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Stanley Nattel

Publications and source records attributed to Stanley Nattel.

120 records · Page 7Linked to original sources
PubMed2002

Remodeling of Ca(2+)-handling by atrial tachycardia: evidence for a role in loss of rate-adaptation.

BACKGROUND: Loss of rate-dependent action potential (AP) duration (APD) adaptation is a characteristic feature of atrial tachycardia-induced remodeling (ATR). ATR causes sarcolemmal ion-channel remodeling (ICR) and changes in Ca(2+)-handling. The present studies were designed to quantify Ca(2+)-handling changes and then to apply a mathematical AP model to assess the contributions of Ca(2+)-handling abnormalities and ICR to loss of APD rate-adaptation. METHODS: Indo-1 fluorescence was used to measure intracellular Ca(2)-transients and whole-cell patch-clamp to record APs in atrial myocytes from control dogs and dogs subjected to atrial pacing at 400/min for 6 weeks. A previously developed ionic model of the canine atrial AP was modified to reproduce measured Ca(2+)-transients of control and ATR myocytes. RESULTS: In control, APD to 95% repolarization (APD(95)) decreased by 91 ms experimentally and by 88 ms in the model over the 1-6 Hz range. In ATR myocytes, APD(95) failed to decrease over the 1-6 Hz range. Ca(2+)-handling abnormalities in ATR myocytes included slowed upstroke, decreased amplitude and strong single-beat post-rest potentiation. Unaltered Ca(2+)-handling properties included caffeine-releasable Ca(2+)-stores and Ca(2+)-transient relaxation before and after exposure to the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor cyclopiazonic acid (CPA). Including ICR alone in the model accounted for loss of APD(50) rate-adaptation; however, KR alone reduced APD(95) rate-adaptation by only 19% to 71 ms. When both ICR and Ca(2+)-handling changes were incorporated, APD(95) rate-adaptation decreased to 6 ms, accounting for experimental observations. CONCLUSION: ICR alone does not fully account for loss of APD rate-adaptation with atrial remodeling: Ca(2+)-handling changes appear to contribute to this clinically significant phenomenon.

Action Potentials↗
PubMed2002

Atrial fibrillation and congestive heart failure: specific considerations at the intersection of two common and important cardiac disease sets.

Atrial fibrillation (AF) and congestive heart failure (CHF) are two increasingly common cardiac disorders with a growing prevalence in the overall population. Improved treatment of acute medical conditions has increased the incidence of these cardiac disorders. AF and CHF have similar epidemiologic characteristics and adversely affect quality of life and life expectancy of affected patients. CHF predisposes to AF, and AF may worsen the prognosis of CHF. The relevant literature was intensively reviewed with emphasis on aspects at the intersection of both disease sets. Recent advances in basic research have provided a more in-depth view of changes promoting the occurrence of AF in CHF. Data from clinical trials have provided means to improve medical treatment of AF. Precautions must be taken for specific CHF-related side effects, such as torsades de pointes tachycardia, when treating AF. The specific electrophysiologic basis of AF associated with CHF may provide targets for improved treatment modalities. New treatment approaches, both pharmacologic and nonpharmacologic, as well as the results of ongoing controlled clinical studies are likely to greatly alter AF therapy over the next 5 to 10 years in patients with CHF.

Anti-Asthmatic Agents↗
PubMed2002

Development of a computer algorithm for the detection of phase singularities and initial application to analyze simulations of atrial fibrillation.

