Cessation Of Pacing Research Articles

Long-term effect of VVI pacing on atrial and ventricular function in patients with sick sinus syndrome.

We conducted a prospective, 6-month echocardiographic study on the effect of VVI pacing on left atrial and ventricular function and dimensions in patients with sick sinus syndrome. Thirty-nine patients (23 women and 16 men, aged 71 +/- 9.2 years; 30 in sinus rhythm and 9 in atrial fibrillation) who had a VVI pacemaker implanted because of sick sinus syndrome were recruited in the study. In 26 patients who presented with and remained in sinus rhythm, paced left ventricular ejection fraction and stroke volume were significantly decreased (71.4% +/- 11.8% to 67.0% +/- 13.6%, and 73.9 +/- 29.0 cm3 to 66.3 +/- 21.1 cm3, respectively, P < 0.001 for both), whereas the paced diastolic dimension of the left atrium was significantly increased (3.2 +/- 0.7 cm to 3.7 +/- 0.9 cm, P < 0.001) at 6 months as compared with preimplantation. In nine patients with atrial fibrillation at implantation paced left ventricular ejection fraction at follow-up was significantly decreased (67.7% +/- 10.1% to 64.2% +/- 10.6%, P =0.003), but paced stroke volume and left atrial diastolic dimension were not significantly changed (75.1 +/- 25.6 cm3 to 79.0 +/- 22.7 cm3, and 4.3 +/- 1.2 cm to 4.6 +/- 1.5 cm, P = NS for both) at follow-up. Cessation of pacing and restoration of sinus rhythm in 21 patients at follow-up did not result in any significant change of ejection fraction (67.5% +/- 10.2% ti 67.6% +/- 9.7%, P = NS) whereas stroke volume was increased (59.1 +/- 19.6 cm3 to 69.1 +/- 22.3 cm3, P < 0.0001) in comparison with paced values. However, compared with preimplantation values, ejection fraction was significantly decreased (70.4% +/- 10.0% to 67.6% +/- 9.7%, P = 0.001), whereas stroke volume was not significantly changed (68.4 +/- 22.3 cm3 to 69.1 +/- 22.3 cm3, P = NS) during sinus rhythm at follow-up. In 14 of those patients, discontinuation of pacing resulted in a significant increase of left atrial fractional shortening (8.1% +/- 1.7% to 20.1% +/- 4.3%, P < 0.001) and significant increase of left atrial diastolic dimension compared with paced and preimplantation levels (3.8 +/- 0.7 cm vs 3.6 +/- 0.7 cm and 3.0 +/- 0.5 cm, respectively, P < 0.001). Long-term VVI pacing in patients with sick sinus syndrome results in increase of the left ventricular end-systolic dimension and permanent reduction of the left ventricular ejection fraction. In the left atrium, VVI pacing causes an immediate reduction of the fractional shortening as well as long-term increase of the diastolic dimension.

Relation Between QT Dispersion and the Extent of Myocardial Ischemia in Patients With Three-Vessel Coronary Artery Disease

The aim of the study was to examine the relation between the extent of myocardial ischemia and changes in QT interval dispersion in patients with obstructive coronary artery disease and in patients with normal coronary arteries. QT interval dispersion reflects regional variations in ventricular repolarization and cardiac electrical instability. Previous studies showed QT interval dispersion changes during episodes of myocardial ischemia in patients with coronary artery disease, but no data on the relation between extent of myocardial ischemia and degree of QT interval dispersion changes are available. To assess the effects of myocardial ischemia on myocardial repolarization by analyzing the change in QT dispersion during incremental atrial pacing, we studied 33 patients (7 women and 26 men, mean age 60.1 ± 5.1 years, 18 patients with normal coronary arteries, 15 patients with coronary 3-vessel disease). QT dispersion was measured at baseline, after each pacing period, within 30 seconds after cessation of pacing (“peak ischemic stress”), and at 1-minute intervals for up to 5 minutes. Paired blood samples for determination of serum lactate were withdrawn from the coronary sinus and radial artery to determine the cardiac lactate extraction ratio at each point of electrocardiographic registration. In patients with coronary artery disease, QT dispersion increased from a baseline value of 39 ± 7 ms to a peak ischemic stress value of 63 ± 10 ms (p <0.0001). Patients with normal coronary arteries showed almost unchanged values of QT dispersion (41 ± 9 vs 42 ± 7 ms). There was a significant relation between the pacing-induced change in QT dispersion and the induced change in myocardial lactate extraction ratio (r = 0.76, p <0.0001). The change in QT dispersion (baseline vs peak pacing stress) was related to the extent of the cardiac lactate extraction ratio (r = −0.79, p <0.0001). These data indicate that the severity or extent of induced myocardial ischemia was related to the degree of induced changes of the variability in the timing of the ventricular recovery pattern.

