The utility of ultrasound to determine ventricular capture in external cardiac pacing.

Determining electrical capture when using an external cardiac pacemaker is often difficult and confusing, especially when the resulting clinical signs of an effective blood pressure and pulse are inadequate or nondetectable. The objective of this study was to determine the efficacy of using 2-dimensional ultrasound (US) in determining the presence of ventricular capture of an external cardiac pacemaker in a swine model. Five anesthetized swine underwent external cardiac pacing (ECP) at variable levels of energy output while concurrent US images and electrocardiograph monitoring were recorded on videotape. Determinations of capture/no capture were made in the laboratory. Segments of videotape were selected to be reviewed by 2 physicians blinded to these laboratory determinations of capture and to each other. Kappa levels of agreement were determined among the 3 pairs of comparisons. Seventeen segments were reviewed. Kappa levels of agreement were 0.76 for Reviewer A versus Laboratory determination, 0.88 for Reviewer B versus Laboratory determination, and 0.88 for Reviewer A versus Reviewer B. All P values were <.001. These excellent levels of agreement show that 2D US in this animal model is highly effective in determining the presence of ventricular capture in ECP.

Endocardial activation during ventricular fibrillation in normal and failing canine hearts.

Because congestive heart failure (CHF) promotes ventricular fibrillation (VF), we compared VF in seven dogs with CHF induced by combined myocardial infarction and rapid ventricular pacing to VF in six normal dogs. A noncontact, multielectrode array balloon catheter provided full-surface real-time left ventricular (LV) endocardial electrograms and a dynamic color-coded display of endocardial activation projected onto a three-dimensional model of the LV. Fast Fourier transform (FFT) analysis of virtual electrograms showed no difference in peak or centroid frequency in CHF dogs compared with normals. The average number of simultaneous noncontiguous wavefronts present during VF was higher in normals (2.4 +/- 1.0 at 10 s of VF) than in CHF dogs (1.3 +/- 1.0, P < 0.005) and decreased in both over time. The wavefront "turnover" rate, estimated using FFT of the noncontiguous wavefront data, did not differ between normals and CHF and did not change over 5 min of VF. Thus the fundamental frequency characteristics of VF are unaltered by CHF, but dilated abnormal ventricles sustain fewer active wavefronts than do normal ventricles.

Anticoagulant use in nonvalvular atrial fibrillation. Determining risk and choosing the safest course.

Previous TIA or stroke, diabetes, advanced age, impaired left ventricular function, and a history of hypertension are strong risk factors in patients with nonvalvular AF. When none of these factors is present, aspirin in a dose of 325 mg offers effective protection against future stroke. When any of these factors are present, warfarin adjusted to an INR of 2.0 to 3.0 offers greater protection against future stroke than aspirin alone or aspirin and fixed-dose warfarin (INR 1.2-1.5). More data are needed before newer anticoagulants can be recommended for treatment.

Heart rate recovery post-exercise as an index of parasympathetic activity.

The time constant (T) obtained by fitting post-exercise heart rate (HR) recovery to a first order exponential decay curve has been promoted as an index of parasympathetic activity. However, acceptance has been limited because reported data are inadequate to assess goodness of fit for the model, determine the best exercise protocol, or optimize the duration of post exercise monitoring. Consequently, we evaluated T for nine healthy volunteers (age 24-46) following treadmill exercise at maximal (max) and two stages sub-max exercise (Bruce protocol). T stabilized only after 3 min of post-exercise monitoring. With max exercise, T varied unacceptably with small changes in onset of monitoring, e.g. -16.7+/-16.6 (-13.2%) in the first 5 s, and residuals of the fitted curve were non-random. In contrast, sub-max exercise produced consistent T values, e.g. -1.9+/-3.2 (-4.2%) in the first 5 s, and residuals were more nearly random. In conclusion, first order decay is an inadequate model for HR recovery following max exercise, but may be reasonable for sub-max levels.

