Remote monitoring with cardiac implantable electronic device to follow up pharmacodynamic effects of sacubitril/ valsartan treatment: A case report.

Cardiac implantable electronic devices include remote monitoring tools intended to guide heart failure management. These tools allow for observation of some physiological functions, such as intrathoracic impedance (ITI), patient activity (PA), and heart rate variability (HRV). Sacubitril/valsartan is recommended in the current guidelines as foundational therapy for patients with heart failure and reduced ejection fraction. However, the effects of sacubitril/valsartan treatment on these physiological parameters remain unclear. To the best of our knowledge, this is the first case objectively documenting improvements in ITI, PA, and HRV values with sacubitril/valsartan treatment.

Safety pharmacology studies using EFP and impedance.

INTRODUCTION: While extracellular field potential (EFP) recordings using multi-electrode arrays (MEAs) are a well-established technique for monitoring changes in cardiac and neuronal function, impedance is a relatively unexploited technology. The combination of EFP, impedance and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has important implications for safety pharmacology as functional information about contraction and field potentials can be gleaned from human cardiomyocytes in a beating monolayer. The main objectives of this study were to demonstrate, using a range of different compounds, that drug effects on contraction and electrophysiology can be detected using a beating monolayer of hiPSC-CMs on the CardioExcyte 96. METHODS: hiPSC-CMs were grown as a monolayer on NSP-96 plates for the CardioExcyte 96 (Nanion Technologies) and recordings were made in combined EFP and impedance mode at physiological temperature. The effect of the hERG blockers, E4031 and dofetilide, hERG trafficking inhibitor, pentamidine, ß-adrenergic receptor agonist, isoproterenol, and calcium channel blocker, nifedipine, was tested on the EFP and impedance signals. RESULTS: Combined impedance and EFP measurements were made from hiPSC-CMs using the CardioExcyte 96 (Nanion Technologies). E4031 and dofetilide, known to cause arrhythmia and Torsades de Pointes (TdP) in humans, decreased beat rate in impedance and EFP modes. Early afterdepolarization (EAD)-like events, an in vitro marker of TdP, could also be detected using this system. Isoproterenol and nifedipine caused an increase in beat rate. A long-term study (over 30h) of pentamidine, a hERG trafficking inhibitor, showed a concentration and time-dependent effect of pentamidine. DISCUSSION: In the light of the new Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative to improve guidelines and standardize assays and protocols, the use of EFP and impedance measurements from hiPSCs may become critical in determining the proarrhythmic risk of potential drug candidates. The combination of EFP offering information about cardiac electrophysiology, and impedance, providing information about contractility from the same area of a synchronously beating monolayer of human cardiomyocytes in a 96-well plate format has important implications for future cardiac safety testing.

Combined cardiopulmonary assessments with implantable telemetry device in conscious freely moving cynomolgus monkeys.

Female cynomolgus monkeys were surgically implanted with telemetry transmitters recording ECG (DII), arterial pressure, physical activity, body temperature, and tidal volume. Respiratory rate (RR) and tidal volume (TV) were monitored simultaneously with the telemetry transmitter using impedance. Impedance-based monitoring of RR and TV by telemetry correlated with controlled TV and with pneumotachometer (>98%) in restrained animals. Control drugs with cardiovascular and respiratory effects, including saline, medetomidine (0.01, 0.02 and 0.04mg/kg) and cocaine (0.5, 1.0 and 1.5mg/kg) were administered intravenously. An averaging epoch of 5min was used for analysis of respiratory data. Medetomidine induced significant respiratory depression with decrease in RR and TV in freely moving animals while cocaine increased TV, RR and minute ventilation (MV) with concomitant increase in heart rate when compared with time matched values from saline-treated animals. The onset, duration and magnitude of cardiovascular and respiratory changes were correlated. This highlights the dependency of the cardiovascular and respiratory systems. The use of cardiopulmonary monitoring can allow continuous monitoring including during night time when variability of respiratory parameters is lower. Monitoring of cardiovascular and respiratory parameters in the same animals could also help to decrease the number of animals used in research.

Non-invasive measurement of the haemodynamic effects of inhaled salbutamol, intravenous L-arginine and sublingual nitroglycerin.

