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Biomedical subjects

C R Kerr

Publications and source records attributed to C R Kerr.

At least 19 recordsLinked to original sources
PubMed1996

How useful is thyroid function testing in patients with recent-onset atrial fibrillation? The Canadian Registry of Atrial Fibrillation Investigators.

BACKGROUND: Patients with recent-onset atrial fibrillation often undergo routine thyroid function screening to rule out thyroid disease as a cause of atrial fibrillation. METHODS: Patients with recent (< 3 months) onset of documented atrial fibrillation or flutter were enrolled in the Canadian Registry of Atrial Fibrillation from outpatient clinics, emergency departments, and hospital wards across Canada. Seven hundred twenty-six patients underwent baseline thyroid function screening and were assessed for presence of clinical thyroid disease. Serum thyrotropin level (TSH) was measured in 707 patients (97%), and thyroxine level (T4) in 407 patients (56%). RESULTS: A TSH level less than 0.1 mU/L was present in 5 patients (0.7%). A TSH level less than normal but more than 0.1 mU/L was present in 34 patients (4.7%). No patient had definite hypothyroidism (TSH > 20 mU/L), but 56 patients (7.7%) had an elevated TSH level that was less than 20 mU/L. During 1.7 years of follow-up, only 7 patients were found to have clinical hyperthyroidism, and 11 patients (1.5%) had hypothyroidism. Logistic regression analysis showed that palpitations (odds ratio, 4.9; 95% confidence interval, 1.7-14.0) and asymptomatic presentation (odds ratio, 5.5; 95% confidence interval, 1.9-16.2) were risk factors for low TSH level, and increasing age (odds ratio, 1.32 every 10 years; 95% confidence interval, 1.01-1.66) was a risk factor for high TSH level. The positive predictive value of palpitations and asymptomatic presentation for low TSH level were 9% and 8%, respectively. CONCLUSIONS: An abnormal TSH level is common in patients with recent-onset atrial fibrillation. However, clinical thyroid disease is uncommon. Routine TSH screening of patients who have atrial fibrillation has a low yield and may be better applied to those patients at higher risk of having undiagnosed clinical thyroid disease.

Atrial Fibrillation↗
PubMed1996

Atrial fibrillation--future directions.

AF has finally been reviewed with an importance compatible with its huge burden on the health care system. Careful evaluation of the knowledge to date reveals many areas that require further research. Many hurdles remain to be overcome in order to make a significant impact on this arrhythmia that is both troublesome and carries significant morbidity and mortality.

Anti-Arrhythmia Agents↗
PubMed1996

pH-dependent actions of 4-aminopyridine on atrial repolarization: effects on the transient outward current.

Effects of extracellular pH (pHo) were examined on the changes in atrial repolarization induced by 4-aminopyridine (4AP), which is a selective blocker of the transient outward potassium channel, I(to). Action potential parameters were measured, using the conventional microelectrode technique, in the absence and presence of 4AP (0.1-3.0 mM) at pHo 6.5, 7.25, and 8.0. Phase 1 amplitude served as an index of I(to). The onset and recovery kinetics of phase 1 amplitude were assessed at a basic cycle length of 0.5 s, and time constants (tau on and tau r) were computed. Both onset and recovery kinetics had monoexponential functions. Tonic blockade was influenced by external pH, and Kd for half block was 0.19, 0.44, and 2.43 mM for pHo 8.0, 7.25, and 6.5, respectively. Phasic block was defined and exhibited cycle length dependence. Phasic block was also modified by external pH with the greatest effect at pHo 8.0. 4AP (0.3 mM) accelerated tau on, 0.62 +/- 0.2, 0.55 +/- 0.1, and 2.0 +/- 0.8 beats for pHo 8.0, 7.25, and 6.5 compared with control 6.8 +/- 1.9, 6.3 +/- 1.9, and 5.1 +/- 1.4 beats. In contrast, 4AP slowed tau r by about 1 s from control value to 1.5 +/- 0.5 s at pHo 6.5, 4.8 +/- 1.5 s at pHo 7.25 (p < 0.05), and 5.7 +/- 2.0 s at pHo 8.0. We conclude that an increase in extracellular pH enhances block of Ito induced by 4AP, whereas low pHo attenuates the block.

4-Aminopyridine↗
PubMed1995

Characterization of junctional rhythm after atrioventricular node ablation.

