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Diastolic Depolarization (diastolic + depolarization)
Selected AbstractsHeterogeneity of Ventricular Fibrillation Dominant Frequency During Global Ischemia in Isolated Rabbit HeartsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 8 2007Ch.B. , JANE CALDWELL M.B. Introduction: Ventricular fibrillation (VF) studies show that ECG-dominant frequency (DF) decreases as ischemia develops. This study investigates the contribution of the principle ischemic metabolic components to this decline. Methods and Results: Rabbit hearts were Langendorff-perfused at 40 mL/min with Tyrode's solution and loaded with RH237. Epicardial optical action potentials were recorded with a photodiode array (256 sites, 15 × 15 mm). After 60 seconds of VF (induced by burst pacing), global ischemia was produced by low flow (6 mL/min), or the solution changed to impose hypoxia (95% N2/5% CO2), low pHo (6.7, 80% O2/20% CO2), or raised [K+]o (8 mM). DF of the optical signals was determined at each site. Conduction velocity (CV), action potential duration (APD90), effective refractory period (ERP), activation threshold, dV/dtmax, and membrane potential were measured in separate experiments during ventricular pacing. During VF, ischemia decreased DF in the left ventricle (LV) (to [58 ± 6]%, P < 0.001), but not the right (RV) ([93 ± 5]%). Raised [K+]o reproduced this DF pattern (LV: [67 ± 12]%, P < 0.001; RV: [95 ± 9]%). LV DF remained elevated in hypoxia or low pHo. During ventricular pacing, ischemia decreased CV in LV but not RV. Raised [K+]o did not change CV in either ventricle. Ischemia and raised [K+]o shortened APD90 without altering ERP. LV activation threshold increased in both ischemia and raised [K+]o and was associated with diastolic depolarization and decreased dV/dtmax. Conclusions: These results suggest that during VF, decreased ECG DF in global ischemia is largely due to elevated [K+]o affecting the activation thresholds in the LV rather than RV. [source] The Pacemaker Current: From Basics to the ClinicsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 3 2007ANDREA BARBUTI Ph.D. Activation of the pacemaker ("funny," If) current during diastole is the main process underlying generation of the diastolic depolarization and spontaneous activity of cardiac pacemaker cells. If modulation by autonomic transmitters is responsible for the chronotropic regulation of heart rate. Given its role in pacemaking, If has been a major target of investigation aimed to exploit its rate-controlling function in a clinical perspective. In this short review, we describe some of the most recent clinically relevant applications of the concept of If -based pacemaking. [source] Engineering physiologically controlled pacemaker cells with lentiviral HCN4 gene transferTHE JOURNAL OF GENE MEDICINE, Issue 5 2008Gerard J. J. Boink Abstract Background Research on biological pacemakers for the heart has so far mainly focused on short-term gene and cell therapies. To develop a clinically relevant biological pacemaker, long-term function and incorporation of autonomic modulation are crucial. Lentiviral vectors can mediate long-term gene expression, while isoform 4 of the Hyperpolarization-activated Cyclic Nucleotide-gated channel (encoded by HCN4) contributes to pacemaker function and responds maximally to cAMP, the second messenger in autonomic modulation. Material and Methods Action potential (AP) properties and pacemaker current (If) were studied in single neonatal rat ventricular myocytes that overexpressed HCN4 after lentiviral gene transduction. Autonomic responsiveness and cycle length stability were studied using extracellular electrograms of confluent cultured monolayers. Results Perforated patch-clamp experiments demonstrated that HCN4-transduced single cardiac myocytes exhibited a 10-fold higher If than non-transduced single myocytes, along with slow diastolic depolarization, comparable to pacemaker cells of the sinoatrial node, the dominant native pacemaker. HCN4-transduced monolayers exhibited a 47% increase in beating rate, compared to controls. Upon addition of DBcAMP, HCN4-transduced monolayers had beating rates which were 54% faster than baseline and significantly more regular than controls. Conclusions Lentiviral vectors efficiently transduce cardiac myocytes and mediate functional gene expression. Because HCN4-transduced myocytes demonstrate an increase in spontaneous beating rate and responsiveness to autonomic modulation, this approach may be useful to create a biological pacemaker. Copyright © 2008 John Wiley & Sons, Ltd. [source] Hyperpolarization-activated cyclic nucleotide-modulated ,HCN' channels confer regular and faster rhythmicity to beating mouse embryonic stem cellsTHE JOURNAL OF PHYSIOLOGY, Issue 3 2008Yang Qu The hyperpolarization-activated cation current (If), and the hyperpolarization-activated cyclic nucleotide-modulated ,HCN' subunits that underlie it, are important components of spontaneous activity in the embryonic mouse heart, but whether they contribute to this activity in mouse embryonic stem cell-derived cardiomyocytes has not been investigated. We address this issue in spontaneously beating cells derived from mouse embryonic stem cells (mESCs) over the course of development in culture. If and action potentials were recorded from single beating cells at early, intermediate and late development stages using perforated whole-cell voltage- and current-clamp techniques. Our data show that the proportion of cells expressing If, and the density of If in these cells, increased during development and correlated with action potential frequency and the rate of diastolic depolarization. The If blocker ZD7288 (0.3 ,m) reduced If and the beating rate of embryoid bodies. Taken together, the activation kinetics of If and results from Western blots are consistent with the presence of the HCN2 and HCN3 isoforms. At all stages of development, isoproterenol (isoprenaline) and acetylcholine shifted the voltage dependence of If to more positive and negative voltages, respectively, and they also increased and decreased the beating rate of embryonic cell bodies, respectively. Together, the data suggest that current through HCN2 and HCN3 channels confers regular and faster rhythmicity to mESCs, which mirrors the developing embryonic mouse heart, and contributes to modulation of rhythmicity by autonomic stimulation. [source] | ||||||||||