Robert M. Gill

Eli Lilly, Indianapolis, Indiana, United States

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Publications (31)193.02 Total impact

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    ABSTRACT: Activation of phosphoinositide-3 kinase (PI3K) is essential for cell growth, relating to adaptive and maladaptive cardiac hypertrophy. This longitudinal canine study was designed to investigate the role of PI3Kalpha and PI3Kgamma in cardiac remodelling during congestive heart failure (CHF) and cardiac recovery (CR). All dogs were surgically instrumented. Congestive heart failure was induced by cardiac pacing for 3-4 weeks and CR was allowed by terminating pacing for 5-6 weeks after induction of HF. Control dogs had sham surgery, but did not undergo pacing. Left ventricular (LV) contractile function was depressed in CHF and restored to 80-90% of the normal level in CR, with a 25% increase in LV weight. The expression of PI3Kgamma was increased four-fold in CHF, but returned to control levels in CR. In contrast, the expression of PI3Kalpha in CHF was not different from that in controls, but increased three-fold in CR and was accompanied by increases in phosphorylation of Akt (five-fold), GSK-3beta (five-fold), beta-catenin (three-fold), mTOR (two-fold), and P70S6K (two-fold). Our results indicate that PI3K isoforms are regulated differently during the course of CHF/CR and that the selective activation of PI3Kalpha, through Akt, GSK-3beta, and mTOR signalling pathways, may be involved in the development of cardiac compensatory hypertrophy and functional restoration.
    European Journal of Heart Failure 09/2009; 11(8):739-48. DOI:10.1093/eurjhf/hfp094 · 6.58 Impact Factor
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    ABSTRACT: In congestive heart failure (CHF), coronary vascular relaxation is associated with endothelial dysfunction and nitric oxide (NO) deficiency. This study explored the reversibility of this process in hearts recovering from CHF and its related mechanisms. Dogs were chronically instrumented to measure cardiac function and coronary blood flow (CBF). Heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk, and cardiac recovery (CR) was allowed by the termination of cardiac pacing for 3-4 wk after the development of CHF, in which left ventricular contractile function was restored by 80-90%. The endothelium-dependent CBF response to bradykinin and acetylcholine was depressed in CHF and fully restored in CR. Myocardial NOx (nitrate/nitrite), endothelial NO synthase (eNOS) mRNA expression, total protein, and phosphorylated eNOS decreased significantly in failing hearts. However, myocardial NOx recovered to 78% of control and phosphorylated eNOS was fully restored in CR, despite the fact that eNOS mRNA expression and protein levels remained lower than control. Furthermore, the endothelium-independent CBF response to nitroglycerin did not change in CHF; however, it increased by 75% in CR, in conjunction with a near threefold increase in the phosphorylation of vasodilation-stimulated phosphoprotein (VASP) at Ser(239) in recovering hearts. Thus the complete restoration of endothelium-dependent coronary vascular relaxation during cardiac recovery from CHF was mediated by 1) a restoration of phosphorylated eNOS for partial recovery of the NO production and 2) an increase in cGMP/cGMP-dependent protein kinase-I pathway signaling activity for the enhancement of coronary vascular smooth muscle relaxation in response to NO.
    AJP Heart and Circulatory Physiology 07/2007; 292(6):H2782-90. DOI:10.1152/ajpheart.00831.2006 · 4.01 Impact Factor
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    ABSTRACT: Left ventricular (LV) diastolic dysfunction is a fundamental impairment in congestive heart failure (CHF). This study examined LV diastolic function in the canine model of CHF induced by chronic coronary embolization (CCE). Dogs were implanted with coronary catheters (both left anterior descending and circumflex arteries) for CCE and instrumented for measurement of LV pressure and dimension. Heart failure was elicited by daily intracoronary injections of microspheres (1.2 million, 90- to 120-microm diameter) for 24 +/- 4 days, resulting in significant depression of cardiac systolic function. After CCE, LV maximum negative change of pressure with time (dP/dt(min)) decreased by 25 +/- 2% (P < 0.05) and LV isovolumic relaxation constant and duration increased by 19 +/- 5% and 25 +/- 6%, respectively (both P < 0.05), indicating an impairment of LV active relaxation, which was cardiac preload independent. LV passive viscoelastic properties were evaluated from the LV end-diastolic pressure (EDP)-volume (EDV) relationship (EDP = be(alpha*EDV)) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient (alpha) increased by 62 +/- 10% (P < 0.05) and the stiffness constant (k) increased by 66 +/- 13% after CCE. The regional myocardial diastolic stiffness in LV anterior and posterior walls was increased by 70 +/- 25% and 63 +/- 24% (both P < 0.05), respectively, after CCE, associated with marked fibrosis, increase in collagen I and III, and enhancement of plasminogen activator inhibitor-1 (PAI-1) protein expression. Thus along with depressed LV systolic function there is significant impairment of LV diastolic relaxation and increase in chamber stiffness, with development of myocardial fibrosis and activation of PAI-1, in the canine model of CHF induced by CCE.
