECG-based algorithm including R″ in V1 and/or NTP ≥80 ms in aVF can identify rTOF patients with a SCAI 3 and may contribute to non-invasive risk stratification for VT.

Tolerability and beneficial effects of sacubitril/valsartan on systemic right ventricular failure.

OBJECTIVE: Patients with a systemic right ventricle (sRV) in the context of transposition of the great arteries (TGA) after atrial switch or congenitally corrected TGA (ccTGA) are prone to sRV dysfunction. Pharmacological options for sRV failure remain poorly defined. This study aims to investigate the tolerability and effects of sacubitril/valsartan on sRV failure in adult patients with sRV. METHODS: In this two-centre, prospective cohort study, all consecutive adult patients with symptomatic heart failure and at least moderately reduced sRV systolic function were initiated on sacubitril/valsartan and underwent structured follow-up. RESULTS: Data of 40 patients were included (40% female, 30% ccTGA, median age 48 (44-53) years). Five patients discontinued therapy during titration. Median follow-up was 24 (12-36) months. The maximal dose was tolerated by 49% of patients. No episodes of hyperkalaemia or renal function decline occurred. Six-minute walking distance increased significantly after 6 months of treatment (569±16 to 597±16 m, p=0.016). Serum N-terminal-prohormone brain natriuretic peptide (NT-proBNP) levels decreased significantly after 3 months (567 (374-1134) to 404 (226-633) ng/L, p<0.001). Small, yet consistent echocardiographic improvements in sRV function were observed after 6 months (sRV global longitudinal strain: -11.1±0.5% to -12.6±0.7%, p<0.001, and fractional area change: 20% (16%-24%) to 26% (19%-30%), p<0.001). The linear mixed-effects model illustrated that after first follow-up moment, no time effect was present for the parameters. CONCLUSIONS: Treatment with sacubitril/valsartan was associated with a low rate of adverse effects in this adult sRV cohort. Persisting improvement in 6-minute walking test distance, NT-proBNP levels and echocardiographic parameters of sRV function was observed in an on-treatment analysis and showed no differential response based on sex or anatomy.

Genetic variant in the BRAF gene compatible with Noonan spectrum disorders in an adult Fontan patient with refractory protein losing enteropathy: a follow-up report.

Background: Patients with a univentricular heart form a morphological heterogenous group of patients at the most severe end of the congenital heart disease (CHD) spectrum. Over the past decades, more awareness and knowledge has been raised on the genetic contributions to CHD. To date, only a limited number of genes have been identified in the hypoplastic heart, mainly in left-sided hypoplasia. There is still much more to be elucidated in this field. Case summary: Here, we present a follow-up report of a case of an adult patient after Fontan palliation, born with a.o. tricuspid atresia with hypoplastic right ventricle and pulmonary stenosis. This patient encountered a myriad of late sequalae involving multiple organ systems during the course of his young adult life, including refractory protein losing enteropathy (PLE). Concomitant extracardiac anomalies, in addition to the complex CHD and its complications, prompted for genetic evaluation. Whole exome sequencing showed a variant of uncertain significance in the BRAF gene [NM_004333.4:c.1897T > C p.(Tyr633His)], associated with Noonan spectrum disorders, that is also infamous for lymphoedema and PLE. The variant regards an evolutionarily highly conserved amino acid and is assumed pathogenic according to all prediction programmes. The mutation was most likely de novo. Discussion: Genetic screening can provide new insights in the complex and varied phenotype of the (adult) Fontan patient and in the myriad of complications encountered. Adult CHD cardiologists should be aware of genetic syndromes underlying a CHD, concomitant extracardiac anomalies, and a complex clinical course with a broad spectrum of late sequelae.

Cardiac Fibrosis and Innervation State in Uncorrected and Corrected Transposition of the Great Arteries: A Postmortem Histological Analysis and Systematic Review.

