Tedisamil Sesquifumarate

We conduct a systematic review and Bayesian network meta-analysis to indirectly compare and rank antidysrhythmic drugs for pharmacologic cardioversion of recent-onset atrial fibrillation and atrial flutter in the emergency department (ED).

We searched MEDLINE, EMBASE, and Web of Science from inception to March 2019, limited to human subjects and English language. We also searched for unpublished data. We limited studies to randomized controlled trials that enrolled adult patients with recent-onset atrial fibrillation or atrial flutter and compared antidysrhythmic agents, placebo, or control. We determined these outcomes before data extraction: rate of conversion to sinus rhythm within 4 hours, time to cardioversion, rate of significant adverse events, and rate of thromboembolism within 30 days. We extracted data according to Preferred Reporting Items for Systematic Reviews and Meta-analyses network meta-analysis and appraised selected trials with the Cochrane review handbook.

The systematic review initially identified 640 studies; 19 met inclusion criteria. Eighteen trials that randomized 2,069 atrial fibrillation patients provided data for atrial fibrillation conversion rate outcome. Bayesian network meta-analysis using a random-effects model demonstrated that antazoline (odds ratio [OR] 24.9; 95% credible interval [CrI] 7.4 to 107.8), tedisamil (OR 12.0; 95% CrI 4.3 to 43.8), vernakalant (OR 7.5; 95% CrI 3.1 to 18.6), propafenone (OR 6.8; 95% CrI 3.6 to 13.8), flecainide (OR 6.1; 95% CrI 2.9 to 13.2), and ibutilide (OR 4.1; 95% CrI 1.8 to 9.6) were associated with increased likelihood of conversion within 4 hours compared with placebo or control. Overall quality was low, and the network exhibited inconsistency.

For pharmacologic cardioversion of recent-onset atrial fibrillation within a 4-hour ED visit, there is insufficient evidence to determine which treatment is superior. Several agents are associated with increased likelihood of conversion within 4 hours compared with placebo or control. Limited data preclude any recommendation for cardioversion of recent-onset atrial flutter. Further high-quality study is necessary.

The β1-adrenergic regulation of cardiac myocyte contraction plays an important role in regulating heart function. Activation of this system leads to an increased heart rate and stronger myocyte contraction. However, chronic stimulation of the β1-adrenergic signaling system can lead to cardiac hypertrophy and heart failure. To understand the mechanisms of action of β1-adrenoceptors, a mathematical model of cardiac myocyte contraction that includes the β1-adrenergic system was developed and studied. The model was able to simulate major experimental protocols for measurements of steady-state force-calcium relationships, cross-bridge release rate and force development rate, force-velocity relationship, and force redevelopment rate. It also reproduced quite well frequency and isoproterenol dependencies for intracellular Ca2+ concentration ([Ca2+]i) transients, total contraction force, and sarcomere shortening. The mathematical model suggested the mechanisms of increased contraction force and myocyte shortening on stimulation of β1-adrenergic receptors is due to phosphorylation of troponin I and myosin-binding protein C and increased [Ca2+]i transient resulting from activation of the β1-adrenergic signaling system. The model was used to simulate work-loop contractions and estimate the power during the cardiac cycle as well as the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The developed mathematical model can be used further for simulations of contraction of ventricular myocytes from genetically modified mice and myocytes from mice with chronic cardiac diseases. NEW & NOTEWORTHY A new mathematical model of mouse ventricular myocyte contraction that includes the β1-adrenergic system was developed. The model simulated major experimental protocols for myocyte contraction and predicted the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The model also allowed for simulations of work-loop contractions and estimation of the power during the cardiac cycle.