Effects of cardiac resynchronisation therapy in patients with heart failure having a narrow QRS Complex enrolled in PROSPECT.

INTRODUCTION: Current guidelines recommend cardiac resynchronisation therapy (CRT) in patients with severe symptomatic heart failure, depressed left ventricular (LV) systolic function and a wide QRS complex (>or=120 ms). However, patients with heart failure having a narrow QRS complex might also benefit from CRT. DESIGN SETTING PATIENTS INTERVENTIONS: During the Predictors of Response to Cardiac Resynchronisation Therapy (PROSPECT) trial, 41 patients were enrolled in a 'narrow' QRS sub-study. These patients had a QRS complex <130 ms, but documented evidence of mechanical dyssynchrony by any of seven pre-defined echocardiographic measures. RESULTS: After 6 months of CRT, 26 (63.4%) patients showed improvement according to the Clinical Composite Score, 4 (9.8%) remained unchanged and 11 (26.8%) worsened. In patients with paired data, the 6-min walking distance increased from 334+/-118 m to 382+/-128 m, (p=0.003) and quality-of-life score improved from 44.2+/-19.7 to 26.8+/-20.2 (p<0.0001). Furthermore, there was a significant decrease in LV end-systolic diameter (from 59+/-9 to 55+/-12 mm, p=0.002) and in LV end-diastolic diameter (from 67+/-9 to 63+/-11 mm, p=0.007). CONCLUSION: The results suggest that CRT may have a beneficial effect in heart failure patients with a narrow QRS complex and mechanical dyssynchrony as assessed by echocardiography. The majority of patients improved on clinical symptoms, and there was an evident reduction in LV diameters. Larger studies are needed to clearly define selection criteria for CRT in patients with a narrow QRS complex.

Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates adenylyl cyclase and phospholipase C activity in rat cerebellar neuroblasts.

The presence of receptors for the novel neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been recently demonstrated in the external granule cell layer of the cerebellum, a germinative matrix that generates the majority of cerebellar interneurons. In the present study, we have taken advantage of the possibility of obtaining a culture preparation that is greatly enriched in immature cerebellar granule cells to investigate the effect of PACAP on the adenylyl cyclase and phospholipase C transduction pathways. The two molecular forms of PACAP, i.e., 27-(PACAP27) and 38-(PACAP38) amino-acid forms of PACAP, induced a dose-dependent stimulation of cyclic AMP production in granule cells. The potencies of PACAP27 and PACAP38 were similar (ED50 = 0.12 +/- 0.01 and 0.23 +/- 0.07 nM, respectively), whereas vasoactive intestinal polypeptide (VIP) was approximately 100 times less potent. PACAP27 and PACAP38 also induced a dose-dependent stimulation of polyphosphoinositide breakdown (ED50 = 19.1 +/- 6.3 and 13.4 +/- 6.0 nM, respectively), whereas VIP had no effect on polyphosphoinositide metabolism. The effect of PACAP38 on inositol phosphate formation was significantly reduced by U-73122 and by pertussis toxin, indicating that activation of PACAP receptors causes stimulation of a phospholipase C through a pertussis toxin-sensitive G protein. In contrast, forskolin and dibutyryl cyclic AMP did not affect PACAP-induced stimulation of inositol phosphates. Taken together, the present results demonstrate that PACAP stimulates independently the adenylyl cyclase and the phospholipase C transduction pathways in immature cerebellar granule cells. These data favor the concept that PACAP may play important roles in the control of proliferation and/or differentiation of cerebellar neuroblasts.