Highlights
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High intensity interval training is a promising method to enhance exercise capacity.
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This study focuses on an understudied population of complex outflow tract disorders.
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Heterogeneous outcome data are expected based upon previous cohorts.
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Multimodal imaging and multi-omics aim to reveal mechanisms related to adaptation.
ABSTRACT
Background
Exercise training is a promising, relatively low-cost strategy to optimize exercise capacity, primarily studied in patients with tetralogy of Fallot and Fontan physiology. However, rare and complex biventricular disorders are understudied. High intensity interval training (HIIT) is a time-efficient alternative to the more commonly studied aerobic training. Despite group-level improvements in exercise capacity, individual variation suggests the existence of responders and non-responders to exercise training. We therefore designed a HIIT intervention trial for patients with complex outflow tract disorders aimed to test efficacy and identify predictors of response.
Methods
The Right HIIT study is a multicenter, randomized controlled trial aiming to enroll 38 patients aged 12 to 45 years with a right ventricle to pulmonary artery conduit. Participants will be randomized to a 12-week home-based HIIT program (intervention) or standard of care group. The primary endpoint is change in peak oxygen consumption from baseline to 12 weeks. Secondary endpoints include other cardiopulmonary exercise testing and imaging parameters, blood biomarkers, gut microbiome composition, quality of life and physical activity levels. After the randomized phase, the SoC group will receive the HIIT program, with repeated data collection after 12 weeks. Thus, pre-post HIIT data will be available in all patients, for the purpose of supportive analyses and identifying predictors of response.
Conclusion
The Right HIIT study will analyze whether a HIIT program improves exercise capacity in patients with a right ventricle to pulmonary artery conduit and which factors are associated with the ability to improve exercise capacity.
Trial Registration
ClinicalTrials.gov, NCT06771687, www.clinicaltrials.gov/study/NCT06771687 .
In recent years, physical activity and sports recommendations for patients with congenital heart disease (CHD) have shifted from a restrictive to a more permissive approach. ,, Nonetheless, patients with CHD remain less physically active and have a lower and faster deteriorating exercise capacity compared with the general population. ,, Several objective measures of exercise capacity obtained with cardiopulmonary exercise testing (CPET) are known predictors of morbidity and mortality in both the general population and in CHD. ,,,,,, These measures include peak oxygen consumption (pVO 2 ) and ventilatory efficiency (ventilation to carbon dioxide production (VE/VCO 2 ) slope), among others. In patients with a Fontan circulation, serial declines in pVO 2 are strongly associated with hospitalization and mortality. ,, Moreover, pVO 2 correlates with functional outcomes, such as quality of life and the New York Heart Association functional class. Hence, improving exercise capacity in patients with CHD may play a key role in reducing long-term adverse outcomes.
Evidence is growing that exercise training is a promising, low cost, safe and accessible strategy to optimize exercise capacity in CHD. Yet, current research has largely concentrated on aerobic training in more common CHD types, such as tetralogy of Fallot. Also, due to their unique physiology, patients with a univentricular circulation have been extensively studied. In contrast, the potential of high intensity interval training (HIIT) in rarer, complex types of biventricular corrected CHD involving outflow tract lesions, eg, truncus arteriosus and pulmonary atresia, remains relatively understudied. This article describes the rationale and design of the Right HIIT study, which aims to address this gap by analyzing the effects of a 12-week home-based HIIT program in patients with a right ventricle to pulmonary artery conduit in a randomized controlled trial (RCT).
Exercise training in congenital heart disease: responders and non-responders
Previous studies have primarily analyzed group-level differences in pVO2 after exercise training in patients with CHD. A Cochrane review reported a mean difference in exercise capacity between intervention and control groups of 2.7 mL/kg/min (95%-CI 0.36-5.12, P =.02), representing a crude average difference of 5% to 10%. ,, However, variation in the response to exercise training (change in pVO 2 ) can be observed both between and within studies. , These data suggest the existence of distinct subgroups of responders and non-responders to exercise training. Identifying predictors of response could help tailor training strategies and provide new insight into mechanisms of adaptation.
