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In this paper, a linear driver for travelling wave electrode (TWE) Mach-Zehnder Modulators (MZM) in 0.13 μm SiGe BICMOS technology is presented. The driver is implemented by a six-stage distributed differential amplifier. To drive a specified MZM with 33 Ω impedance, the driver delivers a differential output signal of 3 Vpp, exhibits a small-signal gain of 13 dB and 3-dB bandwidth of over 40 GHz. The driver works from a 6 V supply with a power consumption equal to 720 mW. Post layout simulation results show good eye diagrams of 50 Gbps NRZ and 50 GBps PAM-4 (100 Gbps) signals. The physical layout occupies an area of 1.82 × 0.71 mm2.

In this paper, a segmented Mach-Zehnder Modulators driver using 0.13 µm SiGe:C BiCMOS is demonstrated. The capacitive negative feedback is implemented within the input stage, and inductive peaking and negative capacitance are adopted within each driver segment to broaden the bandwidth. A propagation delay between the output of two driver segments is created by microstrip transmission lines. The simulation results indicate that a differential output swing and a propagation delay are approximately 3 Vppd and 4.3 ps at 25 Gb/s, respectively.

A segmented Mach-Zehnder Modulators (MZM) driver using 0.13\ \mu\mathrm{m}$ SiGe BICMOS with a simulated differential output swing of 3 Vppd and total power consumption of 0.98W is reported in this paper. A compact modeling of the Segmented-Electrode MZM designed using Verilog-A is developed for hybrid BICMOS and photonic system-level simulation in integrated circuit (IC) design environment. Six sub-blocks of the Segmented-Electrode MZM in silicon photonic process platform are discussed and critical device functions of each sub-block is given. A good open eye diagram of the optical output power at 25 Gb/s data rate is shown in this paper as a co-simulation result. The transmitter's −3 dB bandwidth is 23 GHz. The whole Segmented-Electrode MZM transmitter achieves an extinction ratio of 9 dB.

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2′ position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility ...

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4′-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent I

Previously disclosed C6 amido and benzimidazole dihydropyrazolopyrimidines were potent and selective blockers of IKur current. Syntheses and SAR for C6 triazolo and imidazo dihydropyrazolopyrimidines series are described. Trifluoromethylcyclohexyl N(1) triazole, compound 51, was identified as a potent and selective Kv1.5 inhibitor with an acceptable PK and liability profile.

Ischemic focal ventricular tachycardia (VT) occurs in animals and humans. Angiotensin-converting enzyme inhibitors and receptor blockers reduce sudden death in patients with ischemic heart disease. In our dog model of coronary artery occlusion (CAO), we tested the hypothesis that angiotensin II (AGII) will selectively promote focal VT and that the specific AT2 blocker PD-123319 (PD), or AT1 blocker losartan, will affect this VT. Anesthetized dogs ( n = 90) underwent CAO, followed by three-dimensional activation mapping of inducible VT. Dogs without VT in 1–3 h after CAO received AGII, and those with VT received either PD or losartan. Focal endocardium excised from ischemic sites was studied in vitro with standard microelectrode. Of 33 dogs with no inducible VT, AGII infusion resulted in sustained VT of only focal Purkinje origin in 13 (39%) compared with 0 of 20 dogs with saline. Of 26 dogs with inducible VT at baseline, given PD, reinduction was blocked in 8 of 10 ( P < 0.05) focal VT, but only 1 of 15 with reentry. In contrast, of 11 dogs given losartan, reinduction of either mechanism was not blocked. In vitro triggered activity in Purkinje was blocked by PD in 13 of 19 ( P < 0.05), but not by losartan in 8. Also, triggered activity was promoted by AGII, losartan, or the combination in 9 of 12 tissues. AGII promotes only focal, mainly Purkinje ischemic VT. PD, but not losartan, preferentially blocked focal VT, which is likely due to triggered activity due to delayed afterdepolarizations in Purkinje.

