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Biomedical subjects

Stanley Nattel

Publications and source records attributed to Stanley Nattel.

At least 109 records · Page 6Linked to original sources
PubMed2003

Prognostic significance of ventricular arrhythmias post-myocardial infarction.

Despite improvements in management strategies, ventricular arrhythmias remain important markers of electrical instability and contribute to the identification of patients at increased risk of sudden cardiac death post-myocardial infarction (MI). Over the past 20 years, understanding of pathophysiological mechanisms and implications of various types of ventricular arrhythmias has evolved remarkably. This systematic review details the prognostic significance of ventricular arrhythmias classified by type and time of onset post-MI. Subacute and late premature ventricular complexes are associated with increased mortality independent of left ventricular function. Although nonsustained ventricular tachycardia (VT) in the acute phase post-MI is of questionable significance, later onset heralds poorer prognosis. Sustained monomorphic VT in the acute post-MI phase is associated with infarct extension, heart failure and increased mortality. Extensive wall motion abnormalities, left ventricular dysfunction and aneurysm formation correlate with later postinfarct sustained VT. Inhospital mortality is higher when ventricular fibrillation presents in the acute phase but long term prognosis is not adversely affected.

Anti-Arrhythmia Agents↗
PubMed2002

Comparison of ion-channel subunit expression in canine cardiac Purkinje fibers and ventricular muscle.

Although Purkinje fibers (PFs) play an important role in cardiac electrophysiology, almost nothing is known about the expression of ion-channel subunits in PFs. We applied competitive reverse transcription-polymerase chain reaction, Western blotting, and immunocytochemistry to compare the expression of ion-channel subunit mRNA and protein in canine PFs versus ventricular muscle (VM). For transient outward current-related subunits, Kv4.2 was not detected, and Kv1.4 expression was extremely low. Kv4.3 expression was of the same order for VM and PFs. The tetraethylammonium chloride-sensitive subunit Kv3.4 was expressed much more strongly in PFs than in VM, and Kv channel-interacting protein transcript expression was 25-fold stronger in VM than in PFs. For delayed rectifiers, ERG and KvLQT1 expression was lower in PFs at both mRNA and protein levels. Although minK transcripts were more numerous in PFs, minK protein was significantly more strongly expressed in VM. L-type Ca2+ current alpha-subunit (Ca(V)1.2) and Na+-Ca2+ exchanger proteins were more strongly expressed in VM than in PFs. For T-type Ca2+ current, Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3 transcripts were all more strongly expressed in PFs. For the nonselective cation current, hyperpolarization-activated cation channel 1 (HCN1) expression was subquantifiable, HCN2 transcript expression was comparable in PFs and VM, and HCN4 mRNA expression was strong in PFs but below the detection threshold in VM. HCN2 and HCN4 protein expression was much stronger in PFs than in VM. We conclude that ion-channel subunit expression in PFs differs from that in VM in ways that are consistent with, and shed light on the molecular basis of, well-recognized fundamental PF ionic properties.

Animals↗
PubMed2002

New insights into the mechanisms and management of atrial fibrillation.

Atrial fibrillation (AF) is a common contributor to cardiovascular morbidity and mortality. Two generally acceptable strategies exist for long-term AF management, with ongoing studies comparing the overall mortality associated with each. One strategy aims to maintain sinus rhythm, with antiarrhythmic agents if necessary, thereby preserving physiological cardiac electrical function but exposing the patient to the potential side effects of potent drugs. The second approach is to control the ventricular rate and prevent thromboembolic complications with anticoagulants, leaving the patient with AF. Both beta-blocking agents and calcium antagonists are more effective than digoxin in achieving rate control. Several nonpharmacological therapies including catheter ablation, implantable devices and surgical interventions show promise for rate control and maintenance of sinus rhythm. This paper provides an overview of new developments in pharmacological and nonpharmacological therapy. Key features of recently published clinical guidelines, including a unified classification scheme for AF and issues relating to rate control and maintenance of sinus rhythm, are considered. In addition, preliminary results from the recently presented AFFIRM study, the largest AF trial to date, are summarized. Finally, we discuss recent insights into the basic mechanisms underlying AF that have potentially significant clinical implications.