    AJP Heart and Circulatory Physiology 12/2006; 291(6):H3154-8. DOI:10.1152/ajpheart.00052.2006 · 4.01 Impact Factor
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    ABSTRACT: The role of the Frank-Starling mechanism in the regulation of cardiac systolic function in the ischemic failing heart was examined in conscious dogs. Left ventricular (LV) dimension, pressure and systolic function were assessed using surgically implanted instrumentations and non-invasive echocardiogram. Heart failure was induced by daily intra-coronary injections of microspheres for 3-4 weeks via implanted coronary catheters. Chronic coronary embolization resulted in a progressive dilation of the left ventricle (12+/-3%), increase in LV end-diastolic pressure (118+/-19%), depression of LV dP/dt(max) (-19+/-4%), fractional shortening (-36+/-7%), and cardiac work (-60+/-9%), and development of heart failure, while the LV contractile response to dobutamine was depressed. A brief inferior vena caval occlusion in dogs with heart failure decreased LV preload to match the levels attained in their control state and caused a further reduction of LV dP/dt(max), fractional shortening, stroke work and cardiac work. Moreover, in response to acute volume loading, the change in the LV end-diastolic dimension-pressure (DeltaLVEDD-DeltaLVEDP) curve in the failing heart became steeper and shifted significantly to the left, while the increases in LV stroke work and cardiac work were blunted. Thus, our results suggest that the Frank-Starling mechanism is exhausted in heart failure and unable to further respond to increasing volume while it plays an important compensatory role in adaptation to LV dysfunction in heart failure.
    Life Sciences 08/2006; 79(6):536-44. DOI:10.1016/j.lfs.2006.01.045 · 2.30 Impact Factor
  • Journal of Molecular and Cellular Cardiology 06/2006; 40(6):865-865. DOI:10.1016/j.yjmcc.2006.03.287 · 5.22 Impact Factor
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    ABSTRACT: The process of arteriogenesis after occlusion of a major artery is poorly understood. We have used high-resolution microcomputed tomography (mu-CT) imaging to define the arteriogenic response in the mouse model of hindlimb ischemia and to examine the effect of placental growth factor-1 (PlGF-1) on this process. After common femoral artery ligation, mu-CT imaging demonstrated formation of collateral vessels originating near the ligation site in the upper limb and connecting to the ischemic calf muscle region. Three-dimensional mu-CT and quantitative image analysis revealed changes in the number of segments and the segmental volume of vessels, ranging from 8 to 160 microm in diameter. The medium-size vessels (48 to 160 microm) comprising 85% of the vascular volume were the major contributor (188%) to the change in vascular volume in response to ischemia. Intramuscular injections of Ad-PlGF-1 significantly increased Sca1+ cells in the circulation, alpha-actin-stained vessels, and perfusion of the ischemic hindlimb. These effects were predominantly associated with an increase in vascular volume contributed by the medium-size (96 to 144 microm) vessels as determined by mu-CT. High-resolution mu-CT delineated the formation of medium-size collaterals representing a major vascular change that contributed to the restoration of vascular volume after ischemia. This effect is selectively potentiated by PlGF-1. Such selective enhancement of arteriogenesis by therapeutically administered PlGF-1 demonstrates a desirable biological activity for promoting the growth of functionally relevant vasculature.
