Yes / We investigated the steepened dynamic action potential duration (APD) restitution of rats with pulmonary artery hypertension (PAH) and right ventricular (RV) failure and tested whether the observed APD restitution properties were responsible for negative mechanical restitution in these myocytes. PAH and RV failure were provoked in male Wistar rats by a single injection of monocrotaline (MCT) and compared with saline-injected animals (CON). Action potentials were recorded from isolated RV myocytes at stimulation frequencies between 1 and 9Hz. Action potential waveforms recorded at 1Hz were used as voltage clamp profiles (action potential clamp) at stimulation frequencies between 1 and 7Hz to evoke rate-dependent currents. Voltage clamp profiles mimicking typical CON and MCT APD restitution were applied and cell shortening simultaneously monitored. Compared with CON myocytes, MCT myocytes were hypertrophied; had less polarized diastolic membrane potentials; had action potentials that were triggered by decreased positive current density and shortened by decreased negative current density; APD was longer and APD restitution steeper. APD90 restitution was unchanged by exposure to the late Na+-channel blocker (5μM) ranolazine or the intracellular Ca2+ buffer BAPTA. Under AP clamp, stimulation frequency-dependent inward currents were smaller inMCTmyocytes and were abolished by BAPTA. In MCT myocytes, increasing stimulation frequency decreased contraction amplitude when depolarization duration was shortened, to mimic APD restitution, but not when depolarization duration was maintained. We present new evidence that the membrane potential of PAH myocytes is less stable than normal myocytes, being more easily perturbed by external currents. These observations can explain increased susceptibility to arrhythmias. We also present novel evidence that negative APD restitution is at least in part responsible for the negative mechanical restitution in PAH myocytes. Thus, our study links electrical restitution remodeling to a defining mechanical characteristic of heart failure, the reduced ability to respond to an increase in demand.

Cardiovascular complications associated with elevated levels of glucose in the blood (Hyperglycemia, HG) is a growing health concern. HG is known to be associated with a variety of cardiovascular morbidities including higher incidence of electrical disturbances. Although effects of chronic HG have been widely investigated, electrophysiological effects of acute hyperglycemia are relatively less known. Further, hyperglycemic effects on adrenergic response is not widely investigated. We used excised ventricular tissues from mice to record trans-membrane potentials during a variety of pacing protocols to investigate cellular/tissue level electrophysiological effects of acute hyperglycemia and adrenergic stimulation (1µM Isoproterenol, a β-adrenergic agonist). A custom program was used to compute action potential durations (APD), maximal rates of depolarization (dv/dtmax), and action potential amplitudes (APA) from the recorded trans-membrane potentials. From these computed measures, electrical restitution and alternans threshold were quantified. Restitution was quantified using the Standard Protocol (SP; basic cycle length BCL= 200ms), Dynamic Protocol (DP; 200-40ms or until blockade) and a novel diastolic interval (DI) control protocol with Sinusoidal Changes in DI. Results from 6 mice show that acute hyperglycemia causes prolongation of the APD. Effects of adrenergic stimulation during acute hyperglycemia were partially blunted compared with non-hyperglycemic state, i.e. hyperglycemia minimized the decrease in APD that was produced by adrenergic stimulation. Similar, but less consistent (across animals) effects were seen in other electrophysiological parameters such as alternans threshold. These results show that acute hyperglycemia may itself alter cellular level electrophysiology of myocytes and importantly, modify adrenergic response. These results suggest that in addition to long term re-modeling that occurs in diabetes, acute changes in glucose levels also affect electrical function and further may contribute to systemically observed changes in diabetes by blunting adrenergic response. Therefore, further investigation into the electrophysiological effects of acute changes in glucose levels are warranted.