Amiodarone↗
PubMed2002

Kir2.4 and Kir2.1 K(+) channel subunits co-assemble: a potential new contributor to inward rectifier current heterogeneity.

Heteromeric channel assembly is a potential source of physiological variability. The potential significance of Kir2 subunit heterotetramerization has been controversial, but recent findings suggest that heteromultimerization of Kir2.1-3 may be significant. This study was designed to investigate whether the recently described Kir2.4 subunit can form heterotetramers with the important subunit Kir2.1, and if so, to investigate whether the resulting heterotetrameric channels are functional. Co-expression of either dominant negative Kir2.1 or Kir2.4 subunits in Xenopus oocytes with either wild-type Kir2.1 or 2.4 strongly decreased resulting current amplitude. To examine physical association between Kir2.1 and Kir2.4, Cos-7 cells were co-transfected with a His(6)-tagged Kir2.1 subunit (Kir2.1-His(6)) and a FLAG-tagged Kir2.4 subunit (Kir2.4-FLAG). After pulldown with a His(6)-binding resin, Kir2.4-FLAG could be detected in the eluted cell lysate by Western blotting, indicating co-assembly of Kir2.1-His(6) and Kir2.4-FLAG. Expression of a tandem construct containing covalently linked Kir2.1 and 2.4 subunits led to robust current expression. Kir2.1-Kir2.4 tandem subunit expression, as well as co-injection of Kir2.1 and Kir2.4 cRNA into Xenopus oocytes, produced currents with barium sensitivity greater than that of Kir2.1 or Kir2.4 subunit expression alone. These results show that Kir2.4 subunits can co-assemble with Kir2.1 subunits, and that co-assembled channels are functional, with properties different from those of Kir2.4 or Kir2.1 alone. Since Kir2.1 and Kir2.4 mRNAs have been shown to co-localize in the CNS, Kir2.1 and Kir2.4 heteromultimers might play a role in the heterogeneity of native inward rectifier currents.

Animals↗
PubMed2002

HERG K+ channel, a regulator of tumor cell apoptosis and proliferation.

The human ether-a-go-go related gene (HERG) encodes K+ channel identified as a molecular target for mutations underlying some forms of the long Q-T syndrome, a lethal cardiac arrhythmia. Recent studies revealed that HERG is abundantly expressed in a variety of tumor cells. Yet, the role of HERG in tumor cells had remained unclear. Here, we show that HERG conductance markedly promotes H2O2-induced apoptosis of various tumor cells, whereas HERG expression facilitates the tumor cell proliferation caused by tumor necrosis factor (TNF) ligand (TNF-alpha). Immunostaining and immunocoprecipitation reveal coexpression of HERG and TNF receptor 1 on the cytoplasmic membrane, which is correlated with greater activities of nuclear transcription factor, nuclear factor-kappaB, in HERG-expressing tumor cells. Our data suggest that HERG K+ channel is a regulator of tumor cell proliferation and apoptosis and provide a potential new target for cancer therapy.

Adenocarcinoma↗
PubMed2002

Properties of potassium currents in Purkinje cells of failing human hearts.

