Altered Atrial Function and Associated Changes in Proteins Responsible for Myocardial Contraction and Relaxation in Right Atria of Children With Tetralogy of Fallot • 84

The predominant myosin isoform present in the normal human right atrium(RA) is V₁ and the levels of Ca²⁺ handling proteins have not been evaluated in human atrial myocardium. The role of pressure overload (POL) on myosin isoforms and on Ca²⁺ handling proteins of the sarcoplasmic reticulum (SR) in the RA myocardium of children is unknown. We studied 10 children (Age: 0.70-1.9 years) with tetralogy of Fallot (TOF) and evidence of POL of the RA and 7 controls (Age: 1.2-2.2 years). RA function was assessed from RA pressure-area loops generated from simultaneously measured RA micromanometric pressure and RA area determined by echocardiographic automatic border detection. RA loading conditions were altered by caval occlusion and fluid bolus. RA systolic function was assessed from a) slope of the RA end-systolic pressure-area relationship (RA E_es), normalized for body weight and b) RA rate-corrected velocity of fiber shortening (RA Vcf_c). RA relaxation was evaluated from dP/dt_min obtained from RA pressure and RA compliance was assessed from normalized chamber stiffness constant(k_c) using a simple exponential relationship. Our findings indicate that RA “a” wave pressure was significantly higher in TOF group(12.8±2.8 vs 7.4±2.3 mm Hg, p<0.05). Normalized RA E_es remained unaltered in TOF group (22.1±4.1 vs 20.4±3.8 mm Hg·cm^-2·kg, p>0.05), suggesting force-dependent contraction remains unchanged. However, RA Vcf_c was decreased(0.4±0.12 vs 0.6±0.14 circ·s^-1, p<0.05), suggesting velocity-dependent contraction is impaired. RA dP/dt_min was decreased (61.4±14.6 vs 98.6±12.4 mm Hg·s^-1, p<0.05) suggesting impaired relaxation. k_c was increased(1.21±0.28 vs 0.85±0.24, p<0.05) suggesting decreased RA compliance. Samples of RA appendage were obtained at the time of corrective surgery. Quantitative immunoblotting revealed that in TOF group: a) V₃ isoform increased by 4 fold, although total myosin remained unchanged; b) calsequestrin levels remained unchanged; c) phospholamban (PLB) and SR Ca²⁺ ATPase (SERCA) levels decreased by 18% and 42%, respectively; and d) relative PLB/SERCA ratio decreased by 27% above control values, indicating an increased inhibition of the affinity of SERCA for Ca²⁺.

Conclusions: These findings suggest that the slower velocity-dependent contraction and slower relaxation observed in the right atria of TOF children with POL may be due to: a) switches in myosin isoforms; b) decreased SERCA levels; and c) decreased affinity of SERCA for Ca²⁺ due to increased inhibition by phospholamban. These molecular and physiologic changes may have an impact on clinical right atrial function.