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Biomedical subjects

R J Lee

Publications and source records attributed to R J Lee.

At least 109 records · Page 6Linked to original sources
PubMed1996

Results of radiofrequency catheter ablation for atrial flutter.

RF catheter ablation for symptomatic typical atrial flutter is associated with a high procedural success rate, but a second RF procedure may be required in up to one third of subjects, particularly those with right atrial enlargement. In those subjects with both established AF and flutter, RF ablation for atrial flutter may decrease the recurrence rate of AF. However, patients remain at risk for the development of newly documented AF, most likely secondary to the high incidence of underlying structural heart disease.

Aged↗
PubMed1996

Folate-targeted, anionic liposome-entrapped polylysine-condensed DNA for tumor cell-specific gene transfer.

We have developed a lipidic gene transfer vector, LPDII, where DNA was first complexed to polylysine at a ratio of 1:0.75 (w/w) and then entrapped into folate-targeted pH-sensitive anionic liposomes composed of dioleoyl phosphatidylethanolamine (DOPE)/cholesteryl hemisuccinate/folate-polyethlene glycol-DOPE (6:4:0.01 mol/mol) via charge interaction. LPDII transfection of KB cells, a cell line overexpressing the tumor marker folate receptor, was affected by both the lipid to DNA ratio and the lipid composition. At low lipid to DNA ratios (e.g. 4 and 6), LPDII particles were positively charged; transfection and cellular uptake levels were independent of the folate receptor and did not require a pH-sensitive lipid composition. Meanwhile, transfection and uptake of negatively charged LPDII particles, i.e. those with high lipid to DNA ratios (e.g. 10 and 12), were folate receptor-dependent and required a pH-sensitive lipid composition. The transfection activity of LPDII was lost when the inverted cone-shaped DOPE was replaced by dioleoyl phosphatidylcholine. LPDII particles with lipid to DNA ratios of 4, 6, 10, and 12 were approximately 20-30 times more active than DNA.3-beta-[N-(N',N'-dimethylethane)carbamoyl]cholesterol cationic liposome complexes in KB cells and were much less cytotoxic. On the sucrose gradient, LPDII particles had a migration rate in between those of the free DNA and the DNA.polylysine complex. An electron micrograph of LPDII showed a structure of spherical particles with a positively stained core enclosed in a lipidic envelope with a mean diameter of 74 +/- 14 nm. This novel gene transfer vector may potentially be useful in gene therapy for tumor-specific delivery.

Anions↗
PubMed1996

Importance of calcium for the vulnerability to ventricular fibrillation detected by premature ventricular stimulation: single pulse versus sequential pulse methods.

Vulnerability to ventricular fibrillation (VF) is frequently evaluated by VF threshold, a variable which may not be free of confounding factors and which may not be sensitive to all factors contributing to vulnerability. Therefore, we tested whether VF threshold determination affects intracellular free Ca2+ ([Ca2+]i) and whether VF thresholds are sensitive to changes in [Ca2+]i. For this purpose, we analysed [Ca2+]i by surface fluorometry and indo-1 in intact perfused rat hearts undergoing VF threshold determination by a single pulse method and tested whether such thresholds are lowered by increased [Ca2+]i. Additionally, we sought to determine the importance of Ca2+ for the vulnerability to VF under nonischemic conditions. For this purpose, we measured VF thresholds by a new pulse number method which scanned the vulnerable period by an increasing number of sequential pulses at increasing prematurity but constant intensity. We found that VF threshold determination by a single pulse method led to a rise in systolic [Ca2+]i. However, this rise does not perturb VF threshold interpretation because such thresholds were insensitive to changes in [Ca2+]i. Nevertheless, [Ca2+]i is of importance for the vulnerability to VF under nonischemic conditions because the number of VF-free tolerated premature pulses was dependent on [Ca2+]i. This relationship may only be detectable if evaluated by sequential pulse methods. These findings suggest that the method of VF threshold determination may be crucial for the result of studies testing Ca2+ antagonists or situations of altered [Ca2+]i and could explain controversial results of VF threshold studies testing Ca2+ antagonists by varying methods.