Pacing-induced Atrial Electrical Remodeling and its Recovery in Conscious Dog Atria

Background:Pacing-induced atrial electrical remodeling (AER is characterized by shortening of atrial effective refractory period (A-ERP and its altered rate adaptation. In paroxysmal atrial fibrillation (AF, periods of AF occur with interveneing normal sinus rhythm (NSR when atria recover from the preceding AER. Previous episodes of AF may precondition the atrial myocardium and cause different time course of AER in subsequent episodes of AF. But the influence of the preceding AER on the subsequent AER has not been described. Methods:Four mongrel dogs were anesthetized with enflurane. After thoracotomy, silicon band with 3 pairs of electrodes was sutured to the lateral wall of the left atrium. Atrial pacing was performed after 2 wks of recovery and autonomic blockade. Pacing protocol consisted of rapid atrial pacing (RAP at 500 bpm (for 60 min and recovery in NSR (for 60 min which was repeated three times. A-ERP was measured every 10 min. The same pacing protocol was repeated after pretreatment with verapamil (0.1 mg/kg/hr). Results:1 With 60 min of RAP, A-ERP decreased significantly (126±6 ms vs. 105±7 ms, p<0.005. 2 After cessation of pacing, A-ERP returned to 98% of baseline value in 15 minutes. Recovery from AER occurred faster than AER (78 vs 21 ms/h. 3 After pretreatment with verapamil, RAP decreased A-ERP from 127±5 ms to 116±5 ms. AER, the reduction in A-ERP, was significantly attenuated by pretreatment with verapamil (ΔERP=17±7 vs. 9±0.2 %, p<0.05. 4 When RAPs were repeated, AER showed a tendency of acceleration, but it was not statistically significant (ΔERP=22 ms, 24 ms, 28 ms at the end of 60 min pacing for the 1 st , 2 nd , 3 rd pacing. Conclusion:RAP induced AER in conscious dog atria and it was reduced by pretreatment with calcium channel blocking agent, verapamil. Upon repeated atrial stimulations, AER did not accelerate or decelerate when the atria recovered from the preceding AER. (Korean Circulation J 1998;28(6 :961-969

Myocardial ischemia in generalized coronary artery–left ventricular microfistulae

Generalized (multiple) arterio-systemic fistulae are fistulae arising from all three major coronary arteries and drain into the left ventricle are rare and the clinical and hemodynamic sequelae are incompletely understood. This communication is based on the clinical and hemodynamic data of a series of patients (eight cases out of 7 262 consecutive patients) incidentally identified at coronary angiography combined with data from cases previously reported in literature. The aim was to assess the role of generalized coronary artery fistulae as a non-atherosclerotic cause of myocardial ischemia by means of a coronary sinus lactate study. Coronary sinus lactate study demonstrated myocardial ischemia in 6/7 patients. Mean arterio-coronary venous lactate difference decreased from 0.31±0.18 mmol/l (lactate extraction ratio, LER, 29.4±13.9%) at rest to 0.04±0.13 mmol/l (LER –4.0±13.3%) at peak exercise. Five minutes after cessation of pacing, lactate difference increased to 0.22±0.21 mmol/l (LER – 20.7±13.2%). At peak pacing stress, 4/7 patients showed frank lactate production, and two patients presented with a reduced cardiac lactate extraction rate also indicating myocardial ischemia metabolically. In the present study, we demonstrated a possible role of a coronary steal mechanism due to microfistulae pathways in the pathogenesis of myocardial ischemia in patients with generalized coronary artery–left ventricular microfistulae.

