A 73 year-old man received a single chamber automatic implantable cardioverter defibrillator (AICD) after a ventricular fibrillation cardiac arrest. He had known ischaemic cardiomyopathy. Day two post implant he became acutely tachycardic and short of breath, and was subsequently diagnosed with subsegmental pulmonary embolism, and anticoagulation was initiated with intravenous heparin until INR was therapeutic. He was already on dual antiplatelet agents (aspirin and clopidogrel).

Tachycardia-mediated cardiomyopathy is well described, and is a very important and reversible cause of left ventricular (LV) dysfunction [ 1 Packer D.L. Brady G.H. Worley S.J. et al. Tachycardia-induced cardiomyopathy: a reversible form of left ventricular dysfunction. Am J Cardiol. 1986; 57: 563-570 Abstract Full Text PDF PubMed Scopus (456) Google Scholar , 2 Fenelon G. Winjns W. Anbdreas E. Brugada P. Tachycardiomyopathy: mechanisms and clinical implications. Pacing Clin Elecrophysiol. 1996; 19: 95-106 Crossref PubMed Scopus (206) Google Scholar ]. Although reported in many arrhythmias, it appears to be more common in atrial tachycardia with up to 10% of patients with incessant or frequent paroxysmal atrial tachycardia (AT) developing cardiomyopathy [ [3] Roberst-Thomson K.C. Kistle P.M. Kalman J.M. Atrial tachycardia: mechanisms, diagnosis, and management. Curr Probl Cardiol. 2005; 30: 529-573 Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar ]. This diagnosis is usually confirmed retrospectively after improvement or even normalization of LV function following successful treatment of the precipitating arrhythmia [ 4 Felker G.M. Thompson R.E. Hare J.M. et al. Underlying causes and long term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000; 342: 1077-1084 Crossref PubMed Scopus (1285) Google Scholar , 5 Lesh M.D. VanHare G.F. Epstien L.M. et al. Radiofrequency catheter ablation of atrial tachyarrhythmias. Results and mechanism. Circulation. 1994; 89: 1074-1089 Crossref PubMed Scopus (453) Google Scholar ]. We report a challenging case of newly diagnosed catastrophic cardiogenic shock associated with incessant focal atrial tachycardia. We discuss the interaction between incessant arrhythmias and cardiogenic shock, and the role of its early recognition and management with an electrophysiology study and ablation.

Tie, Hui MBBS; Walker, Bruce D. MBBS; Singleton, Cameron B. MBBS; Bursill, Jane A. BTC; Wyse, Ken R. BSc; Campbell, Terry J. MD, DPhil; Valenzuela, Stella M. PhD; Breit, Samuel N. MD Author Information

Objective: To evaluate the effects of azimilide and ambasilide on the biophysical properties of the human-ether-a-go-go-related (HERC) channel. Methods: HERG was stably transfected into Chinese hamster ovary (CHO-K1) cells and currents were measured using a whole cell, voltage-clamp technique. Results: Azimilide had a 'dual effect', inhibiting current at voltage steps above -40 mV and augmenting current at -40 and -50 mV. Tail current inhibition following a step to +30 mV did not vary with temperature (IC50 610 nM at 22 degrees C and 560 nM at 37 degrees C). The agonist effect at -50 mV was concentration-dependent and correlated with a hyperpolarizing shift in the V-1/2 of activation (r = 0.98, P < 0.05). Time constants of inactivation were faster and there was a -10 mV shift in the V-1/2 of steady state inactivation suggestive of open and inactivated state binding. By comparison, ambasilide inhibited HERG channels with lower potency (IC50 3.6 mu M), in a voltage- and time-dependent but frequency-independent manner (0.03-1 Hz). Ambasilide had no effect on activation or inactivation gating but prolonged both fast and slow components of deactivation consistent with unbinding from the open state. The net effect of both drugs was similar during a voltage ramp which simulated a cardiac action potential. Conclusions: Inhibition of HERG channels by azimilide and ambasilide exhibits a similar time and voltage-dependence. While both exhibit affinity for the open state, azimilide also binds to inactivated channels. (C) 2000 Elsevier Science B.V. All rights reserved.

Australian doctors need to be aware of this little-known syndrome, which is a cause of sudden cardiac death. If is more common among Southeast Asian people, who make up a considerable proportion of our population. We report two cases which represent very different clinical presentations of this condition.

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, I(Kr), 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 IC(50) of 196.9 nM. The therapeutic plasma concentration range for halofantrine is 1.67-2.98 microM. 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.