Cardiac Purkinje fibers play an important role in cardiac arrhythmias, but no information is available about ionic currents in human cardiac Purkinje cells (PCs). PCs and midmyocardial ventricular myocytes (VMs) were isolated from explanted human hearts. K(+) currents were evaluated at 37 degrees C with whole cell patch clamp. PCs had clear inward rectifier K(+) current (I(K1)), with a density not significantly different from VMs between -110 and -20 mV. A Cs(+)-sensitive, time-dependent hyperpolarization-activated current was measurable negative to -60 mV. Transient outward current (I(to)) density was smaller, but end pulse sustained current (I(sus)) was larger, in PCs vs. VMs. I(to) recovery was substantially slower in PCs, leading to strong frequency dependence. Unlike VM I(to), which was unaffected by 10 mM tetraethylammonium, Purkinje I(to) was strongly inhibited by tetraethylammonium, and Purkinje I(to) was 10-fold more sensitive to 4-aminopyridine than VM. PC I(sus) was also reduced strongly by 10 mM tetraethylammonium. In conclusion, human PCs demonstrate a prominent I(K1), a time-dependent hyperpolarization-activated current, and an I(to) with pharmacological sensitivity and recovery kinetics different from those in the atrium or ventricle and compatible with a different molecular basis.

Adult↗
PubMed2002

Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs.

BACKGROUND: Clinical atrial fibrillation (AF) often results from pathologies that cause atrial structural remodeling. The reversibility of arrhythmogenic structural remodeling on removal of the underlying stimulus has not been studied systematically. METHODS AND RESULTS: Chronically instrumented dogs were subjected to 4 to 6 weeks of ventricular tachypacing (VTP; 220 to 240 bpm) to induce congestive heart failure (CHF), followed by a 5-week recovery period leading to hemodynamic normalization at 5-week recovery (Wk5(rec)). The duration of burst pacing-induced AF under ketamine/diazepam/isoflurane anesthesia increased progressively during VTP and recovered toward baseline during the recovery period, paralleling changes in atrial dimensions. However, even at full recovery, sustained AF could still be induced under relatively vagotonic morphine/chloralose anesthesia. Wk5(rec) dogs showed no recovery of CHF-induced atrial fibrosis (3.1+/-0.3% for controls versus 10.7+/-1.0% for CHF and 12.0+/-0.8% for Wk5(rec) dogs) or local conduction abnormalities (conduction heterogeneity index 1.8+/-0.1 in controls versus 2.3+/-0.1 in CHF and 2.2+/-0.2 in Wk5(rec) dogs). One week of atrial tachypacing failed to affect the right atrial effective refractory period significantly in CHF dogs but caused highly significant effective refractory period reductions and atrial vulnerability increases in Wk5(rec) dogs. CONCLUSIONS: Reversal of CHF is followed by normalized atrial function and decreased duration of AF; however, fibrosis and conduction abnormalities are not reversible, and a substrate that can support prolonged AF remains. Early intervention to prevent fixed structural abnormalities may be important in patients with conditions that predispose to the arrhythmia.

Animals↗
PubMed2002

Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function.

The cardiac electrical system is designed to ensure the appropriate rate and timing of contraction in all regions of the heart, which are essential for effective cardiac function. Well-controlled cardiac electrical activity depends on specialized properties of various components of the system, including the sinoatrial node, atria, atrioventricular node, His-Purkinje system, and ventricles. Cardiac electrical specialization was first recognized in the mid 1800s, but over the past 15 years, an enormous amount has been learned about how specialization is achieved by differential expression of cardiac ion channels. More recently, many aspects of the molecular basis have been revealed. Although the field is potentially vast, an appreciation of key elements is essential for any clinician or researcher wishing to understand modern cardiac electrophysiology. This article reviews the major regionally determined features of cardiac electrical function, discusses underlying ionic bases, and summarizes present knowledge of ion channel subunit distribution in relation to functional specialization.

Action Potentials↗
PubMed2002

Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties.