Animals↗
PubMed1996

Long-term results of electrophysiologically guided sotalol therapy for life-threatening ventricular arrhythmias.

The efficacy and safety of sotalol therapy for ventricular arrhythmias was evaluated in 133 patients with drug-refractory ventricular arrhythmias. All patients had baseline electrophysiologic studies before and after oral sotalol therapy. Sixty-six patients were discharged home, treated with sotalol (52 patients without inducible ventricular tachycardia or fibrillation and 14 patients with hemodynamically stable inducible ventricular tachycardia). The mean follow-up period was 41 +/- 27 months for the 14 patients with hemodynamically stable ventricular tachycardia. Sotalol was effective in 8 of these 14 patients. Recurrent nonlethal ventricular tachycardia occurred in 3 patients; 2 patients had sudden death; and 1 patient had adverse side effects. The 52 patients without inducible ventricular tachycardia were followed up for a mean period of 36 +/- 30 months. Thirty-five of 52 patients were successfully treated. Two patients had recurrent ventricular tachycardia; both of these episodes of ventricular tachycardia occurred within the first year. Four patients had sudden cardiac death; three of these deaths occurred within the first month, and the last episode of sudden death occurred after 8 years of sotalol therapy. The actuarial incidence of sotalol efficacy was 76% at 1 year, 72% at 2 years, 64% at 4 years, and 52% at 5 years. Approximately 46% of patients receiving long-term sotalol treatment reported side effects. Side effects severe enough to warrant withdrawal of sotalol occurred in 7 (11%) patients. The results of our study suggest that sotalol is effective for selected patients with drug refractory ventricular arrhythmias. Although the incidence of side effects are high, patients appear to tolerate long-term sotalol therapy well.

Adult↗
PubMed1996

Quality of life and outcomes after radiofrequency His-bundle catheter ablation and permanent pacemaker implantation: impact of treatment in paroxysmal and established atrial fibrillation.

One hundred seven patients underwent atrioventricular (AV)-junctional ablation and pacing for atrial fibrillation, and 90 were alive 2.3 +/- 1.2 years later. Quality of life index (1.9 +/- 1.2 to 3.6 +/- 1.1; 3.6 +/- 1.1; p<0.001) and ease of activities of daily living (2 +/- 0.4 to 2.4 +/- 0.3; p<0.001) were significantly improved. Doctor visits (10 +/- 13 to 5.06 +/-7; p<0.03), hospital admissions (2.8 +/- 6.8 vs 0.17 +/- 0.54; p<0.03, and antiarrhythmic drug trials (6.2 +/- 4 to 0.46 +/- 1.5; p<0.001) decreased significantly after treatment. Congestive heart failure episodes decreased from 18 before to 8 afterward. Twenty-eight of 36 patients with dual-chamber pacemakers remained in a dual-chamber mode at follow-up. Radiofrequency AV-junctional catheter ablation and pacing is a highly successful form of treatment for medically refractory atrial fibrillation.

Activities of Daily Living↗
PubMed1996

Mechanism of action of the non-steroidal anti-inflammatory drug flufenamate on [Ca2+]i and Ca(2+)-activated currents in neurons.

We have shown previously that the non-steroidal anti-inflammatory drug flufenamate (FFA) causes a maintained increase in [Ca2+]i and transient increases in a Ca(2+)-activated nonselective cation current (ICAN) and a Ca(2+)-activated slow, outward Cl- current (lo-slow) in molluscan neurons [Shaw T., Lee R.J., Partridge L.D. Action of diphenylamine carboxylate derivatives, a family of non-steroidal anti-inflammatory drugs, on [Ca2+]i and Ca(2+)-activated channels in neurons. Neurosci Lett 1995; 190:121-124]. Here we demonstrate that pretreatment of neurons with 10 microM thapsigargin eliminates the FFA-induced increase in [Ca2+]i and substantially reduces both ICAN and Io-slow supporting the hypothesis that the FFA-induced increase in [Ca2+]i results primarily from Ca2+ release from a thapsigargin-sensitive intracellular store. The [Ca2+]i response appears to be sustained, not by influx of extracellular Ca2+, but by inhibitory effects of FFA on Ca2+ removal from the cytosol. Inhibition of Ca2+ efflux may be an important component of the FFA-induced activation of both ICAN and Io-slow, as Ca2+ release by thapsigargin alone is not sufficient to activate either current. Our data also demonstrate that the effects of FFA on [Ca2+]i, ICAN and Io-slow are reversible and suggest that protein phosphorylation as well as an increase in [Ca2+]i are involved in the FFA-induced activation of Io-slow. Effects on neuronal Ca2+ handling as well as activation of ICAN or Io-slow may partially explain the analgesic effects of FFA.

