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.

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.

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.

Atrioventricular Block Necessitating Chronic Ventricular Pacing After Tricuspid Valve Surgery in Patients With a Systemic Right Ventricle: Long-Term Follow-Up.

Background: Patients with transposition of the great arteries (TGA) after an atrial switch or congenitally corrected TGA (ccTGA) are prone to systemic right ventricular (sRV) failure. Tricuspid valve (TV) regurgitation aggravates sRV dysfunction. Timely TV surgery stabilizes sRV function, yet the development of atrioventricular (AV)-conduction disturbances in the course of sRV failure can contribute to sRV dysfunction through pacing-induced dyssynchrony. This study aims to explore the incidence, timing, and functional consequences of AV-block requiring ventricular pacing after TV surgery in patients with sRV. Methods: Consecutive adolescent and adult patients with an sRV who underwent TV surgery between 1989 and 2020 and followed-up at our center were included in this observational cohort study. Results: The data of 28 patients (53% female, 57% ccTGA, and a mean age at surgery 38 ± 13 years) were analyzed. The mean follow-up was 9.7 ± 6.8 years. Of the remaining 22 patients at the risk of developing high degree AV-block after TV surgery, 9 (41%) developed an indication for chronic ventricular pacing during follow-up, of which 5 (56%) within 24 months postoperatively (3 prior to hospital discharge). The QRS duration, a surrogate marker for dyssynchrony, was significantly higher in patients with chronic left ventricular pacing than in patients with native AV-conduction (217 ± 24 vs. 116 ± 23 ms, p = 0.000), as was the heart failure biomarker NT-pro-BNP [2,746 (1,242-6,879) vs. 495 (355-690) ng/L, p = 0.004] and the percentage of patients with ≥1 echocardiographic class of deterioration of systolic sRV function (27 vs. 83%, p = 0.001). Of the patients receiving chronic subpulmonary ventricular pacing (n = 12), 9 (75%) reached the composite endpoint of progressive heart failure [death, ventricular assist device implantation, or upgrade to cardiac resynchronization therapy (CRT)]. Only 4 (31%) patients with native AV-conduction (n = 13) reached this composite endpoint (p = 0.027). Conclusion: Patients with a failing sRV who undergo TV surgery are prone to develop AV-conduction abnormalities, with 41% developing an indication for chronic ventricular pacing during 10 years of follow-up. Patients with chronic subpulmonary ventricular pacing have a significantly longer QRS complex duration, have higher levels of the heart failure biomarker NT-pro-BNP, and are at a higher risk of deterioration of systolic sRV function and progressive heart failure.

Successful hybrid cardiac resynchronization therapy in a patient with failing systemic right ventricle and significant tricuspid regurgitation in transposition of the great arteries after atrial switch procedure according to Mustard.

Background: Patients with a systemic right ventricle (sRV) in the context of transposition of the great arteries (TGA) late after atrial switch are prone to heart failure. Complications like tricuspid valve regurgitation (TR) can further aggravate sRV dysfunction. Tricuspid valve regurgitation is usually secondary to annular dilatation and restriction. Criteria for cardiac resynchronization therapy (CRT) in this patient group are not well defined and should be considered on a case-by-case basis. Case summary: We present a case of a 42-year-old male with sRV failure and TR in the context of TGA after atrial switch. Patient had progressive reduction in exercise capacity. Electrocardiogram showed a wide QRS complex (right bundle branch block configuration). Echocardiography showed significant TR and signs of electromechanical dyssynchrony of the failing sRV with severely reduced systolic function. He underwent heart catheterization and invasive haemodynamic evaluation to assess the potential benefit of CRT. During sequential atrial-sRV pacing, 20% increase in Dp/Dt was measured, suggesting that he would be a CRT responder. Concomitant angiography showed no baffle leakage nor obstructive coronary artery disease. Hybrid CRT-defibrillator implantation resulted in successful resynchronization and improved sRV function, reduced TR and better exercise capacity. Discussion: Invasive haemodynamic contractility evaluation can help assess the potential benefit of CRT in patients with systemic right ventricular failure in the context of transposition of TGA after atrial switch. Successful CRT can result in improved sRV function, reduced TR and improved exercise capacity.