AIMS: To examine the effects of salbutamol and L-arginine, two compounds acting largely on the endothelium, and the endothelium-independent agent nitroglycerin on blood pressure, arterial compliance, cardiac function and vascular resistance. METHODS: Continuous radial pulse wave analysis, whole-body impedance cardiography, and plethysmographic blood pressure from fingers in the supine position and during head-up tilt were recorded in nine healthy subjects. Data were captured before and after L-arginine (10 mg mg(-1) min(-1)) or saline infusion, salbutamol (400 microg) or placebo inhalation, and sublingual nitroglycerin (0.25 mg) or placebo resoriblet. RESULTS: The results of all measurements were comparable before drug administration. The effects of inhaled salbutamol were apparent in the supine position: systemic vascular resistance (-9.2 +/- 2.6%) and augmentation index (-4.0 +/- 1.5%) decreased, and heart rate (8.6 +/- 2.5%) and cardiac output (8.8 +/- 3.1%) increased. L-arginine had no clear effects on supine haemodynamics, but during head-up tilt blood pressure was moderately decreased and reduction in aortic reflection time prevented, indicating improved large arterial compliance. Nitroglycerin reduced supine vascular resistance (-6.7 +/- 1.8%) and augmentation index (-7.4 +/- 1.6%), and increased cardiac output (+9.2 +/- 2.7%). During head-up tilt, nitroglycerin increased cardiac output (+10.6 +/- 5.6%) and heart rate (+40 +/- 7.5%), decreased vascular resistance (-7.8 +/- 5.8%) and augmentation index (-18.7 +/- 3.2%), and prevented the decrease in aortic reflection time. CONCLUSIONS: Inhaled salbutamol predominantly changed supine haemodynamics, whereas the moderate effects of L-arginine were observed during the head-up tilt. In contrast, small doses of nitroglycerin induced major changes in haemodynamics both supine and during the head-up tilt. Altogether, these results emphasize the importance of haemodynamic measurements in both the supine and upright positions.

A phase 1-2 dose-escalating study evaluating the safety and tolerability of istaroxime and specific effects on electrocardiographic and hemodynamic parameters in patients with chronic heart failure with reduced systolic function.

Istaroxime (PST2744) is a luso-inotrope that stimulates the sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a without chronotropic effects. Additionally, it has beneficial effects on myocardial energetics. This phase 1-2 clinical trial in patients with chronic stable heart failure (HF) is the first evaluation of istaroxime in humans. Three cohorts of 6 patients each were exposed to 4 sequentially increasing 1-hour infusions with a random placebo. Doses were 0.005-5.0 micro/kg per min. Safety and hemodynamics were evaluated by impedance cardiography, digital Holter recorder, and electrocardiography. Pharmacokinetic data were obtained for 1 hour during treatment and for 6 hours after dosing. The mean age was 53+/-7 years, and the mean left ventricular ejection fraction was 0.27+/-0.08. Impedance cardiography demonstrated enhanced contractility as measured by the acceleration index, left cardiac work index, cardiac index, and pulse pressure at doses>or=1 micro/kg per min, with evidence of activity at doses of 0.5 micro/kg per min. Istaroxime shortened QTc. After infusion, the hemodynamic effect rapidly dissipated over 1-2 hours. Istaroxime was pharmacologically active and well tolerated at doses up to 3.33 micro/kg per min. Side effects were related to gastrointestinal symptoms and injection site pain at higher doses, which dissipated within minutes after the infusion ended. Ventricular ectopy was not altered. This study suggests that istaroxime is potentially useful in the treatment of HF and may offer a unique treatment for systolic and/or diastolic dysfunction. Additional studies are under way to further define its utility in acute HF.

Epinephrine infiltration on nasal field causes significant hemodynamic changes: hypotension episode monitored by impedance-cardiography under general anesthesia.

PURPOSE: Local infiltration of epinephrine-containing local anesthetics is widely used in clinics particularly in the procedure of surgeries on vascularity field to provide good analgesia and hemostasis. A prospective randomized double blind control study was designed to observe hemodynamic changes caused by local infiltration of epinephrine- containing lidocaine solution on nasal field under general anesthesia. METHODS: 90 adult patients undergoing elective functional endoscopic sinus surgery under general anesthesia were randomly allocated into three groups and received 1% lidocaine 4 mL with different dose of epinephrine (group I 20 microg; group II 40 microg; and group III 0 microg) respectively. Mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI), and acceleration index (ACI) were recorded through impedance-cardiography at every 45 seconds in 6 minutes after the beginning of local infiltration. RESULTS: Compared with the intra-group baseline, statistically significant hemodynamic changes particularly decrease in MAP with increase in HR at 1.5 minutes time point (P < 0.01), and decrease in SVRI and increase in CI, ACI at and from 1.5 minutes time point (P > 0.05) were observed in group I and group II, but not in group III. CONCLUSION: Local infiltration of epinephrine-containing lidocaine solution on nasal field causes significant decrease in MAP and SVRI, and increase in HR, CI and ACI.