Focal ventricular tachycardia (VT) in acute myocardial ischemia is closely related to triggered activity (TA), which may be blocked by scavenging reactive oxygen species (ROS).This study analyzed effects of acutely administered ROS scavenger-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) on VT in vivo and TA in vitro.Forty-three alpha chloralose anesthetized dogs with coronary artery occlusion were studied. Three-dimensional activation mapping helped to locate the origin of focal or reentrant VT. TEMPO (30 mg/kg intravenously) or vehicle was given. Endocardium excised from the site of origin of VT was studied using standard microelectrode techniques and measures of ROS.Reentry and focal VT induction were both highly reproducible. TEMPO blocked focal VT in 6 of 11 dogs (P.05), but 9 of 9 dogs with reentrant VT continued to have VT re-induced after TEMPO. TEMPO did not alter effective refractory period (168 +/- 3 to 171 +/- 3 ms), mean blood pressure (88 +/- 3 to 81 +/- 3 mm Hg), and size of ischemia (42% +/- 3% vs 40% +/- 4%). In vitro, TEMPO (10(-3) M, n = 14) produced no change in action potentials. Nevertheless, TA was reversibly attenuated from 5.3 +/- 1.1 to 0.4 +/- 0.4 complexes with TEMPO (n = 15, P.05). Lucigenin-enhanced chemiluminescence and dihydroethidium staining showed increased ROS in ischemic endocardium; TEMPO dramatically reduced ROS in ischemic sites.TEMPO, a scavenger of ROS, prevented triggered activity associated with focal VT during myocardial ischemia in areas of increased ROS. Antioxidant therapy may play an important role in blockade of focal VT under the conditions of myocardial ischemia.

A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

Use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor has been associated with reduced implantable defibrillator shocks in several multicenter trials, suggesting an antiarrhythmic effect.The purpose of this study was to determine if lovastatin had an antiarrhythmic effect in a canine model of ischemic and inducible ventricular tachycardia (VT).Forty-seven alpha-chloralose anesthetized dogs underwent left anterior descending coronary occlusion. Three-dimensional activation mapping identified the mechanism of reinducible VT and the response to lovastatin (0.5 mg/kg IV). The endocardium was excised from foci and studied using standard microelectrode techniques with Tyrode's solution.Lovastatin blocked focal VT in 8 of 13 dogs (P.01) compared with only 1 of 12 saline-treated dogs with focal VT. Lovastatin had no effect on reentrant VT. Lovastatin did not alter the effective refractory period, arterial pressure, or percentage of ischemic electrograms. Effective plasma concentration of lovastatin hydroxy acid ranged from 21-157 ng/mL (0.8-3.7 x 10(-7) M). In vitro rapid pacing, mostly with isoproterenol (5 x 10(-7) M) superfusion, produced delayed afterdepolarizations and triggered activity (9 +/- 2 action potentials). Lovastatin (10(-7) M) produced no change in action potentials or delayed afterdepolarizations. However, triggered activity was attenuated to 2 +/- 1 action potentials with lovastatin (P.05, n = 13) but not with vehicle alone. Triggered activity returned to control after lovastatin washout (20 minutes) as well as with co-superfusion with mevalonic acid (10(-6) M, n = 5). 2,2,6,6-Tetramethylpiperidine-N-oxyl, an antioxidant that enters tissues (10(-3) M, n = 8), prevented triggered activity in a fashion similar to lovastatin.Lovastatin, in concentrations achievable in human plasma, specifically suppresses triggered activity and focal VT due to ischemia. A prenylated protein downstream from mevalonic acid may act as an antioxidant, producing the antiarrhythmic effect.