Cardiac Release and Kinetics of Endothelin After Severe Short-Lasting Myocardial Ischemia

Objectives. The aim of this study was to investigate the release kinetics of endothelin after induced short-lasting myocardial ischemia.Background. Endothelin is an endothelium-derived vasoactive peptide. Unequivocal proof of its cardiac release in ischemic syndromes has not yet been demonstrated.Methods. A coronary sinus study with atrial pacing was performed in 23 patients with coronary artery disease. Endothelin (ET), cardiac troponin-T (TnT), myoglobin (Mb) and creatine kinase (CK) samples were withdrawn from the coronary sinus and a peripheral vein before and 1, 5, 10, 30 and 45 min and 1, 2, 3 and 6 h after pacing. The appearance of angina pectoris, abnormal cardiac lactate metabolism and ST segment depression were further criteria for myocardial ischemia.Results. In the study group, pacing stress induced severe ischemia (mean duration ± SD 6.1 ± 1.2 min), with a maximum of 0.34 ± 0.12-mV ST segment depression in 21 of 23 patients and angina pectoris in 22 of 23. The maximal cardiac lactate production was 42.8 ± 17.3% (p < 0.03). TnT and CK levels in the total group were normal; in 14 of 23 patients a transient elevation of Mb with a maximum after 3 h was detected (86.4 ± 27.1 μg/liter, p < 0.03). The ET concentrations increased significantly (p < 0.001) in the coronary sinus (from 4.6 ± 0.8 [baseline] to 12.9 ± 2.7 pg/ml at 1 min after cessation of pacing) and the peripheral vein, respectively (from 4.7 ± 0.7 [baseline] to 8.3 ± 2.1 pg/ml at 1 min). ET further remained elevated for 1 h with persisting higher coronary sinus than peripheral venous concentrations, indicating cardiac ET release. In a control group of 18 patients without heart disease, all variables were unchanged.Conclusions. Short-lasting severe myocardial ischemia was associated with significant ET release of cardiac origin that lasted up to 1 h.

Intracellular Ca2+ handling and vulnerability to ventricular fibrillation in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) with ventricular hypertrophy show an increased vulnerability for the development of potentially lethal ventricular arrhythmias such as ventricular fibrillation (VF). The mechanisms of this increased vulnerability are not fully understood but may be related to abnormal intracellular Ca2+ ([Ca2+]i) handling under stress conditions. We therefore investigated whether [Ca2+]i handling is abnormal in hypertrophied hearts of SHR without heart failure during stimulation stress, and if so whether abnormal [Ca2+]i handling is a determinant of the increased vulnerability to VF in SHR. [Ca2+]i was measured by indo-1 surface fluorescence in perfused hearts of 8- to 10-month-old control Wistar-Kyoto rats (WKY) and age-matched SHR. The state of [Ca2+]i handling was analyzed during three different forms of stimulation stress: rapid pacing, the long rest period after cessation of rapid pacing, and preprogrammed ventricular stimulation that was simultaneously used for the determination of VF threshold. The pulse number VF threshold was used as an index to determine vulnerability to VF and to analyze the relationship of [Ca2+]i handling to vulnerability. Although VF thresholds were lower in SHR than in WKY, we found that both demonstrated similar [Ca2+]i handling during stimulation stress. The extent and rate of [Ca2+]i accumulation during rapid pacing and those of the [Ca2+]i decline after cessation of pacing were similar in SHR and WKY. In addition, the relationship between [Ca2+]i and VF threshold was unaltered in SHR. Thus, we conclude that [Ca2+]i handling is normal in hypertrophied hearts of SHR without heart failure during stimulation stress and that it is not a determinant of the increased vulnerability to VF in SHR.

Left atrial systolic and diastolic function after cessation of pacing in tachycardia-induced heart failure.

