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OBJECTIVES: The study investigated dual antiplatelet therapy (DAPT) patterns over time and patient characteristics associated with the various treatments in a myocardial infarction (MI) population.DESIGN: A registry-based observational cohort study was performed using antecedent data.SETTING: This study linked morbidity, mortality and medication data from Danish national registries.PARTICIPANTS: All 28 449 patients admitted to a Danish hospital with a first-time MI and alive at discharge from 2009 through 2012 were included.PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was initiation of DAPT and secondary outcomes comprised persistence in DAPT treatment and switches between DAPT treatments.RESULTS: The overall proportion of patients prescribed DAPT increased from 68% (CL 95% 67-69%) to 73% (CL 95% 72-74%) from 2009 to 2012. For treatment of patients with and without percutaneous coronary intervention (PCI), the corresponding numbers were from 87% (CL 95% 86-88%) to 91% (CL 95% 90-92%) and from 49% (CL 95% 47-50%) to 52% (CL 95% 51-54%), respectively. Non-PCI patients had a higher cardiovascular risk compared with PCI patients. Among PCI patients, age>75 years, atrial fibrillation, diabetes and peripheral arterial disease were associated with a higher risk of treatment breaks for DAPT. Among patients without PCI, ticagrelor treatment was associated with an increased risk of treatment breaks during the first 12 months compared with clopidogrel treatment.CONCLUSIONS: From 2009 to 2012, there was an increase in the proportion of patients with MI receiving DAPT, and a longer duration of DAPT. Still, a large proportion of patients without PCI are discharged either without DAPT or with a short DAPT duration. These findings may indicate the need for more careful attention to DAPT for patients with MI not undergoing PCI in Denmark. more...

The short QT syndrome is a newly discovered pro-arrhythmic condition, which may cause ventricular fibrillation and sudden death. Short QT can originate from the apparent gain-of-function mutation N588K in the hERG potassium channel that conducts repolarising I(Kr) current. The present study describes a profound biophysical characterization of HERG-N588K revealing both loss-of-function and gain-of-function properties of the mutant. Experiments were conducted after heterologous expression in both Xenopus laevis oocytes and mammalian cells and at both room temperature and at 37 degrees C. Also the impact of the beta-subunits KCNE2 was investigated. The most prominent loss-of-function property of HERG-N588K was reduced tail currents but also the activation properties was compromised. Based on these biophysical results we suggest that the general view of HERG-N588K being a gain-of-function is modified to a mixed gain- and loss-of-function mutation. This might also have impact on the pathological picture of the HERG-N588K channels ability to trigger arrhythmic events. more...

Within the field of new antiarrhythmic compounds, the interesting idea of activating human ether-a-go-go-related gene (HERG1) potassium channels has recently been introduced. Potentially, drugs that increase HERG1 channel activity will augment the repolarizing current of the cardiac myocytes and stabilize the diastolic interval. This may make the myocardium more resistant to events that cause arrhythmias. We here present the compound N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N'-(3'-trifluoromethylphenyl)urea (NS3623), which has the ability to activate HERG1 channels expressed in Xenopus laevis oocytes with an EC50 value of 79.4 microM. Exposure of HERG1 channels to NS3623 affects the voltage-dependent release from inactivation, resulting in a half-inactivation voltage that is rightward-shifted by 17.7 mV. Moreover, the compound affects the time constant of inactivation, leading to a slower onset of inactivation of the macroscopic HERG1 currents. We also characterized the ability of NS3623 to increase the activity of different mutated HERG1 channels. The mutants S620T and S631A are severely compromised in their ability to inactivate. Application of NS3623 to any of these two mutants did not result in increased HERG1 current. In contrast, application of NS3623 to the mutant F656M increased HERG1 current to a larger extent than what was observed with wild-type HERG1 channels. Because the amino acid F656 is essential for high-affinity inhibition of HERG1 channels, it is concluded that NS3623 has a dual mode of action, being both an activator and an inhibitor of HERG1 channels. Finally, we show that NS3623 has the ability to shorten action potential durations in guinea pig papillary muscle. more...