Mapping of atrial activation with a noncontact, multielectrode catheter in dogs.

BACKGROUND: Endocardial mapping of sustained arrhythmias has traditionally been performed with a roving diagnostic catheter. Although this approach is adequate for many tachyarrhythmias, it has limitations. The purpose of this study was to evaluate a novel noncontact mapping system for assessing atrial tachyarrhythmias. METHODS AND RESULTS: The mapping system consists of a 9F multielectrode-array balloon catheter that has 64 active electrodes and ring electrodes for emitting a locator signal. The locator signal was used to construct a 3-dimensional right atrial map; it was independently validated and was highly accurate. Virtual electrograms were calculated at 3360 endocardial sites in the right atrium. We evaluated right atrial activation by positioning the balloon catheter in the mid right atrium via a femoral venous approach. Experiments were performed on 12 normal mongrel dogs. The mean correlation coefficient between contact and virtual electrograms was 0.80+/-0.12 during sinus rhythm. Fifty episodes of atrial flutter induced in 11 animals were evaluated. In the majority of experiments, complete or almost complete reentrant circuits could be identified within the right atrium. Mean correlation coefficient between virtual and contact electrograms was 0.85+/-0.17 in atrial flutter. One hundred fifty-six episodes of pacing-induced atrial fibrillation were evaluated in 11 animals. Several distinct patterns of right atrial activation were seen, including single-activation wave fronts and multiple simultaneous-activation wave fronts. Mean correlation coefficient between virtual and contact electrograms during atrial fibrillation was 0.81+/-0.18. The accuracy of electrogram reconstruction was lower at sites >4.0 cm from the balloon center and at sites with a high spatial complexity of electrical activation. CONCLUSIONS: This novel noncontact mapping system can evaluate conduction patterns during sinus rhythm, demonstrate reentry during atrial flutter, and describe right atrial activation during atrial fibrillation. The accuracy of electrogram reconstruction was good at sites <4.0 cm from the balloon center, and thus the system has the ability to perform high-resolution multisite mapping of atrial tachyarrhythmias in vivo.

Validation of a new noncontact catheter system for electroanatomic mapping of left ventricular endocardium.

BACKGROUND: Improvements in cardiac mapping are required to advance our understanding and treatment of arrhythmias. This study validated a new noncontact multielectrode array catheter and accompanying analysis system to provide electroanatomic mapping of the entire left ventricular (LV) endocardium during a single beat. METHODS AND RESULTS: A 9F 64-electrode balloon array catheter with an inflated size of 1.8x4.6 cm was used to simultaneously record electrical potentials generated by the heart and locate a standard electrophysiology (EP) catheter within the same chamber. By use of the recorded location of the EP-catheter tip, LV geometry was determined. Array potentials served as inputs to a high-order boundary-element method to produce 3360 potential points on the endocardial surface translatable into electrograms or color-coded activation maps. Three methods of validation were used: (1) driven electrodes in an in vitro tank were located; (2) waveforms generated from the array catheter were compared with catheter contact waveforms in canine LV; and (3) sites of local LV endocardial activation were located and marked with radiofrequency lesions. Tank testing located a driven electrode to within 2.33+/-0.44 mm. Correlation of timing and morphology of computed versus contact electrograms was 0.966. Radiofrequency lesions marked 17 endocardial pacing sites to within 4.0+/-3.2 mm. CONCLUSIONS: This new system provides anatomically accurate endocardial isopotential mapping during a single cardiac cycle. The locator component enabled placement of a separate EP catheter to any site within the mapped chamber.

Automatic capture verification by charge-neutral sensing.