Studies in the rapid-pacing model of heart failure have shown that left ventricular (LV) systolic function normalizes on cessation of pacing and LV diastolic dysfunction persists, but there is no information regarding atrial function under these conditions. To determine the effects of cessation of pacing on left atrial (LA) systolic and diastolic function, ten dogs with rapid pacing-induced heart failure (250 beats/min for 3-4 wk), six dogs with regression of heart failure (4 wk after cessation of rapid pacing), and seven control dogs were instrumented with LA sonomicrometers and micromanometers. At matched LA pressure, LA ejection (10.2 +/- 3.0 vs. 17.4 +/- 5.5%), reservoir volume fractions (19 +/- 8 vs. 35 +/- 11%), and heart rate-corrected mean normalized systolic ejection rate (1.25 +/- 0.33 vs. 1.60 +/- 0.44 EF/s) were significantly less, and the volume-normalized diastolic stiffness constant (4.9 +/- 0.8 vs. 3.2 +/- 1.1) was significantly greater, in regression versus control dogs; these changes were associated with incomplete regression of LA hypertrophy and a persistent 77.4% increase in beta-myosin heavy chain (beta-MHC) in the LA body. LV systolic function and weight were not significantly different, whereas the time constant of LV relaxation was longer (52.5 +/- 4.4 vs. 40.8 +/- 7.6 ms; P < 0.05) and LV end-diastolic pressure was greater (12.2 +/- 1.8 vs. 7.1 +/- 2.0 mmHg; P < 0.05) in regression compared with control dogs. Thus, unlike the normalization of LV systolic function observed with cessation of rapid pacing, LA systolic function is persistently abnormal, owing in part to persistent LV diastolic dysfunction, residual LA hypertrophy, and MHC isoform switches.

What Can We Learn from Provoking Ischemia?

What Can We Learn from Provoking Ischemia?

Rapid Atrial Pacing for Detecting Provokable Demand Ischemia in Anesthetized Patients

A stress test that can be performed intraoperatively might be valuable for cardiac risk stratification in patients needing urgent noncardiac surgery and for early evaluation of coronary reserve in patients undergoing aortocoronary bypass surgery.Therefore, we evaluated the sensitivity and safety of rapid atrial pacing combined with electrocardiography and transesophageal echocardiography for inducing and detecting provokable demand ischemia in 20 anesthetized patients with multivessel coronary artery disease. Rapid atrial pacing induced ST segment changes or new segmental wall motion abnormalities (SWMA), which were defined as evidence of induced ischemia in 15 of the 20 patients. Unexpectedly, the new SWMA normalized during the first beat after abrupt cessation of pacing in three patients who did not show any ST segment changes. Simultaneously, left ventricular preload was severely decreased during pacing and recovered to baseline immediately when pacing was abruptly discontinued. Rapid atrial pacing was safe in all patients, but the target heart rate could not be achieved because of heart block or arterial hypotension in 4 of the 20 patients. These findings raise the question of whether rapid atrial pacing is the most appropriate approach for inducing provokable demand ischemia in anesthetized patients. However, its potential usefulness for predicting adverse cardiac outcomes has not been evaluated and would require larger studies. In addition, the immediate normalization of new SWMA after abrupt cessation of pacing in some patients calls into question the validity of new SWMA as evidence of myocardial ischemia when left ventricular preload is severely decreased. (Anesth Analg 1997;84:1180-5)

Verapamil reduces tachycardia-induced electrical remodeling of the atria.

Prolonged periods of atrial fibrillation or rapid atrial pacing induce shortening of the atrial effective refractory period (AERP), which is thought to be related to the lower success rates of various antifibrillatory treatments when the arrhythmia has lasted for a longer period of time. To investigate whether an increase in intracellular calcium could be the stimulus for electrical remodeling, the effects of verapamil on shortening of the AERP in response to 24 hours of rapid atrial pacing (300 bpm) were studied in five chronically instrumented conscious goats during infusion of saline or verapamil. During rapid atrial pacing, the ventricular rate was kept constant by ventricular pacing (150 bpm). The AERP was measured by programmed electrical stimulation at basic cycle lengths of 430, 300, and 200 ms. Verapamil had no effects on the AERP before rapid atrial pacing. However, in the course of 24 hours of rapid atrial pacing, the AERP shortened significantly less (27% to 58%) in the presence of verapamil compared with control (at 430, 300, and 200 ms, P < .001, P < .01, and P < .01, respectively). Also, after cessation of pacing, complete recovery of the AERP during verapamil infusion occurred much sooner than in the control experiments. Despite a significant reduction in electrical remodeling, there was only a minimal reduction in inducibility of atrial fibrillation by verapamil (34% versus 39% in the control experiments, P = .03). Electrical remodeling of the atrium during rapid atrial pacing was significantly attenuated by verapamil. This suggests that electrical remodeling of the atrium is triggered by the high calcium influx during rapid atrial pacing rates.