BACKGROUND: Catheter ablation of the atrioventricular (AV) node with radiofrequency current (RFC) is associated with the short-term onset of a junctional escape rhythm (JER) in nearly all patients. However, the origin of the JER and short-term thermal effects of RFC on this junctional pacemaker activity are ill defined. METHODS AND RESULTS: Short-term and noninvasive long-term follow-up studies were performed to examine the electrophysiological characteristics of the underlying JER in 45 patients who had undergone AV nodal ablation with RFC. Baseline characteristics and responses to overdrive ventricular pacing and intravenous atropine followed by an incremental isoproterenol infusion were determined. Short- and long-term responses were compared. HV intervals before and after ablation were 49 +/- 9 and 48 +/- 9 milliseconds, respectively (P = NS). Follow-up was 11 +/- 8.3 months. JER cycle length was 1526 +/- 298 milliseconds in the short-term setting and was present in 44 patients (98%) in the long-term setting, measuring 1426 +/- 223 milliseconds (P < .005). Junctional recovery times increased exponentially as overdrive pacing rates increased-there was no difference between short-term and long-term responses. Drug responses within each study were all significant when compared with baseline. However, there was no significant difference between short- and long-term responses, except at the highest dose of isoproterenol. Intravenous atropine (1 mg) caused an 8.6 +/- 9.3% decrease in JER cycle length in the short-term setting compared with a 7.6 +/- 7.3% decrease in the long-term setting. The decreases in JER cycle length with isoproterenol infusion (short-term versus long-term) were 10.1 +/- 9.6% versus 9.6 +/- 7.4% with 1 microgram/min, 15.8 +/- 11.7% versus 17.4 +/- 8.5% with 2 micrograms/min, 17.9 +/- 11.2% versus 21.4 +/- 9.1% with 3 micrograms/min (all P = NS), and 20.6 +/- 12.1% versus 24.8 +/- 9.1% with 4 micrograms/min (P < .01). CONCLUSIONS: Radiofrequency ablation of the AV node is associated with development of a JER that is stable in the long-term setting. The lack of change in HV interval after ablation locates the junctional pacemaker proximal to the central fibrous body. The pattern of drug responses suggests an origin within the proximal His bundle at its junction with the AV node rather than the AV node itself. The overall similarity between short- and long-term characteristics of junctional pacemaker activity mitigates against any reversible thermal effects of RFC on this pacemaker focus.

Aged↗
PubMed1995

Pharmacokinetics of mexiletine enantiomers in healthy human subjects. A study of the in vivo serum protein binding, salivary excretion and red blood cell distribution of the enantiomers.

1. The disposition kinetics of serum free (unbound) and total mexiletine enantiomers were studied in 12 healthy subjects following oral administration of 200 mg racemic mexiletine hydrochloride. The disposition of the enantiomers of mexiletine in urine, saliva, and red blood cells was also examined. 2. The mean peak serum total mexiletine concentration of 217 +/- 69 ng/ml for R(-)-mexiletine was found to be significantly greater than a mean of 197 +/- 56 ng/ml for S(+)-mexiletine. The mean serum total R(-)-mexiletine concentrations were also found to be significantly greater than those for S(+)-mexiletine during the first 6 h following drug administration. The oral absorption, as well as the rapid and the terminal disposition kinetic parameters between the mexiletine enantiomers, were not significantly different. 3. Comparative in vitro serum protein binding of mexiletine enantiomers examined by ultrafiltration and equilibrium dialysis indicated a pH-dependent stereoselective binding of the enantiomers to serum proteins. A serum pH ranging from 6.3 to 9.4 was found to correlate with serum protein binding of the enantiomers from approximately 30-80% respectively. Within the same serum pH range, the serum free drug R(-)/S(+) ratios were found to decrease from 1.0 to 0.7 respectively. At serum pH7.4, a mean serum free fraction of 0.57 +/- 0.7 and 0.56 +/- 0.6 were observed for R(-) and S(+)-mexiletine respectively. 4. The overall mean saliva/serum-free mexiletine enantiomer area under the concentration-time curve ratios of 6.10 +/- 2.82 and 7.49 +/- 3.48 for R(-)- and S(+)-mexiletine respectively were found to be significantly different. The overall mean saliva R(-)/S(+) enantiomer ratio of 0.89 +/- 0.02 (mean +/- SE) over 48 h suggested a stereoselective disposition of the mexiletine enantiomers in saliva. 5. The mean mexiletine red blood cells to serum-free drug concentration ratios among 11 subjects studied were found to range from 0.6 to 1.4 for R(-)-mexiletine and from 0.6 to 1.8 for S(+)-mexiletine. The overall mean ratios of 0.85 +/- 0.06 and 0.84 +/- 0.08 (mean +/- SE) over 48 h for R(-)- and S(+)-mexiletine respectively were both slightly but significantly different from unity. This data together with an overall red blood cell mean R(-)/S(+)-mexiletine concentration ratio of 0.91 +/- 0.13 suggested a non-stereoselective and passive diffusion of the enantiomers into red blood cells. 6. The cumulative amounts of unchanged R(-)- and S(+)-mexiletine in the urine were found to be variable among the 12 subjects with a mean percent urinary recovery of 3.49 +/- 3.35% for R(-)-mexiletine and 3.68 +/- 3.94% for S(+)-mexiletine.