Automatic capture verification can prolong pulse generator longevity and increase patient safety. However, the detection of evoked response following pacing is complicated due to afterpotentials caused by polarization of electrodes. This study describes a new capture verification scheme, which neutralizes the charges between the pacing electrodes. The hypothesis of the charge-neutral sensing is that the afterpotentials in the ring and the tip are opposite in polarity when pacing in a bipolar mode between ring and tip. Summing the unipolar signals sensed at the tip and the ring should effectively cancel the afterpotentials. This scheme was implemented in an external computer based system and tested during pacemaker implant/replacement on 23 patients during VVI pacing (17 acutely implanted leads and 6 chronic leads). Surface ECG was recorded to provide a marker for capture and noncapture. The pacing voltage was gradually decreased until a noncapture beat was noted. To avoid fusion beats, the pacing rate was programmed approximately 50% higher than the intrinsic rate. The evoked response was high pass filtered and the integral average was calculated for both capture and noncapture beats. The system signal to noise ratio (SNR) was expressed as ratio of the minimum integral average of all capture beats to the maximum integral average of all noncapture beats. The system SNR was 8.6 +/- 1.3 (mean +/- S.E.M; range 1.5-22.8), indicating that the charge-neutral sensing method has, on average, a ninefold safety margin in providing capture verification. Further, evaluation is needed to fully assess this feature in patients with chronic leads.

Electrophysiologic characteristics of a pulsed iontophoretic drug-delivery system in coronary arteries.

This study evaluated the electrophysiologic effects of a pulsed iontophoretic drug-delivery system when used in the coronary arteries. Prevention of acute thrombosis and restenosis after intravascular procedures may be enhanced by high concentrations of therapeutic agents within the vessel wall. A new intravascular drug-delivery system uses iontophoresis to maximize local tissue concentrations of drug. However, the electrophysiologic effects of such a system in coronary arteries are unknown. An iontophoretic membrane balloon-tipped catheter was placed fluoroscopically in the mid left anterior descending coronary artery of 10 anesthetized dogs. Strength-duration curves and effective refractory period (ERP) were initially determined. Threshold for capture was assessed at pulse widths of 0.5, 1.0, 2.0, 4.0, and 8.0 ms. Capture occurred at 4.9 +/- 0.9, 3.4 +/- 0.5, 2.6 +/- 0.5, 1.6 +/- 0.2, and 1.2 +/- 0.2 mA, respectively. The ERP was 169 +/- 6 ms (4.0-ms pulses at twice threshold). Then square-wave pulses for iontophoresis were R-wave synchronized and delivered at 50 and 75% of the ERP with the balloon inflated to 1 atm. Output was increased until significant arrhythmias occurred [premature beats > 10/min, supraventricular tachycardia (SVT), ventricular tachycardia (VT), ventricular fibrillation (VF)], by using sequential steps of 1, 5, 10, 15, and 20 mA. Highest average outputs achieved without an arrhythmia were 14.1 +/- 2.5 and 4.9 +/- 2.0 mA at 50 and 75% of ERP, respectively (p < 0.05). High-grade arrhythmias (pulseless VT or VF) occurred in three of four animals studied before use of a frequency limiter, which allowed current delivery only at intervals > 400 ms (thus inhibiting current activation during premature beats). No further VT or VF occurred in the remaining six animals, except for one episode of nonsustained VT (11 beats). An R-wave synchronized iontophoretic field with a response-frequency limiter can be safely used within the canine coronary arterial system at 50% of ERP with moderate outputs (5-10 mA). Increasing the stimulus duration to 75% of ERP increases arrhythmogenesis but is tolerated at lower output levels (< 5 mA).

Cardiopulmonary support mitigates the effects of experimental myocardial ischemia.