Atrial flutter: entrainment characteristics.

Entrainment was first described based on observations during rapid (overdrive) pacing of type I atrial flutter. Entrainment is capture of the reentrant circuit of a tachycardia without interrupting the tachycardia, so that with cessation of pacing, the spontaneous reentrant tachycardia is still present. During entrainment, the orthodromic wavefront from the pacing impulse resets the tachycardia to the pacing rate, while the antidromic wavefront either collides with the orthodromic wavefront of the previous beat (usual case) or is blocked by some other mechanism (refractoriness or another cause of block). Entrainment may be either manifest or concealed. The principles of entrainment during type I atrial flutter have permitted identification of targets for successful ablation, of mapping sites within or outside the reentrant circuit, and of appropriate pacing rates to successfully interrupt atrial flutter and restore sinus rhythm.

The delayed recovery of impaired endothelium-dependent vasodilatory response after hemodynamic improvement in dogs with congestive heart failure.

We investigated whether impaired endothelium-dependent vasodilatory response recovers as heart failure improves. The femoral blood flow responses to intra-arterial administration of nitroglycerin (NTG) and acetylcholine (ACh) were examined in dogs with 2-week pacing-induced chronic congestive heart failure (congestive heart failure group; CHF, n = 12). Thereafter, pacing was stopped and hemodynamic changes and femoral blood flow responses were re-examined either 1 week (recover 1 week group; Re 1W, n = 6) or 4 weeks (recover 4 weeks group; Re 4W, n = 6) after the cessation of pacing. Another group in which a pacemaker was implanted without pacing served as the control group (n = 8). In CHF, heart rate and pulmonary artery pressure increased, and echocardiography revealed increased left ventricular diastolic dimension and reduced percent fractional shortening compared with those in the control group. In Re 1W, all hemodynamic parameters returned to the basal levels and did not differ from those in the control group. Although there was no significant difference in the blood flow responses to NTG among the 4 groups, the responses to ACh in CHF were significantly reduced compared with those in the control group. Despite the recovered hemodynamics, femoral blood flow responses to ACh were still reduced in Re 1W, but they returned to the levels of the control group in Re 4W. Thus, vascular endothelial dysfunction recovers along with improvement in CHF, however, the recovery of endothelial function is delayed in comparison with improvement in cardiac function.

Time course of lysophosphatidylcholine release from ischemic human myocardium parallels the time course of early ischemic ventricular arrhythmia.

We determined the kinetics of the release of lysophosphatidylcholine (LPC) into the coronary sinus of patients undergoing stress tests after coronary artery bypass grafting. The kinetics were consistent with a role for this amphiphile in the pathogenesis of ischemic ventricular arrhythmia, a major cause of sudden death. Stress testing was initiated in the operating suite by pacing at a rate of 160 beats/min for 2 min. Ischemia was then induced by clamping the bypass grafts to the anterior wall for a maximal time of 4 min. The pacing procedure induced a prompt but reversible increase in coronary sinus LPC concentration from a baseline of 60.9 +/- 2.5 to 83.8 +/- 5.0 mumol/l via pacing alone, and a further increase to 101.8 +/- 6.7 mumol/l when the grafts were clamped for 2 min (P < 0.01). Six minutes after the cessation of pacing, LPC concentration returned to 67.5 +/- 4.4 mumol/l. These results demonstrate that severe myocardial ischemia is an agonist for rapid release of LPC from the myocardium. Kinetics of this release paralleled the time-course of early onset of electrophysiologic changes in isolated myocytes and perfused heart preparations in vitro. These results indicate that LPC may have an important role in the pathogenesis of ischemic ventricular arrhythmia in patients.

