Inappropriate sinus tachycardia: focus on ivabradine.

Inappropriate sinus tachycardia (IST) is an incompletely understood condition, characterised by an elevation in heart rate (HR) accompanied by wide ranging symptoms in the absence of an underlying physiological stimulus. The condition often takes a chronic course with significant adverse effects on quality of life. Currently, there is no effective treatment for IST. Beta-blockers, generally considered the cornerstone of treatment, are often ineffective and poorly tolerated. Ivabradine is a novel sinus node If 'funny current' inhibitor, which reduces the HR. It has been approved for the treatment of beta-blocker refractory chronic systolic heart failure and chronic stable angina but more recently has shown promise in the treatment of IST. This review provides an overview of IST prevalence and mechanisms followed by an examination of the evidence for the role and efficacy of ivabradine in the treatment of IST.

Amiodarone versus a beta-blocker to prevent atrial fibrillation after cardiovascular surgery.

BACKGROUND: Both amiodarone and beta-blockers have been shown to decrease the incidence of atrial fibrillation after cardiovascular surgery. However, the superior agent has not been identified. METHODS: We performed a pilot study on 102 patients (68 men, mean age 65 +/- 10 years, mean left ventricular ejection fraction 0.53 +/- 0.12) undergoing cardiovascular surgery (94 coronary artery bypass grafting [CABG], 5 valvular surgery only, and 3 CABG + valvular surgery). The patients were randomized to receive amiodarone (1 g/d intravenously x 48 hours, then 400 mg/d orally until discharge) or propranolol (1 mg intravenously every 6 hours x 48 hours, then 20 mg orally four times a day until discharge). Atrial fibrillation was defined as lasting longer than 1 hour or resulting in hemodynamic compromise. RESULTS: The incidence of postoperative atrial fibrillation was 16.0% (8/50) in the amiodarone group and 32.7% (17/52) in the propranolol group (P =.05). The mean length of stay was 8.8 +/- 3.5 days for amiodarone-treated patients and 8.4 +/- 2.7 days for propranolol-treated patients (P not significant). Serious adverse events were uncommon and similar in each group. CONCLUSION: Early intravenous amiodarone, followed by oral amiodarone, appears to be superior to propranolol in the prevention of postoperative atrial fibrillation. It is well tolerated and can be started at the time of surgery. However, the use of amiodarone did not result in a reduction in the length of hospital stay.

Drug-induced QT prolongation in women during the menstrual cycle.

CONTEXT: Women have a higher incidence of torsades de pointes than men, but it is not known if the risk of drug-induced torsades de pointes varies during the menstrual cycle. OBJECTIVES: To determine if the degree of QT prolongation in response to ibutilide varies with the menstrual cycle phase and to compare QT prolongation between women and men. DESIGN AND SETTING: Cohort study of men and women who received the same intervention conducted between November 1998 and November 2000 at a general clinical research center of a university hospital. PARTICIPANTS: A volunteer sample of 58 healthy adults (38 men and 20 women) aged 21 to 40 years. INTERVENTION: A low dose of ibutilide (0.003 mg/kg), infused intravenously for 10 minutes. Subjects were monitored for 120 minutes. Women received the intervention on 3 separate occasions to correspond with menstrual cycle phases, which were verified by using hormonal assays. MAIN OUTCOME MEASURE: QT interval, recorded from electrocardiogram at timed intervals during and after ibutilide infusion and standardized for variations in heart rate (QTc). RESULTS: Maximum (mean [SD]) millisecond increase in QTc after ibutilide infusion was greater for women during menses (63 [13]) and the ovulatory phase (59 [17]) compared with women during the luteal phase (53 [14]) and compared with men (46 [16]; P =.002 vs menses and P =.007 vs ovulation). Progesterone (r = -0.40) and progesterone-to-estradiol ratio (r = -0.41), but not estradiol (r = 0.14) or testosterone (r = 0.09), were inversely correlated with ibutilide-induced QT prolongation. CONCLUSIONS: Menstrual cycle and sex differences exist in QTc responses to ibutilide, with the greatest increase in QTc corresponding to the first half of the menstrual cycle.

Radiofrequency catheter ablation of atrioventricular junctional ("AV nodal") reentrant tachycardia in patients with implantable cardioverter defibrillators.

Catheter ablation of tachycardias has been undertaken successfully in patients with ICDs without damage to the ICD or lead. Ablation of the slow AV nodal pathway, however, is technically challenging because the lead of the ICD lies close to the ablation site. We report successful ablation of AV junctional reentrant tachycardia (AVJRT) in three patients with ICDs. In all cases, the ablation site was within a few millimeters of the ICD lead. The ablation was successful in all cases and did not cause damage to the ICD or lead. The patients have remained free of recurrence of AVJRT during a mean follow-up of 12 months.

A study of the developmental changes in outward currents of rat ventricular myocytes.