The cardiac action potential is generated by a concerted action of different ion channels and transporters. Dysfunction of any of these membrane proteins can give rise to cardiac arrhythmias, which is particularly true for the repolarizing potassium channels. We suggest that an increased repolarization current could be a new antiarrhythmic principle, because it possibly would attenuate afterdepolarizations, ischemic leak currents, and reentry phenomena. Repolarization of the cardiac myocytes is crucially dependent on the late rapid delayed rectifier current (I(Kr)) conducted by ether-a-go-go-related gene (ERG) potassium channels. We have developed the diphenylurea compound 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) and tested whether this small organic molecule could increase the activity of human ERG (HERG) channels expressed heterologously. In Xenopus laevis oocytes, NS1643 increased both steady-state and tail current at all voltages tested. The EC(50) value for HERG channel activation was 10.5 microM. These results were reproduced on HERG channels expressed in mammalian human embryonic kidney 293 cells. In guinea pig cardiomyocytes, studied by patch clamp, application of 10 microM NS1643 activated I(Kr) and significantly decreased the action potential duration to 65% of the control values. The effect could be reverted by application of the specific HERG channel inhibitor 4'-[[1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidinyl]carbonyl]-methanesulfonanilide (E-4031) at 100 nM. Application of NS1643 also resulted in a prolonged postrepolarization refractory time. Finally, cardiomyocytes exposed to NS1643 resisted reactivation by small depolarizing currents mimicking early afterdepolarizations. In conclusion, HERG channel activation by small molecules such as NS1643 increases the repolarization reserve and presents an interesting new antiarrhythmic approach. more...

Animal models of pacing-induced heart failure (HF) are often associated with high acute mortality secondary to high pacing frequencies. The present study therefore exploits lower-frequency left ventricular pacing (300 beats per minute) in rabbits for 11 weeks to produce chronic HF with low acute mortality but profound structural, functional, and electrical remodeling and compare with nonpaced controls. Pacing increased heart weight/body weight ratio and decreased left ventricular fractional shortening in tachypaced only. Electrocardiogram recordings during sinus rhythm revealed QTc prolongation in paced animals. Ventricular arrhythmias or sudden death was not observed. Isoproterenol increased heart rate similarly in both groups but showed a blunted QT-shortening effect in tachypaced rabbits compared with controls. Langendorff experiments revealed significant monophasic action potential duration prolongation in tachypaced hearts and reduced contractility at cycle lengths from 400 to 250 ms. Hyperkalemia caused monophasic action potential duration shortening in controls, whereas crossover was seen in tachypaced with monophasic action potential duration prolongation at short cycle length. Hypokalemia prolonged monophasic action potential duration and increased short-term variability of repolarization in tachypaced hearts. A blunted monophasic action potential duration response was observed ex vivo in tachypaced hearts after isoproterenol. The HF rabbits showed structural, functional, and electrical remodeling but very low mortality. Isokalemic and hyperkalemic responses indicate downregulation of functional IKs. Increased short-term variability during hypokalemia unmasks a reduced repolarization reserve. more...

The ionic current responsible for terminating the action potential (AP), and thereby in part determining the AP duration (APD), is the potassium current (IK), consisting of primarily two components: a rapidly (IKr) and a slowly (IKs) activating delayed rectifier potassium current. The aim of this study was to evaluate potential antiarrhythmic effects of compound induced IKs activation using the benzodiazepine L-364,373 (R-L3). Ventricular myocytes from guinea pigs were isolated and whole-cell current clamping was performed at 35 degrees C. It was found that 1 microM R-L3 significantly reduced the APD90 at pacing frequencies of 1, 2, and 4 Hz when compared to control (40 +/- 6%, 22 +/- 2%, and 32 +/- 2%, respectively). The reduction of APD90 was accompanied by a reduced triangulation (given as APD30-90) when compared to control at all pacing frequencies (62 +/- 7 ms vs. 41 +/- 3 ms, 55 +/- 5 ms vs. 35 +/- 6 ms, and 45 +/- 4 ms vs. 32 +/- 2 ms, at 1 Hz, 2 Hz, and 4 Hz, respectively). The abbreviated APDs also resulted in a reduction in the relative refractory period, and no direct protection against pacing induced early after-depolarizations (EAD) could be observed. However, an increase in repolarizing capacity was seen with 1 microM R-L3, as more complete repolarization of the AP was achieved before EADs could be elicited. Finally, a functional demonstration of the repolarization reserve revealed that increased IKs can counteract a pharmacologically reduced IKr. In conclusion, pharmacological activation of IKs possesses both pro- and antiarrhythmic characters. The most prominent antiarrhythmic propensity is the ability for IKs activation to rescue a cellular model of long QT type 2. more...