Tachycardia induced cardiomyopathy in dogs; relation between chronic supraventricular and chronic ventricular tachycardia

Long-standing ventricular tachycardia (VT) and supraventricular tachycardia (SVT) can produce a reversible left ventricular dysfunction. The onset of cardiomyopathy and the severity of posttachycardic changes depend at least on three parameters of tachycardia, including its type (VT or SVT), rate and duration. Ten dogs (beagles) were paced at 180 beats/min for 3 weeks. Two pacing modalities, supraventricular and ventricular, were used in each dog. In half of them, the study was started by ventricular, and in the other half by supraventricular high-rate pacing. The alternate pacing modality was applied after complete recovery of left ventricular function. Ventricular function and morphology were evaluated by radionuclide ventriculography, echocardiography and Swan-Ganz catheterisation. Posttachycardic changes were studied in sinus rhythm after cessation of pacing. Left ventricular ejection fraction (LVEF) fell significantly after either type of tachycardia (SVT: 53 ± 5%, VT: 48 ± 7%, P < 0.05) compared with baseline values (69.5 ± 2.3%). Significant increases ( P < 0.05) in end-systolic (SVT: 2.1 ± 0.3 cm, VT: 2.4 ± 0.2 cm vs. 1.6 ± 0.3 cm) and end-diastolic dimensions (SVT: 3.0 ± 0.3 cm, VT: 3.3 ± 0.4 cm vs. 2.7 ± 0.3 cm) indicated ventricular dilation in paced animals. Left ventricular pulmonary capillary wedge pressure increased significantly after either type of tachycardia as compared with baseline values (SVT: 7.5 ± 1.2 mmHg, VT: 8.4 ± 1.1 mmHg vs. 1.9 ± 1.5 mmHg, P < 0.05); the difference between tachycardias was not significant. The present study demonstrates that chronic SVT and VT result in left ventricular dysfunction in a relatively short time, even if the heart rate is not very high. Deterioration of left ventricular ejection fraction and dilation of the left ventricle are more marked in chronic VT than in chronic SVT.

Triggered activity as a mechanism for inherited ventricular arrhythmias in German shepherd dogs

Objectives.This study sought to determine whether early after-depolarization-induced triggered activity is responsible for the initiation of ventricular arrythmias in dogs with an inherited predisposition to sudden death.Background.We have identified a colony of German shephered dogs that display inherited ventricular ectopic activity and sudden cardiac death. The arrhythmias in these animals are pause dependent but are not associated with a prolonged QT interval, suggesting that they might be initiated by early afterdepolarization-induced triggered activity in Purkinje fibers.Methods.Cardiac Purkinje fibers obtained from dogs that either did or did not exhibit ventricular tachyarrhythmias at the time of study were superfused in vitro with normal. Tyrode solution (extracellular potassium ion concentration 4 mmol/liter) and were studied using standard microelectrode techniques.Results.Early afterdepolarizations and triggered activity occurred spontaneously in Purkinje fibers obtained from affected dogs (n = 7) but not in fibers obtained from unaffected dogs (n = 13). Exit conduction block of triggered responses occurred to varying degrees within the Purkinje fiber but not at the Purkinje-muscle junction. Overdrive pacing suppressed triggered activity. The reemergence of triggered activity after cessation of pacing was both time and rate dependent. Triggered activity in fibers obtained from affected dogs was potentiated by phenylephrine and epinephrine and was suppressed by isoproterenol. Triggered activity was not induced by phenylephrine or epinephrine in fibers obtained from unaffected dogs.Conclusions.These results support the hypothesis that early afterdepolarization-induced triggered activity in Purkinje fibers is responsible for the initiation of ventricular arrhythmias in this canine model of inherited sudden death.

Rapid ventricular pacing produces myocardial protection by nonischemic activation of KATP+ channels.

