Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles.

Hyperkalemic periodic paralysis (HyperKPP) manifests as stiffness or subclinical myotonic discharges before or during periods of episodic muscle weakness or paralysis. Ingestion of Ca2+ alleviates HyperKPP symptoms, but the mechanism is unknown because lowering extracellular [Ca2+] ([Ca2+]e) has no effect on force development in normal muscles under normal conditions. Lowering [Ca2+]e, however, is known to increase the inactivation of voltage-gated cation channels, especially when the membrane is depolarized. Two hypotheses were tested: (1) lowering [Ca2+]e depresses force in normal muscles under conditions that depolarize the cell membrane; and (2) HyperKPP muscles have a greater sensitivity to low Ca2+-induced force depression because many fibers are depolarized, even at a normal [K+]e. In wild type muscles, lowering [Ca2+]e from 2.4 to 0.3 mM had little effect on tetanic force and membrane excitability at a normal K+ concentration of 4.7 mM, whereas it significantly enhanced K+-induced depression of force and membrane excitability. In HyperKPP muscles, lowering [Ca2+]e enhanced the K+-induced loss of force and membrane excitability not only at elevated [K+]e but also at 4.7 mM K+. Lowering [Ca2+]e increased the incidence of generating fast and transient contractures and gave rise to a slower increase in unstimulated force, especially in HyperKPP muscles. Lowering [Ca2+]e reduced the efficacy of salbutamol, a ß2 adrenergic receptor agonist and a treatment for HyperKPP, to increase force at elevated [K+]e. Replacing Ca2+ by an equivalent concentration of Mg2+ neither fully nor consistently reverses the effects of lowering [Ca2+]e. These results suggest that the greater Ca2+ sensitivity of HyperKPP muscles primarily relates to (1) a greater effect of Ca2+ in depolarized fibers and (2) an increased proportion of depolarized HyperKPP muscle fibers compared with control muscle fibers, even at normal [K+]e.

Systematic review of biological therapies for atrial fibrillation.

Biological therapies that increase or suppress the expression of transcripts underlying atrial fibrillation (AF) progression are increasingly being explored to create novel treatment paradigms beyond simply suppressing or destroying tissue. To date, there has been no systematic overview of the preclinical evidence exploring manipulation of fundamental biological principles in the treatment of AF. As such, the objective of this study was to establish the effect of biological approaches used in the treatment of AF within large and small animals. We performed a systematic search using predefined terms, which yielded 25 studies. We determined the effect of biological approaches on primary efficacy outcomes and assessed the quality of included studies or possible bias in the treatment of AF. Compared with non-transduced or transduced controls, biological therapies reduced AF inducibility (85% less AF; odds ratio 0.15; 95% confidence interval [CI] 0.07-0.35; P < .01) and atrial scar burden (6.7% smaller scars; 95% CI 4.2-9.2; P < .01) or increased number of days in sinus rhythm (6.4 more days in sinus rhythm; 95% CI 5.83-6.97; P < .01). Similar effects were seen in both large and small animals, while a minor tendency to higher risk of bias was observed in small animal studies. In conclusion, treatment with any biological therapy significantly improved AF in preclinical animal models compared with controls. Although biological therapies target markedly different fundamental mechanisms, we observed a consistent difference in their effect on AF outcomes.