Adult↗
PubMed1994

High-performance liquid chromatographic analysis using a highly sensitive fluorogenic reagent, 2-anthroyl chloride, and stereoselective determination of the enantiomers of mexiletine in human serum.

A stereoselective and highly sensitive HPLC assay was developed for mexiletine enantiomers using a new fluorogenic derivatization reagent, 2-anthroyl chloride. The reagent was synthesized and utilized for the fluorescent detection (excitation at 270 nm, emission at 400 nm) of mexiletine enantiomers as their N-anthroyl derivatives on a Pirkle phenylglycine ionic HPLC column. The assay had a lower limit of quantitation at 2.5 ng/ml with a limit of detection measured at 0.5 ng/ml for each enantiomer in serum with a signal-to-noise ratio of 5:1. In a preliminary pharmacokinetic study, 200 mg of racemic mexiletine hydrochloride were administered orally to two healthy volunteers. Serum samples were collected at timed intervals over 48 h. The terminal elimination half-lives determined for total R(-)- and S(+)-mexiletine were 10.9 and 11.5 h, respectively. The serum free fractions for R(-)- and S(+)-mexiletine were found to be 0.56 and 0.53, respectively.

Anthracenes↗
PubMed1994

Efficacy of sotalol guided by programmed electrical stimulation for sustained ventricular arrhythmias secondary to coronary artery disease.

Sotalol is a class III antiarrhythmic drug with additional beta-blocker activity that has been shown to be effective in supraventricular and ventricular arrhythmias. Its long-term efficacy for ventricular arrhythmias is not as well described. Patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) who had their clinical arrhythmia inducible at baseline electrophysiologic study received sotalol 320 to 640 mg/day. Repeat programmed stimulation was performed after a minimum of 72 hours while receiving the final dose. Of 28 patients (25 men and 3 women) whose arrhythmias were inducible at baseline, 15 had their arrhythmias suppressed with sotalol. Sotalol had greater success in suppressing arrhythmias in those with VF (8 of 9, 89%) than in those with VT (7 of 19, 37%, p < 0.01). In patients with a history of coronary artery disease but no history of myocardial infarction the arrhythmia was suppressed in 7 of 8 (88%) compared with 8 of 20 (40%, p < 0.05) patients with a history of myocardial infarction. All 15 patients in whom ventricular arrhythmias were suppressed continued to take long-term sotalol, and at a follow-up of 10.3 +/- 6.4 months none has had arrhythmia recurrence. Thus, sotalol is an effective drug for the suppression of ventricular arrhythmias as judged by programmed electrical stimulation. It appears to be more effective in patients in whom the clinical arrhythmia is VF rather than VT.

Aged↗
PubMed1994

Electrophysiologic properties of a narrow isthmus in rabbit atrial tissue: cycle length dependent effect of quinidine.

The modulation of quinidine's effect by pacing cycle lengths was assessed over an isthmus of atrial myocardium, simulating the Wolff-Parkinson-White syndrome. Isolated rabbit atria were dissected so that two tissue blocks, A and B, were linked by an isthmus, 1 mm in width. Effective refractory period in the tissue blocks and over the isthmus was measured at cycle lengths of 1,000, 600, and 400 ms, and the minimum cycle length to sustain 1:1 conduction over the isthmus was measured before treatment, during quinidine superfusion (4 mg/L), and after washout. Longitudinal velocity over the isthmus was also measured. The increment in the effective refractory period in the tissue blocks by quinidine appeared to be similar, about 10% at three pacing cycle lengths (p > 0.05). However, the increment of the effective refractory period over the isthmus was modulated by pacing cycle lengths: greater increase at shorter cycle lengths (p < 0.001). Quinidine prolonged the minimum cycle length over the isthmus by 44 +/- 17%. Regression analysis showed that after quinidine there was a correlationship between conduction velocity and refractoriness over the isthmus (R = 0.85, p < 0.001). Intracellular implements showed stable action potentials, confirming the integrity of the preparation. We conclude that (i) quinidine preferentially prolongs refractoriness over the isthmus and (ii) quinidine's effect on refractoriness over the isthmus is cycle length dependent.