Cardiovascular effects of acute oxygen administration in healthy adults.

Supplementary oxygen is commonly administered in current medical practice. However, attention has recently been drawn to the potentially disadvantageous hemodynamic consequences in certain patients. Possible mechanisms underlying the cardiovascular responses to acute hyperoxia are unclear. The effects of acute oxygen administration on heart rate, blood pressure, cardiac output, systemic vascular resistance, and baroreflex sensitivity were studied in a series of randomised, placebo-controlled studies in healthy individuals, using validated, non-invasive techniques. The effects of oxygen administration on forearm blood flow responses to locally administered acetylcholine, an endothelium-dependent vasodilator, sodium nitroprusside, an endothelium-independent vasodilator, and l-NG-monomethylarginine, a nitric oxide synthase inhibitor, were studied using venous occlusion plethysmography. Oxygen administration for 1 hour caused a reduction in heart rate (P < 0.01) and cardiac index (P < 0.05), and an increase in mean arterial pressure (P < 0.01), systemic vascular resistance (P < 0.05), large artery stiffness (P < 0.05), and baroreflex sensitivity (P < 0.05). There were no effects on vascular responses in the isolated forearm bed. These findings indicate that oxygen administration causes acute effects on cardiovascular function, which might be important in the context of acute illness.

The trans-cardiac conductance method for on-line measurement of left ventricular volume: assessment of parallel conductance offset volume.

The trans-cardiac conductance (TCC) method provides on-line left ventricular (LV) volume signals by determining the electrical conductance of blood in the LV by means of central venous and epithoracic electrodes. Conductive structures outside the LV blood pool cause a "parallel conductance" offset term (Vp) that can be determined by bolus injections of hypertonic saline in the pulmonary artery (Vp(saline)), which cause a transient increase in blood conductivity. This study in anesthetized sheep evaluates the accuracy of the saline calibration method and the variabilities of Vp between animals, between hemodynamic conditions and during the cardiac cycle. The conventional intra-cardiac conductance catheter method was used to obtain independent estimates of Vp by the zero-volume method (Vp(zero volume)). Mean baseline Vp(saline) and Vp(zerovolume) were 104 +/- 6 ml and 106 +/- 6 ml, respectively. Bland-Altman analysis showed a small nonsignificant bias (-2.5 ml) and narrow limits of agreement (4.6 ml). Vp was not significantly different between hemodynamic conditions (baseline, dobutamine, volume load, propranolol), but had a substantial interanimal variability (IAV) (38%). Average variations during the cardiac cycle were < 10% of mean Vp. We conclude that the saline method can be applied to determine Vp for TCC. IAV is substantial, so that Vp must be determined in each animal, but within-animal variability is relatively small.

The effects of epinephrine administration on impedance cardiographic measures of cardiovascular function.

The effects of epinephrine administration on cardiovascular function were examined in 26 men who were given a bolus injection of either 1:10,000 epinephrine hydrochloride or physiological saline. Impedance cardiographic and continuous blood pressure measures were recorded during a 2-min pre-injection baseline and in the post-injection period. Compared to a saline control, epinephrine elicited greater shortening of heart period, pre-ejection period, and the R-B interval; greater increases in cardiac output, stroke volume, dZ/dt amplitude, Heather Index, and systolic and diastolic pressures; and greater decreases in total peripheral resistance (all P < 0.05). Left ventricular ejection time and the Q-R interval were not affected. The results indicate that inotropic indices that are readily measured by impedance cardiography should be considered as important non-invasive indices of adrenergically mediated responses to stress.

[Measuring bioelectric myocardial impedance as a noninvasive method for diagnosis of graft rejection after heart transplantation]. / Die Messung der bioelektrischen myokardialen Impedanz als nichtinvasive Methode zur Abstossungsdiagnostik nach Herztransplantation.