One potential predictor, is non-coding ribonucleic acid (RNA). This type of RNA does not encode for proteins, but is described to regulate gene expression at epigenetic and (post)transcriptional levels. Altered levels of expression of non-coding RNA have been related to both the development of and protection against cardiovascular diseases. ,, Non-coding RNA includes microRNA (typically 18-25 nucleotides) and long non-coding RNA (>200 nucleotides). Recent studies have described exercise-regulated types of non-coding RNA and have identified profiles of microRNA differentiating responders to exercise training from non-responders in adults with heart failure. Hence, profiles of non-coding RNA could help predict response to exercise training.
High intensity interval training
Most RCTs in patients with CHD have focused on aerobic training. HIIT is an alternative training type, generally described as exercise protocols involving short bouts of nearly maximum intensity followed by a recovery phase. Protocols vary in the number, duration, and intensity of intervals. Growing evidence in healthy populations and adults with heart failure indicates that HIIT yields similar or even superior results in improving exercise capacity compared to aerobic training. , One RCT comparing HIIT to moderate intensity continuous training in patients with tetralogy of Fallot supports these findings.
According to the ClinicalTrials.gov database, only one prospective non-randomized HIIT trial is currently active in pediatric patients with moderate to complex CHD (NCT04575883), in addition to the Right HIIT study. An RCT from our center in patients with tetralogy of Fallot with the same HIIT protocol as the current study recently reported significant increases in exercise capacity and workload after the training program (3.9 mL/kg/min with 95% CI 2.1-5.7 and 21 Watts with 95% CI 10-28). Notably, HIIT requires shorter training sessions and is experienced as at least as enjoyable as aerobic training. As these features make HIIT a promising and time-efficient training strategy for patients with CHD, HIIT was selected as the intervention strategy for the current study.
Exercise training in rare, complex congenital heart disease
Exercise training trials in CHD have primarily included patients with single ventricle physiology or tetralogy of Fallot, groups at relatively high risk for adverse long-term outcomes. In the Cochrane review of 11 trials, 8 included patients with a Fontan circulation and/or tetralogy of Fallot. ,,,,,,, In contrast, less common types of complex CHD, such as truncus arteriosus or pulmonary atresia, have been scarcely studied, with only 2 out of the 11 studies including these patients. , Evaluating the Right HIIT cohort may therefore provide important insights: confirmation of prior findings would support a broader application of current recommendations, while a distinct response pattern could highlight unique mechanisms in this understudied population.
A distinct response pattern may, in part, result from the presence of the RV-PA conduit and potential restrictive RV physiology, which could modulate the positive vascular effects of exercise. Exercise promotes vasodilation and angiogenesis through increased flow and laminar shear stress-mediated biochemical signaling. However, a (stenotic) RV-PA conduit and restrictive RV may blunt increases in pulmonary blood flow and generate aberrant shear stress, potentially attenuating nitric oxide-mediated responses. Myocardial fibrosis and restrictive RV physiology could potentially further alter cardiac adaptation to exercise. If present, a unique response pattern may provide clues to such underlying mechanisms, which could be explored with advanced imaging techniques.