Animals↗
PubMed1996

Reduced cyclin D1 expression in the cerebella of nutritionally deprived rats correlates with developmental delay and decreased cellular DNA synthesis.

Nutritional deprivation in the early postnatal period severely inhibits cerebellar growth and development, which is related in part to reduced levels of growth factors. Cyclin D1 encodes a growth factor-inducible regulatory subunit of a serine/thereonine kinase that is capable of phosphorylating the tumor suppressor pRB, thereby allowing normal progression through the G1 phase of the cell-cycle. Because the abundance of cyclin D1 is rate limiting in this progression, we examined the regulation of cyclin D1 expression in vivo, using a model of nutritional deprivation. Cyclin D1 expression in cerebella of fed control rats was detected in the external granular layer and was associated with cellular proliferation within this layer. Nutritional deprivation of rats reduced cerebellar weight, as well as the thickness of the molecular layer that largely consists of cells migrating from the external granular layer. Refeeding partially restored cerebellar weight, molecular layer thickness and increased external granular layer cyclin D1 immunostaining. Since nutritional deprivation is accompanied by lower levels of circulating insulin-like growth factor-I (IGF-I), we determined whether IGF-I directly stimulated the cyclin D1 promoter. The human cyclin D1 promoter linked to the luciferase reporter gene was stably integrated into PC12 cells. IGF-I stimulated cyclin D1 promoter activity 4- to 6-fold at 6 hours (h). These findings are consistent with the notion that nutritional deprivation may affect proliferative growth by altering expression of cyclin D1 in the germinal cell layer and that regulation of cyclin D1 expression by growth factors may contribute to normal neonatal cerebellar development. The reduction in cyclin D1 expression as cells differentiate in the cerebellum is consistent with a potential role for cyclin D1 in this process.

Animals↗
PubMed1996

Phenylephrine-induced ventricular arrhythmias in dogs with inherited sudden death.

INTRODUCTION: Dogs with an inherited predisposition to sudden death display ventricular arrhythmias having certain characteristics, such as pause dependence, that are suggestive of early afterdepolarization-induced triggered activity. We hypothesized that alpha-adrenergic stimulation may facilitate the development of these arrhythmias by inducing a reflex bradycardia and by exerting a direct myocardial effect. METHODS AND RESULTS: Twenty affected dogs and 7 unaffected dogs were studied. The incidence and severity of ventricular arrhythmias were determined after administration of phenylephrine (0.01 mg/kg IV), with or without pretreatment with propranolol (0.1 to 0.3 mg/kg IV), atropine (0.04 mg/kg IV), or prazosin (0.5 mg/kg IV). Third-degree heart block was induced by AV nodal ablation in 4 affected dogs. Phenylephrine increased ventricular arrhythmias in affected dogs, with or without pretreatment with propranolol, but did not induce ventricular arrhythmias in unaffected dogs. In dogs with intact AV nodal conduction, atropine increased sinus rate, which suppressed baseline and phenylephrine-induced arrhythmias. In dogs with heart block, arrhythmias were increased during baseline and after phenylephrine, with or without pretreatment with atropine. Prazosin and overdrive ventricular pacing suppressed phenylephrine-induced arrhythmias. CONCLUSION: Phenylephrine increases ventricular arrhythmias in dogs with inherited sudden death via both an induction of reflex bradycardia and a direct myocardial effect. Superimposition of heightened alpha-adrenergic and vagal tone may facilitate the development of sudden death in these animals.