Rapid ventricular pacing reduces the incidence of ventricular arrhythmias during a subsequent sustained period of ischemia and reperfusion. We investigated whether rapid ventricular pacing also limits myocardial infarction and determined the role of KATP+ channels in the protection afforded by ventricular pacing. Myocardial infarction was produced by a 60-minute coronary artery occlusion in open chest pigs. Infarct size of pigs subjected to 10 minutes of ventricular pacing at 200 beats per minute followed by 15 minutes of normal sinus rhythm before the occlusion (79 +/- 3% of the area at risk, mean +/- SEM) was not different from control infarct size (84 +/- 2%). Thirty-minute pacing followed by 15-minute sinus rhythm resulted in modest reductions in infarct size (71 +/- 2%, P<.05 versus control). Thirty minutes of pacing immediately preceding the occlusion without intervening sinus rhythm resulted in considerable limitation of infarct size (63 +/- 4%, P<.05), which was abolished by pretreatment with the KATP+ channel blocker glibenclamide (78 +/- 4%, P=NS). KATP+ channel activation did not appear to involve ischemia: (1) myocardial endocardial/epicardial blood flow ratio was 1.07 +/- 0.08, (2) phosphocreatine and ATP levels and arterial-coronary venous differences in pH and PCO2 were unchanged, (3) end-systolic segment length did not increase and postsystolic shortening was not observed during pacing, and (4) systolic shortening recovered immediately to baseline levels and coronary reactive hyperemia was absent after cessation of pacing. Administration of glibenclamide after 30 minutes of pacing at the onset of 15 minutes of normal sinus rhythm did not attenuate the protection (73 +/- 3%, P<.05 versus control), suggesting the KATP+ channels did not contribute to the moderate degree of protection that was still present 15 minutes after cessation of pacing. Rapid ventricular pacing protects the myocardium against infarction via nonischemic KATP+ channel activation. Continued activation of KATP+ channels does not appear mandatory for the protection that is still present 15 minutes after cessation of pacing.

Animal models of heart failure for pharmacological studies.

1. Animals for the study of congestive heart failure (HF) should have chronic, stable disease produced by methods which allow controllable damage and hence predictable disease severity. 2. Pressure and volume loading have commonly been used in the past but these methods are limited by the difficulty of controlling the disease severity. 3. HF induced by cardiotoxic agents, particularly doxorubicin, has been widely used for experimental purposes, but again, control of the degree of damage may be difficult. 4. Coronary artery ligation or occlusion produces heart failure in experimental animals, with clear clinical relevance. Disadvantages of such techniques include fatal arrhythmias and collateral vessel growth that prevents or slows the onset of HF. 5. A minimally invasive model of HF which is relatively controllable can be produced by repeated or single DC shocks across the left ventricle. 6. Chronic rapid ventricular pacing produces a technically simple, predictable, stable and controllable preparation of HF with neurohumoral and haemodynamic changes which mimic the clinical pattern. These changes are reversible in the short term but after pacing for 1 year or longer complete recovery does not occur after cessation of pacing. 7. It has recently been suggested that a single DC shock, three to seven times the threshold defibrillating current, administered to the left ventricle, might provide the basis for the development of a model of heart failure which is technically simple and controllable.

Protective effect of the serotonin receptor antagonist cinanserin in two canine models of pacing-induced myocardial ischemia.

Previous studies have indicated that structurally dissimilar serotonin2 (5HT2) antagonists can protect globally ischemic/reperfused reperfused rat hearts. We therefore determined if the 5HT2 antagonist cinanserin can protect the ischemic myocardium in two models of pacing-induced ischemia in anesthetized dogs. In one model, dogs were subjected to repeated 5-min episodes of pacing superimposed upon left anterior descending coronary artery stenosis such that an ST segment elevation of 10-11 mV was obtained and upon cessation of pacing, a return of ST segment elevation to baseline. In vehicle-treated animals, this ST segment elevation to baseline. In vehicle-treated animals, this ST segment elevation was constant for all pacing-induced ischemic episodes. After infusion of 20 micrograms/kg/min cinanserin (intracoronary, i.c.), ST segment elevation was significantly reduced during pacing-induced ischemia at all times measured postdrug. In the second model, animals were subjected to pacing-induced ischemia for 15 min such that segmental shortening was reduced to zero. Upon cessation of pacing-induced ischemia, recovery of shortening was assessed. In vehicle-treated dogs, function recovered to only 40% of baseline at 3 h into recovery. Pretreatment with 5 micrograms/kg/min cinanserin i.c. significantly improved recovery of postischemic function. In both protocols, cinanserin had no effect on ischemic regional blood flow or peripheral hemodynamics. Thus, cinanserin appears to exert profound protective effects in two models of effort-induced ischemia.