Atrial fibrillation (AF) is a common cardiac arrhythmia, but its mechanisms are incompletely understood. The identification of phase singularities (PSs) has been used to define spiral waves involved in maintaining the arrhythmia, as well as daughter wavelets. In the past, PSs have often been identified manually. Automated PS detection algorithms have been described previously, but when we attempted to apply a previously developed algorithm we experienced problems with false positives that made the results difficult to use directly. We therefore developed a tool for PS identification that uses multiple strategies incorporating both image analysis and mathematical convolution for automated detection with optimized sensitivity and specificity, followed by manual verification. The tool was then applied to analyze PS behavior in simulations of AF maintained in the presence of spatially distributed acetylcholine effects in cell grids of varying size. These analyses indicated that in almost all cases, a single PS lasted throughout the simulation, corresponding to the central-core tip of a single spiral wave that maintained AF. The sustained PS always localized to an area of low acetylcholine concentration. When the grid became very small and no area of low acetylcholine concentration was surrounded by zones of higher concentration, AF could not be sustained. The behavior of PSs and the mechanisms of AF were qualitatively constant over an 11.1-fold range of atrial grid size, suggesting that the classical emphasis on tissue size as a primary determinant of fibrillatory behavior may be overstated. (c) 2002 American Institute of Physics.

Journal Article↗
PubMed2002

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts.

Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K(+) current (I(K1)) was homogeneously reduced by approximately 41% (at -60 mV) in the three cell types. Transient outward K(+) current (I(to1)) was decreased by 43-45% at +30 mV, and the slow component of the delayed rectifier K(+) current (I(Ks)) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K(+) current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I(K1), I(to1), and I(Ks) increases APD and favors occurrence of EADs.

Action Potentials↗
PubMed2002

Time-dependent transients in an ionically based mathematical model of the canine atrial action potential.

Ionically based cardiac action potential (AP) models are based on equations with singular Jacobians and display time-dependent AP and ionic changes (transients), which may be due to this mathematical limitation. The present study evaluated transients during long-term simulated activity in a mathematical model of the canine atrial AP. Stimulus current assignment to a specific ionic species contributed to stability. Ionic concentrations were least disturbed with the K(+) stimulus current. All parameters stabilized within 6-7 h. Inward rectifier, Na(+)/Ca(2+) exchanger, L-type Ca(2+), and Na(+)-Cl(-) cotransporter currents made the greatest contributions to stabilization of intracellular [K(+)], [Na(+)], [Ca(2+)], and [Cl(-)], respectively. Time-dependent AP shortening was largely due to the outward shift of Na(+)/Ca(2+) exchange related to intracellular Na(+) (Na) accumulation. AP duration (APD) reached a steady state after approximately 40 min. AP transients also occurred in canine atrial preparations, with the APD decreasing by approximately 10 ms over 35 min, compared with approximately 27 ms in the model. We conclude that model APD and ionic transients stabilize with the appropriate stimulus current assignment and that the mathematical limitation of equation singularity does not preclude meaningful long-term simulations. The model agrees qualitatively with experimental observations, but quantitative discrepancies highlight limitations of long-term model simulations.

Action Potentials↗
PubMed2002

Differential distribution of Kir2.1 and Kir2.3 subunits in canine atrium and ventricle.

Ventricular inward rectifier K(+) current (I(K1)) is substantially larger than atrial, producing functionally important action potential differences. To evaluate possible molecular mechanisms, we recorded I(K1) with patch-clamp techniques and studied Kir2.1 and Kir2.3 subunit expression. I(K1) density was >10-fold larger in the canine ventricle than atrium. Kir2.1 protein expression (Western blot) was 78% greater (P < 0.01) in the ventricle, but Kir2.3 band density was 228% greater (P < 0.01) in the atrium. Immunocytochemistry showed transverse tubular localization of Kir2.1 in 89% (17 of 19) of ventricular and 26% (5 of 19, P < 0.0001) of atrial cells. Both exhibited a weakly positive Kir2.1 signal at intercalated disks. Kir2.3 was strongly expressed at the intercalated disks in all cells and in the transverse tubular regions in 78% (14 of 18) of atrial and 22% (4 of 18, P < 0.001) of ventricular cells. Tissue immunohistochemical results qualitatively resembled isolated cell data. We conclude that the expression density and subcellular localization of Kir2.1 and Kir2.3 subunits differ in the canine atrium versus ventricle. Overall protein density differences are insufficient to explain I(K1) discrepancies, which may be related to differences in subcellular distribution.