    Circulation 06/2006; 113(20):2445-53. DOI:10.1161/CIRCULATIONAHA.105.586818 · 14.95 Impact Factor
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    ABSTRACT: Decreases in total creatine kinase (CK) activity and creatine [Cr] combine to limit the capacity of the failing heart to rapidly re-synthesize ATP (energy reserve). If the loss in energy reserve could be reversed, cardiac contractile reserve may be improved. Here we test whether these changes are reversible during recovery from heart failure. Left ventricular (LV) contractile function was measured in chronically instrumented conscious dogs with heart failure (CHF) induced by cardiac pacing for 3-4 weeks, and after recovery from heart failure (Recovery) (unpaced) for 5-6 weeks. LV contractile function and contractile reserve were depressed in CHF but returned to control in Recovery. CK capacity fell by 55% in CHF due to decreases in [Cr] (-39%) and CK activity (-25%), but was fully restored in Recovery. CK-B isozyme activity, protein (Western) and mRNA levels (real time PCR), respectively, were higher by 2-, 5.4- and 11-fold in CHF and higher by 3-, 2- and 2-fold in Recovery. CK-MM activity was decreased (-30%) in CHF but returned to normal levels during Recovery; CK-M protein was 30% lower in both CHF and Recovery even though there were no changes in mRNA levels. A similar pattern was found for mitochondrial CK (sMtCK). Deceases in CK activity and [Cr] in CHF are reversible. Decreases in CK-MM and sMtCK activities, but not the increases in CK-BB and CK-MB, also reversed. Neither the changes in protein nor mRNA levels for CK-B and CK-M correlated to their activities, suggesting that CK is under complex post-transcriptional regulation.
    Journal of Molecular and Cellular Cardiology 10/2005; 39(3):537-44. DOI:10.1016/j.yjmcc.2005.05.003 · 5.22 Impact Factor
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    ABSTRACT: We compared the cardiac inotropic, lusitropic, and chronotropic responses to the Na(+) channel enhancer LY-368052 in conscious dogs before and after development of congestive heart failure (CHF). We also examined the effect of LY-368052 on baroreflex sensitivity and the efferent neural mechanisms of the bradycardic response in heart failure. Dogs were chronically instrumented, and heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk. LY-368052 dose-dependently increased left ventricular contractile performance before and after the development of CHF to a similar extent. The inotropic effect of LY-368052 in heart failure was not altered by either ganglionic or beta-adrenergic receptor blockade. LY-368052 improved cardiac relaxation and induced bradycardia in dogs with heart failure but not in normal dogs. The negative chronotropic effect of LY-368052 was eliminated by ganglionic blockade but not beta-adrenergic blockade, suggesting that the bradycardia was mediated by the autonomic nervous system via enhanced parasympathetic tone. Baroreflex sensitivity was assessed as the pulse interval-mean arterial pressure slope in response to temporary pharmacological (nitroglycerin or phenylephrine) and mechanical (brief occlusion of inferior vena cava) alterations of arterial pressure in conscious dogs before and after development of heart failure. Baroreflex sensitivity was significantly depressed in heart failure and restored completely by acute treatment with LY-368052. Thus the Na(+) channel enhancer LY-368052 maintains its beta-receptor-independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function.
    AJP Heart and Circulatory Physiology 05/2005; 288(4):H1508-14. DOI:10.1152/ajpheart.00337.2004 · 4.01 Impact Factor
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    ABSTRACT: We compared the cardiac inotropic, chronotropic, and myocardial O(2) consumption (MVO(2)) responses to the sodium (Na(+)) channel enhancer, LY341311 [(S)-4-[3-[[1-(diphenyl-methyl)-3-azetidinyl]oxy]-2-hydroxypropoxy]-1H-indole-2-carbonitrile monohydrate], with the beta-receptor agonist dobutamine in conscious dogs with heart failure. Heart failure was induced in chronically instrumented dogs by right ventricular pacing at 240 beats per minute for 3 to 4 weeks. LY341311 (10-100 microg/kg/min i.v.) dose dependently increased cardiac contractile function as reflected, at the highest dose, by increases in left ventricular dP/dt(max) (55 +/- 7%), and fractional shortening (62 +/- 9%), accompanied by increases in cardiac stroke work (111 +/- 18%) and minute work (34 +/- 10%) and decreases in heart rate (33 +/- 4%). Dobutamine (2-15 microg/kg/min i.v.) increased contractile responses to a similar degree but also increased heart rate (15 +/- 5%) at the highest dose. Complete ganglionic blockade with hexamethonium and atropine or with hexamethonium alone abolished the bradycardic effect but not the inotropic response to LY341311. At similar levels of inotropic response, dobutamine (10 microg/kg/min) increased MVO(2) by 23 +/- 7% (P < 0.05), whereas LY341311 (100 microg/kg/min) had no effect. In the presence of left atrial pacing at a constant heart rate and at matched contractile work, MVO(2) was increased by LY341311 to the same extent as dobutamine. These data indicate that autonomically mediated bradycardia produced by LY341311 contributes to a favorable net metabolic effect on myocardial O(2) utilization in the failing heart while providing inotropic support comparable to a beta-receptor-mediated agonist.