Advanced cardiovascular magnetic resonance
Cardiovascular imaging plays a crucial role in detecting remodeling in cardiac size and function. Cardiovascular magnetic resonance (CMR) is the reference standard for quantifying cardiac volumes and provides complementary information to echocardiography. This is particularly relevant for the right ventricle, as its complex crescent geometry and the presence of a reconstructed conduit in our cohort complicate comprehensive evaluation by echocardiography alone. Previous exercise training studies in patients with tetralogy of Fallot have not demonstrated significant structural or functional changes. ,
Advanced CMR techniques may capture more subtle adaptation. Four-dimensional flow enables noninvasive assessment of flow-based metrics such as kinetic energy and viscous energy loss. Ventricular kinetic energy has been identified as an early marker of ventricular efficiency, ,,, while viscous energy loss, representing the dissipation of mechanical energy related to frictional forces, has been associated with right ventricular ejection fraction, , exercise capacity, and major adverse cardiovascular events in patients with tetralogy of Fallot. The Right HIIT study includes CMR to evaluate adverse cardiac remodeling, explore novel flow-based markers, and gain deeper insights into the cardiovascular adaptations to exercise training.
Exercise and the gut microbiome
The gut microbiome has emerged as a modulator of cardiovascular health and disease. Exercise may influence intestinal permeability, gut microbial composition, and levels of microbial metabolites produced. , These exercise-induced gut microbial changes have been proposed as a potential mechanism contributing to the widespread health benefits of physical exercise. 16S ribosomal RNA sequencing is the most popular technique to cost-effectively characterize gut microbiome composition. It enables bacterial identification up to genus and sometimes species level and quantifies the relative abundance of each taxon within the community. Exploring gut microbiome in the Right HIIT study, assessing both baseline composition and subsequent changes, may identify microbial signals associated with training response. Dietary and medication effects will not be controlled for and represent potential confounders. Any medication change during the study period will be recorded and considered in the analyses.
Methods
Study design and endpoints
This multicenter study is an RCT with an additional non-controlled pre-post intervention phase, based on previous exercise training intervention studies ( Figure 1 ). , Participants will be randomized 1:1 to a 12-week home-based exercise training program (HIIT intervention) or standard of care (SoC). The primary endpoint is the change in pVO 2 from baseline to the end of the 12-week period. Secondary endpoints are listed in Table 1 . After the RCT phase, SoC patients will also complete the HIIT program, with repeat assessment at 12 weeks. This design ensures that all participants receive the intervention, which may enhance recruitment rates. Also, pre-post HIIT data on all parameters will be available for all patients, which increases power for exploratory secondary analyses. Follow-up data for the full cohort will be collected at outpatient visits 1 year after completion of the HIIT intervention ( Figure 1 , Table 1 ). This enables evaluation of the durability of intervention effects on exercise capacity, physical activity level, quality of life, and cardiac function.
Study design. The one-year follow-up visit is scheduled one year after completion of the HIIT intervention for both groups. C, Control; HIIT, high intensity interval training; I, Intervention; SoC, standard of care .
Table 1
Primary and secondary endpoints.
| Primary |
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| Change in peak oxygen consumption after intervention and standard of care in randomized phase (mL/kg/min) |
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Due to the nature of the intervention, the study will be unblinded. Ethical approval has been obtained from the Medical Ethical Research Committee Erasmus MC (reference number MEC-2023-0777). We have designed the study protocol with patient input.
Study population
Patient eligibility is defined by the inclusion and exclusion criteria outlined in Table 2 . Age limits have been selected to ensure that participants can follow instructions for CPET, CMR, and the home-based intervention, while balancing homogeneity and sample size requirements. We focus on a relatively young cohort, as the intervention is aimed at improving modifiable risk factors for adverse outcomes. To select clinically stable patients and minimize potential confounding due to surgical or medical interventions, patients with recent interventions, medication changes, or hospitalizations are excluded. Additionally, subjects will be excluded from further participation if baseline CPET shows an oxygen saturation below 90% during exercise or a pVO 2 below 12 mL/kg/min or less than 50% of the predicted value. These lower boundaries were included in the selection criteria to reduce the risk of unmonitored desaturation at home during training and dropout due to intolerance to HIIT. Participants will be identified through clinical databases and the outpatient clinic. Recruitment started October 3, 2024. Anticipated trial completion is October 2028.
Table 2
Inclusion and exclusion criteria
| Inclusion criteria |
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