Action Potentials↗
PubMed1994

Regional differences in rabbit atrial repolarization: importance of transient outward current.

Regional differences in rabbit atrial repolarization were investigated using a conventional microelectrode technique. A more rapid phase 1 repolarization (lower phase 1 amplitude) was seen in the left atrial (LA) roof area compared with the right atrial (RA) roof area: 54 +/- 10 vs. 82 +/- 6 mV at 1,000 ms (P < 0.001). In addition, action potential duration at 40 mV above the resting potential (APD40) was shorter in LA and was associated with a slower phase 3 repolarization rate. Furthermore, the recovery time constant of phase 1 amplitude at 500 ms was 0.9 +/- 0.2 s in LA and 3.5 +/- 1.5 s in RA (P < 0.001). Pacing cycle lengths (2,000, 1,500, 1,000, 800, and 500 ms) modulated phase 1 amplitude, APD40, and phase 3 rate in both regions. 4-Aminopyridine (4-AP; 1 mM), a selective transient outward current (I(to)) blocker, abolished cycle length dependence of the above action potential parameters and diminished the differences in electrophysiological properties between the two regions. 4-AP also flattened the restitution curve of phase 1 amplitude in both regions. In conclusion, the findings suggest that the different kinetics of I(to) play an important role in regional differences of atrial repolarization.

4-Aminopyridine↗
PubMed1994

Atrioventricular nodal reentrant tachycardia in patients with ventriculo-atrial conduction block.

OBJECTIVE: To demonstrate the reversibility of retrograde ventriculo-atrial block by isoproterenol in patients with atrioventricular nodal reentrant tachycardia (AVNRT). DESIGN: Three case reports and their electrophysiological features. PATIENTS: Three patients with documented or suspected paroxysmal supraventricular tachycardia. INTERVENTIONS: At routine electrophysiology study, no supraventricular tachycardia was inducible in the baseline state. Infusion of isoproterenol (1 to 5 micrograms/min) was given and stimulation procedures were repeated. RESULTS: At baseline, all three patients had discontinuous antegrade atrioventricular (AV) nodal conduction, but very poor (two patients) or absent (one patient) ventriculo atrial conduction prevented induction of AVNRT. During infusion of isoproterenol, retrograde conduction was enhanced so that 1:1 retrograde occurred to cycle lengths of 300, 340 and 260 ms. AVNRT was then inducible in all patients, reproducing their clinical symptoms. CONCLUSION: Absent or poor ventriculo-atrial conduction in patients with suspected AV node reentry does not preclude the development of tachycardia with sympathomimetic enhancement. Isoproterenol should be given to attempt reversal of retrograde block in these patients.

Adult↗
PubMed1992

In vitro protein binding of propafenone and 5-hydroxypropafenone in serum, in solutions of isolated serum proteins, and to red blood cells.

The binding of propafenone (PF) and 5-hydroxypropafenone (5-OH-PF) in serum and in solutions of isolated serum proteins was examined by equilibrium dialysis. Both PF and 5-OH-PF displayed pH-dependent binding in serum and in a solution of alpha-1-acid glycoprotein (AAG). PF displayed extensive binding to AAG (i.e., free fraction of 0.08 +/- 0.02), whereas the binding of 5-OH-PF to AAG was moderate (i.e., free fraction of 0.54 +/- 0.10). The removal of lipoproteins from serum did not alter the free fraction of PF but significantly increased the free fraction of 5-OH-PF compared with that in intact serum. Both PF and 5-OH-PF displayed concentration-dependent binding in a 19.3-mumol AAG solution. Concentration-independent binding was apparent in solutions of human serum albumin, high-density lipoproteins, low-density lipoproteins, and very low density lipoproteins over the PF and 5-OH-PF concentration ranges examined. By use of previously determined binding parameters (affinities and capacities), the binding model of PF provided an estimate of the free fraction in serum that was similar to the observed free fraction, although the free fraction of 5-OH-PF was overestimated. The distribution of PF and 5-OH-PF into red blood cells was extensive when buffer was used as the supernatant; however, when serum was used as supernatant, the amounts of PF and 5-OH-PF that were distributed into red blood cells decreased substantially. PF and 5-OH-PF interacted with all of the proteins examined.

Anti-Arrhythmia Agents↗