Neutrophils contain a soluble guanine-nucleotidebinding protein, made up of two components with molecular masses of 23 and 26 kDa, that mediates stimulation of phospholipase C-beta2 (PLCbeta2). We have identified the two components of the stimulatory heterodimer by amino acid sequencing as a Rho GTPase and the Rho guanine nucleotide dissociation inhibitor LyGDI. Using recombinant Rho GTPases and LyGDI, we demonstrate that PLCbeta2 is stimulated by guanosine 5'-O-(3-thiotriphosphate) (GTP[S])-activated Cdc42HsxLyGDI, but not by RhoAxLyGDI. Stimulation of PLCbeta2, which was also observed for GTP[S]-activated recombinant Rac1, was independent of LyGDI, but required C-terminal processing of Cdc42Hs/Rac1. Cdc42Hs/Rac1 also stimulated PLCbeta2 in a system made up of purified recombinant proteins, suggesting that this function is mediated by direct protein-protein interaction. The Cdc42Hs mutants F37A and Y40C failed to stimulate PLCbeta2, indicating that the Cdc42Hs effector site is involved in this interaction. The results identify PLCbeta2 as a novel effector of the Rho GTPases Cdc42Hs and Rac1, and as the first mammalian effector directly regulated by both heterotrimeric and low-molecular-mass GTP-binding proteins.

Our study demonstrated that right ventricular-pulmonary arterial coupling is impaired in patients with tetralogy of Fallot and is mainly affected by the surgical strategy used at the primary repair. These results elucidate the emerging role of ventricular-arterial interactions as a contributing mechanism for deterioration in right ventricular performance and impaired response to inotropic drugs in patients with tetralogy of Fallot.

Diastolic RV stiffness of repaired ToF patients with restrictive physiology is increased. The lusitropic response of the RV to β adrenergic agents is abnormal after ToF repair regardless of whether restrictive physiology is present or not. This has potential implications, particularly for postoperative drug management.

In the majority of patients, secundum atrial septal defects (ASDs) are treated interventionally or surgically, before the onset of clinical symptoms, between 3 and 6 years of age. Because right-ventricular dimensions usually normalize after ASD closure, it has been assumed that cardiac function and exercise performance also normalize at long-term follow-up. The aim of our study was to determine cardiac index (CI) at rest and during exercise at medium-term follow-up of children who had undergone surgical or interventional closure of ASD because no such reports have been published thus far. Seventeen patients (age range 8.8-17.3 years) who underwent surgical correction were included together with 17 subjects who received an interventional procedure with Amplatzer and Helex occluders (age range 12.2-17.3 years). The study was performed after a median interval of 8.6 years (range 6.5-11.6) after the procedure. Twelve healthy children of comparable age served as controls. CI measurements were performed based on the inert gas-rebreathing method with the Innocor system. For exercise testing, the standard treadmill protocol of the German Society of Pediatric Cardiology was used. CI, stroke volume (SV), and heart rate (HR) were determined at rest and at two standardized submaximal exercise levels (levels 3 and 6). CI increased in all subjects under exercise conditions. Neither SV nor HR displayed significant differences between the three groups either at rest or under exercise conditions. Although HR increased continuously, no increase of indexed SV occurred beyond level 3. Noninvasive determination of CI at rest and during exercise with the IGR method is feasible in the pediatric age group. At medium-term follow-up, we found no significant differences between patients who underwent surgical or interventional ASD closure compared with normal controls.