The effectiveness of cardiopulmonary support (CPS) as a rescue method following failed angioplasty is unknown. The proximal left anterior descending (LAD) was occluded for 20 min in 21 dogs. Group 1 animals (n=15) were given CPS and group 2 animals (n=6) served as controls. During coronary occlusion, animals receiving CPS had increased mean arterial pressure (71+/- 12 vs 58+/-7 mm Hg), decreased left atrial pressure (3+/-3 vs 12+/-3 mm Hg), increased ischemic area blood flow (0.20+/-0.16 vs 0.02+/-0.04 mL/min/g) and myocardial oxygen consumption (0.014+/- 0.008 vs 0.003+/-0.006 mL O2/min/g), decreased remote area myocardial oxygen consumption (0.026+/-0.010 vs 0.091+/-0.047 mL O2/min/g), and an improved myocardial oxygen consumption index (0.60+/-0.33 vs 0.02+/-0.03) when compared with controls (p<0.05). During reperfusion (no CPS), group 1 animals had increased cardiac index (210+/-95 vs 117+/-46 mL/min/kg), renal blood flow (110+/-38% vs 53+/-45%), ischemic area blood flow (1.13+/-0.40 vs 0.58+/-0.27), and myocardial oxygen consumption (0.066+/-0.015 vs 0.032+/-0.018) when compared with controls (p<0.05). CPS improves oxidative metabolism in selective myocardial segments during coronary occlusion, promotes recovery of the postischemic myocardium, and results in improved peripheral circulation.

Role of transesophageal echocardiography in the detection of left atrial thrombus in patients with chronic nonrheumatic atrial fibrillation.

Transesophageal echocardiography was used to assess cardiac abnormalities associated with embolization in patients who had completed the Department of Veterans Affairs Cooperative Study of Stroke Prevention in Nonrheumatic Atrial Fibrillation at the Minneapolis and West Haven Department of Veterans Affairs Medical Centers without an embolic event. Patients were men, 71 +/- 7 years old, with atrial fibrillation of 6.2 +/- 4.3 years' duration who had received warfarin (n = 32) or placebo (n = 23) for 2 years. Thrombi were found in 5 of 55 patients (warfarin 4 and placebo 1; p = 0.39); spontaneous echo contrast was seen in 4 of 5 patients. Other abnormalities identified included spontaneous echo contrast (47%), patent foramen ovale (54%), atrial septal aneurysm (7.3%), and left ventricular thrombus (3.6%). During 34 months of posttreatment follow-up, 5 patients had a stroke (1 fatal), and 10 died. Potential sources of emboli did not predict subsequent outcome. Thus warfarin therapy did not preclude the presence of thrombi. Stroke reduction likely involves the prevention of emboli from sources in addition to the atrial appendage.

Mildly symptomatic pulmonary emboli associated with electrophysiologic procedures. Indications for anticoagulant use.

Symptomatic pulmonary emboli complicating electrophysiologic procedures are uncommon. Asymptomatic or mildly symptomatic embolic are likely much more common. This case report highlights the problem of extensive, but mildly symptomatic, pulmonary emboli occurring as a complication of electrophysiologic procedures, including catheter ablation. The role of anticoagulation during and following electrophysiologic procedures in preventing pulmonary emboli (which can have long-term sequelae) is unknown. Currently, there appears to be no consensus regarding the use of anticoagulants either during or following electrophysiologic procedures, including those involving catheter ablation. Based on the presumed frequency and potential long-term complications of pulmonary emboli, anticoagulation during electrophysiologic procedures should be recommended.

Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators.