The first experience with sodium-glucose cotransporter 2 inhibitor for the treatment of systemic right ventricular failure.

In congenitally corrected transposition of the great arteries, the morphological right ventricle supports the systemic circulation. This chronic exposure to pressure overload ultimately leads to systemic right ventricular (sRV) dysfunction and heart failure. Pharmacological options for the treatment of sRV failure are poorly defined and no solid recommendations are made in the most recent guidelines. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a new class of antihyperglycaemic drugs that have been demonstrated to significantly reduce the risk of worsening heart failure and death from cardiovascular causes in patients with chronic heart failure with reduced left ventricular ejection fraction, yet no data are available in sRV patients. We report on the treatment and clinical follow-up of a patient with advanced heart failure and poor sRV function in the context of congenitally corrected transposition of the great arteries, who did not tolerate sacubitril/valsartan and had a high burden of heart-failure-related hospitalizations. Treatment with dapagliflozin was well tolerated and resulted in (small) subjective and objective functional and echocardiographic improvement and a reduction in heart-failure-related hospitalizations.

Case report of the broad spectrum of late complications in an adult patient with univentricular physiology palliated by the Fontan circulation.

BACKGROUND: At the most severe end of the spectrum of congenital heart disease are patients with an univentricular physiology. They comprise a heterogeneous group of congenital heart malformations that have the common characteristic that the cardiac morphology is not equipped for sustaining a biventricular circulation. CASE SUMMARY: Here, we present a case of an adult patient after Fontan palliation, illustrative of the complex clinical course and the broad spectrum of complications that can be encountered during follow-up, highlighting the need for a multidisciplinary approach in the clinical care for these patients. DISCUSSION: During the surgical Fontan procedure, the inferior vena cava is connected to the pulmonary circulation, after prior connection of the superior vena cava to the pulmonary arterial circulation. The resulting cavopulmonary connection, thus lacking a subpulmonic ventricle, provides non-pulsatile passive flow of oxygen-poor blood from the systemic venous circulation into the lungs, and the functional monoventricle pumps the oxygen-rich pulmonary venous return blood into the aorta. With an operative mortality of <5% and current 30-year survival rates up to 85%, the adult population of patients with a Fontan circulation is growing. This increase in survival is, however, inevitably accompanied by long-term complications affecting multiple organ systems, resulting in decline in cardiovascular performance. CONCLUSION: For optimal treatment, the evaluation in a multidisciplinary team is mandatory, using the specific expertise of the team members to timely detect and address late complications and to support quality of life.

Failing systemic right ventricle in a patient with dextrocardia and complex congenitally corrected transposition of the great arteries: a case report of successful transvenous cardiac resynchronization therapy.

BACKGROUND: Patients with congenitally corrected transposition of the great arteries (ccTGA) are prone to the development of advanced atrio-ventricular block requiring chronic ventricular pacing. The morphological right ventricle (RV) often develops systolic dysfunction as it is unable to withstand the chronic pressure overload it is exposed to when supporting the systemic circulation. CASE SUMMARY: A 56-year-old woman with dextrocardia and complex ccTGA with a history of dual-chamber implantable cardioverter-defibrillator (DDD-ICD, high degree atrio-ventricular-block and syncopal ventricular tachycardia), presented with progressive heart failure and symptomatic atrial arrhythmias. She underwent a successful ablation and concomitant invasive haemodynamic evaluation of potential alternative/biventricular pacing modalities. During biventricular pacing, the QRS narrowed and the systemic RV intraventricular pressure (Dp/Dt) increased with 30%. She underwent a successful transvenous upgrade to cardiac resynchronization therapy (CRT). The electrocardiogram post-implantation showed biventricular capture and patient showed subjective and objective clinical improvement. DISCUSSION: Systemic RV dysfunction in ccTGA can be aggravated by chronic pacing-induced dyssynchrony, contributing to progression of heart failure in this patient group. Transvenous CRT is feasible in ccTGA anatomy and may be pursued in order to improve or preserve the functional status of pacing-dependent ccTGA patients. Invasive haemodynamic contractility evaluation can help assess the potential benefit of CRT in patients with complex anatomy.