Animals↗
PubMed1996

Effect of patient characteristics on the yield of prolonged baseline head-up tilt testing and the additional yield of drug provocation.

OBJECTIVE: To define the value of tilt testing and hte additional yield of drug provocation over prolonged baseline tilt in different patient subgroups. (Many different protocols are in use for head-up tilt testing in heterogeneous groups of patients. Not all patients in reported series have recurrent syncope, and there is often a wide age range and a variable incidence of structural heart disease.) DESIGN: In a prospective study, baseline 60 degrees head-up tilt testing was undertaken for 45 minutes, initially without drug provocation. Patients who remained symptom free were given intravenous isoprenaline (isoproterenol) and further tilting or edrophonium (10 mg bolus) during tilt, in an order determined randomly before the start of the test. If they were symptom free after the first drug, they were given the other drug. A positive test was recorded when syncope or pre-syncope occurred with a rapid fall (> 30%) in blood pressure. The impact on tilt result of the type of symptoms, presence of significant structural heart disease (SHD), presence of a non-cardiovascular cause of sudden diminished consciousness (SDC), and age was then assessed by subgroup analysis. PATIENTS: 145 patients (73 female, mean age 51 (25), range 8-94) with one or more episodes of pre-syncope or syncope. RESULTS: 39 patients (27%, 21 female, age 49 (25) years) had positive tests and 106 (73%, 52 female, age 52 (25) years) negative tests. 27 (69%) had a positive test during baseline tilt at 20.5 (10.8) minutes, five (13%) with isoprenaline infusion, and seven (18%) with edrophonium bolus. Patients with recurrent syncope rather than single syncopal episodes or single or recurrent pre-syncope were more likely to have a positive tilt test (41% v 17%, P < 0.005) and patients with SHD or SDC (69/14 patients) were much less likely than patients without (16% v 42%, P < 0.0001). The yield of positive tests was similar if patients were below (26%) or above (27%) the mean age (50 years). When multiple factors were combined, the yield ranged from 0% for 21 patients under 50 years with SHD or SDC and without recurrent syncope to 73% in 11 patients over 50 years with recurrent syncope and no SHD or SDC. The additional yield in subgroups over 45 minute baseline tilt (70 (11)%) of isoprenaline (13 (10)%) was similar to that of edrophonium (17 (8)%, P = NS), but six (50% of those who were drug positive) patients required a second drug to produce a positive result (two with isoprenaline second, four with edrophonium second). CONCLUSIONS: Head-up tilt testing in a heterogeneous population has a low yield. Simple clinical characteristics define the type of patient who is likely to have a positive tilt test and the patient who is not and in whom other investigations should receive priority. The great majority of positive tests will occur during prolonged baseline testing if this is used. Isoprenaline and edrophonium produced similar additional yields of positive tests.

Age Factors↗
PubMed1996

Effect of Ca2+ influx on intracellular free Ca2+ responses in antigen-stimulated RBL-2H3 cells.

We undertake a quantitative investigation of changes in intracellular free Ca2+ concentration ([Ca2+]i) in antigen-stimulated rat basophilic leukemia (RBL-2H3) cells, which include contributions of both Ca2+ store release and Ca2+ influx from the medium. Following Keizer and De Young (J. Keizer and G. De Young. Biophys. J. 61: 649-660, 1992), we develop a highly constrained mathematical model for [Ca2+]i oscillations in RBL-2H3 cells, which includes activation of the inositol trisphosphate receptor (IP3R) by inositol 1,4,5-trisphospate, indirect Ca2+ activation of the IP3R via Ca2+ -dependent activity of phospholipase C-gamma, slow inhibition of the IP3R by cytosolic Ca2+, refilling of Ca2+ stores by a Ca2+ -ATPase (SERCA)-type pump, and a simple representation of the dependence of plasma membrane (PM) fluxes on experimental conditions. Using this full (open cell) model, we simulate [Ca2+]i responses for protocols in which antigen concentration and external Ca2+ are manipulated and compare out calculations with experimental data. In protocol A, cells are stimulated in the presence of external Ca2+, in protocols B and C, cells are stimulated in the absence of external Ca2+, with external Ca2+ later reapplied in protocol C. We are able to reproduce quantitatively the important features of all three protocols, including the dose response of protocol B, the [Ca2+]i response to thapsigargin, and lag time results, and we provide qualitative explanations for the responses derived from our calculations. We also develop a simplified (closed cell) version of the model in which PM fluxes are neglected and total free Ca2+ concentration ([Ca2+]T) is a slowly varying parameter. This permits us to explain in a simple graphical fashion how PM fluxes may influence [Ca2+]i responses in RBH-2H3 cells through modulation of [Ca2+]T.