Animals↗
PubMed2002

Effects of sustained beta-adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes.

Short-term stimulation of beta-receptors is known to affect cardiac ion channels; however, the impact of longer-term stimulation on intrinsic channel function is poorly understood. To evaluate this, cultured guinea pig ventricular myocytes were exposed to isoproterenol (10 nM), vehicle, or isoproterenol plus propranolol (1 microM) for 48 h. Sustained exposure to isoproterenol decreased the density of the inward rectifier (I(K1)), slow delayed rectifier (I(Ks)), and L-type Ca2+ (I(Ca L)) currents, effects that were fully prevented by propranolol. Changes in K+ currents were prevented by the beta1-selective antagonist CGP-20712A, unaffected by the beta2-antagonist ICI-118,551, and mimicked by the membrane-permeable cAMP analog 8-bromo-cAMP. Isoproterenol did not alter the current-voltage relationship of the K+ currents but increased the density of T-type Ca2+ current (I(Ca T)) and thereby increased the proportion of the total Ca2+ current at more negative potentials. We conclude that sustained exposure to isoproterenol reduces I(K1), I(Ks), and I(Ca L) density and increases the density of I(Ca T). The direct ionic current remodeling effects of sustained beta-adrenoceptor stimulation resemble changes reported with heart failure and may be important in arrhythmogenic ionic remodeling.

Action Potentials↗
PubMed2002

Ultrarapid delayed rectifier K(+) current in H9c2 rat ventricular cell line: biophysical property and molecular identity.

Ultrarapid delayed rectifier K(+) currents (I(Kur)s) contribute importantly to cardiac repolarization. However, understanding of I(Kur)s has been hampered by the difficulty of dissecting them from overlapping currents in primary cells. We found with whole-cell patch-clamp recordings that H9c2 cells, a rat ventricular cell line, under 50% confluence (single myoblasts) express exclusively I(Kur)-like current which activates rapidly upon depolarization and partially inactivates during 150-ms pulses. The H9c2 I(Kur) activates within the same voltage range as native cardiac I(Kur)s, with a half-activation voltage of -13 mV. The H9c2 I(Kur) can be completely blocked by tetraethylammonium and 4-aminopyridine. Reversal potential (-79 mV) and envelope-of tail analyses indicate that the H9c2 I(Kur) is carried by a single population of K(+) channels. H9c2 I(Kur) was increased by beta-adrenoceptor-PKA and decreased by alpha(1)-adrenoceptor-PKC activation by isoproterenol and phenylephrine, respectively. Immunocytochemistry was performed with antibodies against 11 different K(+) channels. Positive immuno-stain-ing of the cytoplasmic membrane of H9c2 cells was seen only with Kv3.1b antibody. Antisense oligodeoxynucleotides directed against Kv3.1b subunit sequence significantly inhibited the H9c2 I(Kur). We conclude that the H9c2 cells at the myoblast stage express mainly I(Kur) and Kv3.1b may be a molecular component of the H9c2 I(Kur), and H9c2 cells provide a suitable system for studying I(Kur).

