The Long QT Syndrome and Torsade De Pointes

The LQTS is a prime example of how molecular biology, ion channel, cellular, and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and acquired LQTS are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying cardiac repolarization. In this review, the continually unraveling molecular biology of congenital LQTS is discussed. The various pharmacological agents associated with the acquired LQTS are listed. Although it is difficult to predict which patients are at risk for TdP, careful assessment of the risk-benefit ratio is important before prescribing drugs known to be able to cause QT prolongation. The in vivo electrophysiological mechanism of TdP in the LQTS is described using, as a paradigm, the anthopleurin-A canine model, a surrogate for LQT3. In the LQTS, prolonged repolarization is associated with increased spatial dispersion of repolarization. Prolongation of repolarization also acts as a primary step for the generation of EADs. The focal EAD induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant VT, sometimes having the characteristic twisting QHS configuration known as TdP. The review concludes by discussion of the clinical manifestations and current management of both the congenital and acquired LQTS. The initial therapy of choice for the large majority of patients with the congenital LQTS is a beta-blocking drug. This therapy seems to be effective in LQT1 and LQT2 patients, but may not be as effective in LQT3 patients. Other therapeutic options include pacemakers, cervicothoracic sympathectomy, and the implantable cardioverter defibrillator. Recent molecular genetic studies have suggested several genotype specific therapies; however, long-term efficacy data are not available.     

Thiocyanates in Sputum: Relation to Welding Fumes, Tobacco Smoking and Carcinogenicity

Thiocyanate in sputum has been examined among 60 individuals.Thirty-two were exposed to welding fumes, 28 were not. The smokinghistory of the cases has been examined.Thiocyanate level washigher among smokers both among those exposed to welding fumesand control cases. Workers exposed to welding fumes did nothave higher thiocyanate levels in sputum.Thiocyanate is a catalystof N-nitrosamine compounds which is a supposed carcinogen inman.The relevance of carcinogenicity to exposure to weldingfumes cannot be concluded from this study. Although there issome evidence of this relationship in international literature,this might be among subgroups of welders. Requests for reprints should be addressed to: Professor Nabil I. Ebeid, 99, 26 July Street, Boulac, Cairo, Egypt.     

An Automatic Microcomputer System for Analysis of Monophasic Action Potentials

A computer system for rapid measurement and analysis of monophasic action potentials (MAPs) recorded in vivo was developed. MAPs recorded from the epicardium of mongrel dogs using a contact electrode were digitized by analog-to-digital conversion at a sampling rate of 1 kHz per channel for computer data acquisition. Activation time was detected using a sliding 10-point window at the location where the average positive dV/dT exceeds an adjustable threshold value in order to eliminate spurious detection due to baseline variability or motion artifact. Action potential duration (APD) was determined at 50% and 90% (APD50, APD90) repolarization levels at the first sample point below these detection levels. In addition, a tangent algorithm (APDtan) that detects peak negative dV/dT during repolarization was developed. APDtan was determined from the location of onset of activation to the intersection of tangent and baseline. APDtan allowed estimation of APD in the presence of subsequent premature beats when APD90 was not measurable. To validate activation time measurements, 4,600 action potentials were analyzed during fixed rate pacing. Over a range of paced coupling intervals from 200 to 1000 msec, an R2 value of 0.99968 and a slope of 0.9959 were obtained by linear regression between paced and calculated intervals. To validate APD measurements, 5035 action potentials were analyzed in five animals during fixed rate pacing (longer than 3 minutes) when action potential duration should be constant. Average coefficient of variation of 1.25%, 1.65%, and 1.14% were obtained for APD50, APD90, and APDtan, respectively. This algorithm provides a rapid and accurate method to analyze MAP activation and duration for basic physiological studies such as the determination of initiation of arrhythmias.     

Unitary Current Analysis of L-type Ca2+ Channels in Human Fetal Ventricular Myocytes