Animals↗
PubMed1996

Stimulation of the P-450 side chain cleavage enzyme (CYP11A1) promoter through ras- and Ets-2-signaling pathways.

Expression of the ovine P-450 side-chain cleavage enzyme gene (CYP11A1) is stimulated by epidermal growth factor (EGF) through a pathway that involves c-Jun in JEG-3 placental cells. Growth factor signaling involves ras-dependent and ras-independent signaling pathways, which in turn regulate gene transcription through related but distinct mitogen-activated protein kinase pathways (MAPKs) including the extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs). We investigated the intracellular signaling pathways governing EGF induction of the CYP11A1 promoter. EGF stimulation of the CYP11A1 promoter (4-fold) was reduced 60% by a dominant negative mutant of ras (N17), and 30-40% by antisense ras. EGF induced both ERK and SAPK activity in JEG-3 cells. EGF-induced CYP11A1 promoter activity was reduced 60% by the MEK1 inhibitor PD098059 and 50% by a dominant negative mutant of the ERK-specific regulator MEK1. In contrast, dominant negative mutants of the SAPK-specific activator, SEK1, induced a further increase in EGF-induced CYP11A1 promoter activity. Constitutively active mutants of ras (V12 or L61) increased CYP11A1 promoter activity 6- to 8-fold. Deletion of the EGF response element (EGF-RE) between -92 and -77 bp reduced ras induction by 60%; however, a residual 3-fold induction remained through the proximal -77 bp. Mutation of the EGF-RE AP-1-like sequence in the context of the native promoter reduced CYP11A1 promoter activation by ras 60%. The EGF-RE sequence was sufficient for 6-fold activation by ras in the context of an heterologous thymidine kinase promoter. Candidate transcription factor targets (c-Jun, c-Ets-2) for the ras-signaling cascade were examined for their effects on CYP11A1 promoter activity. Overexpression of c-Jun induced the CYP11A1 promoter through the EGF-RE; however, c-Ets-2 activation of the CYP11A1 promoter (12-fold) required the proximal ras-responsive promoter sequences that are distinct from the EGF/MEK/c-Jun-responsive element. Induction of the CYP11A1 promoter by EGF involves a ras/MEK1/AP-1-dependent pathway that is distinct from induction by ras/c-Ets-2.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1996

Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate.

UNLABELLED: The receptor-mediated endocytosis uptake pathway for the vitamin folate was investigated as a target for tumor-selective radiopharmaceutical delivery. The molecular target for this delivery mechanism is a membrane-associated folate binding protein (FBP) that is overexpressed by a variety of malignant cell lines. METHODS: The ability of a 67Ga-labeled deferoxamine-folate conjugate (67Ga-DF-folate) to target tumor cells in vivo was examined using an athymic mouse tumor model. Subcutaneous inoculation of approximately 4 X 10(6) folate-receptor-positive KB (human nasopharyngeal carcinoma) cells into athymic mice yielded approximately 0.20 g tumors in 15 days, at which time either 67Ga-DF-folate, 67Ga-deferoxamine (67Ga-DF) or 67Ga-citrate was administered by intravenous injection. RESULTS: The 67Ga-DF-folate conjugate showed marked tumor-specific deposition in vivo, with 1.0 +/- 0.3% of the injected dose (%ID) in tumor at 4 hr postinjection (equating to 5.2 +/- 1.5 %ID/g tumor; n = 3 mice). Corresponding tumor-to-background ratios at 4 hr postinjection were: tumor/blood = 409 +/- 195; tumor/muscle = 124 +/- 47; tumor/liver = 11 +/- 3; and tumor/kidney = 2.6+/-0.9. Tumor uptake of 67Ga-DF-folate conjugate was effectively blocked by co-injection of 2.4+/-1.0 mg free folate. In control experiments, 67Ga-citrate exhibited tumor uptake of 2.2 +/- 0.4% of the injected dose (10.9 +/- 0.2 %ID/g tumor), but very poor target-to-background contrast (tumor/blood = 0.84 +/- 0.19; tumor/muscle = 5.4 +/- 0.7; tumor/liver = 2.3 +/- 0.2; and tumor/kidney = 2.4 +/- 0.3). Unconjugated 67Ga-deferoxamine showed no tumor affinity. CONCLUSION: Receptor-mediated endocytosis of radiolabeled folate-conjugates may offer a suitable mechanism for selectively delivering radiopharmaceuticals to tumors for diagnostic imaging and/or radiation therapy.