Sacubitril/valsartan in the treatment of systemic right ventricular failure.

OBJECTIVE: Pharmacological options for patients with a failing systemic right ventricle (RV) in the context of transposition of the great arteries (TGA) after atrial switch or congenitally corrected TGA (ccTGA) are not well defined. This study aims to investigate the feasibility and effects of sacubitril/valsartan treatment in a single-centre cohort of patients. METHODS: Data on all consecutive adult patients (n=20, mean age 46 years, 50% women) with a failing systemic RV in a biventricular circulation treated with sacubitril/valsartan in our centre are reported. Patients with a systemic RV ejection fraction of ≤35% who were symptomatic despite treatment with ß-blocker and ACE-inhibitor/angiotensin II receptor-blockers were started on sacubitril/valsartan. This cohort underwent structural follow-up including echocardiography, exercise testing, laboratory investigations and quality of life (QOL) assessment. RESULTS: Six-month follow-up data were available in 18 out of 20 patients, including 12 (67%) patients with TGA after atrial switch and 6 (33%) patients with ccTGA. N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) decreased significantly (950-358 ng/L, p<0.001). Echocardiographic systemic RV fractional area change and global longitudinal strain showed small improvements (19%-22%, p<0.001 and -11% to -13%, p=0.014, respectively). The 6 min walking distance improved significantly from an average of 564 to 600 m (p=0.011). The QOL domains of cognitive function, sleep and vitality improved (p=0.015, p=0.007 and p=0.037, respectively). CONCLUSIONS: We describe the first patient cohort with systemic RV failure treated with sacubitril/valsartan. Treatment appears feasible with improvements in NT-pro-BNP and echocardiographic function. Our positive results show the potential of sacubitril/valsartan for this patient population.

Potential of eHealth smart technology in optimization and monitoring of heart failure treatment in adults with systemic right ventricular failure.

Aims: Patients with a systemic right ventricle (sRV) in the context of transposition of the great arteries (TGA) after atrial switch or congenitally corrected TGA are prone to heart failure and arrhythmias. This study evaluated feasibility, patient adherence, and satisfaction of a smart technology-based care pathway for heart failure treatment optimization in these patients. Methods and results: Patients with symptomatic sRV failure eligible for initiation of sacubitril/valsartan were provided with four smartphone compatible devices (blood pressure monitor, weight scale, step counter, and rhythm monitor) and were managed according to a smart technology-based care pathway. Biweekly sacubitril/valsartan titration visits were replaced by electronical visits, patients were advised to continue measurements at least weekly after titration. Data of 24 consecutive sRV patients (median age 47 years, 50% female) who participated in the smart technology-based care pathway were analysed. Median home-hospital distance was 65 km (maximum 227 km). Most patients (20, 83.3%) submitted weekly measurements; 100% submitted prior to electronical visits. Titration conventionally occurs during a hospital visit. By implementing eHealth smart technology, 68 such trips to hospital were replaced by virtual visits facilitated by remote monitoring. An eHealth questionnaire was completed by 22 patients (92%), and 96% expressed satisfaction. After titration, 30 instances of remote adjustment of heart failure medication in addition to scheduled outpatient clinic visits occurred, one (4%) heart failure admission followed, despite ambulant adjustments. Five patients (21%) sent in rhythm registrations (n = 17), of these 77% showed sinus rhythm, whereas supraventricular tachycardia was detected in the remaining four registrations. Conclusion: These data suggest that implementation of a smart technology-based care pathway for optimization of medical treatment sRV failure is feasible with high measurement adherence and patient satisfaction.