Objective— In cultured endothelium, stretch induces release of growth factors that contribute to angiogenesis. We tested the hypothesis that bradycardia, which prolongs ventricular diastolic filling time and volume, promotes collateral vessel growth. Methods and Results— An ameroid occluder was placed on coronary arteries of dogs with normal heart rates (AM) or bradycardia (55 bpm; AM+BC). A third group had normal heart rates and no ameroid (control [CON]). Four weeks after occluder placement, myocardial blood flow at rest and maximal vasodilation (adenosine) at equivalent heart rates and vascular morphometry of hearts were measured. In AM dogs, conductance (myocardial flow/diastolic pressure) of collateral-dependent myocardium was similar to collateral-independent myocardium during rest but increased to only one third of CON during maximal vasodilation. In contrast, in AM+BC dogs, conductance was similar in collateral-dependent and -independent regions during maximal vasodilation. Arteriolar length density in collateral-dependent myocardium was 80% greater in AM+BC than AM dogs. Capillary length density in collateral-dependent region of AM dogs was lower than CON but normal in AM+BC dogs. The angiopoietin receptor Tie-2 increased in collateral-dependent regions of AM and AM+BC groups, whereas vascular endothelial growth factor increased in collateral-dependent and -independent regions only in AM+BC dogs. Conclusion— Chronic bradycardia during gradual coronary artery occlusion facilitates angiogenesis/arteriogenesis in collateral-dependent myocardium and preserves maximal perfusion.

Entrainment can be a useful method to identify reentry as a mechanism of ventricular tachycardia (VT). In this study, we evaluated the effect of gradually decreasing cycle lengths of overdrive pacing for stable VT induced in a canine model 1–3 h after coronary occlusion. Intact dogs underwent anterior descending coronary artery occlusion after instrumentation of the risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Overdrive pacing was attempted if the animals had sustained hemodynamically stable VT, looking for evidence of entrainment. Subsequent three-dimensional mapping determined the mechanism of VT. Fifteen of the 21 dogs studied demonstrated entrainment with overdrive pacing by progressive QRS fusion alone ( 1 ), the first nonpaced QRS entrained to the paced cycle length only ( 7 ), or both ( 7 ). Five of these 15 dogs also had postpacing acceleration of the VT at a subsequent faster pacing cycle length. The mechanism of acceleration in four was a change to a VT with a focal origin. The prepacing mechanism in all 15 dogs was subsequently mapped to reentry. Regarding the six VTs, which demonstrated no evidence for entrainment, the site of earliest activity was mapped to a focal origin in all. These data showing entrainment of inducible reentrant VTs and lack of such for focal VTs support that the focal VTs seen in this study are unlikely the result of microreentry but possibly a mechanism as triggered activity.

This study for the first time systematically evaluated the site of origin of focal ventricular tachycardia (VT) induced 1–3 h after acute coronary artery ligation in dogs. We determined whether delayed afterdepolarizations (DADs) and triggered activity (TA) are more often recorded from ischemic endocardium excised from focal sites of VT origin. A total of 145 α-chloralose-anesthetized dogs were studied: in 54 dogs without inducible VT, normal or ischemic endocardium was investigated in vitro; in 91 dogs, inducible VT was studied by three-dimensional activation mapping, with in vitro study of 51 endocardial foci compared with 40 endocardial ischemic sites not of VT origin. Incidence of DADs (71% vs. 33%, P < 0.05) and TA (32% vs. 11%, P < 0.05) was greater in ischemic than in normal Purkinje tissues. Purkinje sites of origin of focal VT demonstrated the greatest frequency of DADs (92%, P < 0.05) and TA (75%, P < 0.05), with repetitive TA predominating. Similar results were obtained in endocardial sites of origin. Action potentials were mildly depolarized and prolonged in the focal sites of origin. These abnormalities were stable up to 2.5 h of recording. This study demonstrated that DADs and TA may underlie a majority of focal VTs in ischemic endocardium and Purkinje tissue.

