Previous studies have shown reduced effects of cAMP-dependent positive inotropic agents in the failing human myocardium; thus other cAMP-independent mechanisms of action may be useful to increase force of contraction in this condition. The purpose of this investigation was to determine whether a positive inotropic effect of the cAMP-phosphodiesterase (PDE) inhibitor pimobendan is observed in the failing human myocardium and to study whether other factors, such as an increase in the Ca2+ sensitivity of myofilaments, play a functional role in the increase in force of contraction. Pimobendan produced a positive inotropic effect in isolated preparations from nonfailing donor hearts; however, in moderately (New York Heart Association class II-III, NYHA II-III) and severely (NYHA IV) failing myocardium, this effect was reduced. In addition, in NYHA IV specimens pimobendan inhibited the crude cAMP-PDE (crude PDE) and the isoenzymes I-III (PDE I-III) in a concentration-dependent way. As judged from the IC50 values found in this tissue for the inhibition of PDE III and of crude PDE, the potency of the compound was 18.1 times greater on PDE III. Consistent with a cAMP-PDE-dependent mechanism of action, the positive inotropic effect was potentiated by isoproterenol and inhibited by adenosine in failing myocardium. In failing myocardium, pimobendan also increased the sensitivity of skinned cardiac fibers to Ca2+ and shifted the Ca(2+)-tension relation to the left. This sensitizing effect began at 0.01 mumol/l in NYHA II-III and NYHA IV and rose to about 200% at 300 mumol/l in both groups. In contrast, the demethylated metabolite UD-CG 212 Cl failed to produce positive inotropic effects in failing myocardium alone, but in the presence of isoproterenol, it exerted an increase in force of contraction. The potency of UD-CG 212 Cl for PDE III inhibition in NYHA IV was greater than that of pimobendan. The metabolite pronouncedly decreased the sensitivity of skinned cardiac fibers to Ca2+ at 30-300 mumol/l in NYHA II-III and NYHA IV. It is concluded that in the failing human heart pimobendan inhibited PDE III and sensitized contractile proteins for Ca2+. Both effects appear to be involved in the positive inotropic effect of the compound, because its metabolite, UD-CG 212 Cl, had no effect on force of contraction and on the Ca2+ sensitivity of skinned cardiac fibers but inhibited PDE III even more potently than pimobendan.(ABSTRACT TRUNCATED AT 400 WORDS)

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Introduction: Time-to-isolation (TTI) guided ablation protocols have been developed to ensure durable pulmonary vein isolation (PVI) in cryoballoon ablation (CBA). The aim was to determine the feasibility and safety of the fourth generation cryoballoon (CBG4) with a shortened tip. Methods and Results:Consecutive patients scheduled for initial atrial fibrillation (AF) ablation were prospectively included. PVI with the 28 mm CBG4 and the latest 20 mm spiral-mapping catheter (SMC) was performed.A total of 302 pulmonary veins (PVs) in 76 patients (64.8 ± 10.4 years, paroxysmal AF 49%) were treated with 617 applications. Left atrium (LA) time, fluoroscopy time, and dose-area product were 65.5 ± 19.2 minutes, 14.6 ± 5.6 minutes, and 1094 (738; 2097) cGy·cm 2 , respectively. PVI in cryoballoon technique was achieved in 302 of 302 (100%) PVs. TTI was determined in 256 (84.8%) of PVs. The mean TTI was 45.3 ± 26.4 seconds. Single-shot isolation was achieved in 247 (82%) PVs. In 6 of 302 (2.0%) PV the SMC was changed to a stiff wire to isolate the PV because of instability, and in 17 of 302 (5.6%) of PVs, the 23 mm CB was used to isolate. No radiofrequency touch-up applications were applied. The mean nadir balloon temperature was −44.8°C ± 6.6°C. Balloon dislodgement during positioning occurred in 3 of 617 (0.5%) applications without complications. One PN palsy occurred which resolved until discharge. One patient suffered from the inflammatory syndrome. Conclusion:The CBG4 with a shorter distal tip seems to be safe and effective, and allows determining the TTI in 84.8% of PVs. In case of balloon instability, the exchange of the SMC to a stiff wire or, in small PV, the 23 mm cryoballoon facilitate PVI. K E Y W O R D S atrial fibrillation, catheter ablation, cryoballoon, spiral mapping catheter, time to isolation

This study, the largest to date, showed that real-time monitoring of PV conduction during cryoballoon freezing can be safely performed with a circular mapping catheter. A cutoff time of 83 s to PV isolation was predictive of sustained procedural PV isolation success without reconduction.