    Journal of Pharmacology and Experimental Therapeutics 11/2002; 303(2):673-80. DOI:10.1124/jpet.303.2.673 · 3.86 Impact Factor
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    ABSTRACT: Catecholamines and many inotropic agents increase cardiac contractility but also cause excessive myocardial O2 consumption (MVO2). We determined if the novel Na+ channel enhancer LY341311, which increases myocardial contractility independent of beta receptors, can produce significant cardiac inotropic effects compared with dobutamine but at lower oxygen cost in conscious dogs. Mongrel dogs were chronically instrumented for measurement of arterial pressure, left ventricular (LV) pressure and internal diameter, coronary blood flow, and arterial and coronary sinus O2 content. Both LY341311 and dobutamine produced dose-dependent increases in LV dP/dt, dP/dt/40, fractional shortening, and cardiac stroke work and minute work estimated from the LV pressure-diameter loop. The major difference between LY341311 and dobutamine was an opposing effect on heart rate with LY341311 slightly reducing it but dobutamine markedly increasing it. LY341311 caused a significantly smaller increase in MVO2 than dobutamine (P <.05) and produced similar cardiac inotropic effects, yielding a higher cardiac mechanical efficiency than dobutamine. However, after pacing to match heart rate with dobutamine LY341311 increased MVO2 markedly, approaching the same level as with dobutamine. The novel Na+ channel enhancer LY341311 caused significant increases in myocardial contractility and contractile performance without increasing heart rate. It had a beneficial energetic effect on the heart with significantly less O2 cost and improved cardiac mechanical efficiency.
    Journal of Cardiac Failure 02/2002; 8(1):33-42. DOI:10.1054/jcaf.2002.31110 · 3.07 Impact Factor
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    ABSTRACT: Implantable ventricular cardioverter defibrillator (ICD) shocks can cause atrial fibrillation/flutter (AF). This study investigated the pathogenesis of AF after ICD shocks in a canine model. The study was conducted in 8 dogs. In 5 dogs (group 1), truncated exponential (8 ms, 78% tilt) monophasic and biphasic shocks were delivered through a bipolar epicardial (patch) or endocardial lead. After the last S1 of atrial pacing at a cycle length of 350 ms, shocks of 0.1 to 7.6 A (0.005 to 27.7 J) were delivered, timed to the atrial effective refractory period (AERP). Ventricular defibrillation thresholds were also determined. In 3 dogs (group 2), the effect of the open versus closed chest technique on AF induction was tested in the endocardial biphasic shock configuration. AF was induced in all 8 dogs and in all waveforms and configurations. Mean AF duration was 11.5+/-6 s, with a mean ventricular rate of 184+/-37 bpm. Ventricular shocks could induce AF only if they were timed between an AERP of -60 to 40 ms, -40 to 60 ms, -40 to 60 ms, and -20 to 60 ms in the epicardial monophasic, epicardial biphasic, endocardial monophasic, and endocardial biphasic configurations, respectively. The mean+/-SD of the upper limit of vulnerability (ULV) for AF induction (in J) was 5. 2+/-0.6, 3.5+/-0.4, 5.2+/-1.2, and 2.5+/-0.1 for the epicardial monophasic, epicardial biphasic, endocardial monophasic, and endocardial biphasic configurations, respectively (P<0.05). The lower limit of vulnerability (LLV) was 0.8+/-0.1, 0.8+/-0.1, 0.9+/-0, and 0.6+/-0 for the epicardial monophasic, epicardial biphasic, endocardial monophasic, and endocardial biphasic configurations, respectively (P=NS). The ventricular defibrillation threshold (in J) for all wave forms and configurations was higher than the ULV (P<0. 05). (1) An atrial LLV and ULV exist for ventricular ICD shock-induced AF; (2) the shock-induced AF is related to both shock intensity and its timing to AERP; and (3) avoiding this atrial window of vulnerability may minimize the risk of post-ICD shock AF.
