Pathophysiologic Mechanism for Arrhythmias and Impaired Aerobic Capacity in Tetralogy of Fallot

Project: Research project

Project Details

Description

PROJECT SUMMARY/ABSTRACT Right heart failure (RHF) is the leading cause of mortality in people with repaired tetralogy of Fallot (TOF), and the sequence of events leading to this suboptimal outcome begins with pulmonary regurgitation (PR) and right heart (RH) remodeling. Arrhythmias and impaired aerobic capacity are the most common presentations prior to the onset of RHF, but performing pulmonary valve replacement (PVR) after the onset of these symptoms is not associated with improved outcomes. Recent data show that elevated right atrial pressure (RA hypertension), as estimated by echocardiographic assessment of inferior vena cava (IVC) size and collapsibility (IVC hemo- dynamics), precedes the onset of arrhythmias and impaired aerobic capacity in TOF patients, and it is associ- ated with accelerated RH remodeling, symptomatic deterioration and mortality in this population. However, the mechanism linking RA hypertension, RH remodeling and symptomatic deterioration, and the extent to which performing PVR prior to the onset of RA hypertension improves clinical outcomes are unknown. The long-term goal is to prevent premature cardiovascular deaths in TOF patients by modifying the risk factors for mortality. The overall objective is to delineate the pathophysiologic mechanism linking RA hypertension, RH remodeling and onset of symptoms such as arrhythmias and impaired aerobic capacity, since symptomatic status is a risk factor for mortality in the TOF population. Our central hypothesis is that RA hypertension leads to accelerated RH remodeling and onset of symptoms (arrhythmias and impaired aerobic capacity), and that performing PVR prior to onset of RA hypertension is associated with RH reverse remodeling and improvement of symptoms. This hypothesis will be tested by pursuing two specific aims: (1) Determine the mechanism linking RA hyper- tension (assessed by IVC hemodynamics), RH remodeling and onset of symptoms (arrhythmias and impaired aerobic capacity) in TOF patients with moderate-severe PR; (2) Determine the extent to which performing PVR prior to the onset of RA hypertension is associated with RH reverse remodeling (improvement of imaging and biomarker indices of RH remodeling) and improvement of symptoms (less arrhythmias and improved aerobic capacity). Under the first aim, 150 asymptomatic subjects (75 in each arm) will undergo imaging, laboratory blood tests, exercise test, and patient reported quality of assessment at baseline, 12 months and 24 months. Under the second aim, 120 subjects (60 in each arm) undergoing PVR for clinical indications will be enrolled to undergo multi-domain assessments at baseline (prior to PVR), 12 months and 24 months similar to the first aim. This proposal is innovative because it will delineate the mechanisms responsible for symptomatic deterio- ration, and the impact of PVR on these mechanisms. The results will be significant because it will set the stage for future clinical trials to test the survival benefits of PVR performed at different stages of disease pathogene- sis, and development of novel therapies for the prevention and early treatment of RHF.
StatusActive
Effective start/end date8/1/217/31/22

Funding

  • National Heart, Lung, and Blood Institute: $592,231.00

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