12 beagle dogs underwent neck-heart transplantation and were immunosuppressed with cyclosporine and methylprednisolone. Intramyocardial impedance was determined twice daily with four screw-in electrodes in the right and left ventricle. Transmyocardial biopsies and the intra-myocardial electrogram (IMEG) were performed as reference methods. 19 rejection episodes were induced. When acute rejection was seen in histology the animals were treated with pulsed 125 mg methylprednisolone over 5 consecutive days and immunosuppression was raised to sufficient levels. Successful treatment of rejection was controlled by biopsy. All hearts showed a uniform decrease of impedance of about 28.3% +/- 5.5% immediately after implantation, then reaching a stable plateau after 7 to 8 days. Impedance values then remained unchanged as long as rejection was absent. Biopsy findings of grade 1A to 1B (ISHLT) were accompanied by a statistically significant increase of impedance of 12.2% +/- 2.5%, of grade 2 to 3A of 19.2% +/- 3.2%, and of grade 3B to 4 of 27.0% +/- 2.9%. Sensitivity was 95%, specificity 91%. Successful treatment of rejection led to a uniform decrease of impedance to intramyocardial impedance for high frequencies can reliably indicate alterations of the cell membrane and the intracellular space during acute cardiac allograft rejection. The amount of increase of impedance is a reliable noninvasive parameter to graduate acute cardiac allograft rejection. The success of treatment of rejection can also be monitored by impedance. This noninvasive method is applicable for telemetric rejection monitoring via an implantable device, which would allow continuous rejection surveillance of a patient at home without hospital admission.

ACE inhibition with spirapril improves diastolic function at rest independent of vasodilation during treatment with spirapril in mild to moderate hypertension.

The effects of the ACE inhibitor spirapril and of hydrochlorothiazide on left ventricular diastolic function were studied. Thirteen patients with mild to moderate essential hypertension completed this randomized, double-blinded, placebo-controlled, crossover study. After a three-week run-in period the patients entered three periods lasting four weeks each, wherein they were treated with placebo, spirapril, or hydrochlorothiazide. Blood pressure, hemodynamic variables (stroke volume, heart rate, cardiac output, index of contractility, and systemic vascular resistance), echocardiography (left ventricular mass), and Doppler-derived atrial to early (A/E)-ratio velocity time integrals (VTI) were measured at the end of each of the four periods. Spirapril lowered the A/E-ratio VTIs (0.57, 0.12-1.00) (P < 0.02) as compared with both placebo (0.80, 0.50-2.67) and hydrochlorothiazide (0.83, 0.44-1.25), and the drug normalized the A/E-ratio VTI in those patients with elevated values. The hemodynamic variables, left ventricular mass, and end-systolic wall stress were unchanged during all three treatments. There were no significant changes in mean blood pressure during the treatment periods. These results indicate that spirapril lowers A/E ratio within four weeks in patients with mild to moderate essential hypertension. It thereby seems able to improve left ventricular diastolic function. The effect is not dependent upon changes in hemodynamic variables, blood pressure, left ventricular mass, or end-systolic wall stress.

[Clinical observation on effect of yiqi huoxue decoction over the left ventricular diastolic dysfunction].

The left ventricular diastolic function, grade of heart function and degree of Heart-Qi Deficiency of 52 aged patients with left ventricular diastolic dysfunction (LVDD) were measured by means of Doppler echocardiography and left ventricular impedance cardiography before and after treatment with Buqi Qiangxin decoction (BQQXD), a recipe of TCM for reinforcing Qi and promoting blood circulation. The data were compared with that of control group (15 cases) treated with verapamil. Results showed that 92.3% of the LVDD patients were associated with Heart-Qi Deficiency and 69.2% were complicated with blood stasis. After treated with BQQXD, the grade of heart function was elevated in 82.6%, the degree of Heart-Qi Deficiency was improved in 89.6% of the patients. The parameters reflecting the left ventricular diastolic function were all improved in different degree (P < 0.05-0.01), but the parameters reflecting left ventricular compliance were changed insignificantly (P > 0.05). It indicated that besides controlling on the etiological factors, the mechanism of BQQXD in treating left ventricular dysfunction might be related with its calcium antagonistic effect.

[Clinical observation on treatment of 45 angina pectoris patients of coronary heart disease with taponin].

Forty-five patients suffering from angina pectoris of coronary heart disease (CHD) were successfully treated with Taponin. The effect of the treatment was compared with that of nifedipine. The clinical practice showed that the group treated with Taponin yielded better results. After medication, the patients were markedly relieved from angina pectoris of CHD. Meanwhile the improvement of electrocardiogram (EKG) and impedance cardiogram were also observed. The effective rate of EKG improvement was 83.7%. The treatment of angina pectoris of CHD with Taponin was significantly more effective in comparing with control group (P < 0.05).