    Circulation 09/1999; 100(10):1125-30. DOI:10.1161/01.CIR.100.10.1125 · 14.95 Impact Factor
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    ABSTRACT: Multiple-pathway electrode configurations generally allow improved current distribution over the heart and lower defibrillation thresholds than single-pathway systems. However, current distributions using multiple pathways are largely determined by electrode type and location. We hypothesized that switching the current among multiple pathways at high frequency (HF) could allow the switching duty cycle to control the proportion of time-averaged current flowing in each pathway, thus permitting altered (possibly improved) defibrillation efficacy using the same electrodes and shock waveform. In dogs, we measured the current (I50) for 50% defibrillation success using catheter electrodes in the right ventricular apex (cathode) and superior vena cava (A-pathway anode) and a subcutaneous patch on the left chest wall (B-pathway anode). In group 1 (N = 7), we measured I50s for shocks that used HF to proportion 10% to 90% of the current to the A-pathway. Shocks with 10% to 30% of the current in the A-pathway had significantly lowr I50s than nonproportioned shocks using all three electrodes. However, the resistance differed among single and simultaneous pathways so energy did not necessarily parallel these changes. In group 2 (N = 6), we measured I50s for shocks to the B-pathway alone, for nonproportioned shocks to A and B, and for shocks that proportioned 80% of the current to the B-pathway using either HF, sequential, or amplitude proportioning methods. All proportioning methods had similar I50s that were significantly lower than the I50 for nonproportioned shocks to A and B and that were comparable to shocks to the B-pathway alone. Shocks with most current proportioned to the B-pathway had lower defibrillation currents than nonproportioned shocks using both pathways. Thus, defibrillation efficacy was changed by HF proportioning without changing the electrodes or shock waveform. These findings suggest that HF proportioning may be a method to improve defibrillation.
    Journal of Cardiovascular Electrophysiology 04/1997; 8(3):271-80. DOI:10.1111/j.1540-8167.1997.tb00790.x · 2.88 Impact Factor
  • R M Gill, R J Sweeney, P R Reid
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    ABSTRACT: Refractory period extension (RPE) has been proposed as a basic mechanism for defibrillation but it remains unclear if RPE exists at the fast rates associated with ventricular fibrillation. In 7 pentobarbital anesthetized dogs, we measured refractory periods with and without 8 ms rectangular transcardiac shocks at left ventricular pacing rates of 200-600 beats/min. To achieve these high rates, an incremental rate pacing method was used to produce pacing train timing sequences requiring 4.5-27 seconds. A variably timed premature stimulus followed the last stimulus in each pacing train. To determine refractoriness, a 128 electrode array (4 x 4 cm) was used to detect the presence, or absence of an activation sequence sweeping away from the pacing site. At each rate, a control refractory period (RPc) was measured and refractory periods were also measured for 8 and 12 V/cm shocks with coupling intervals of 60% to 90% of RPc. RPc decreased as the rate increased with a minimum RPc of 94 ms at a rate of 600 beats/min (100 ms cycle length). RPE/RPc versus shock coupling interval was similar at all pacing rates. RPE/RPc increased with increased coupling interval or higher shock intensity. We conclude that during ventricular pacing at fibrillatory rates tissue is nearly always in a refractory state; that RPE exists at fibrillatory activation rates; and that RPE/RPc versus shock coupling interval does not vary strongly with pacing rate. These findings support the hypothesis that RPE contributes to defibrillation.