Sarcoplasmic reticulum Ca-release channel and ATP-synthesis activities are early myocardial markers of heart failure produced by rapid ventricular pacing in dogs.

The contraction-relaxation cycle of the heart is dependent on a cycle of ATP production and utilization and a cycle of Ca uptake and Ca release by the sarcoplasmic reticulum (SR). Heart failure (HF) is associated with abnormalities of myocardial Ca and ATP cycling, but the time course of their development is unknown. This study tested the hypothesis that, compared with ATP-utilizing and Ca-uptake activities, decreases in ATP-synthesis and Ca-release activities occurred earlier in the development of HF and persisted longer during recovery from HF. HF was induced by right ventricular pacing of dogs at 250 beats/min. Dogs were studied after 1 week of pacing (n = 8, early HF), at HF (n = 11, severe HF), and 4 weeks after cessation of pacing (n = 9) and were compared with dogs not subjected to pacing. At early HF, there were decreased activities (p < 0.05) of the SR Ca-release channel (rate constant from 199 +/- 36 x 10(-4) to 90 +/- 16 x 10(-4) s-1), mitochondrial ATP synthesis (from 11.2 +/- 2.4 to 7.0 +/- 2.2 international units (IU)/g), and creatine kinase (CK) from 2028 +/- 266 to 1811 +/- 79 IU/g). The decreased Ca-channel activity was due to a 32% decrease in maximal activity (rate constant from 249 +/- 50 x 10(-4) to 170 +/- 29 x 10(-4) s-1) and to a 2-fold increase (from 19.1 +/- 12.4 to 42.0 +/- 14.2%) in inhibition of maximal channel activity (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery of attenuated baroreflex sensitivity in conscious dogs after reversal of pacing induced heart failure

Rapid ventricular pacing reliably induces severe congestive heart failure in dogs, with an associated attenuation of baroreflex sensitivity. Unique to this model is the capacity for rapid recovery of haemodynamics and plasma noradrenaline following the cessation of pacing; however, whether baroreflex sensitivity will similarly recover is unknown. The aims of this study were (1) to assess baroreflex control of heart rate in response to acute hypertensive and hypotensive stimuli during the development of and recovery from severe heart failure, and (2) to correlate baroreflex sensitivity with haemodynamic and echocardiographic indices and with noradrenaline concentrations. Serial assessments were performed on six dogs paced to severe heart failure and then allow to recover for four weeks. R-R interval and systolic blood pressure were monitored during administrations of phenylephrine and nitroprusside and the slope (ms.mm Hg-1) of the resultant R-R interval-systolic blood pressure relationship was used to define baroreflex sensitivity. Control phenylephrine and nitroprusside derived slopes were 27.05(SD 7.88) and 17.1(11.03) ms.mm Hg-1 respectively. After one week of pacing the phenylephrine derived slope was unchanged while the nitroprusside slope tended to be attenuated. In severe heart failure, both slopes were severely attenuated, at 1.88(6.45) ms.mm Hg-1 (phenylephrine) and 4.21(3.28) ms.mm Hg-1 (nitroprusside) (both p < 0.05). Intrinsic heart rate, noradrenaline concentrations and cardiac filling pressures were raised at severe heart failure while cardiac output and systolic blood pressure were significantly reduced. Recovery of baroreflex control of heart rate was evident as early as 48 h following pacing cessation and was maintained after four weeks recovery. Haemodynamics, cardiac output, and noradrenaline also returned to control while cardiac dilatation persisted. Nitroprusside and phenylephrine derived slopes were inversely correlated with intrinsic heart rate and pulmonary arterial/capillary wedge pressures respectively. Despite marked attenuation of baroreflex control of heart rate at severe heart failure, rapid recovery was seen in response to both hypotensive and hypertensive stimuli. The speed with which recovery occurs suggests that attenuation of baroreflex sensitivity at severe heart failure is likely to be mediated by functional alterations rather than morphological damage.