Acute hemodynamic effects of nisoldipine in young hypertensive patients.

The hemodynamic effects of oral nisoldiopine in 12 hypertensive patients aged 35-55 years were determined using the impedance cardiography method. Hemodynamic measurements were performed at hourly intervals before and following ingestion of the medication. Nisoldipine significantly decreased systolic and diastolic blood pressure, with a slight increase in heart rate. Stroke volume did not change significantly following the medication. Total peripheral resistance decreased gradually reaching its lowest values 2 h after ingestion of nisoldipine. We conclude that nisoldipine is a potent oral antihypertensive agent that induces peripheral vasodilatation without decrease in cardiac output.

Consistency of cardiovascular response pattern to caffeine across multiple studies using impedance and nuclear cardiography.

This paper illustrates the use of impedance cardiography in an applied research setting to examine some of the pharmacological effects of caffeine on cardiovascular function. A primary advantage of the technique was in providing a noninvasive approach for studying cardiac versus vascular mechanisms underlying blood pressure responses to acute caffeine challenge. Impedance cardiography allowed the quantification of stroke volumes and cardiac output, and the change in these variables over time in a within-subjects design. Systemic vascular resistances were then calculated when impedance data were combined with simultaneously measured blood pressures. Results from four studies are summarized in which caffeine significantly elevated systolic and diastolic blood pressures. Impedance-derived measures indicate that caffeine's pressor response can be attributed to increased systemic vascular resistance rather than to elevated cardiac output. Our findings were consistent across all four studies, and across all protocols within those studies. Furthermore, these response patterns were confirmed by obtaining similar results using nuclear ventriculography. Thus, with respect to the outcome of testing an applied question, impedance-derived findings were found to be reliable and valid when compared with another technique used more commonly in clinical settings.

Reduced left ventricular diameters at onset of bradycardia during epidural anaesthesia.

Pathophysiologic mechanisms of bradycardia during epidural anaesthesia (L3-L4 with 1% lidocaine, 38 ml) were evaluated by studying changes in selected cardiovascular and hormonal parameters. Six of eight subjects (analgesia to T8-T10) remained circulatory stable with no significant changes in heart rate (HR), mean arterial pressure (MAP) and thoracic impedance (TI). In one of two subjects MAP decreased after 25 min from 85 to 50 mmHg (11.3 to 6.7 kPa), HR from 80 to 45 beats.min-1 while thoracic impedance increased from 25.5 to 26.5 ohm. End-systolic diameter (ESD) and end-diastolic diameter (EDD) of the left ventricle determined with echocardiography were reduced from 3.8 to 3.2 cm (17%) and 5.6 to 5.0 cm (11%), respectively. In the other subject MAP decreased after 25 min from 75 to 50 mmHg (10.0 to 6.7 kPa) and HR from 82 to 60 beats.min-1 while thoracic impedance increased from 28.8 to 29.6 ohm. ESD was reduced from 3.8 to 3.3 cm (13%), and EDD from 5.6 to 5.0 cm (11%). Both subjects recovered after infusion of saline and being placed in the head-down position. There were no consistent changes in plasma catecholamines, whereas pancreatic polypeptide increased from 5 and 3 to 152 and 69 pmol.l-1, vasopressin from 3 and 2 to 152 and 46 pmol.l-1, and aldosterone from 282 and 229 to 383 and 485 pmol.l-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential cardiovascular effects of propranolol, atenolol, and pindolol measured by impedance cardiography.

We have evaluated Sramek's method of impedance cardiography as a non-invasive way of detecting the cardiovascular effects of drugs. We made cardiovascular measurements using the method during passive tilting and exercise 2 h after the oral administration of atenolol (50 and 100 mg), propranolol (40 and 80 mg), pindolol (5 and 10 mg), and placebo in seven separate studies involving eight healthy male volunteers. Equivalent doses of the pure antagonists atenolol (beta 1) and propranolol (beta 1, beta 2) produced similar reductions in heart rate, systolic blood pressure, and cardiac index, and increases in stroke volume and total peripheral resistance, particularly during exercise. In contrast the partial agonist pindolol produced increases in heart rate and cardiac index, and reductions in peripheral resistance at rest. During passive tilting and exercise pindolol reduced heart rate, but cardiac output and total peripheral resistance were unchanged except at the highest levels of exercise. The similar cardiovascular effects of atenolol and propranolol, but differing effects of pindolol, are consistent with reports using other methods of measurement. This suggests that impedance cardiography may have a place in the non-invasive assessment of the cardiovascular effects of drugs.