    Pacing and Clinical Electrophysiology 04/1997; 20(3 Pt 1):647-53. · 1.25 Impact Factor
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    ABSTRACT: Refractory period extension (RPE) bas been proposed as a basic mechanism for defibrillation but it remains unclear if RPE exists at the fast rates associated with ventricular fibrillation. In 7 pentobarbital anesthetized dogs, we measured refractory periods with and without 8 ms rectangular transcardiac shocks at left ventricular pacing rates of 200–600 beats/min. To achieve these high rates, an incremental rate pacing method was used to produce pacing train timing sequences requiring 4.5–27 seconds. A variably timed premature stimulus followed the last stimulus in each pacing train. To determine refractoriness, a 128 electrode arrav (4 × 4 cm) was used to detect the presence, or absence of an activation sequence sweeping away from the pacing site. At each rate, a control refractory period (RPc) was measured and refractory periods were also measured for 8 and 12 V/cm shocks with coupling intervals of 60% to 90% of RPc. RPc decreased as the rate increased with a minimum RPc of 94 ms at a rate of 600 beats/min (100 ms cycle length). RPE/RPc versus shock coupling interval was similar at all pacing rates. RPE/RPc increased with increased coupling interval or higher shock intensity. We conclude that during ventricular pacing at fibrillatory rates tissue is nearly always in a refractory state: that RPE exists at fibrillatory activation rates; and that RPE/RPc versus shock coupling interval does not vary strongly with pacing rate. These findings support the hypothesis that RPE contributes to defibrillation.
    Pacing and Clinical Electrophysiology 02/1997; 20(3):647 - 653. DOI:10.1111/j.1540-8159.1997.tb03883.x · 1.25 Impact Factor
  • R J Sweeney, R M Gill, P R Reid
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    ABSTRACT: Measurements of refractory period extension by shocks during ventricular pacing at fast rates predict that all tissue should be refractory for a brief interval after shocks during fibrillation. This study experimentally determined whether a refractory interval was present just after a shock during fibrillation. In pentobarbital-anesthetized dogs, rectangular monophasic (4-ms) or biphasic (2.5/1.5-ms) shocks were followed with a 2-ms postshock stimulus (PSS) delivered to the defibrillation electrodes. We measured the effect of PSS on the shock current (I50) required for 50% defibrillation success. In group 1 (n = 6), a 1.0-A PSS had no effect on I50 when delivered up to 35 ms after monophasic shocks but greatly increased I50 when delivered at 50 to 90 ms. A 0.5-A PSS had no effect at any timing. In group 2 (n = 6), we compared 1.0-A PSSs after monophasic and biphasic shocks. The effect of PSS after monophasic shocks was similar to group 1. After biphasic shocks, PSS at the same timings had similar effects but caused even greater increases in I50. We conclude that after both monophasic and biphasic shocks during fibrillation, there is a postshock interval during which the heart is refractory to the refibrillating effect of PSS. The interval is shorter for biphasic than for monophasic shocks with the same duration and defibrillation efficacy. These findings support the refractory period extension hypothesis for defibrillation and suggest that propagating depolarization activity is absent immediately after defibrillation shocks but that it develops again at the end of the refractory interval or later.
    Circulation 01/1997; 94(11):2947-52. DOI:10.1161/01.CIR.94.11.2947 · 14.95 Impact Factor
  • R.J. Sweeney, R.M. Gill, P.R. Reid
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    ABSTRACT: Recent studies suggest that defibrillation success is influenced by the production of new activations at (or after) the end of a post-shock refractory period. The authors examined if post-shock spatial gradients of transmembrane potential (GTMP) could serve as a possible source for electrotonically evoking post-shock activations. Previously measured action potential prolongations were used to mathematically model the post-shock recovery of tissue along a simple one-dimensional strip and to find GTMP. Following both monophasic and biphasic shocks, GTMP first increased and then decreased with time (peak at 65 to 90 ms). Peak GTMP decreased for stronger shocks and occurred earlier (/spl ap/15 ms) after biphasic shocks. These results are consistent with the effect of shock intensity and waveform on defibrillation and with the hypothesis that GTMP can cause defibrillation failure by evoking post-shock activations.