BACKGROUND: Nonrheumatic atrial fibrillation is common among the elderly and is associated with an increased risk of stroke. We investigated whether anticoagulation with warfarin would reduce this risk. METHODS: We conducted a randomized, double-blind, placebo-controlled study to evaluate low-intensity anticoagulation with warfarin (prothrombin-time ratio, 1.2 to 1.5) in 571 men with chronic nonrheumatic atrial fibrillation; 525 patients had not previously had a cerebral infarction, whereas 46 patients had previously had such an event. The primary end point was cerebral infarction; secondary end points were cerebral hemorrhage and death. RESULTS: Among the patients with no history of stroke, cerebral infarction occurred in 19 of the 265 patients in the placebo group during an average follow-up of 1.7 years (4.3 percent per year) and in 4 of the 260 patients in the warfarin group during an average follow-up of 1.8 years (0.9 percent per year). The reduction in risk with warfarin therapy was 0.79 (95 percent confidence interval, 0.52 to 0.90; P = 0.001). The annual event rate among the 228 patients over 70 years of age was 4.8 percent in the placebo group and 0.9 percent in the warfarin group (risk reduction, 0.79; P = 0.02). The only cerebral hemorrhage occurred in a 73-year-old patient in the warfarin group. Other major hemorrhages, all gastrointestinal, occurred in 10 patients: 4 in the placebo group, for a rate of 0.9 percent per year, and 6 in the warfarin group, for a rate of 1.3 percent per year. There were 37 deaths that were not preceded by a cerebral end point--22 in the placebo group and 15 in the warfarin group (risk reduction, 0.31; P = 0.19). Cerebral infarction was more common among patients with a history of cerebral infarction (9.3 percent per year in the placebo group and 6.1 percent per year in the warfarin group) than among those without such a history. CONCLUSIONS: Low-intensity anticoagulation with warfarin prevented cerebral infarction in patients with nonrheumatic atrial fibrillation without producing an excess risk of major hemorrhage. This benefit extended to patients over 70 years of age.

Endothelium dependent vasodilatation following brief ischaemia and reperfusion in anaesthetised swine.

STUDY OBJECTIVE: The aim as to compare the responses of intracoronary infusions of ATP, an endothelium dependent vasodilator, with adenosine following brief ischaemia (10 min) and reperfusion in a model of myocardial stunning. DESIGN: In group 1 (n = 6), coronary blood flow and endocardial (endo) and epicardial (epi) percent segment length shortening were measured in the distribution of the left anterior descending coronary artery before and during maximal intracoronary infusions of either adenosine or ATP (20 micrograms.kg-1.min-1). Measurements were obtained before and after myocardial stunning both at control heart rate and during atrial pacing (150 beats.min-1). In group 2 (n = 6), myocardial blood flows by microspheres and arterial-venous lactate and oxygen differences were determined following the same ischaemia-reperfusion protocol to characterise transmural changes in blood flow and metabolism in this model of stunning. EXPERIMENTAL MATERIAL: The experiments were done on 12 anaesthetised swine, weight 25-39 kg. MEASUREMENTS AND MAIN RESULTS: In group 1, baseline endo and epi segment length shortening were 16(SD 3)% and 14(6)% and following reperfusion were reduced to 10(4)% and 8(6)% respectively (p less than 0.05). Prior to stunning, minimal coronary resistances during adenosine and ATP were 0.81(0.40) and 0.76(0.25) mm Hg.min.ml-1 respectively and following reperfusion were 0.86(0.31) (NS) and 0.85(0.23) (NS) mm Hg.min.ml-1 respectively. Infusion of either vasodilator enhanced function by 30% following reperfusion whereas no such effect was observed prior to ischaemia. In group 2, no maldistribution of blood flow was observed following the same ischaemia-reperfusion protocol to account for this vasodilator enhancement in function. Percent lactate extraction values were 29(11)% and 25(14)% at preischaemic control and paced heart rates respectively, and following reperfusion were lowered to 0(12)% without pacing (p less than 0.05) and -1(34)% during pacing (p less than 0.05). CONCLUSIONS: Brief ischaemia and reperfusion in swine induces myocardial stunning without altering the vasodilator responses of either ATP, an endothelium dependent vasodilator, or adenosine. Recruitment in postischaemic segment length shortening was observed during infusions of both vasodilators at a time when maldistribution of flow was not observed. Possible mechanisms include either enhanced washout of lactate from the reperfused myocardium or greater utilisation of substrates during higher blood flows.

Usefulness of disopyramide for prevention of upright tilt-induced hypotension-bradycardia.