Recent studies have shown the presence of postjunctional α2-adrenergic receptors on canine Purkinje fibers but not muscle cells. Stimulation of these receptors results in prolongation of the action potential duration and the Purkinje relative refractory period. We studied the effect of α2-adrenergic agonists on inducible ischemic ventricular tachycardia (VT) of both Purkinje fiber and myocardial origin. Open-chest dogs in whom VT was induced with extrastimuli after occlusion of the anterior descending coronary artery were studied. A mapping system, incorporating Purkinje signals, characterized the mechanisms of VT. The α2-adrenergic agonists clonidine (0.5–4.0 μg/kg) or UK 14,304 (4–5 μg/kg) versus saline were given intravenously after reproducibility of inducible sustained monomorphic VT had been demonstrated. Eighteen dogs were given clonidine, eleven of which had focal Purkinje VT. Of these 11 dogs, clonidine blocked VT induction in 9 (81.9%) and rendered VT nonsustained in 1 (9.1%), and VT remained inducible in 1 dog (9.1%), although this was focal midmyocardial VT only. In the seven dogs with VT of myocardial origin, six (85.6%) remained inducible with clonidine, whereas one dog (14.4%) had only nonsustained VT after clonidine. Of the six dogs, UK 14,304 blocked VT induction in four (66.6%) and rendered VT nonsustained in one (16.7%), and VT remained inducible in one dog (16.7%). In four dogs with VT of myocardial origin, VT remained inducible. In the eight control dogs that were given saline, focal Purkinje VT was repeatedly inducible. Pharmacological stimulation of postjunctional α2-adrenoceptors on Purkinje fibers may selectively prevent induction of VT of Purkinje fiber origin in the ischemic canine ventricle.

A numerical model for semiconductor laser diodes that predicts laser performance in high speed optical interconnect applications has been developed. The model is based on the temporal numerical simulation of the rate equation for semiconductor laser diodes. The popular math package MATLAB has been used to simulate the dynamic behavior of carrier and photon density. The term turn on delay time is defined to describe the different response of carrier and photon when injection current is applied. The results under constant and varying injection current are also analyzed in detail.

In this study we tested the hypothesis that alpha-2 adrenergic antagonism could facilitate induction of previously non-inducible ventricular tachycardia (VT) during acute ischemia. Previous reports suggest that VT during ischemia may be modulated by (alpha-2 adrenergic agonists.The left anterior descending artery was occluded after instrumentation of the ischemic risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Three dimensional mapping characterized the mechanism of VT induced with extrastimuli.Of 16 non-inducible dogs included, eight which were given the alpha-2 adrenergic antagonist yohimbine all had inducible VT, while all eight in the control group remained non-inducible (p0.05). Six of the VTs were of focal Purkinje origin. The cycle length of the VTwas 119 +/- 4 ms. Mean arterial pressure (81+/- 8 to 82 +/- 8 mmHg, p = ns), ventricular effective refractory period (146 +/- 6 to 144 +/- 5 ms, p = ns) and ischemic zone size (55 +/-6% vs. 61 +/- 4%, p = 0.45) were not altered by yohimbine indicating minimal central or pre-junctional effects of the drug.Yohimbine facilitates induction of VT, especially those with focal Purkinje fiber origin, suggestive of an effect mediated through antagonism of post-junctional alpha-2 adrenoceptors on Purkinje fibers.

Aim and Methods: To analyze the relationship of Purkinje and endocardial focal VT versus epicardial reentry VT to varying ischemic size (IS), one hundred seven alpha chloralose anesthetized dogs we...