INTRODUCTION: L-type calcium channels were studied in cell-attached patches from ventricular cell membranes of human fetal heart. METHODS AND RESULTS: Experiments were performed in the presence of 70 mM Ba2+ as the charge carrier at 22 degrees C to 24 degrees C. Unitary current sweeps were evoked by 300-msec depolarizing pulses to 0 mV from a holding potential of -50 mV at 0.5 Hz. Recorded currents were blocked by nisoldipine (1 microM) and stimulated by (-)Bay K 8644 (1 microM). During control, channel activity was seen in 13.9%+/-4.2% of the total 200 sweeps. Ensemble average current amplitude was 0.03+/-0.01 pA (n = 6) and average conductance was 20.4+/-0.2 pS (n = 5). Analysis of single channel kinetics showed open time and closed time histograms were best fit by one and two exponentials, respectively. Mean open time was tau(o) = 0.99+/-0.05 msec (n = 6). Mean closed time fast (tau(cf)) and slow (tau(cs)) component values were tau(cf) = 0.85+/-0.09 msec and tau(cs) = 8.0+/-0.94 msec (n = 6), respectively. With intrapipette (-)Bay K 8644 (1 microM), mean open time was best fit by two exponentials, tau(of) = 0.9+/-0.2 msec (n = 10) and tau(os) = 13.4+/-2.6 msec (n = 10); mean close time values were tau(cf) = 0.6+/-0.1 msec (n = 10) and tau(cs) = 9.8+/-1.9 msec (n = 10), respectively. With (-)Bay K 8644, channel activity was 66.5%+/-7.4%, the ensemble average current was 0.52+/-0.04 pA (n = 10) and the conductance 20.7+/-0.5 pS (n = 5). CONCLUSION: (1) the data establishes the characteristics of L-type Ca channels of human fetal hearts and their modulation by dihydropyridines; (2) the open time kinetics differ from those of avian embryonic and rat fetal hearts; and (3) the findings provide new and relevant information for understanding the physiologic behavior of unitary Ca2+ channels in the developing human heart and the baseline comparison for diseases that implicate Ca2+ channels in their etiology, such as autoimmune-associated congenital heart block.     

His Bundle Extrasystoles Revisited: The Great Electrocardiographic Masquerader

A 74‐year‐old man with past history of near syncope presented with frequent periods of second‐degree atrioventricular block (2° AVB). An electrophysiological study revealed prolonged atrial‐His and His‐ventricular (HV) intervals and frequent His bundle (H) extrasystoles. The latter manifested in the surface electrocardiogram as premature atrial, junctional, or ventricular beats, as well as 2° AVB that mimicked Wenckebach or Mobitz II block. Procainamide markedly suppressed H extrasystole. However, because of the presence of prolonged HV interval and history of presyncope, a permanent pacemaker was inserted. The case illustrates the varied manifestation of H extrasystole and presents guidelines for management. (PACE 2011; e56–e59)     

Standards for analysis of ventricular late potentials using high resolution or signal-averaged electrocardiography: A statement of by a Task Force Committee between the European Society of Cardiology, the American College of Cardiology,the American Heart Association and the American college of cardiology

Sufficient data are avaliable to recommend that the high-resolutionor signal-averaged electrocardiogram can be used in patientsrecovering from myocardial infracation without bundle blockto help to determine thier risk for developing sustained ventriculartachyarrhythmias,However, no data are avaliable regarding theextent to which pharmacologic or non-pharmocologic intervationsin patients with late potentials have an impact on the incidenceof sudden cardic death. Therfore,Controlled, prospective studiesare required before this issue can be definitely answered. Asrefinements in techniquens evlove, it is anticipated that theclinical value of high-resolution or signal-averaged electrocrdiographywill continue to increase in the future.     

Design and synthesis of novel inhibitors of prohormone convertases

Prohormone convertase-1 (PC1) and furin are subtilisin-like endopeptidases involved in the biosynthesis of peptide hormones. Five decapeptides representing the junction between the pro-region and the catalytic region of PC1 were prepared. The core sequence corresponded to D-Tyr-Arg-Ser-Lys-Arg-Xaa-Val-Gln-Lys-Asp where D-Tyr replaces the native Glu residue and Xaa, representing the P1′ position, corresponds to L-Ser, L-Leu or the unnatural amino acids, D-Ser, β-Ala, γ-Abu, β-Cha or γ-Hyp. Another analog incorporating an Orn residue in place of the Arg at the P1 site was also prepared. These peptides, synthesized by solid-phase Fmoc chemistry, were fully characterized by FAB-MS, ¹H-NMR and amino acid composition. Except for Orn, γ-Hyp, L/D-Ser and L-Leu containing analogs, the others were found to be moderate to potent competitive inhibitors of hPCl activity in the following order: γ-Abu>β-Cha>β-Ala, with K_i values ranging from 1 to 8.6 μM. Both L-Ser and L-Leu analogs were correctly cleaved at the acyl carbon COOH-terminal to the Lys-Arg pair by human PCl, whereas β-Cha, γ-Abu, β-Ala and D-Ser analogs proved to be very poor substrates. The Orn and γ-Hyp derivatives were not cleaved by the enzyme at all. The three analogs containing β-Cha, γ-Abu and β-Ala also proved to be potent inhibitors of the human furin activity in the following order: β-Ala>β-Cha> γ-Abu, with K₁ ranging from 0.8 to 2.2μM. Two more peptides, modified at the P1 position by addition of a semicarbazone (SC) moiety, were also synthesized by liquid-phase chemistry. These peptides, Arg-Ser-Lys-argininal-SC and Arg-Lys-Lys-argininal-SC, also proved to be potent competitive inhibitors of hPCl and exhibited K_i values 3.6 and 2.3 μM, respectively.