AF in humans leads to important changes in atrial potassium and calcium currents that likely contribute to the decrease in APD and APD rate adaptation. These changes contribute to electrical remodeling in AF and are therefore important factors for the perpetuation of the arrhythmia.

Rapid atrial activation causes time-dependent decreases in ERP, conduction velocity, and wavelength, which, along with increased regional heterogeneity, provide a substrate for AF. The conduction abnormalities and increased regional heterogeneity previously noted in patients with AF may be a consequence, as well as a cause, of the tachyarrhythmia.

Background-Although downregulation of L-type Ca 2ϩ current (I Ca,L ) in chronic atrial fibrillation (AF) is an important determinant of electrical remodeling, the molecular mechanisms are not fully understood. Here, we tested whether reduced I Ca,L in AF is associated with alterations in phosphorylation-dependent channel regulation. Methods and Results-We used whole-cell voltage-clamp technique and biochemical assays to study regulation and expression of I Ca,L in myocytes and atrial tissue from 148 patients with sinus rhythm (SR) and chronic AF. Basal I Ca,L at ϩ10 mV was smaller in AF than in SR (Ϫ3.8Ϯ0.3 pA/pF, nϭ138/37 [myocytes/patients] and Ϫ7.6Ϯ0.4 pA/pF, nϭ276/86, respectively; PϽ0.001), though protein levels of the pore-forming ␣ 1c and regulatory ␤ 2a channel subunits were not different. In both groups, norepinephrine (0.01 to 10 mol/L) increased I Ca,L with a similar maximum effect and comparable potency. Selective blockers of kinases revealed that basal I Ca,L was enhanced by Ca 2ϩ /calmodulindependent protein kinase II in SR but not in AF. Norepinephrine-activated I Ca,L was larger with protein kinase C block in SR only, suggesting decreased channel phosphorylation in AF. The type 1 and type 2A phosphatase inhibitor okadaic acid increased basal I Ca,L more effectively in AF than in SR, which was compatible with increased type 2A phosphatase but not type 1 phosphatase protein expression and higher phosphatase activity in AF. Conclusions-In AF, increased protein phosphatase activity contributes to impaired basal I Ca,L . We propose that protein phosphatases may be potential therapeutic targets for AF treatment.

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We have previously shown that chronic rapid atrial activation (400 bpm) reduces atrial conduction velocity in dogs, contributing to the development of a substrate supporting sustained atrial fibrillation (AF). However, the cellular and ionic mechanisms underlying these functional changes have not been defined. We applied whole-cell patch-clamp techniques to atrial myocytes from dogs subjected to atrial pacing at 400 bpm for 7 days (P7, n = 6) and 42 days (P42, n = 5) and compared the results with those from sham-operated dogs similarly instrumented but without pacemaker activation (P0, n = 6). Rapid atrial pacing allowed for the induction of sustained AF in 67% and 100% of dogs paced for 7 and 42 days, respectively, and significantly decreased conduction velocity under P7 and P42 conditions. In dogs paced for 7 days, Na+ current (INa) density was reduced by 28% at -40 mV (P < .0001, n = 59 cells). INa changes were even more decreased under P42 conditions, by approximately 52% at -40 mV (P < .0001): from -78.7 +/- 4.6 pA/pF (P0, n = 28 cells) to -37.7 +/- 3.0 pA/pF (P42, n = 43 cells). INa was significantly reduced at all voltages ranging from -65 to -10 mV. Voltage-dependent activation and inactivation properties, activation kinetics, and recovery from inactivation were not altered by rapid atrial pacing; however, inactivation kinetics were slowed. AF duration was related to mean INa in each dog (r2 = .573, P < .001). We conclude that rapid atrial activation significantly reduces both conduction velocity and INa density. Since INa is a major determinant of conduction velocity, our data point to INa reduction as a potentially important mechanism contributing to the substrate for AF in this model.

Among ICD patients with advanced HF, fluid status telemedicine alerts did not significantly improve outcomes. Adherence to treatment protocols by physicians and patients might be challenge for further developments in the telemedicine field.

The mechanism of action potential abbreviation caused by increasing rate in human ventricular myocytes is unknown. The present study was designed to determine the potential role of Ca2+ current ( I Ca) in the rate-dependent changes in action potential duration (APD) in human ventricular cells. Myocytes isolated from the right ventricle of explanted human hearts were studied at 36°C with whole cell voltage and current-clamp techniques. APD at 90% repolarization decreased by 36 ± 4% when frequency increased from 0.5 to 2 Hz. Equimolar substitution of Mg2+ for Ca2+ significantly decreased rate-dependent changes in APD (to 6 ± 3%, P < 0.01). Peak I Ca was decreased by 34 ± 3% from 0.5 to 2 Hz ( P < 0.01), and I Ca had recovery time constants of 65 ± 12 and 683 ± 39 ms at −80 mV. Action potential clamp demonstrated a decreasing contribution of I Ca during the action potential as rate increased. The rate-dependent slow component of the delayed rectifier K+current ( I Ks) was not observed in four cells with an increase in frequency from 0.5 to 3.3 Hz, perhaps because the I Ks is so small that the increase at a high rate could not be seen. These results suggest that reduction of Ca2+influx during the action potential accounts for most of the rate-dependent abbreviation of human ventricular APD.

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