Susceptibility to transient hypotension-bradycardia of neurally mediated origin has been attributed in part to accentuated afferent neural traffic arising from cardiopulmonary mechanoreceptors, and consequently, may be diminished by agents with anticholinergic and negative inotropic effects, such as disopyramide phosphate. This study assessed electrocardiographic and hemodynamic responses to upright tilt testing (alone or during isoproterenol infusion) before and after disopyramide therapy in 10 patients (age range 16 to 74 years) with recurrent syncopal episodes of neurally mediated origin. Untreated, syncope occurred at less than or equal to 7 minutes of tilt alone (6 patients) or tilt plus isoproterenol at less than or equal to 3 micrograms/min (4 patients) and was associated with hypotension (mean arterial pressure, 40 +/- 16 mm Hg vs baseline 76 +/- 10 mm Hg, p less than 0.001) and inappropriate heart rate slowing (mean heart rate, 59 +/- 39 beats/min vs baseline 88 +/- 18 beats/min, p less than 0.005). After oral disopyramide 150 mg 3 times daily (mean plasma level, 3.0 +/- 0.64 micrograms/ml), all patients tolerated 10 minutes of both tilt and tilt plus isoproterenol (maximum dose, 3 micrograms/min) without symptoms, hypotension (mean arterial pressure; tilt 1 min, 79 +/- 7 mm Hg vs tilt 10 min, 77 +/- 8 mm Hg, difference not significant) or bradycardia (mean heart rate; tilt 1 min, 81 +/- 12 beats/min vs tilt 10 min, 83 +/- 11 beats/min, difference not significant). Furthermore, during subsequent 20 +/- 5 months of disopyramide therapy, all but 1 patient remain asymptomatic. Thus, oral disopyramide may be effective for preventing inducible and spontaneous neurally mediated syncope.

Timing and magnitude of serum creatine kinase-MB after transcatheter cardiac tissue fulguration in man.

This study examined the impact of transcatheter fulguration on creatine kinase-MB release in 21 patients (age range 17-71 years). Arrhythmia diagnoses were ventricular tachycardia 9, atrial fibrillation with a rapid ventricular response 7, atrioventricular nodal reentry 2, and reciprocating tachycardia utilizing a posteroseptal accessory pathway 3. Seven patients had apparently normal hearts while 8 had ischemic heart disease and 6 cardiomyopathy. Timing of initial elevated creatine kinase-MB activity (mean 1.34 +/- 0.69 SD hours) and peak creatine kinase-MB activity (mean 3.73 +/- 0.89 SD hours) was relatively uniform in all patients. Time to peak creatine kinase-MB activity was unrelated to either underlying cardiac disease (normal: 3.9 +/- 1.0 hours; ischemic heart disease: 3.5 +/- 0.9 hours; cardiomyopathy: 3.8 +/- 0.9 hours), or fulguration site (His bundle (n = 9): 4.2 +/- 0.9 hours, proximal coronary sinus (n = 3): 3.3 +/- 0.3 hours, ventricle (n = 9): 3.4 +/- 0.8 hours). The magnitude of peak serum creatine kinase-MB activity was independent of myocardial diagnosis or fulguration site, but was linearly related to total energy delivered (r = 0.5, P less than 0.022). The latter correlation was particularly strong within cardiac diagnosis subgroups (normal: r = 0.92, P less than 0.002; ischemic heart disease: 0.73, P less than 0.04; non-ischemic cardiomyopathy: r = 0.57, P = NS). Thus, serum creatine kinase-MB activity following transcatheter fulguration is linearly related to the magnitude of delivered energy, and is similar to that observed after transient coronary artery occlusion and reperfusion.

Cardiac asystole: a manifestation of neurally mediated hypotension-bradycardia.