The role of gap junction intercellular communication (GJIC) in ischemia-induced focal ventricular tachycardia (VT) is unknown. We have developed a new, stable antiarrhythmic peptide analog named ZP123 that selectively increases GJIC and prevents reentrant VT. Our aim in this study was to use ZP123 as a tool to assess the role of GJIC on occurrence of ischemia-induced focal VT and triggered activity (TA) due to delayed afterdepolarizations (DADs). Focal VT was induced by programmed stimulation in α-chloralose-anesthetized, open-chest dogs 1–4 h after coronary artery occlusion. Three-dimensional activation mapping was done using 6 bipolar electrograms on each of 23 multipolar needles in the risk zone. Dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (an intravenous bolus followed by a 30-min infusion per dose). Attempts to induce VT were repeated in each dose. Mass spectrometry was used to measure plasma ZP123 concentrations. Standard microelectrode techniques were used for in vitro study of DADs and TA. Twenty-six dogs with focal VT were included. ZP123 did not affect the inducibility of focal VT at any plasma concentrations vs. saline (0.8 ± 0.1 nM, 77 vs. 75%; 7.8 ± 0.4 nM, 86 vs. 77%; and 78.8 ± 5.0 nM, 77 vs. 91%). In vitro, ZP123 did not affect the induction of DADs (12/12) and TAs (10/10) in ischemic tissues or tissue removed from the origin of focal VT (DADs, 8/8; TAs, 4/4). Therefore, although indirect, the data with the doses and concentrations used suggest that GJIC may not play a major role in the genesis of focal activity in the ischemic models studied.

Introduction: The aim of this study was to determine if the stable antiarrhythmic peptide (AAP) analogue ZP123 increases gap junctional intercellular conductance and prevents reentrant ventricular tachycardia (VT) during coronary artery occlusion. Methods and Results: Voltage clamp experiments demonstrated that 10 nM ZP123 improved gap junctional intercellular conductance by69%± 20%in pairs of guinea pig ventricular myocytes. VT was induced by programmed stimulation in α-chloralose anaesthetized open chest dogs 1 to 4 hours after coronary artery occlusion. Three-dimensional activation mapping was done using six bipolar electrograms on each of 23 multipolar needles in the risk zone. When VT was reproducibly induced, dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (intravenous bolus followed by 30-min infusion per dose). Attempts to induce VT were repeated in each infusion period. Mass spectrometry was used to measure ZP123 plasma concentrations. Twenty-six dogs with reentrant VT were included. ZP123 significantly prevented reentrant VT at all plasma concentrations vs saline:1.0 ± 0.2 nM: 6/12 vs 0/12; 7.7 ± 0.6 nM: 7/13 vs 1/12; and69.2 ± 5.4 nM: 9/13 vs 1/13. The preventive effect of ZP123 on reentrant VT was closely correlated to reversal of functional, unidirectional conduction block. ZP123 did not affect effective refractory period, surface ECG parameters, mean arterial pressure, or infarct size. Conclusion: The stable AAP analogue ZP123 increased gap junctional intercellular conductance and specifically prevented the induction of reentrant VT during ischemia in a broad dose range without proarrhythmic or hemodynamic side effects. ZP123 is a promising candidate for use in preventing ischemia-induced VT.(J Cardiovasc Electrophysiol, Vol. 14, pp. 510-520, May 2003)

Background Endothelin (ET), one of the most potent vasoconstrictors, is known to influence ventricular tachycardia (VT). The mechanism thought to be involved includes triggered activity (TA). We investigated effects of ET-1 and the ET-1A receptor blocker BQ123 in a canine model of focal and reentrant VT in a combined in vivo and in vitro study to test the hypothesis that focal VT and TA were selectively affected. Methods Thirty-eight alpha-chloralose-anesthetized dogs with 1 to 3 hours of coronary artery occlusion were studied. Three-dimensional activation mapping identified the mechanism of VT. If VT was not inducible at baseline, incremental doses of ET-1 were given until the VT was induced. If VT was reproducibly induced at baseline, BQ123 was given (2.5 μg/kg, IV), and then induction was repeated. The effect of these agents on action potentials (APs), delayed and early afterdepolarizations (DADs and EADs), and TA measured from ischemic endocardium were studied in vitro by standard microelectrode techniques. Results Of 15 dogs with no VT inducible, ET-1 (0.2 μg/kg, IV) produced sustained VT of mixed reentrant and focal origin in five dogs (p Conclusion ET-1 promotes focal and reentrant VT under conditions of myocardial ischemia; however, in vitro tissues do not show TA as we expected. The specific ET-1A receptor blocker BQ123 significantly blocked only reentrant VT. Endothelin plays a major role in reentrant VTs in the dog model of myocardial ischemia probably by promoting AP alternans.

