Adrenergic Induction of Delayed Afterdepolarizations in Ventricular Myocardial Cells: β Induction and α Modulation

Adrenergic Afterdepolarizations in Ventricular Cells. Introduction: The purpose of these studies was to expose canine multicellular ventricular endocardial preparations and disaggregated myocytes to adrenergic agonists and antagonists, and to investigate the generation of delayed afterdepolarizations and triggered action potentials. Methods and Results: We used multicellular preparations and disaggregated myocytes from canine ventricles. The threshold concentration for induction of delayed afterdepolarizations in isolated myocytes for norepinephrine was between 1 × 10^?8 M and 5 × 10^?5 M, with 50% of the cells showing delayed afterdepolarizations at 4.3 × 10^?8 M. Higher concentrations of epinephrine are required with 50% of the cells responding to 8.3 × 10^?8 M. The threshold concentrations for induction of delayed afterdepolarizations in myocardial cells of multicellular preparations were an order of magnitude higher. Delayed afterdepolarizations could not be induced in Purkinje fibers with concentrations up to 10^?4 M with norepinephrine. Adrenergic delayed afterdepolarizations were inhibited promptly by reduction of pO₂ in superfusate that was equilibrated with N₂ (95%) in place of O₂. The amplitudes of adrenergic delayed afterdepolarizations and the propensity to triggered action potentials were inversely related to cycle length down to the shortest cycle length tested (330 msec). Adrenergic delayed afterdepolarizations were induced by isoproterenol but not by α-adrenergic agonists (methoxamine or phenylephrine). They were inhibited by a β antagonist (propranolol) but not by α antagonists (prazosin or yohimbine). Delayed afterdepolarizations induced by isoproterenol were inhibited by α agonists (methoxamine or phenylephrine). The α-adrenergic inhibitory effects on β-adrenergic delayed afterdepolarizations could be reversed by prazosin, but not by yohimbine. Conclusions: We conclude the natural catecholamines norepinephrine and epinephrine generate delayed afterdepolarizations in myocardial cells, but not in Purkinje cells, by activating β receptors, but activation of α₁ receptors inhibits adrenergic delayed afterdepolarizations. Individual myocytes exhibit widely varying sensitivities for induction of adrenergic delayed afterdepolarizations, but some cells respond to concentrations similar to those that may exist in vivo. Therefore, sympathetic activation in vivo may generate delayed afterdepolarizations, triggered action potentials, and arrhythmias.     

Long‐Term Results of Transcatheter Atrial Fibrillation Ablation in Patients with Impaired Left Ventricular Systolic Function

AF Ablation and Impaired Left Ventricular Function. Introduction: Long‐term outcome of AF ablation in patients with impaired LVEF is unknown. The aim of this study is to evaluate sinus rhythm (SR) maintenance, clinical status, and echocardiographic parameters over a long‐term period following atrial fibrillation (AF) transcatheter ablation in patients with left ventricular ejection fraction (LVEF) <50%. Methods and Results: A total of 196 patients (87.2% males, age 60.5 ± 10.2 years) with LVEF <50% underwent radiofrequency transcatheter ablation for paroxysmal (22.4%) or persistent (77.6%) AF. Patients were followed up for 46.2 (16.4–63.5) months regarding AF recurrences, functional class, and echocardiographic parameters. All patients underwent pulmonary vein isolation, while 167 (85.2%) required additional atrial lesions. Eleven (5.6%) patients suffered procedural complications. During follow‐up, 58 (29.6%) patients required repeated ablations. At the follow‐up end, 15 (7.7%) patients died, while 74 (37.8%) documented at least one episode of AF, atrial flutter, or atrial ectopic tachycardia. Eighty‐three (47.2%) patients maintained antiarrhythmic drugs. During follow‐up, NYHA class improved by at least one class more frequently among patients maintaining SR compared to those experiencing relapses (70.6% vs 47.9%, P = 0.003). LVEF showed a broader relative increase in patients maintaining SR (32.7% vs 21.4%; P = 0.047) and mitral regurgitation grading significantly decreased (P <0.001) only within these patients. At multivariable analysis SR maintenance emerged as an independent predictor (odds ratio 4.26, 95% CI 1.69–10.74, P = 0.002) of long‐term clinical improvement (reduction in NYHA class ≥1 and relative increase in LVEF ≥10%). Conclusions: Although not substantially worse than in patients with preserved LVEF, AF ablation in patients with impaired LVEF is affected by high long‐term recurrence rate. Among these patients SR maintenance is associated with greater clinical improvement. (J Cardiovasc Electrophysiol, Vol. 24, pp. 24‐32, January 2013)     

Oral Loading with Propafenone: A Placebo-Controlled Study in Elderly and Nonelderly Patients with Recent Onset Atrial Fibrillation

