—Chronic atrial fibrillation (AF) is characterized by decreased atrial contractility, shortened action potential duration, and decreased accommodation of action potential duration to changes in activation rate. Studies on experimental animal models of AF implicate a reduction in L-type Ca ²⁺ current ( I _Ca ) density in these changes. To evaluate the effect of AF on human I _Ca , we compared I _Ca in atrial myocytes isolated from 42 patients in normal sinus rhythm at the time of cardiac surgery with that of 11 chronic AF patients. I _Ca was significantly reduced in the myocytes of patients with chronic AF (mean −3.35±0.5 pA/pF versus −9.13±1.0 pA/pF in the controls), with no difference between groups in the voltage dependence of activation or steady-state inactivation. Although I _Ca was lower in myocytes from the chronic AF patients, their response to maximal β-adrenergic stimulation was not impaired. Postoperative AF frequently follows cardiac surgery. Half of the patients in the control group (19/38) of this study experienced postoperative AF. Whereas chronic AF is characterized by reduced atrial I _Ca , the patients with the greatest I _Ca had an increased incidence of postoperative AF, independent of patient age or diagnosis. This observation is consistent with the concept that calcium overload may be an important factor in the initiation of AF. The reduction in functional I _Ca density in myocytes from the atria of chronic AF patients may thus be an adaptive response to the arrhythmia-induced calcium overload.

Chronic atrial fibrillation is associated with a shortening of the atrial action potential duration and atrial refractory period. To test the hypothesis that these changes are mediated by changes in the density of specific atrial K ⁺ currents, we compared the density of K ⁺ currents in left and right atrial myocytes and the density of delayed rectifier K ⁺ channel α-subunit proteins (Kv1.5 and Kv2.1) in left and right atrial appendages from patients (n=28) in normal sinus rhythm with those from patients (n=15) in chronic atrial fibrillation (AF). Contrary to our expectations, nystatin–perforated patch recordings of whole-cell K ⁺ currents revealed significant reductions in both the inactivating ( I _TO ) and sustained ( I _Ksus ) outward K ⁺ current densities in left and right atrial myocytes isolated from patients in chronic AF, relative to the I _TO and I _Ksus densities in myocytes isolated from patients in normal sinus rhythm. Quantitative Western blot analysis revealed that although there was no change in the expression of the Kv2.1 protein, the expression of Kv1.5 protein was reduced by >50% in both the left and the right atrial appendages of AF patients. The finding that Kv1.5 expression is reduced in parallel with the reduction in delayed rectifier K ⁺ current density is consistent with recent suggestions that Kv1.5 underlies the major component of the delayed rectifier K ⁺ current in human atrial myocytes, the ultrarapid delayed rectifier K ⁺ current, I _Kur . The unexpected finding of reduced voltage-gated outward K ⁺ current densities in atrial myocytes from AF patients demonstrates the need to further examine the details of the electrophysiological remodeling that occurs during AF to enable more effective and safer therapeutic strategies to be developed.

Aging is usually accompanied by a significant reduction in muscle mass and force. To determine the relative contribution of inactivity and aging per se to this decay, we compared muscle function and structure in (a) male participants belonging to a group of well-trained seniors (average of 70 years) who exercised regularly in their previous 30 years and (b) age-matched healthy sedentary seniors with (c) active young men (average of 27 years). The results collected show that relative to their sedentary cohorts, muscle from senior sportsmen have: (a) greater maximal isometric force and function, (b) better preserved fiber morphology and ultrastructure of intracellular organelles involved in Ca²⁺ handling and ATP production, (c) preserved muscle fibers size resulting from fiber rescue by reinnervation, and (d) lowered expression of genes related to autophagy and reactive oxygen species detoxification. All together, our results indicate that: (a) skeletal muscle of senior sportsmen is actually more similar to that of adults than to that of age-matched sedentaries and (b) signaling pathways controlling muscle mass and metabolism are differently modulated in senior sportsmen to guarantee maintenance of skeletal muscle structure, function, bioenergetic characteristics, and phenotype. Thus, regular physical activity is a good strategy to attenuate age-related general decay of muscle structure and function (ClinicalTrials.gov: NCT01679977).

—The properties of the transient outward current (I_to) differ between rabbit and human atrial myocytes. In particular, rabbitI_tois known to recover more slowly than its human counterpart and to show much more frequency dependence. To assess the possibility that these physiological differences may reflect differing expression of K⁺channel subunit gene products, we used a combination of whole-cell voltage-clamp, heterologous expression, pharmacological, antisense, and Western blot techniques. The inactivation ofI_toin rabbit atrial myocytes was significantly slowed by hydrogen peroxide, with humanI_tobeing unaffected. Use-dependent unblocking with 4-aminopyridine was not seen for rabbitI_tonor for Kv1.4 currents inXenopusoocytes, whereas humanI_toshowed strong use-dependent unblock (as did Kv4 currents). Western blots indicated the presence of Kv4 proteins in both human and rabbit atrial membranes, but Kv1.4 was only detected in the rabbit. Antisense oligodeoxynucleotides directed against Kv4.3, Kv4.2, or Kv1.4 subunit sequences significantly inhibitedI_tocurrent density in cultured rabbit atrial myocytes, whereas only Kv4.3 antisense significantly inhibitedI_toin human cells. Neither mismatch oligodeoxynucleotides nor vehicle altered currents in either species. We conclude that, unlike human atrial myocytes, rabbit atrial myocytes express Kv1.4 channel subunits, which likely contribute to a number of important physiological differences inI_toproperties between the species. To our knowledge, these studies constitute the first demonstration of a functional role for Kv1.4 channels in cardiac membranes and provide insights into the molecular mechanisms of an important cardiac repolarizing current.

Background. Spinal cord injury causes muscle wasting and loss of function, which are especially severe after complete and permanent damage to lower motor neurons. In a previous cross-sectional study, long-standing denervated muscles were rescued by home-based functional electrical stimulation (h-bFES) training. Objective. To confirm results by a 2-year longitudinal prospective study of 25 patients with complete conus/cauda equina lesions. Methods. Denervated leg muscles were stimulated by h-bFES using a custom-designed stimulator and large surface electrodes. Muscle mass, force, and structure were determined before and after 2 years of h-bFES using computed tomography, measurements of knee torque during stimulation, and muscle biopsies analyzed by histology and electron microscopy. Results. Twenty of 25 patients completed the 2-year h-bFES program, which resulted in ( a) a 35% cross-sectional increase in area of the quadriceps muscle from 28.2 ± 8.1 to 38.1 ± 12.7 cm ² ( P < .001), a 75% increase in mean diameter of muscle fibers from 16.6 ± 14.3 to 29.1 ± 23.3 μm ( P < .001), and improvements of the ultrastructural organization of contractile material; and ( b) a 1187% increase in force output during electrical stimulation from 0.8 ± 1.3 to 10.3 ± 8.1 N m ( P < .001). The recovery of quadriceps force was sufficient to allow 25% of the subjects to perform FES-assisted stand-up exercises. Conclusions. Home-based FES of denervated muscle is an effective home therapy that results in rescue of muscle mass and tetanic contractility. Important immediate benefits for the patients are the improved cosmetic appearance of lower extremities and the enhanced cushioning effect for seating.

The histologic features of aging muscle suggest that denervation contributes to atrophy, that immobility accelerates the process, and that routine ex