Animals↗
PubMed1996

Personal defense sprays: effects and management of exposure.

BACKGROUND: Most personal defense sprays contain o-chlorobenzylidene malononitrile (CS), w-chloroacetophenone (CN), oleoresin capsicum (OC), or a combination of these ingredients as the active agent. They are designed to incapacitate by causing acute ocular irritation, lacrimation, conjunctivitis, blepharospasm, and mild to moderate respiratory distress. METHODS: To assess the ocular effects of sprays containing OC as the active agent. Snellen visual acuities and anterior segment appearances of 22 police officers were determined before and after spray exposure. To assess the effects of OC spray contamination on soft contact lenses, four brands of lenses were sprayed and cleaned twice with an alcohol-based cleaner. Gas chromatography was used to search for residual OC in the lenses. RESULTS: All officers experienced intense blepharospasm, lacrimation, conjunctivitis, and incapacitation as the result of spray exposure. Acute effects lasted about 5 to 10 min, with relatively complete recovery occurring in about 30 to 60 min. All had significant conjunctivitis, and some had water-drop-shaped corneal defects that stained with fluorescein. These defects resolved within 24 hours without treatment. OC residue was found to be present in the soft lenses that had been sprayed and cleaned twice. CONCLUSIONS: Optometrists can manage uncomplicated spray exposure patients by directing at-home irrigation with water, and following up with an in-office examination. Soft lenses contaminated by OC spray should be discarded.

Aerosols↗
PubMed1996

A potential role for cell cycle control proteins in regulation of the cyclic adenosine 5'-monophosphate-responsive glycoprotein hormone alpha subunit gene.

The production of chorionic gonadotropin is coupled to the differentiation of the placenta. Expression of the alpha subunit of chorionic gonadotropin [glycoprotein hormone alpha (GPH-alpha)] is also known to be stimulated by treatment of placental cells with either cAMP or DNA synthesis inhibitors. Given these features, we used adenovirus E1A as a molecular probe to investigate a potential role for cell cycle regulatory proteins and kinases in the regulation of GPH-alpha expression. The E1A protein contains well-characterized domains that interact with a variety of cell cycle regulatory proteins. The E1A conserved regions 1 and 2 bind proteins that regulate cell cycle progression, including pRB, p107, and p130. The amino-terminal region of E1A binds several high molecular weight proteins and inhibits the transcriptional coactivator function of p300 and the homologous cAMP response element (CRE)-binding protein. We found that coexpression of E1A13S activated the GPH-alpha promoter, whereas E1A12S caused marked repression. Deletion mutants and point mutations revealed that repression by E1A12S required the CRE of the GPH-alpha promoter. Several distinct domains in E1A12S were necessary for maximal repression. A mutation of the E1A amino terminus (RG2), which inhibits binding of p300 and related high molecular weight proteins, reduced 12S repression by 40%. Mutation of the pocket protein-binding domains reduced repression by 20%, and mutations of both domains reduced repression by 80%. Overexpression of p300 or the pocket proteins (pRB, p130, and p107) induced GPH-alpha promoter activity 2-4-fold. Because the E1A amino terminus and pocket protein-binding domains together induce p34cdc2 kinase activity, the effect of p34cdc2 kinase expression on GPH-alpha activity was also assessed. Coexpression of p34cdc2 kinase or the activating p34cdc2 kinase mutant (T14AY15F) inhibited GPH-alpha promoter activity and acted through the CRE. We conclude that the GPH-alpha gene CRE is subject to regulation by cell cycle regulatory kinases and proteins.