    Computers in Cardiology, 1996; 10/1996
  • RJ Sweeney, RM Gill, PR Reid
    Resuscitation 04/1996; 31(2):163. · 3.96 Impact Factor
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    ABSTRACT: Capacitor-discharge type waveforms are practical for defibrillation devices but may not be optimum. Discharging a capacitor as a series of high-frequency (HF) pulses may allow effective waveform shaping by modulating the pulses. This approach could lead to improved defibrillation by allowing waveforms that would otherwise be unachievable with a capacitor-discharge approach. However, little is known about defibrillation with HF. In open chest pentobarbital anesthetized dogs, we measured defibrillation thresholds for continuous rectangular waveforms with 5-, 10-, and 20-msec durations and for 10- and 20-msec long series of HF rectangular pulses. HF series had a 50% "on-time" duty cycle at 100 Hz to 20 kHz. At 1 kHz and above, defibrillation with HF required the same time-averaged current but approximately twice the peak current and energy as defibrillation with continuous waveforms having the same envelope duration. At lower frequencies, defibrillation peak current and energy approached values required for the continuous waveforms. While waveforms were not actually filtered, the heart responded as though the HF series were low-pass filtered. A filtered effective waveform model with a 3.7-msec time constant predicts these HF data and makes reasonable predictions for various continuous waveform shapes. Defibrillation is possible using HF pulses up to 20 kHz and has a frequency response similar to a low-pass filter. A filtered effective waveform model predicts these HF results and may help explain how waveforms influence defibrillation efficacy. While the unmodulated HF pulsing used in this study increased defibrillation requirements, these findings support the concept that HF pulse modulation can be used to change the effective shape of a waveform, which could permit more efficacious waveform shapes and a net reduction of thresholds.
    Journal of Cardiovascular Electrophysiology 03/1996; 7(2):134-43. DOI:10.1111/j.1540-8167.1996.tb00508.x · 2.88 Impact Factor
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    Journal of the American College of Cardiology 02/1996; 27(2):146-147. DOI:10.1016/S0735-1097(96)80808-4 · 15.34 Impact Factor
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    ABSTRACT: The mechanisms by which pharmacological agents alter electrical defibrillation are not fully understood. It has been proposed that, in addition to directly stimulating tissue, defibrillation may involve refractory period extension (RPE) produced by the shock. Accordingly, pharmacological agents might modulate defibrillation by altering RPE. This study examined the effect of Class I and Class III antiarrhythmic agents on RPE by transcardiac shocks. In four groups of pentobarbital anesthetized dogs, RPE was measured during rapid ventricular pacing before and after administration of either the Class I agents flecainide (n = 7) or encainide (n = 7), the Class III agent clofilium (n = 7), or vehicle (n = 5). Measurements included QRS duration during sinus rhythm and a conduction time, QTC interval and refractory period, and RPE for 4- to 10-V/cm shocks delivered 20-80 ms before the end of the tissue absolute refractory period. For the 6-V/cm shocks, the interval after the shock during which tissue remained refractory (RIAS) was also computed. Drugs affected QRS duration, conduction time, QTC, and refractory period ( without shocks) in accordance with their anticipated Class I and Class III actions. Without drugs, significant RPE was observed in all animals for all shocks delivered 40 ms or less before the end of the refractory period. Clofilium, encainide, and flecainide had a tendency to increase RPE but only clofilium produced a significant increase. For 6-V/cm shocks with different timings, the minimum RIAS was found to be approximately 43 ms, and occurred for shocks given 20-30 ms before the end of the refractory period. At drug dosages that produced moderate Class III ( approximately equal to 15%) or strong Class I (approximately equal to 35%) effects, only the Class III agent significantly increased RPE and RIAS. Thus, in addition to altering tissue excitability, the effect of antiarrhythmic agents to increase RPE and the minimum RIAS may help explain their influence on defibrillation threshold.
    Pacing and Clinical Electrophysiology 02/1996; 19(1):50-60. DOI:10.1111/j.1540-8159.1996.tb04790.x · 1.25 Impact Factor

Publication Stats

314 Citations
193.02 Total Impact Points

Institutions

  • 1995–2009
    • Eli Lilly
      • • Lilly Research Laboratories
      • • Department of Electrophysiology Research
      Indianapolis, Indiana, United States
  • 2007
    • East China Normal University
      Shanghai, Shanghai Shi, China
  • 2006
    • Columbia University
      New York, New York, United States
  • 2002
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
  • 1997
    • St. Jude Medical
      Little Canada, Minnesota, United States