Safety pharmacology studies using EFP and impedance.

INTRODUCTION: While extracellular field potential (EFP) recordings using multi-electrode arrays (MEAs) are a well-established technique for monitoring changes in cardiac and neuronal function, impedance is a relatively unexploited technology. The combination of EFP, impedance and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has important implications for safety pharmacology as functional information about contraction and field potentials can be gleaned from human cardiomyocytes in a beating monolayer. The main objectives of this study were to demonstrate, using a range of different compounds, that drug effects on contraction and electrophysiology can be detected using a beating monolayer of hiPSC-CMs on the CardioExcyte 96. METHODS: hiPSC-CMs were grown as a monolayer on NSP-96 plates for the CardioExcyte 96 (Nanion Technologies) and recordings were made in combined EFP and impedance mode at physiological temperature. The effect of the hERG blockers, E4031 and dofetilide, hERG trafficking inhibitor, pentamidine, ß-adrenergic receptor agonist, isoproterenol, and calcium channel blocker, nifedipine, was tested on the EFP and impedance signals. RESULTS: Combined impedance and EFP measurements were made from hiPSC-CMs using the CardioExcyte 96 (Nanion Technologies). E4031 and dofetilide, known to cause arrhythmia and Torsades de Pointes (TdP) in humans, decreased beat rate in impedance and EFP modes. Early afterdepolarization (EAD)-like events, an in vitro marker of TdP, could also be detected using this system. Isoproterenol and nifedipine caused an increase in beat rate. A long-term study (over 30h) of pentamidine, a hERG trafficking inhibitor, showed a concentration and time-dependent effect of pentamidine. DISCUSSION: In the light of the new Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative to improve guidelines and standardize assays and protocols, the use of EFP and impedance measurements from hiPSCs may become critical in determining the proarrhythmic risk of potential drug candidates. The combination of EFP offering information about cardiac electrophysiology, and impedance, providing information about contractility from the same area of a synchronously beating monolayer of human cardiomyocytes in a 96-well plate format has important implications for future cardiac safety testing.

A phase 1-2 dose-escalating study evaluating the safety and tolerability of istaroxime and specific effects on electrocardiographic and hemodynamic parameters in patients with chronic heart failure with reduced systolic function.

Istaroxime (PST2744) is a luso-inotrope that stimulates the sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a without chronotropic effects. Additionally, it has beneficial effects on myocardial energetics. This phase 1-2 clinical trial in patients with chronic stable heart failure (HF) is the first evaluation of istaroxime in humans. Three cohorts of 6 patients each were exposed to 4 sequentially increasing 1-hour infusions with a random placebo. Doses were 0.005-5.0 micro/kg per min. Safety and hemodynamics were evaluated by impedance cardiography, digital Holter recorder, and electrocardiography. Pharmacokinetic data were obtained for 1 hour during treatment and for 6 hours after dosing. The mean age was 53+/-7 years, and the mean left ventricular ejection fraction was 0.27+/-0.08. Impedance cardiography demonstrated enhanced contractility as measured by the acceleration index, left cardiac work index, cardiac index, and pulse pressure at doses>or=1 micro/kg per min, with evidence of activity at doses of 0.5 micro/kg per min. Istaroxime shortened QTc. After infusion, the hemodynamic effect rapidly dissipated over 1-2 hours. Istaroxime was pharmacologically active and well tolerated at doses up to 3.33 micro/kg per min. Side effects were related to gastrointestinal symptoms and injection site pain at higher doses, which dissipated within minutes after the infusion ended. Ventricular ectopy was not altered. This study suggests that istaroxime is potentially useful in the treatment of HF and may offer a unique treatment for systolic and/or diastolic dysfunction. Additional studies are under way to further define its utility in acute HF.

Epinephrine infiltration on nasal field causes significant hemodynamic changes: hypotension episode monitored by impedance-cardiography under general anesthesia.

PURPOSE: Local infiltration of epinephrine-containing local anesthetics is widely used in clinics particularly in the procedure of surgeries on vascularity field to provide good analgesia and hemostasis. A prospective randomized double blind control study was designed to observe hemodynamic changes caused by local infiltration of epinephrine- containing lidocaine solution on nasal field under general anesthesia. METHODS: 90 adult patients undergoing elective functional endoscopic sinus surgery under general anesthesia were randomly allocated into three groups and received 1% lidocaine 4 mL with different dose of epinephrine (group I 20 microg; group II 40 microg; and group III 0 microg) respectively. Mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI), and acceleration index (ACI) were recorded through impedance-cardiography at every 45 seconds in 6 minutes after the beginning of local infiltration. RESULTS: Compared with the intra-group baseline, statistically significant hemodynamic changes particularly decrease in MAP with increase in HR at 1.5 minutes time point (P < 0.01), and decrease in SVRI and increase in CI, ACI at and from 1.5 minutes time point (P > 0.05) were observed in group I and group II, but not in group III. CONCLUSION: Local infiltration of epinephrine-containing lidocaine solution on nasal field causes significant decrease in MAP and SVRI, and increase in HR, CI and ACI.