The efficacy and safety of propafenone as an oral loading dose (600-mg single oral dose) in converting recent-onset atrial fibrillation (≤ 7 days duration) to sinus rhythm were evaluated in a single-blind, placebo-controlled study according to patients' age. Overall, 240 hospitalized patients, NYHA Class ≤ 2 without signs or symptoms of heart failure were enrolled: among patients aged ≤ 60 years, 55 were allocated to propafenone treatment and 59 to placebo, respectively, and among patients aged > 60 years, 64 were allocated to propafenone treatment and 62 to placebo, respectively. Results: In each age group, the likelihood of conversion to sinus rhythm was significantly greater after propafenone compared with plocebo at 3 and 8 hours. For patients aged ≤ 60 years, corresponding odd ratios were 3.78 (95% CI = 1.80–7.92, P = 0.04) at 3 hours and 4.74 (95% CI = 2.12–10.54, P = 0.02) at 8 hours; for patients aged > 60 years odd ratios were 5.03 (95% CI = 2.08–12.12, P = 0.02) at 3 hours and 6.75 (95% CI = 3.28–73.86, P = 0.01) at 8 hours, respectively. Logistic regression analysis showed that conversion to sinus rhythm within 3 hours was predicted by age ≤ 60 years (P = 0.0064) and by propafenone treatment (P < 0.0001), and conversion to sinus rhythm within 8 hours was predicted by age ≤ 60 years (P = 0.0467) and by propafenone treatment (P < 0.0001). The occurrence of adverse effects was observed in 14%-16% of propafenone treated patients and in 8% of placebo treated patients without significant differences according to age. In conclusion, in patients with recent-onset atrial fibrillation without signs of heart failure, propafenone as a single oral loading dose is effective. It is also effective in selected elderly subjects with a favorable safety profile. Moreover, spontaneous conversion to sinus rhythm appears to occur less frequently in elderly patients.     

Sleep and time course of consolidation of visual discrimination skills in patients with narcolepsy–cataplexy

The level of procedural skills improves in normal individuals when the acquisition is followed by a period of sleep rather than wake. If sleep plays an important role in the consolidation process the advantage it provides should be reduced or delayed when its organization is altered, as in patients with chronic sleep disorders. To test this prediction in patients with narcolepsy–cataplexy (NC), who usually have a more fragmented organization of sleep than normals, we compared the initial, intermediate and delayed level of consolidation of visual skills . Twenty-two drug-naive NC patients and 22 individually-matched controls underwent training at a texture discrimination task (TDT) and were re-tested on the next morning (after a night spent in laboratory with polysomnography) and after another six nights (spent at home). TDT performance was worse in patients than controls at training and at both retrieval sessions and the time course of consolidation was different in NC patients (who improved mainly from next-day to 7th-day retrieval session) compared with controls. Moreover, the less-improving patients at next-day retrieval had a wider disorganization of sleep, probably because of an episode of rapid eye movement (REM) sleep at sleep onset REM, on post-training night more frequently than more-improving patients. These findings suggest that the time course of the consolidation process of procedural skills may be widely influenced by the characteristics of sleep organization (varying night-by-night much more in NC patients than controls) during post-training night.     

α-Adrenoceptor subtypes and Ca2+ mobilization the rabbit ear artery†

The mobilization of cellular and extracellular Ca²⁺ pools by selective α₁-adrenoceptor (phenylephrine) and α₂-adrenoceptor (xylazine) agonists as well as noradrenaline was evaluated in rabbit ear artery. Noradrenaline and phenylephrine possess full instrinsic activity for both types of Ca²⁺ mobilization whereas xylazine up to 1 mM had only a limited contractile effect, being more effective in inducing extracellular Ca²⁺-dependent response. However, extracellular Ca²⁺ was mobilized by xylazine in a concentration 20 times higher than that required to stimulate pre-junctional α₂-adrenoceptors. Noradrenaline (5 μM) and xylazine (1 mM) induced cellular and extracellular Ca²⁺-dependent contractions which were prazosin-sensitive and yohimbine-resistant. Xylazine-induced contractile activity, particularly that dependent upon the extracellular Ca²⁺ pool, was markedly reduced by selective adrenergic denervation with 6-hydroxydopamine, but the actions of noradrenaline were unaffected. These results suggest that: (1) rabbit ear artery contain post-junctional α¹-adrenoceptor but not α₂-adrenoceptors; (2) stimulation of these α₁-adrenoceptors can account for the overall contractile activity of exogenously added noradrenaline and (3) stimulation of α₁-adrenoceptors results in mobilization of cellular as well as extracellular Ca²⁺ pools.     

EVIDENCE FOR A HYPOTHALAMIC ALTERATION OF CATECHOLAMINE METABOLISM IN POLYCYSTIC OVARY SYNDROME

The role of brain catecholamine (CA) activity in the neuroendocrine regulation of the GnRH-LH system in polycystic ovary syndrome (PCO) was investigated by high-performance liquid chromatography (HPLC) with electrochemical detector. We measured urinary dopamine (DA), noradrenaline (NA), adrenaline (A), vanillylmandelic acid (VMA), homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC) and total 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in a group of 12 women with PCO before and during peripheral dopa-decarboxylase blockade, by carbidopa. HVA and DOPAC concentrations were significantly lower (P less than 0.001 and P less than 0.005, respectively) in PCO patients compared with twelve control subjects in early follicular phase, whereas total MHPG concentrations and MHPG/VMA ratio were significantly higher (P less than 0.005) in PCO patients. Moreover, HVA and DOPAC concentrations in PCO patients were similar to those of the control subjects in preovulatory phase, while MHPG concentrations remained higher in PCO patients (P less than 0.01). DA, NA, A and VMA concentrations were similar to those of control subjects in both phases of the cycle. During carbidopa administration the concentrations of all urinary CAs and metabolites were unchanged, except those of DA which dropped markedly (P less than 0.001). These data suggest that (1) an altered central catecholamine metabolism consisting of DA deficiency and NA excess is present in PCO, and (2) the site of DA deficiency may be located in the hypothalamus.