Adenoviridae↗
PubMed1995

Radiofrequency catheter modification of the sinus node for "inappropriate" sinus tachycardia.

BACKGROUND: Radiofrequency catheter ablation is the treatment of choice for patients with paroxysmal supraventricular tachycardias refractory to medical therapy. However, in symptomatic patients with inappropriate sinus tachycardia resistant to drug therapy, catheter ablation of the His' bundle with permanent pacemaker insertion is currently applied. We evaluated the safety and efficacy of radiofrequency modification of the sinus node as alternative therapy for patients with inappropriate sinus tachycardia. METHODS AND RESULTS: Sixteen patients with disabling episodes of inappropriate sinus tachycardia refractory to drug therapy (4.2 +/- 0.3 drug trials) underwent either total sinus node ablation or sinus node modification. The region of the sinus node was identified as the region of earliest atrial activation in sinus rhythm during electrophysiological study. This region was further defined by use of intracardiac echocardiography (ICE) in 9 patients, in whom it was found that an ablation catheter could be guided reliably and maintained on the crista terminalis. Radiofrequency energy was delivered during tachycardia between either a standard 4-mm or custom 10-mm thermistor-imbedded catheter tip and a skin patch. Total sinus node ablation was performed successfully in all 4 patients in whom it was attempted and was characterized by a junctional escape rhythm. Sinus node modification was successfully achieved in all 12 patients in whom it was attempted and was characterized by a 25% reduction in the sinus heart rate. For the group as a whole, exercise stress testing after ablation revealed a gradual chronotropic response, with a significant reduction in maximal heart rate (132.8 +/- 6.5 versus 179.5 +/- 3.6 beats per minute [bpm]; P < .001) without evidence of an exaggerated heart rate response to a light workload (103.0 +/- 4.1 versus 139.5 +/- 3.5 bpm; P < .001). Twenty-four-hour ambulatory ECG monitoring revealed a significant decrease in maximal heart rate and mean heart rate after ablation (167.2 +/- 2.6 versus 96.7 +/- 5.0 bpm, P < .001, and 125.6 +/- 5.0 versus 54.1 +/- 5.3 bpm, P < .001, respectively). There was a significant decrease in the number of applications of radiofrequency energy required in patients undergoing modification of the sinus node when guided by ICE compared with fluoroscopy alone (3.6 +/- 0.8 versus 10.4 +/- 2.1; P < .01) as well as a decrease in fluoroscopy time (33.0 +/- 9.5 versus 58.5 +/- 8.4 minutes). After a mean follow-up period of 20.5 +/- 0.3 months, there were no recurrences of inappropriate sinus tachycardia in patients who underwent a total sinus node ablation. However, 2 patients who had a total sinus node ablation subsequently required permanent pacing because of symptomatic pauses, and 1 patient developed an ectopic atrial tachycardia. After a mean follow-up of 7.1 +/- 1.7 months, there were two recurrences of inappropriate sinus tachycardia in patients who underwent sinus node modification. However, no significant bradycardia or pauses were observed. Complications encountered during the study included 1 patient who developed transient right diaphragmatic paralysis and another patient who developed transient superior vena cava syndrome. CONCLUSIONS: Sinus node modification is feasible in humans and should be considered as an alternative to complete atrioventricular junctional ablation for patients with disabling inappropriate sinus tachycardia refractory to medical management. Sinus node modification may be aided by ICE.

Adult↗
PubMed1995

Radiofrequency catheter modification of sinus pacemaker function guided by intracardiac echocardiography.