[Measuring bioelectric myocardial impedance as a noninvasive method for diagnosis of graft rejection after heart transplantation]. / Die Messung der bioelektrischen myokardialen Impedanz als nichtinvasive Methode zur Abstossungsdiagnostik nach Herztransplantation.

12 beagle dogs underwent neck-heart transplantation and were immunosuppressed with cyclosporine and methylprednisolone. Intramyocardial impedance was determined twice daily with four screw-in electrodes in the right and left ventricle. Transmyocardial biopsies and the intra-myocardial electrogram (IMEG) were performed as reference methods. 19 rejection episodes were induced. When acute rejection was seen in histology the animals were treated with pulsed 125 mg methylprednisolone over 5 consecutive days and immunosuppression was raised to sufficient levels. Successful treatment of rejection was controlled by biopsy. All hearts showed a uniform decrease of impedance of about 28.3% +/- 5.5% immediately after implantation, then reaching a stable plateau after 7 to 8 days. Impedance values then remained unchanged as long as rejection was absent. Biopsy findings of grade 1A to 1B (ISHLT) were accompanied by a statistically significant increase of impedance of 12.2% +/- 2.5%, of grade 2 to 3A of 19.2% +/- 3.2%, and of grade 3B to 4 of 27.0% +/- 2.9%. Sensitivity was 95%, specificity 91%. Successful treatment of rejection led to a uniform decrease of impedance to intramyocardial impedance for high frequencies can reliably indicate alterations of the cell membrane and the intracellular space during acute cardiac allograft rejection. The amount of increase of impedance is a reliable noninvasive parameter to graduate acute cardiac allograft rejection. The success of treatment of rejection can also be monitored by impedance. This noninvasive method is applicable for telemetric rejection monitoring via an implantable device, which would allow continuous rejection surveillance of a patient at home without hospital admission.

Reduced left ventricular diameters at onset of bradycardia during epidural anaesthesia.

Pathophysiologic mechanisms of bradycardia during epidural anaesthesia (L3-L4 with 1% lidocaine, 38 ml) were evaluated by studying changes in selected cardiovascular and hormonal parameters. Six of eight subjects (analgesia to T8-T10) remained circulatory stable with no significant changes in heart rate (HR), mean arterial pressure (MAP) and thoracic impedance (TI). In one of two subjects MAP decreased after 25 min from 85 to 50 mmHg (11.3 to 6.7 kPa), HR from 80 to 45 beats.min-1 while thoracic impedance increased from 25.5 to 26.5 ohm. End-systolic diameter (ESD) and end-diastolic diameter (EDD) of the left ventricle determined with echocardiography were reduced from 3.8 to 3.2 cm (17%) and 5.6 to 5.0 cm (11%), respectively. In the other subject MAP decreased after 25 min from 75 to 50 mmHg (10.0 to 6.7 kPa) and HR from 82 to 60 beats.min-1 while thoracic impedance increased from 28.8 to 29.6 ohm. ESD was reduced from 3.8 to 3.3 cm (13%), and EDD from 5.6 to 5.0 cm (11%). Both subjects recovered after infusion of saline and being placed in the head-down position. There were no consistent changes in plasma catecholamines, whereas pancreatic polypeptide increased from 5 and 3 to 152 and 69 pmol.l-1, vasopressin from 3 and 2 to 152 and 46 pmol.l-1, and aldosterone from 282 and 229 to 383 and 485 pmol.l-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Rate-modulated cardiac pacing based on transthoracic impedance measurements of minute ventilation: correlation with exercise gas exchange.

The relation of pacing rate to physiologic variables of metabolic demand was examined in 10 consecutive patients with a minute ventilation-sensing, rate-modulating ventricular pacemaker implanted for complete heart block. All patients had paroxysmal (seven patients) or chronic (three patients) atrial fibrillation and were referred for catheter ablation of the atrioventricular junction. Treadmill exercise testing with measurement of expired gas exchange and respiratory flow was performed before ablation and 4 weeks after pacemaker implantation, with the pacemaker programmed to both the fixed-rate VVI and rate-modulating minute ventilation VVIR pacing modes in random sequence. The relation of pacing rate to oxygen consumption (VO2), expired carbon dioxide concentration (VCO2), respiratory quotient, tidal volume, respiratory rate and minute ventilation was determined during exercise in the rate-modulating minute ventilation pacing mode. Pacing rate was highly correlated with minute ventilation (r = 0.89), respiratory quotient (r = 0.89), VCO2 (r = 0.87), tidal volume (r = 0.87), VO2 (r = 0.84) and respiratory rate (r = 0.84). The mean exercise duration increased from 8.3 +/- 2.8 min in the fixed rate pacing mode to 10.2 +/- 3.4 min in the rate-modulating, minute ventilation mode (p = 0.0001). The maximal VO2 increased from 13.4 +/- 3.4 to 16.3 +/- 4.1 cc/kg per min (p = 0.0004). The maximal heart rate achieved in the minute ventilation pacing mode was 136 +/- 9.7 beats/min, similar to that observed in the patient's intrinsic cardiac rhythm before ablation (134.9 +/- 30.1 beats/min, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)