Clinical trial NCT06258083: Systemic Right Ventricle Long-term Outcome
Official title: Systemic Right Ventricle Long-term Outcome: a Multicentre Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Transposition of the Great Arteries
Systemic Right Ventricle
Keywords: Long-term outcome
Heart failure
Arrhythmias
Mortality
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Hartekind
name: Hartstichting
First posted: 2024-02-14
Enrollment: 542
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with systemic right ventricles who are followed up in different academic centers in the Netherlands and Belgium.

Brief summary: Patients with the transposition of great arteries (TGA) who undergo atrial switch operation and congenitally corrected TGA (ccTGA) patients have the right ventricle as their systemic ventricle. Function of the systemic right ventricle (SRV) could deteriorate which is associated with impaired prognosis. It is of paramount importance to understand the course and fate of these patients during a long-term follow-up to identify the determinants of adverse outcomes.

Detailed description: In the year 2000, the prevalence of congenital heart diseases (CHD) patients with transposition of great arteries (TGA) was 0.027% in living children and 0.004% in living adults (1). Considering a complete transition to arterial switch operation in the 1990s, it is expected that the number of patients with systemic right ventricle (SRV) decrease over time (2). However, considering the existing number of patients with the TGA who have not undergone arterial switch surgery, SRV remains a challenging issue in the practice of adult congenital heart disease (ACHD) specialists.

TGA is characterized by AV concordance and ventriculo-arterial discordance and is called simple without the presence of associated congenital anomalies. However, complex TGA is when other anomalies are present including VSD (∼45%), LVOTO (∼25%), and CoA (∼5%). TGA's pathogenesis is controversial and there is rare familial occurrence. Male are two times more affected than females. The prognosis of TGA patients without surgery is poor and only exceptional cases survive to adulthood (3).

Heart failure and sudden cardiac death (SCD) are the predominant causes of mortality in TGA patients (4). Patients who undergo atrial switch operation and congenitally corrected TGA (ccTGA) patients are at risk of developing SRV failure in the future (3). The RV is a thin-walled triangular structure acting as a low pressure pump in the normal heart. Because of having only 2 layers, the RV cannot cause the torsion caused by the LV. Due to this geometry and anatomy, the right ventricular function is highly dependent on the loading conditions. The increased afterload that the RV faces in the systemic position causes compensatory RV dilation to maintain the stroke volume. Subsequently, there is increased myocardial wall stress and oxygen demand. The development of heart failure in the SRV is multifactorial. Other potential factors contributing to the SRV failure are impaired coronary reserve or ischemia, myocardial fibrosis, chronotropic incompetence, volume overload from tricuspid regurgitation and arrhythmias (4). Another contributing factor is the reduced baffle compliance in patients with atrial switch. This impairs the preload and stroke volume, especially when there is increased demand. The non-contractile atrial baffles cause impaired atrioventricular transport during tachycardia, therefore causing an inadequate RV filling (4).

Unfortunately, at the moment, the hypothesis that angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers (ARBs), aldosterone antagonists, and beta-blockers can improve the outcome of such patients alone or in combination is not supported by data and evidence. There is no solid recommendation in the 2020 guidelines for the management of ACHD (3).

Previous studies evaluating the fate and outcome of patients with an SRV are either mostly single-centered with a small number of patients or have a short follow-up period (5,6). In a study done by Richard Dobson and colleagues on a national cohort in Scotland, the investigators concluded that patients with an SRV who survive to adulthood have low mortality and good functional status up to the age of 40 (7).

It is of paramount importance to understand the course and fate of these patients during a long-term follow-up to identify the determinants of adverse outcomes. This will enable the investigators to investigate mechanistic pathways of such outcomes. By understanding the risk factors and pathophysiological basis, the investigators can also investigate new diagnostic methods and therapeutic options to improve the quality of life and reduce the mortality of patients with an SRV.