BACKGROUND: The sinus P wave arises from a pacemaker complex distributed along the crista terminalis. We investigated the feasibility of modification of sinus pacemaker function using graded applications of radiofrequency energy along the crista terminalis in dogs to achieve sinus rate control. METHODS AND RESULTS: Modification of sinus pacemaker function (30 +/- 5% reduction in intrinsic heart rate with retention of a normal P-wave axis) was performed in 11 dogs (group 1). Total sinus pacemaker ablation (> 50% reduction in intrinsic heart rate with development of a low ectopic atrial or a junctional rhythm) was performed in 4 dogs (group 2). Intracardiac echocardiography was used to identify the crista terminalis as an anatomic marker of sinus node location. Sinus pacemaker modification caused a significant decrease in intrinsic heart rate (31% reduction, P < .001), heart rate responsiveness to isoproterenol (30% reduction, P < .0001), and average (20% reduction, P = .0002) and maximal (22% reduction, P = .0007) heart rates during 24-hour Holter monitoring. In 6 of the 11 animals, the targeted rate reduction of 30 +/- 5% was accurately achieved (mean, 31.6 +/- 4.3%; P < .001), and in the other 5, significant reduction of intrinsic heart rate was achieved but with greater variation (28.0 +/- 17.3%, P < .005). Corrected sinus node recovery time was not prolonged. After modification, earliest activation was mapped to the crista terminalis inferior to the lesion in all animals. In long-term follow-up (3.7 +/- 1.0 months), effects were maintained. After total sinus pacemaker ablation, junctional and low atrial escape pacemakers were unstable. CONCLUSIONS: This study demonstrates the feasibility of modification of sinus pacemaker function for sinus rate control using catheter-based radiofrequency ablation guided by intracardiac echocardiography. This can be done while pacemaker stability and attenuated responsiveness to autonomic influences are preserved. Intracardiac echocardiography accurately defined the crista terminalis and provided a reliable means to anatomically localize catheter position in relation to the sinus node.

Animals↗
PubMed1995

Use of P wave configuration during atrial tachycardia to predict site of origin.

OBJECTIVES: This study sought to construct an algorithm to differentiate left atrial from right atrial tachycardia foci on the basis of surface electrocardiograms (ECGs). BACKGROUND: Atrial tachycardia is an uncommon form of supraventricular tachycardia, often resistant to drug therapy. METHODS: A total of 31 consecutive patients with atrial tachycardia due to either abnormal automaticity or triggered rhythm underwent detailed atrial endocardial mapping and successful radiofrequency catheter ablation of a single atrial focus. P wave configuration was analyzed from 12-lead ECGs during tachycardia during either spontaneous or pharmacologically induced atrioventricular block. P waves inscribed above the isoelectric line (TP interval) were classified as positive, below as negative, above and below (or conversely, below and above) as biphasic and flat P waves as isoelectric (0). In 17 patients the tachycardia was located in the right atrium: crista terminalis (n = 4); right atrial appendage (n = 4); lateral wall (n = 4); posteroinferior right atrium (n = 3); tricuspid annulus (n = 1); and near the coronary sinus (n = 1). In 14 patients, atrial tachycardia was located in the left atrium: at the entrance of the right (n = 6) or left (n = 4) superior pulmonary veins; left inferior pulmonary vein (n = 1); inferior left atrium (n = 1); base of left atrial appendage (n = 1); and high lateral left atrium (n = 1). RESULTS: There were no differences in P wave vectors between sites at the right atrial lateral wall versus the right atrial appendage or between sites at the entrance of right versus left superior pulmonary veins. However, analysis of P wave configuration showed that leads aVL and V1 were most helpful in distinguishing right atrial from left atrial foci. The sensitivity and specificity of using a positive or biphasic P wave in lead aVL to predict a right atrial focus was 88% and 79%, respectively. The sensitivity and specificity of a positive P wave in lead V1 in predicting a left atrial focus was 93% and 88%, respectively. CONCLUSIONS: 1) Analyses of surface P wave configuration proved to be reasonably good in differentiating right atrial from left atrial tachycardia foci. 2) Leads II, III and aVF were helpful in providing clues for differentiating superior from inferior foci.

Adolescent↗