Classical concepts of atrial fibrillation (AF) have been rooted in Moe's multiple-wavelet hypothesis and simple cellular-automaton computer model. Recent experimental work has raised questions about the multiple-wavelet mechanism, suggesting a discrete "driver region" underlying AF. We reexplored the theoretical basis for AF with a 2-dimensional computer model of a 5x10-cm sheet of atrial cells with realistic ionic and coupling properties. Vagal actions were formulated based on patch-clamp studies of acetylcholine (ACh) effects. In control, a single extrastimulus resulted in a highly meandering unstable spiral wave. Simulated electrograms showed fibrillatory activity, with a dominant frequency (DF, 6.5 Hz) that correlated with the mean rate. Uniform ACh reduced core meander of the spiral wave by approximately 70% (as measured by the standard deviation of spiral-wave tip position) and accelerated the DF to 17.0 Hz. Simulated vagally induced refractoriness heterogeneity caused wavefront breakup as accelerated reentrant activity in regions of short refractoriness impinged on regions unable to respond in a 1:1 fashion because of longer refractoriness. In 7 simulations spanning the range of conditions giving sustained AF, 5 were maintained by single dominant spiral waves. On average, 3.0+/-1.3 wavelets were present (range, 1 to 7). Most wavelets were short-lived and did not contribute to AF maintenance. In contrast to predictions of the multiple-wavelet hypothesis, but in agreement with recent experimental evidence, our model indicates that AF can result from relatively stable primary spiral-wave generators and is significantly organized. Our results suggest that vagal AF may arise from ACh-induced stabilization of the primary spiral-wave generator and disorganization of the heterogeneous tissue response. The full text of this article is available at http://www.circresaha.org.

Acetylcholine↗
PubMed2002

A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link?

Although it has been suggested that coexpression of minK related peptide (MiRP1) is required for reconstitution of native rapid delayed-rectifier current (I(Kr)) by human ether-a-go-go related gene (HERG), currents resulting from HERG (I(HERG)) and HERG plus MiRP1 expression have not been directly compared with native I(Kr). We compared the pharmacological and selected biophysical properties of I(HERG) with and without MiRP1 coexpression in Chinese hamster ovary (CHO) cells with those of guinea-pig I(Kr) under comparable conditions. Comparisons were also made with HERG expressed in Xenopus oocytes. MiRP1 coexpression significantly accelerated I(HERG) deactivation at potentials negative to the reversal potential, but did not affect more physiologically relevant deactivation of outward I(HERG), which remained slower than that of I(Kr). MiRP1 shifted I(HERG) activation voltage dependence in the hyperpolarizing direction, whereas I(Kr) activated at voltages more positive than I(HERG). There were major discrepancies between the sensitivity to quinidine, E-4031 and dofetilide of I(HERG) in Xenopus oocytes compared to I(Kr), which were not substantially affected by coexpression with MiRP1. On the other hand, the pharmacological sensitivity of I(HERG) in CHO cells was indistinguishable from that of I(Kr) and was unaffected by MiRP1 coexpression. We conclude that the properties of I(HERG) in CHO cells are similar in many ways to those of native I(Kr) under the same recording conditions, and that the discrepancies that remain are not reduced by coexpression with MiRP1. These results suggest that the physiological role of MiRP1 may not be to act as an essential consituent of the HERG channel complex carrying native I(Kr).

Adrenergic alpha-Antagonists↗
PubMed2002

Predicting the entrainment of reentrant cardiac waves using phase resetting curves.

Excitable media, such as the Belousov-Zhabotinsky medium or the heart, are capable of supporting excitation waves that circulate in a closed repetitive path--a phenomenon known as reentrant excitation. A single stimulus, depending on its magnitude, timing, and location, can cause a time shift of the reentrant excitation called resetting. The present study examines the ability of resetting data to predict the effects of periodic stimuli on reentrant excitation circulating on an annular domain. We compare the results of the theoretical models with experiments carried out in an animal model of a dangerous reentrant cardiac rhythm. The current work may lead to improved approaches to therapy through a better understanding of how typical clinical stimuli interact with abnormal reentrant cardiac rhythms.

Animals↗
PubMed2002

Consequences of atrial tachycardia-induced remodeling depend on the preexisting atrial substrate.

