Hui Tie

Long-Term Impact of Right Ventricular Septal Versus Apical Pacing on Left Ventricular Synchrony and Function in Patients With Second-or Third-Degree Heart Block

Right ventricular (RV) septal pacing has been advocated as an alternative to apical pacing to avoid long-term detrimental effects. There is conflicting evidence on the benefits of RV septal pacing. Fifty-five subjects (22 normal healthy controls, 17 with RV septal pacing, and 17 with apical pacing) were recruited. Midventricular short-axis left ventricular (LV) circumferential and radial strains were determined. Circumferential and radial strain dyssynchrony and longitudinal systolic dyssynchrony were determined. Echocardiographic determination of pacing sites were compared with electrocardiogram and chest x-ray. Septal pacing is a heterogenous group of different pacing sites, and there was only modest agreement among echocardiogram, electrocardiogram, and chest x-ray. Median pacing durations were 436 days for septal pacing and 2,398 days for apical pacing. Mean QRS duration for apical pacing was longest, followed by septal pacing and control (p <0.001). LV mass index, end-systolic volume index, and ejection fraction were more impaired in septal than in apical pacing (all p values <0.05). Septal pacing was associated with more impaired circumferential strain (p <0.001) and worse LV dyssynchrony than apical pacing and control. In conclusion, standard fluoroscopic and electrocardiographic implantation techniques for RV septal pacing resulted in a heterogenous group of different pacing sites. This heterogenous RV septal pacing group was associated with poorer long-term LV function and greater dyssynchrony than RV apical pacing and control.

Inhibition of HERG potassium channels by the antimalarial agent halofantrine

Halofantrine is a widely used antimalarial agent which has been associated with prolongation of the ‘QT interval’ of the electrocardiogram (ECG), torsades de pointes and sudden death. Whilst QT prolongation is consistent with halofantrine‐induced increases in cardiac ventricular action potential duration, the cellular mechanism for these observations has not been previously reported. The delayed rectifier potassium channel, IKr, is a primary site of action of drugs causing QT prolongation and is encoded by the human‐ether‐a‐go‐go‐related gene (HERG). We examined the effects of halofantrine on HERG potassium channels stably expressed in Chinese hamster ovary (CHO‐K1) cells. Halofantrine blocked HERG tail currents elicited on repolarization to −60 mV from +30 mV with an IC50 of 196.9 nM. The therapeutic plasma concentration range for halofantrine is 1.67–2.98 μM. Channel inhibition by halofantrine exhibited time‐, voltage‐ and use‐dependence. Halofantrine did not alter the time course of channel activation or deactivation, but inactivation was accelerated and there was a 20 mV hyperpolarizing shift in the mid‐activation potential of steady‐state inactivation. Block was enhanced by pulses that render channels inactivated, and channel blockade increased with increasing duration of depolarizing pulses. We conclude that HERG channel inhibition by halofantrine is the likely underlying cellular mechanism for QT prolongation. Our data suggest preferential binding of halofantrine to the open and inactivated channel states.

Inhibition of HERG channels stably expressed in a mammalian cell line by the antianginal agent perhexiline maleate.

Perhexiline has been used as an anti‐anginal agent for over 25 years, and is known to cause QT prolongation and torsades de pointes. We hypothesized that the cellular basis for these effects was blockade of IKr. A stable transfection of HERG into a CHO‐K1 cell line produced a delayed rectifier, potassium channel with similar properties to those reported for transient expression in Xenopus oocytes. Perhexiline caused voltage‐ and frequency‐dependent block of HERG (IC50 7.8 μM). The rate of inactivation was increased and there was a 10 mV hyperpolarizing shift in the voltage‐dependence of steady‐state inactivation, suggestive of binding to the inactivated state. In conclusion, perhexiline potently inhibits transfected HERG channels and this is the probable mechanism for QT prolongation and torsades de pointes. Channel blockade shows greatest affinity for the inactivated state.

Blockade by N-3 polyunsaturated fatty acid of the Kv4.3 current stably expressed in Chinese hamster ovary cells.

The Kv4.3 gene is believed to encode a large proportion of the transient outward current (Ito), responsible for the early phase of repolarization of the human cardiac action potential. There is evidence that this current is involved in the dispersion of refractoriness which develops during myocardial ischaemia and which predisposes to the development of potentially fatal ventricular tachyarrhythmias. Epidemiological, clinical, animal, and cellular studies indicate that these arrhythmias may be ameliorated in myocardial ischaemia by n‐3 polyunsaturated fatty acids (n‐3 PUFA) present in fish oils. We describe stable transfection of the Kv4.3 gene into a mammalian cell line (Chinese hamster ovary cells), and using patch clamp techniques have shown that the resulting current closely resembles human Ito. The current is rapidly activating and inactivating, with both processes being well fit by double exponential functions (time constants of 3.8±0.2 and 5.3±0.4 ms for activation and 20.0±1.2 and 96.6±6.7 ms for inactivation at +45 mV at 23°C). Activation and steady state inactivation both show voltage dependence (V1/2 of activation=−6.7±2.5 mV, V1/2 of steady state inactivation=−51.3±0.2 mV at 23°C). Current inactivation and recovery from inactivation are faster at physiologic temperature (37°C) compared to room temperature (23°C). The n‐3 PUFA docosahexaenoic acid blocks the Kv4.3 current with an IC50 of 3.6 μmol L−1. Blockade of the transient outward current may be an important mechanism by which n‐3 PUFA provide protection against the development of ventricular fibrillation during myocardial ischaemia.

Spontaneous coronary dissection following exertion: support for a hypothesis.

We read with interest a recent article by Yeoh and Kritharides, describing a 35-year-old woman suffering an anterior myocardial infarction following spiral left anterior descending coronary artery (LAD) dissection and vessel occlusion, occurring following an aerobics class.1 As the authors pointed out, spontaneous coronary dissection is rare, may occur as a result of pre-existing atherosclerotic plaque rupture and has not been previously reported to occur after exercise.1–3 They hypothesized that an intimal tear occurred during exertion, but was only evident when the dissection later extended to cause coronary occlusion.1 We report a patient in whom coronary artery dissection was also thought to present following exercise, lending support to this hypothesis.