Eligibility criteria: Inclusion Criteria:

* Patients aged 12 years old and older
* Surgically corrected transposition of the great arteries (TGA) patients with a systemic right ventricle (SRV) (Mustard, Senning)
* Congenitally corrected TGA patients with a systemic right ventricle

Exclusion Criteria:

\* None.

Primary outcomes:
measure: All-cause mortality
timeFrame: Through study completion, an average of 18 years
measure: Incident heart failure
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with heart failure hospitalization
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with arrhythmias
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with thromboembolic events
timeFrame: Through study completion, an average of 18 years
measure: Infective endocarditis
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with tricuspid valve surgery
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with ventricular Assist Device implantation
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with heart transplantation
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with aortic aneurysm or dissection
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with pulmonary artery hypertension
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with baffle interventions
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with coronary artery interventions
timeFrame: Through study completion, an average of 18 years
measure: Number of patients with device implantation
timeFrame: Through study completion, an average of 18 years
Secondary outcomes:
measure: Number of patients with decreased exercise capacity
timeFrame: At two time points. 1: Baseline 2. Through study completion, an average of 18 years
measure: Number of patients with right ventricular systolic dysfunction
timeFrame: At two time points. 1: Baseline 2. Through study completion, an average of 18 years
measure: Number of patients with left ventricular systolic dysfunction
timeFrame: At two time points. 1: Baseline 2. Through study completion, an average of 18 years
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centre
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente Enschede
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Centre
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Centre
city: Utrecht
country: Netherlands
facility: University Medical Centre Utrecht
Study officials:
affiliation: University Medical Center Groningen
name: Joost P van Melle, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation. 2007 Jan 16;115(2):163-72. doi: 10.1161/CIRCULATIONAHA.106.627224. Epub 2007 Jan 8.
citation: Bull C, Yates R, Sarkar D, Deanfield J, de Leval M. Scientific, ethical, and logistical considerations in introducing a new operation: a retrospective cohort study from paediatric cardiac surgery. BMJ. 2000 Apr 29;320(7243):1168-73. doi: 10.1136/bmj.320.7243.1168.
citation: Baumgartner H, De Backer J, Babu-Narayan SV, Budts W, Chessa M, Diller GP, Lung B, Kluin J, Lang IM, Meijboom F, Moons P, Mulder BJM, Oechslin E, Roos-Hesselink JW, Schwerzmann M, Sondergaard L, Zeppenfeld K; ESC Scientific Document Group. 2020 ESC Guidelines for the management of adult congenital heart disease. Eur Heart J. 2021 Feb 11;42(6):563-645. doi: 10.1093/eurheartj/ehaa554. No abstract available.
citation: Andrade L, Carazo M, Wu F, Kim Y, Wilson W. Mechanisms for heart failure in systemic right ventricle. Heart Fail Rev. 2020 Jul;25(4):599-607. doi: 10.1007/s10741-019-09902-1.
citation: Dennis M, Kotchetkova I, Cordina R, Celermajer DS. Long-Term Follow-up of Adults Following the Atrial Switch Operation for Transposition of the Great Arteries - A Contemporary Cohort. Heart Lung Circ. 2018 Aug;27(8):1011-1017. doi: 10.1016/j.hlc.2017.10.008. Epub 2017 Oct 31.
citation: Smood B, Kirklin JK, Pavnica J, Tresler M, Johnson WH Jr, Cleveland DC, Mauchley DC, Dabal RJ. Congenitally Corrected Transposition Presenting in the First Year of Life: Survival and Fate of the Systemic Right Ventricle. World J Pediatr Congenit Heart Surg. 2019 Jan;10(1):42-49. doi: 10.1177/2150135118813125.
citation: Dobson R, Danton M, Nicola W, Hamish W. The natural and unnatural history of the systemic right ventricle in adult survivors. J Thorac Cardiovasc Surg. 2013 Jun;145(6):1493-501; discussion 1501-3. doi: 10.1016/j.jtcvs.2013.02.030. Epub 2013 Mar 13.