1. In ventricular muscle of rat heart, the action potential undergoes a major developmental change in shape in the days and weeks immediately after birth. Potassium (K+) currents which may affect the shape of the action potential have been studied using a whole-cell voltage-clamp technique with single cells from the ventricles of rats aged 1-10 days. All recordings were made at 22-23 degrees C. 2. Three discrete ages were chosen. 1-day (cells isolated within 24 h of birth), 5-day and 10-day rats. These parallel the developmental action potential shortening from neonatal towards adult type. Action potentials of single myocytes were initially of long duration at 1 day with a prominent plateau phase, but had shortened somewhat by 10 days of age. The 5-day group exhibited an action potential transitional in character between the earlier and later groups of cells. 3. Potassium current blocking agents were used to assess the importance of the various outward K+ currents for the action potential waveform at different ages. 4-Aminopyridine (4-AP; 2 x 10(-3) M) which preferentially blocks voltage-activated transient outward currents affected action potentials at all ages, but increases in duration were most pronounced in the 10-day group. Only a small prolongation of the initial phase of repolarization of 1-day action potentials was seen. Extracellular barium chloride, 0.1-2 x 10(-3) M, a blocker of inwardly rectifying potassium channels, had a marked slowing effect on repolarization in all the three age groups. Resting membrane depolarization was also produced by barium. 4. Developmental changes in the inwardly rectifying background current (IK1) and the cardiac transient outward current, It, were investigated. IK1 was recorded as the current sensitive to 2 x 10(-3) M-BaCl2 during voltage-clamp steps from a holding potential of -90 mV. It was found to decrease in magnitude, approximately by a factor of three, from 15 to 5 pA/pF during the first ten postnatal days. This reduction can explain the maturational slowing of repolarization during the final phase of the action potential in rat heart. 5. Current-voltage relations for IK1 from the three age groups crossed at the zero current potential at approximately -90 mV, near the calculated VK for the pipette filling solution and an external bath K+ concentration of 5 x 10(-3) M. This suggests that IK1 channels in these cells are quite selective for K+ ions and that developmental changes in the potassium selectivity are not responsible for changes in IK1.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of periods of conditioning stimulation and of neuropeptides on vagal action at the heart.

The strength of action of the parasympathetic innervation of the heart was tested, in anaesthetized dogs, by regular delivery of bursts of supramaximal electrical pulses at low frequency to the cut, cardiac end of the vagus nerve. Periods of 'conditioning' stimulation of the same nerve at relatively high frequencies (15-30 Hz, for 15-300 s) were found to cause a slowly developing potentiation (up to 280% increase in the vagally induced prolongation of pulse interval) of the cardiac action of the low-frequency stimulation. This potentiation lasted for periods of up to 30 min after the conditioning period. Similar potentiation could be elicited for the action of one vagus nerve by conditioning the vagus on the other side. Potentiation of vagal action was not associated with an enhancement of the response of the heart to injected methacholine. Several neuropeptides, reported to be present in cardiac autonomic nerves, were tested for ability to mimic this effect when administered by intravenous injection. Vasoactive intestinal polypeptide, neurotensin, somatostatin and substance P all failed to do so at the doses tested. Vasopressin did induce an enhancement of cardiac vagal efficacy, but effective pharmacological blockade of its action did not block the potentiation caused by conditioning stimulation. In the absence of any evidence of neuromodulation of vagal action by these neuropeptides, it was presumed that the effect could be attributed to a classical homosynaptic post-tetanic potentiation mechanism involving intracellular accumulation of calcium ions in prejunctional nerve terminals.

Neuromodulation of the cardiac vagus: comparison of neuropeptide Y and related peptides.

Neuropeptide Y (NPY), a putative co-transmitter in noradrenergic sympathetic nerves of the cardiovascular system, inhibits the negative chronotropic action of the cardiac vagus. In the present study, peptides related to NPY were tested for potency in producing this effect. In bilaterally vagotomized, anaesthetised dogs, the increase in pulse interval caused by electrical stimulation of the peripheral stump of the right vagus was measured before and after intravenous administration of peptide. The effects of doses of NPY were compared with those of equimolar doses of peptide YY (PYY), and of avian and human pancreatic polypeptides (APP and HPP). PYY inhibited the vagal action more effectively than did NPY. APP and HPP, however, caused no change in strength of vagal action at the doses used. The response to a second injection of NPY, given soon after the injection of APP or HPP, was not significantly different from the original. Thus no evidence was obtained for a competitive inhibition of the action of NPY by either pancreatic polypeptide. A C-terminal hexapeptide fragment of human pancreatic polypeptide was also tested. Like APP and HPP, it neither inhibited the cardiac vagus nor blocked the action of NPY. The order of potency obtained here (PYY greater than NPY much greater than APP, HPP, CFPP) can be expected to be of use in efforts to distinguish the active site(s) of the NPY molecule, and to characterise the receptors involved in these modulatory effects.