The heart rate-lowering agent ivabradine inhibits the pacemaker current I(f) in human atrial myocytes

Introduction: It has been speculated that pacemaker current (I _f ) in human atria could play a role in causing ectopic atrial automaticity. Ivabradine is a novel selective and specific I _f inhibitor in the sinus node that reduces heart rate without any negative inotropic effect. The aim of the study was to explore possible effects of ivabradine on I _f in atrial myocytes.
Methods and Results:  Using patch-clamp technique, we studied effects of ivabradine on I _f present in atrial myocytes isolated from human right appendages of patients undergoing cardiac surgery. The identification of HCN isoforms was obtained by means of multiplex single-cell RT-PCR. Ivabradine induced a marked concentration and use-dependent I _f inhibition with an IC₅₀ at steady state of 2.9 μM. Time constant of block development (Tau_on) decreases with the increase in the ivabradine concentration. Use-dependent inhibition induced by ivabradine (3 μM) was not modified in the presence of cAMP (10 μM) in the pipette solution. Multiplex single-cell RT-PCR indicates that the major HCN gene subtype detected in atria was HCN2. HCN4 is detected weakly and HCN1 is not significantly detected.
Conclusions:  Ivabradine inhibits I _f current in the nonpacemaker cell with characteristics similar to those described previously in rabbit sinus node cells, but revealed a lesser sensitivity for I _f recorded in human atrial cell than hHCN4 subunits considered as the major contributors to native f -channels in human sinoatrial node. A potential protection of atrial arrhythmias by ivabradine is discussed.     

Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis

1. Download : Download high-res image (370KB)
2. Download : Download full-size image

     

Prediction of spontaneous preterm delivery in the first trimester of pregnancy

Objective

To develop a model for predicting premature delivery before 37 weeks’ gestation based on maternal factors, obstetric history and biomarkers in the first trimester of pregnancy.

Study design

Cohort study based on data collected prospectively between 1 January 2000 and 30 November 2011. Multivariate logistic regression was used to construct a model of the risk of premature delivery.

Results

31,834 pregnancies were included, of which 1188 cases were spontaneous premature deliveries before 37 weeks (3.7%). We built a predictive model based on maternal age, body mass index, smoking status and previous obstetric history. This could identify 23.3% of premature deliveries in our study population, with a false positive rate of 10%. In the group of patients who had already had at least one pregnancy at or beyond 16 weeks, the detection level increased to 29.7%. The positive predictive value was 7.4 and 7.3% respectively, while negative predictive value was 97.2 and 97.9%.

Conclusions

Predicting preterm delivery on the basis of maternal characteristics and obstetric history needs to be further improved. PAPP-A levels and ultrasonographic measurement of cervical length could not be integrated in the model but require further investigations.     

Somatic calcium level reports integrated spiking activity of cerebellar interneurons in vitro and in vivo

We examined the relationship between somatic Ca2? signals and spiking activity of cerebellar molecular layer interneurons (MLIs) in adult mice. Using two-photon microscopy in conjunction with cell-attached recordings in slices, we show that in tonically firing MLIs loaded with high-affinity Ca2? probes, Ca2?-dependent fluorescence transients are absent. Spike-triggered averages of fluorescence traces for MLIs spiking at low rates revealed that the fluorescence change associated with an action potential is small (1% of the basal fluorescence). To uncover the relationship between intracellular Ca2? concentration ([Ca2?](i)) and firing rates, spikes were transiently silenced with puffs of the GABA(A) receptor agonist muscimol. [Ca2?](i) relaxed toward basal levels following a single exponential whose amplitude correlated to the preceding spike frequency. The relaxation time constant was slow (2.5 s) and independent of the probe concentration. Data from parvalbumin (PV)-/- animals indicate that PV controls the amplitude and decay time of spike-triggered averages as well as the time course of [Ca2?](i) relaxations following spike silencing. The [Ca2?](i) signals were sensitive to the L-type Ca2? channel blocker nimodipine and insensitive to ryanodine. In anesthetized mice, as in slices, fluorescence traces from most MLIs did not show spontaneous transients. They nonetheless responded to muscimol iontophoresis with relaxations similar to those obtained in vitro, suggesting a state of tonic firing with estimated spiking rates ranging from 2 to 30 Hz. Altogether, the [Ca2?](i) signal appears to reflect the integral of the spiking activity in MLIs. We propose that the muscimol silencing strategy can be extended to other tonically spiking neurons with similar [Ca2?](i) homeostasis.