Background Ventricular tachycardia (VT) of focal endocardial and Purkinje origin occurs in humans. Pharmacological blockade of adrenoceptors on endocardial tissues may selectively prevent the induction of focal VT. We tested the hypothesis that alpha adrenoceptor blocker WB4101(WB), beta-1 receptor blocker metoprolol (Met), and beta-2 receptor blocker ICI 118,511(ICI) prevent the induction of focal ischemic VT and evaluated possible mechanisms. Methods Fifty alpha chloralose anesthetized dogs with 1 to 4 hours of coronary artery occlusion (CAO) were involved. Twenty-three multipolar plunge electrodes were placed in and surrounding the risk zone of anterior descending coronary artery. three-dimensional activation mapping off-line helped to identify the origin of VT. If VT was reproducibly induced, WB (0.3 μg/kg, IV), Met (1 mg/kg), or ICI (0.2 mg/kg, IV) was given. The effects of blockers on delayed afterdepolarizations (DADs) and triggered activity (TA) recorded from endocardium and Purkinje tissue excised from the focal origin of VT were studied in vitro by standard microelectrode techniques. Results Eleven dogs were given WB; two had VTs blocked with the same or more extrastimuli. Twelve dogs were received ICI; only 3 had VT blocked, which were no different compared to focal endocardial or Purkinje VT in dogs with saline treatment, of which 1 of 12 had apparent block ( p = ns). However, 7 of 15 dogs given Met had focal VT blocked, which was different from the saline treated ( p -7 M, in 2 of 6, p = ns), ICI (10 -7 M, in 0 of 4, p = ns) and Met (10 -7 M, in 6 of 8, p Conclusions Pharmacological blockade of beta-1 adrenoceptor in acute ischemia selectively prevents induction of focal VT due to DADs and TA but alpha adrenoceptor and beta-2 receptor blockade does not.

Background AVID and MADIT-II trials showed that patients with coronary artery disease taking HMG-CoA reductase inhibitors have fewer ICD shocks suggesting anti-arrhythmic effects. Our aim was to analyze the effects of acutely administered lovastatin (LOVA): 1) on ICD defibrillation threshold (DFT) since antiarrhythmics can worsen DFT, and 2) on triggered activity (TA) recorded from ischemic endocardium excised from the anterior wall of anesthetized dogs with anterior descending coronary occlusion. Methods and Results Dogs received LOVA dissolved in DMSO. DMSO alone produced no effect on DFT. LOVA 10 mg IV did not alter effective refractory period and tended to improve defibrillation success (from 20 ± 3 to 17 ± 3 J, P = 0.09 vs control). Ischemic endocardium was studied using standard microelectrode techniques with normal Tyrode9s solution. There were no delayed afterdepolarizations (DADs) or TA at baseline in this depolarized tissue (-71 ± 4 mV). Isoproterenol (5 × 10-7 M) superfusion, produced sustained TA with DAD amplitudes of 4.2 ± 1 mV. LOVA (10-7 M) produced no change in resting membrane potential (-70 ± 4 mV), action potential duration at 90% (from 231 ± 11 to 229 ± 8 msec, ns), action potential duration at 50% (168 ± 7 to 166 ± 6 msec, ns), action potential amplitude (89 ± 5 to 85 ± 5 mV, ns), overshoot (11 ± 1 to 10 ± 1 mV) or DAD amplitude (4.0 ± 1 mV, ns). Interestingly, TA was attenuated to 1-5 complexes with LOVA (p Conclusions These results are consistent with the possibility that a prenylated protein down-stream from the mevalonic acid pathway may underlie this effect. Thus LOVA in concentrations achievable in human plasma may be antiarrhythmic for TA without a deleterious effect on DFT.