[Paeonia Lactiflora injection in treating chronic cor pulmonale with pulmonary hypertension].

The changes of clinical features of blood stasis, hemorheology, arterial blood gas and hemodynamics which was determined by impedance cardiogram and pheopneumogram, hemorheologic examination, blood gaseous analysis and right heart catheterization were observed in 42 patients (male 35, female 7; age 64 +/- 16.5 years), 32 patients with decompensative chronic cor pulmonale (CCP), served as noninvasive methods group (NMG) treated by intravenous injecting 100% Paeonia lactifiora injection 5 ml per day, 10 patients with CCP as well as pulmonary hypertension, which was proved through right heart catheterization were considered as invasive methods group (IMG) treated by pulmonary artery injecting 100% Paeonia lactiflora 5 ml (one-time). After the treatment, the clinical features of blood stasis were improved significantly in NMG (P less than 0.05). Also the results of impedance cardiogram and pheopneumogram (such as: Q-B, B-Y interval and Q-B/B-Y ratio, cardiac output), the hemorheologic parameters (such as: blood viscosity, plasma viscosity, hematocrit and erythrocyte electrophoresis) and oxygen consumption of myocardium were improved significantly in NMG and IMG. In IMG, PAP was reduced by 0.71 +/- 0.27 kPa; PaO2 was promoted significantly in NMG. All of these have statistical significance (P less than 0.05 or 0.01). There are no statistical significance about the change of PaCO2, SaO2, blood pH and Bp (P less than 0.05).

Noninvasive assessment of the inodilator action of amrinone in healthy man.

The effects of a single dose of 2 mg/kg amrinone (60 min constant rate IV infusion) have been assessed in a double-blind, placebo-controlled, within-subject cross-over study in six healthy volunteers. Combined impedance cardiography, phonocardiography and electrocardiography revealed a protracted drop in mean ventricular ejection time and electromechanical systole together, with a protracted rise in the "contractility" indices dZ/dtmax and the Heather index HI. The profile is compatible with combined venous vasodilation and positive inotropic action. In spite of the methodological constraints, endpoints were reached that were both detectable and relevant. The profiling permitted a better distinction to be made between the possible levels of action than systolic time intervals alone could have done. Therefore, these methods may be of value in the early development of "inodilator" drugs.

Rate-modulated cardiac pacing based on transthoracic impedance measurements of minute ventilation: correlation with exercise gas exchange.

The relation of pacing rate to physiologic variables of metabolic demand was examined in 10 consecutive patients with a minute ventilation-sensing, rate-modulating ventricular pacemaker implanted for complete heart block. All patients had paroxysmal (seven patients) or chronic (three patients) atrial fibrillation and were referred for catheter ablation of the atrioventricular junction. Treadmill exercise testing with measurement of expired gas exchange and respiratory flow was performed before ablation and 4 weeks after pacemaker implantation, with the pacemaker programmed to both the fixed-rate VVI and rate-modulating minute ventilation VVIR pacing modes in random sequence. The relation of pacing rate to oxygen consumption (VO2), expired carbon dioxide concentration (VCO2), respiratory quotient, tidal volume, respiratory rate and minute ventilation was determined during exercise in the rate-modulating minute ventilation pacing mode. Pacing rate was highly correlated with minute ventilation (r = 0.89), respiratory quotient (r = 0.89), VCO2 (r = 0.87), tidal volume (r = 0.87), VO2 (r = 0.84) and respiratory rate (r = 0.84). The mean exercise duration increased from 8.3 +/- 2.8 min in the fixed rate pacing mode to 10.2 +/- 3.4 min in the rate-modulating, minute ventilation mode (p = 0.0001). The maximal VO2 increased from 13.4 +/- 3.4 to 16.3 +/- 4.1 cc/kg per min (p = 0.0004). The maximal heart rate achieved in the minute ventilation pacing mode was 136 +/- 9.7 beats/min, similar to that observed in the patient's intrinsic cardiac rhythm before ablation (134.9 +/- 30.1 beats/min, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)