4-Aminopyridine↗
PubMed2002

New approaches to atrial fibrillation management: a critical review of a rapidly evolving field.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, the prevalence of which is increasing with the aging of the population. Because of its clinical importance and the lack of highly satisfactory management approaches, AF is the subject of active clinical and research efforts. This paper reviews recent and on-going developments in pharmacological and non-drug management of AF. The ideal therapeutic goal for AF is the production and maintenance of sinus rhythm. Comparative studies suggest that available class I and III drugs have comparable and modest efficacy for sinus rhythm maintenance. Amiodarone, with actions of all antiarrhythmic classes, has recently been shown to have clearly superior efficacy compared with other available drugs. Newer agents are in development, but their advantages are as yet unclear and appear limited. A potentially interesting approach is the prescription of drugs upon the occurrence of an attack, rather than on a continuous basis. Recent insights into AF mechanisms may permit therapy to prevent development of the AF substrate. An alternative to sinus rhythm maintenance is a rate control approach, with no attempt to prevent AF. Drugs to effect rate control include digitalis, beta-blockers and calcium channel antagonists. Digitalis has limited value for control of exercise heart rate and for paroxysmal AF, but is particularly well suited for patients with concomitant AF and congestive heart failure. AV-nodal ablation and pacing is an effective alternative for rate control but leaves the patient pacemaker dependent. The relative merits of rate versus rhythm control are being evaluated in ongoing trials, preliminary results of which indicate no statistically significant differences in primary endpoints but highlight the risks of rhythm control therapy. In patients requiring pacemakers, physiological pacing (dual chamber devices or atrial pacing) has an advantage over purely ventricular pacemakers in AF prevention. Newer pacing modalities that produce more synchronised atrial activation, as well as pacemakers that prevent excessive atrial rate swings, show promise in AF prevention and may soon see wider use. The usefulness of automatic atrial defibrillators is presently limited by discomfort during shocks. Targeted destruction of pulmonary vein foci by radiofrequency catheter ablation suppresses paroxysmal AF. Efficacy in persistent AF is lower and still under study. Problems include potential recurrence in other veins and a small but nontrivial risk of pulmonary vein stenosis. Surgical division of the atria into zones with limited electrical connection, the MAZE procedure, is highly effective in AF prevention but is a major intervention that is not applicable to most patients. In conclusion, significant advances are being made in the management of patients with AF but much more work remains to be done.

Anti-Arrhythmia Agents↗
PubMed2001

Dofetilide block involves interactions with open and inactivated states of HERG channels.

Rapidly activating delayed rectifier current ( IKr) is the key target of class III antiarrhythmic drugs including dofetilide. Due to its complex gating properties, the precise channel state or states that interact with these agents remain poorly defined. We have undertaken a careful analysis of the state dependence of HERG channel block by dofetilide in Xenopus oocytes and Chinese Hamster Ovary (CHO) cells by devising a protocol in which brief sampling pulses were superimposed over a wide range of test potentials. The rate of block onset, maximal steady-state block and IC50 were similar for all test potentials over the activation range, demonstrating that the drug probably interacts with open and/or inactivated but not resting HERG channels with high affinity. Reducing the fraction of inactivated channels at 0 mV by augmenting the external potassium concentration did not alter the sensitivity to dofetilide. In contrast, the S631A and S620T HERG mutations both eliminated inward rectification and reduced dofetilide affinity by approximately 10- and approximately 100-fold respectively. We have also found a novel ultra-slow activation process which occurs in wild type HERG channels at threshold potentials. Overall, our data imply that dofetilide block occurs equally at all voltages positive to the activation threshold, and that the drug interacts with HERG channels in both the open and inactivated states.

Animals↗
PubMedDate not supplied

Mechanisms of atrial fibrillation: lessons from animal models.

Studies in animal models have provided extremely important insights about atrial fibrillation (AF). The classic mechanisms that still form the framework for our understanding of AF (focal activity, single-circuit or "mother wave" reentry, and multiple circuit reentry) were established based on animal studies almost 100 years ago. The past 10 years have witnessed a tremendous acceleration of animal work in this area, including the development of a range of AF models in clinically relevant pathological substrates (eg, atrial tachycardia remodeling, congestive heart failure, pericarditis, ischemic heart disease, mitral valve disease, volume overload states, respiratory failure) and the establishment of an increasing number of genetically defined transgenic mouse models. This article reviews the contribution of animal models to our knowledge about AF mechanisms and to clinical management, dealing with such issues as the theory of reentry; the specific applications of various animal models and their contribution to our understanding of electrophysiologic, ionic, and molecular mechanisms; the role of the autonomic nervous system and regional factors; and the development of novel therapeutic approaches. The complementary nature of animal research and clinical investigation is emphasized and the clinical relevance of findings in experimental models is highlighted.

Action Potentials↗