Background—Although multiple approaches have been used to create biological pacemakers in animal models, induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) have not been investigated for this purpose. We now report pacemaker function of iPSC-CMs in a canine model.Methods and Results—Embryoid bodies were derived from human keratinocytes, their action potential characteristics determined, and their gene expression profiles and markers of differentiation identified. Atrioventricular blocked dogs were immunosuppressed, instrumented with VVI pacemakers, and injected subepicardially into the anterobasal left ventricle with 40 to 75 rhythmically contracting embryoid bodies (totaling 1.3–2×106 cells). ECG and 24-hour Holter monitoring were performed biweekly. After 4 to 13 weeks, epinephrine (1 μg kg−1 min−1) was infused, and the heart removed for histological or electrophysiological study. iPSC-CMs largely lost the markers of pluripotency, became positive for cardiac-specific markers. and manifested If-dependent automaticity. Epicardial pacing of the injection site identified matching beats arising from that site by week 1 after implantation. By week 4, 20% of beats were electronically paced, 60% to 80% of beats were matching, and mean and maximal biological pacemaker rates were 45 and 75 beats per minute. Maximum night and day rates of matching beats were 53±6.9 and 69±10.4 beats per minute, respectively, at 4 weeks. Epinephrine increased rate of matching beats from 35±4.3 to 65±4.0 beats per minute. Incubation of embryoid bodies with the vital dye, Dil, revealed the persistence of injected cells at the site of administration.Conclusions—iPSC-CMs can integrate into host myocardium and create a biological pacemaker. Although this is a promising development, rate and rhythm of the iPSC-CMs pacemakers remain to be optimized.

Background-Drugs are screened for delayed rectifier potassium current (I Kr ) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some I Kr blockers (eg, dofetilide) prolongs repolarization additionally by increasing late sodium current (I Na-L ) via inhibition of phosphoinositide 3-kinase. We hypothesized that chronic dofetilide administration to intact dogs prolongs repolarization by blocking I Kr and increasing I Na-L . Methods and Results-We continuously infused dofetilide (6-9 μg/kg bolus+6-9 μg/kg per hour IV infusion) into anesthetized dogs for 7 hours, maintaining plasma levels within the therapeutic range. In separate experiments, myocardial biopsies were taken before and during 6-hour intravenous dofetide infusion, and the level of phospho-Akt was determined. Acute and chronic dofetilide effects on action potential duration (APD) were studied in canine left ventricular subendocardial slabs using microelectrode techniques. Dofetilide monotonically increased QTc and APD throughout 6.5-hour exposure. Dofetilide infusion during ≥210 minutes inhibited Akt phosphorylation. I Na-L block with lidocaine shortened QTc and APD more at 6.5 hours than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration. In comparison, moxifloxacin, an I Kr blocker with no effects on phosphoinositide 3-kinase and I Na-L prolonged APD acutely but no additional prolongation occurred on chronic superfusion. Lidocaine shortened APD equally during acute and chronic moxifloxacin superfusion. Conclusions-Increased I Na-L contributes to chronic dofetilide effects in vivo. These data emphasize the need to include time and I Na-L in evaluating the phosphoinositide 3-kinase inhibition-derived proarrhythmic potential of drugs and provide a mechanism for benefit from lidocaine administration in clinical acquired long QT syndrome.(Circ Arrhythm Electrophysiol. 2016;9:e003655.

An arachnoidal cyst must be considered as a rare cause, when a lesion is found at the Meckel's cave with intermittent clinical symptoms of a trigeminal nerve affection. As surgical treatment we favour fenestration and cyst wall resection.

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The respiratory control system is highly dynamic; however, typical measures of respiratory variability are often limited to computing the mean±SE and/or the coefficient of variation (CV), which do not distinguish between short‐term and long‐term variability. To overcome this limitation, some studies have employed Poincaré plot (PP), irregularity score (IS), or approximate entropy (ApEn) analyses; however, these analysis methods have not been implemented and compared on a single data set. To address this issue, we used all of the above analysis methods to quantify burst‐to‐burst variability of basal phrenic nerve discharge (n=300 bursts) recorded from anesthetized or decerebrate adult rat. We found that while all methods provide insight into the overall burst‐to‐burst variability, PP, IS, and ApEn analyses provide novel information about the patterning of the data spread. Moreover, these methods provide novel information about the short‐term vs long‐term variability. We suggest that these additional analysis methods be used to more fully capture patterns of long‐term variability and provide complementary insight into the dynamics underlying the respiratory control system. Supported by HL63175