Australian and New Zealand Journal of MedicineVolume 30, Issue 2 p. 246-251 N-3 polyunsaturated fatty acids and cardiac mortality C. B. Singleton, Corresponding Author C. B. Singleton Cardiac Electrophysiology Fellow, Royal Prince Alfred Hospital, Sydney, NSW.Cardiology Department, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050.Search for more papers by this authorB. D. Walker, B. D. Walker Cardiac Electrophysiology Fellow, St Vincent's Hospital, Sydney, NSW.Search for more papers by this authorT. J. Campbell, T. J. Campbell Professor of Medicine, St Vincent's Hospital, Sydney, NSW.Search for more papers by this author C. B. Singleton, Corresponding Author C. B. Singleton Cardiac Electrophysiology Fellow, Royal Prince Alfred Hospital, Sydney, NSW.Cardiology Department, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050.Search for more papers by this authorB. D. Walker, B. D. Walker Cardiac Electrophysiology Fellow, St Vincent's Hospital, Sydney, NSW.Search for more papers by this authorT. J. Campbell, T. J. Campbell Professor of Medicine, St Vincent's Hospital, Sydney, NSW.Search for more papers by this author First published: 25 March 2008 https://doi.org/10.1111/j.1445-5994.2000.tb00815.xCitations: 9AboutRelatedInformationPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume30, Issue2April 2000Pages 246-251 RelatedInformation RecommendedConfusion over different types of n-3 polyunsaturated fatty acidsJohn C. Stanley, Lipid TechnologyEnzymatic modification of evening primrose oil: Incorporation of n−3 polyunsaturated fatty acidsCasimir C. Akoh, Brenda H. Jennings, Dorris A. Lillard, Journal of the American Oil Chemists' SocietyElongation of polyunsaturated fatty acids in trypanosomatidsVerónica I. Livore, Karina E. J. Tripodi, Antonio D. Uttaro, The FEBS JournalA Simple Method of Supplementation of Omega‐3 Polyunsaturated Fatty AcidsKaren C. McCowen MD, MRCPI, Pei Ra Ling MD, Eric Decker MD, D. Djordjevic PhD, R.F. Roberts PhD, J.N. Coupland PhD, Bruce R. Bistrian MD, PhD, Nutrition in Clinical PracticeLabelling reference intake values for n‐3 and n‐6 polyunsaturated fatty acidsEuropean Food Safety Authority (EFSA), EFSA Journal

1 Cisapride is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations is high affinity blockade of IKr (encoded by HERG). 2 In a chronic transfection model using CHO-K1 cells, cisapride inhibited HERG tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC50 16. 4 nM at 20-22 degrees C and 23.6 nM at 37 degrees C). 3 Channel inhibition exhibited time-, voltage- and frequency-dependence. In an envelope of tails test, channel blockade increased from 27+/-8% after a 120 ms depolarizing step to 50+/-4% after a 1.0 s step. These findings suggested affinity for open and/or inactivated channel states. 4 Inactivation was significantly accelerated by cisapride in a concentration-dependent manner and there was a small (-7 mV) shift in the voltage dependence of steady state inactivation. 5 Channel blockade by cisapride was modulated by [K+]o, with a 26% reduction in the potency of channel blockade when [K+]o was increased from 1 to 10 mM. 6 In conclusion, HERG channel inhibition by cisapride exhibits features consistent with open and inactivated state binding and is sensitive to external potassium concentration. These features may have significant clinical implications with regard to the mechanism and treatment of cisapride-induced proarrhythmia.

1. 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. 2. 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. 3. 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. 4. 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 degrees 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 degrees C). Current inactivation and recovery from inactivation are faster at physiologic temperature (37 degrees C) compared to room temperature (23 degrees C). 5. The n-3 PUFA docosahexaenoic acid blocks the Kv4.3 current with an IC50 of 3.6 micromol 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.

Australian and New Zealand Journal of MedicineVolume 29, Issue 6 p. 811-813 Bedside pacetermination of arrhythmias using an explanted automatic defibrillator C. B. SINGLETON, Corresponding Author C. B. SINGLETON Cardiac Electrophysiology Research Fellow, Cardiac Electrophysiology Laboratory, Cardiology Department, St Vincent's Hospital, Sydney, NSW. Dr Cameron Singleton, Cardiac Electrophysiology Laboratory, Cardiology Department, St Vincent's Hospital, Victoria Street, Darlinghurst, NSW 2010. Email: [email protected]Search for more papers by this authorD. L. KUCHAR, D. L. KUCHAR Director, Coronary Care Unit, Cardiology Department, St Vincent's Hospital, Sydney, NSW.Search for more papers by this authorC. W. THORBURN, C. W. THORBURN Visiting Cardiologist, Cardiology Department, St Vincent's Hospital, Sydney, NSW.Search for more papers by this author C. B. SINGLETON, Corresponding Author C. B. SINGLETON Cardiac Electrophysiology Research Fellow, Cardiac Electrophysiology Laboratory, Cardiology Department, St Vincent's Hospital, Sydney, NSW. Dr Cameron Singleton, Cardiac Electrophysiology Laboratory, Cardiology Department, St Vincent's Hospital, Victoria Street, Darlinghurst, NSW 2010. Email: [email protected]Search for more papers by this authorD. L. KUCHAR, D. L. KUCHAR Director, Coronary Care Unit, Cardiology Department, St Vincent's Hospital, Sydney, NSW.Search for more papers by this authorC. W. THORBURN, C. W. THORBURN Visiting Cardiologist, Cardiology Department, St Vincent's Hospital, Sydney, NSW.Search for more papers by this author First published: 25 March 2008 https://doi.org/10.1111/j.1445-5994.1999.tb00784.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume29, Issue6December 1999Pages 811-813 RelatedInformation

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. British Journal of Pharmacology (1999) 127, 243–251; doi:10.1038/sj.bjp.0702502