It has been proposed that prolonged cardiac asystole mimicking an episode of sudden cardiac death may occur as a manifestation of neurally mediated hypotension-bradycardia syndrome. To assess this possibility, electrocardiographic and hemodynamic findings during upright tilt testing were evaluated in six survivors of suspected asystolic sudden cardiac arrest with normal conventional electrophysiologic evaluation (Group I). These observations were compared with findings in two control groups: six patients with syncope but without evident asystole and with normal conventional electrophysiologic evaluation but demonstrable neurally mediated hypotension-bradycardia (Group II), and six patients with syncope in whom conventional electrophysiologic evaluation provided a presumptive diagnosis (Group III). Patients in all three groups ranged in age from 16 to 59 years. During head-up tilt testing (either alone or with isoproterenol infusion), patients in both Groups I and II developed syncope in less than or equal to 5 min, whereas patients in Group III remained asymptomatic. Patients in Groups I and II exhibited a similar tilt-induced decrease in mean arterial pressure (-46 +/- 9 and -40 +/- 9 mm Hg, respectively, p = NS) and heart rate (-44 +/- 28 and -49 +/- 12 beats/min, respectively, p = NS). In contrast, patients in Group III manifested only a moderate decrease in mean arterial pressure (-14 +/- 5 mm Hg) and had an increase in heart rate (+14 +/- 8 beats/min). Both mean arterial pressure and heart rate changes in Group I and Group II patients differed significantly (p less than 0.001) from values in Group III patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological effects of left ventricular free wall traction in intact hearts.

Transmural multipolar electrodes, sonomicrometers implanted within the left ventricular wall, and cardiac electrical stimulation techniques were used to examine the effect of transient mechanically applied traction to the left ventricular free wall on local electrophysiological properties. Twenty-five open-chest dogs were atrially paced (cycle length 400 ms) followed by insertion of timed premature extrastimuli at left ventricular epicardial pacing sites either in the vicinity of (traction zone) or remote from (nontraction-control zone) the site of left ventricular free wall traction. Electrophysiological recordings were made before and during intermittent left ventricular free wall traction applied in late diastole (rate 25 cm/s; duration 170 ms). In 22 of 25 dogs, application of traction resulted in early local ventricular activation (mean activation advancement 64 +/- 15 ms), altered QRS morphology of the last conducted atrial drive train beat, and a relative prolongation of ventricular refractoriness in the traction zone. Conversely, in the nontraction-control zone, early activation did not occur and refractoriness was unchanged. Alterations in regional myocardial blood flow (assessed by microsphere technique) did not appear responsible for the observed changes. Furthermore, phenol interruption of local sympathetic or combined sympathetic and parasympathetic innervation or verapamil pretreatment had no impact on the mechanically induced electrophysiological changes. Thus, in normal myocardium in situ, regional abnormalities in wall motion may be associated with alterations of local ventricular activation and refractoriness, factors that in the diseased heart could lead to increased susceptibility to arrhythmias.

Cardiac electrophysiologic effects of orally administered DPI 201-106 in conscious canines: effects of pharmacologic autonomic blockade or cardiac transplantation.

This study assessed the cardiac electrophysiologic effects of DPI 201-106 (DPI), a novel orally absorbable positive inotropic agent, the administration of which has been associated with electrocardiographic (ECG) QT and T-wave changes. In the intact conscious dog, oral administration of both 8 and 16 mg/kg DPI produced marked sinus cycle length prolongation (8 mg/kg, + 11%; 16 mg/kg, + 9%) within 60 min of DPI administration (p less than 0.05 vs. baseline). DPI also tended to prolong right atrial refractory periods, and increase sinus node recovery time. In addition, DPI exhibited a negative dromotropic effect on the atrioventricular (AV) node, prolonging both AV node effective and functional refractory periods and tending to increase the minimum atrial paced cycle length at which AV conduction of 1:1 was maintained. DPI also significantly increased right ventricular effective refractory period (ERP) at both doses studied and increased ventricular functional refractory period (FRP) at the 16-mg/kg dose. Finally, although DPI administration was associated with QT interval prolongation, this effect was slight when corrected for sinus cycle length (SCL) (QTc, +3%). When administered concomitantly with propranolol and atropine or after surgical cardiac denervation, DPI-induced electrophysiologic changes were largely attenuated or abolished. Thus, findings in this study indicate that the apparent cardiac electrophysiologic effects of DPI are predominantly of neurally mediated origin in this animal model.