In the transposition of the great arteries (TGA), alterations in hemodynamics and oxygen saturation could result in fibrotic remodeling, but histological studies are scarce. We aimed to investigate fibrosis and innervation state in the full spectrum of TGA and correlate findings to clinical literature. Twenty-two human postmortem TGA hearts, including TGA without surgical correction (n = 8), after Mustard/Senning (n = 6), and arterial switch operation (ASO, n = 8), were studied. In newborn uncorrected TGA specimens (1 day-1.5 months), significantly more interstitial fibrosis (8.6% ± 3.0) was observed compared to control hearts (5.4% ± 0.8, p = 0.016). After the Mustard/Senning procedure, the amount of interstitial fibrosis was significantly higher (19.8% ± 5.1, p = 0.002), remarkably more in the subpulmonary left ventricle (LV) than in the systemic right ventricle (RV). In TGA-ASO, an increased amount of fibrosis was found in one adult specimen. The amount of innervation was diminished from 3 days after ASO (0.034% ± 0.017) compared to uncorrected TGA (0.082% ± 0.026, p = 0.036). In conclusion, in these selected postmortem TGA specimens, diffuse interstitial fibrosis was already present in newborn hearts, suggesting that altered oxygen saturations may already impact myocardial structure in the fetal phase. TGA-Mustard/Senning specimens showed diffuse myocardial fibrosis in the systemic RV and, remarkably, in the LV. Post-ASO, decreased uptake of nerve staining was observed, implicating (partial) myocardial denervation after ASO.

Contemporary Management Strategies of Baffle Leaks in Adults with a Failing Systemic Right Ventricle Late after Atrial Switch: A Case Series and Literature Overview.

Baffle leaks are a frequently encountered and often overlooked complication after the atrial switch procedure for transposition of the great arteries. Baffle leaks are present in up to 50% of non-selected patients, and while they initially may not cause clear symptoms, they can complicate the hemodynamic course and influence the prognosis in this complex patient group. A shunt from the pulmonary venous atrium (PVA) to the systemic venous atrium (SVA) can lead to pulmonary overflow and subpulmonary left ventricular (LV) volume overload, while a shunt from the SVA to the PVA can result in (exercise-associated) cyanosis and paradoxical embolism. We report three cases of baffle leaks in patients with systemic right ventricular (sRV) failure late after the atrial switch procedure. Two symptomatic patients who presented with exercise-associated cyanosis due to SVA to PVA shunting over the baffle leak underwent successful percutaneous baffle leak closure with a septal occluder device. One patient with overt sRV failure and signs of subpulmonary LV volume overload due to PVA to SVA shunting was managed conservatively, as baffle leak closure was expected to lead to an increase in sRV end-diastolic pressure and aggravation of sRV dysfunction. These three cases illustrate the considerations made, challenges faced, and necessity of a patient-tailored approach when addressing baffle leaks.

Outcomes of the modified Yacoub aortocoronary flap technique for 'non-separable' single sinus coronary arteries with intramural course in the neonatal arterial switch operation.

OBJECTIVES: Coronary transfer remains the most crucial part of the arterial switch operation (ASO); yet, certain coronary anatomies prohibit the use of button or trap-door transfer techniques. In the rare setting of 'non-separable' single sinus coronary arteries with intramural course, the modified Yacoub aortocoronary flap technique is a viable option. The aim of this study is to describe this operative technique and review its early- and mid-term outcomes. METHODS: This retrospective analysis included all cases with 'non-separable' single sinus coronary arteries with intramural course where the modified Yacoub aortocoronary flap technique served as a bail-out option. RESULTS: Of 516 patients who underwent ASO at our institution between January 1977 and April 2022, 14 underwent the modified Yacoub aortocoronary flap technique. The median age at ASO was 10 (interquartile range 7-19) days. Hospital mortality occurred in 3 patients (21.4%), all being related to coronary complications. All hospital survivors were still alive at a median of 9.1 (interquartile range 4.2-18.3) years after the ASO. None of them developed complaints of ischaemia, ventricular arrhythmias, ventricular dysfunction or exercise intolerance. Surveillance computed tomography angiography showed stable aortocoronary relationships free from stenosis, compression and kinking. No reoperations for coronary artery problems and/or neoaortic valve or root problems were needed. CONCLUSIONS: Although close monitoring of early coronary events seems crucial to prevent perioperative mortality, the modified Yacoub aortocoronary flap technique may serve as a viable bail-out option in patients with 'non-separable' single sinus coronary anatomy with intramural course, with excellent results among hospital survivors.