BACKGROUND: All animal studies of atrial tachycardia (AT) remodeling to date have been performed in normal hearts, but clinical atrial fibrillation (AF) often occurs in the setting of heart disease. This study evaluated the effects of a pathological AF substrate on AT-induced remodeling. METHODS AND RESULTS: Fourteen control dogs, 12 AT-only dogs (400 bpm for 1 week), 14 congestive heart failure (CHF) dogs (CHF only, ventricular tachypacing, 220 to 240 bpm for 5 weeks), and 13 CHF+AT dogs (ventricular tachypacing-induced CHF, 1 week of AT superimposed on the last week of ventricular tachypacing) were studied for evaluation of AT effects in normal hearts (AT-only versus control dogs) and CHF hearts (CHF+AT versus CHF-only dogs). In normal hearts, AT strongly decreased the effective refractory period (ERP) and abolished ERP rate adaptation, whereas conduction velocity was unaltered. In CHF dogs, AT reduced ERP to a significantly lesser extent, did not alter ERP rate adaptation, and reduced conduction velocity. AT alone increased atrial vulnerability to extrastimuli and prolonged AF. In the presence of CHF, AT had no clear effect on atrial vulnerability but increased the prevalence of prolonged AF. CONCLUSIONS: The electrophysiological effects of AT are different in hearts with a CHF-induced pathological substrate for AF than in normal hearts. These findings have potentially important implications for understanding how AF occurring in diseased hearts begets AF.

Adaptation, Physiological↗
PubMed2002

New ideas about atrial fibrillation 50 years on.

Atrial fibrillation is a condition in which control of heart rhythm is taken away from the normal sinus node pacemaker by rapid activity in different areas within the upper chambers (atria) of the heart. This results in rapid and irregular atrial activity and, instead of contracting, the atria only quiver. It is the most common cardiac rhythm disturbance and contributes substantially to cardiac morbidity and mortality. For over 50 years, the prevailing model of atrial fibrillation involved multiple simultaneous re-entrant waves, but in light of new discoveries this hypothesis is now undergoing re-evaluation.

Animals↗
PubMed2002

A mathematical model of human atrioventricular nodal function incorporating concealed conduction.

This work develops a mathematical model for the atrioventricular (AV) node in the human heart, based on recordings of electrical activity in the atria (the upper chambers of the heart) and the ventricles (the lower chambers of the heart). Intracardiac recordings of the atrial and ventricular activities were recorded from one patient with atrial flutter and one with atrial fibrillation. During these arrhythmias, not all beats in the atria are conducted to the ventricles. Some are blocked (concealed). However, the blocked beats can affect the properties of the AV node. The activation times of the atrial events were regarded as inputs to a mathematical model of conduction in the AV node, including a representation of AV nodal concealment. The model output was compared to the recorded ventricular response to search for and identify the best possible parameter combinations of the model. Good agreement between the distribution of interbeat intervals in the model and data for durations of 5 min was achieved. A model of AV nodal behavior during atrial flutter and atrial fibrillation could potentially help to understand the relative roles of atrial input activity and intrinsic AV nodal properties in determining the ventricular response.

Atrial Fibrillation↗
PubMed2002

Effects of inhibiting Na(+)/H(+)-exchange or angiotensin converting enzyme on atrial tachycardia-induced remodeling.

