Relative Impact of Right Ventricular Electromechanical Dyssynchrony Versus Pulmonary Regurgitation on Right Ventricular Dysfunction and Exercise Intolerance in Patients After Repair of Tetralogy of Fallot

Abstract

Background The relative impact of right ventricular ( RV ) electromechanical dyssynchrony versus pulmonary regurgitation ( PR ) on exercise capacity and RV function after tetralogy of Fallot repair is unknown. We aimed to delineate the relative effects of these factors on RV function and exercise capacity. Methods and Results We retrospectively analyzed 81 children with tetralogy of Fallot repair using multivariable regression. Predictor parameters were electrocardiographic QRS duration reflecting electromechanical dyssynchrony and PR severity by cardiac magnetic resonance. The outcome parameters were exercise capacity (percentage predicted peak oxygen consumption) and cardiac magnetic resonance ejection fraction (RV ejection fraction). To understand the relative effects of RV dyssynchrony versus PR on exercise capacity and RV function, virtual patient simulations were performed using a closed-loop cardiovascular system model (CircAdapt), covering a wide spectrum of disease severity. Eighty-one patients with tetralogy of Fallot repair (median [interquartile range { IQR} ] age, 14.48 [11.55-15.91] years) were analyzed. All had prolonged QRS duration (median [IQR], 144 [123-152] ms), at least moderate PR (median [IQR], 40% [29%-48%]), reduced exercise capacity (median [IQR], 79% [68%-92%] predicted peak oxygen consumption), and reduced RV ejection fraction (median [IQR], 48% [44%-52%]). Longer QRS duration, more than PR , was associated with lower oxygen consumption and lower RV ejection fraction. In a multivariable regression analysis, oxygen consumption decreased with both increasing QRS duration and PR severity. CircAdapt modeling showed that RV dyssynchrony exerts a stronger limiting effect on exercise capacity and on RV ejection fraction than does PR , regardless of contractile function. Conclusions In both patient data and computer simulations, RV dyssynchrony, more than PR , appears to be associated with reduced exercise capacity and RV systolic dysfunction in patients after TOF repair.

Keywords: computer‐based model; pulmonary regurgitation; right ventricular dysfunction; right ventricular dyssynchrony; tetralogy of Fallot; volume overload.

Figure 1

Predicted exercise capacity as function of right ventricular (RV) dyssynchrony and pulmonary regurgitation (PR) in the clinical patient cohort with tetralogy of Fallot repair. Exercise capacity is represented by peak oxygen consumption (VO₂) (Panel A), whereas QRS duration is taken as a surrogate of RV dyssynchrony. Predicted peak VO ₂ values (Panel B) are presented without (left panel) as well as with (right panel) adjustment for covariates.

Figure 2

Predicted resting right ventricular (RV) systolic function as function of RV dyssynchrony and pulmonary regurgitation (PR) in the clinical patient cohort with tetralogy of Fallot repair. RV systolic function is represented by RV ejection fraction (RVEF), whereas QRS duration is taken as a surrogate of RV dyssynchrony. Predicted resting RVEF values are presented without (left panel) as well as with (right panel) adjustment for covariates.

Figure 3

Univariable correlations of the outcome parameters in the clinical cohort. Circles and edges represented variables and pairwise Spearman's correlation, respectively. Red circles represent independent variables (ie, pulmonary regurgitation and QRS duration); blue circles represent the outcome variables. Orange edges show a positive correlation between 2 variables; green edges show a negative one. The thicker an edge is, the stronger the correlation is. RVEF indicates right ventricular ejection fraction; VO ₂, oxygen consumption. PRF indicates pulmonary regurgitant fraction.

Figure 4

Exercise capacity as function of right ventricular (RV) dyssynchrony and pulmonary regurgitation (PR) in the virtual patient cohorts with tetralogy of Fallot repair (rTOF) and normal (A) and decreased (B) contractile function of the RV and right atrial (RA) myocardium. The upper panels show how central venous pressure (CVP) increases with CO during exercise in 4 representative virtual patients with rTOF. Those virtual patients are marked by circles in the heat plots showing continuous effects of RV dyssynchrony and PR on exercise capacity. Simulated exercise capacity is defined as the virtual patient's cardiac output (CO _max‐exc) associated with the exercise‐limiting CVP threshold. In general, RV dyssynchrony and contractile dysfunction are more limiting for exercise capacity than PR.

Figure 5

Resting right ventricular (RV) systolic function (A and B) and end‐diastolic (C and D) and end‐systolic (E and F) volumes as a function of RV dyssynchrony and pulmonary regurgitation (PR) in the virtual patient cohorts with tetralogy of Fallot repair and normal (A, C, and E) and decreased (B, D, and F) contractile function of the RV and right atrial (RA) myocardium. Simulated RV systolic function is represented by the virtual patient's RV ejection fraction (RVEF). RVEF decreased with increasing RV dyssynchrony, but increased with PR severity, regardless of myocardial contractile function (A and B). PR and RV delay causes a similar increase in RV end‐diastolic volume (RVEDV; C and D), whereas RV end‐systolic volume (RVESV) increased more strongly with RV activation delay than with PR (E and F).

Figure 6

Valvular regurgitation (top) and global right ventricular (RV) contractility (bottom) as functions of exercise level in virtual patients with tetralogy of Fallot repair (rTOF) and normal (A) and decreased (B) contractile function of the RV and right atrial (RA) myocardium. The 4 representative virtual patients with rTOF are the same as in Figures 4 and 5. Lines are plotted until maximal cardiac output during exercise (CO _max‐exc) is reached. The pathological consequences of pulmonary regurgitation (PR), as quantified by PR fraction, decrease with exercise level (top), whereas RV dyssynchrony reduces RV global contractility and this effect becomes more pronounced as exercise level increases. dp/dt_max indiicates maximal change in pressure over time.