BACKGROUND: Inhibitors of the Na(+)/H(+)-exchanger (NHE1) and of angiotensin-converting enzyme (ACE) have been shown to reduce short-term (<6 h) tachycardia-induced atrial electrical remodeling. The role of NHE1 and ACE in longer-term electrical remodeling, as might occur with persistent AF, has not been studied. METHODS: Dogs were subjected to atrial-tachypacing (400 bpm) for 7 days during treatment with 240 mg/day (standard clinical dose) of the NHE1 inhibitor cariporide (CariL, n=6), 1000 mg/day cariporide (CariH, n=6), 2 mg/kg/day of the ACE inhibitor enalapril (E, n=6), or no-drug controls (n=7). To ensure steady state concentrations at the onset of pacing, treatment began 3 days before the initiation of atrial tachypacing. Results were compared to those of unpaced dogs (n=9). RESULTS: Atrial tachypacing reduced atrial effective refractory period (ERP), e.g. at a basic cycle length of 300 ms from 126+/-4 ms (unpaced, mean+/-S.E.) to 79+/-8 ms (no-drug controls, P<0.001). ERP abbreviation was unchanged by CariL (83+/-8 ms), CariH (80+/-7 ms), or E (76+/-5 ms). Atrial tachypacing increased mean duration of the longest AF episode in each dog (DAF) from 130+/-80 s (unpaced) similarly in all groups: 864+/-364 s, no-drug controls; 609+/-376 s, CariL; 709+/-353 s, CariH; 645+/-365 s, E (P=NS for differences among groups). Sustained AF requiring cardioversion for termination was induced in 0% of unpaced dogs vs. 33% of CariL, 33% of CariH, 33% of E, and 43% of control dogs. AF inducibility by single extrastimuli increased from 4+/-2% in unpaced dogs to 48+/-13% (P<0.01) in no-drug control dogs, an effect not changed by CariL (33+/-14%), CariH (35+/-17%) or E (48+/-16%). CONCLUSIONS: In contrast to short-term (several-hour) atrial tachycardia-induced remodeling, remodeling by 7-day tachycardia is not affected by NHE1 or ACE inhibition. These results support the notion that short-term atrial tachycardia remodeling involves different mechanisms from longer-term remodeling, and urges caution in extrapolating results from studies of short-term remodeling to effects in longer-term remodeling as often occurs clinically.

Action Potentials↗
PubMed2002

Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management?

Atrial fibrillation (AF) is a very common clinical problem, and presently available treatment options are suboptimal. A tremendous amount has been learned over the past 10 years about the atrial substrates that support sustained AF at the tissue, ionic and molecular levels. This understanding of the fundamental mechanisms underlying AF has opened up a variety of new, rationally-based therapeutic approaches. The present paper reviews what is known about the mechanistic substrates that lead to AF and discusses the potential therapeutic consequences.

Action Potentials↗
PubMed2002

Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure.

OBJECTIVE: Atrial remodeling contributes to the maintenance of atrial fibrillation (AF) in several cardiac disorders. There is evidence that angiotensin-converting enzyme (ACE) inhibitors reduce the prevalence of AF in patients with congestive heart failure (CHF). There have been no studies performed to assess the effects of ACE inhibitors on atrial dimensions and emptying function in relationship to vulnerability to AF in the setting of experimental CHF. METHODS: CHF was produced in 20 dogs by rapid right ventricular pacing during 5 weeks. The dogs were randomized to enalapril (EN) therapy (2 mg/kg/day, n=10) or to a control group (n=10). Echocardiography was performed at baseline and weekly thereafter. At the 5-week electrophysiological study, AF was induced by burst pacing and AF duration was measured. RESULTS: Atrial areas increased significantly with CHF. Left atrial (LA) fractional area shortening (FAS) decreased by 42% (P=0.0001) in controls but by 9% (P=NS) in the EN group (P=0.01, EN vs. controls). Similar findings were observed for right atrial (RA) changes (P=0.02). Atrial fibrosis was highly correlated with the decrease in LA FAS (r=0.85, P<0.01) and was reduced by EN (from 11.2+/-1.6 to 8.3+/-0.7%, P=0.008). AF duration was 720+/-461 s for controls and 138+/-83 s for EN (P=0.001). LA and RA areas and FAS at 5 weeks correlated with AF duration (P< or =0.001 for all). FAS decrease in both atria also correlated with AF duration at follow-up (r=0.78 and 0.77 for LA and RA, P< or =0.001 for both). CONCLUSIONS: Experimental CHF causes structural and functional abnormalities in both atria, which are correlated with AF duration. ACE inhibition attenuates CHF-induced atrial fibrosis and remodeling and reduces associated AF promotion. These results indicate a role for the renin-angiotensin system in arrhythmogenic atrial structural remodeling in CHF.

Action Potentials↗