Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin.

Essentials MEDI2452 is a specific antidote of the platelet P2Y12 receptor antagonist ticagrelor. Hemostatic effects of MEDI2452 were evaluated in pigs treated with ticagrelor and aspirin. MEDI2452 eliminated free ticagrelor within 5 min and gradually normalized platelet aggregation. Improvements in blood pressure (significant) and in blood-loss and survival (non-significant) were observed. SUMMARY: Background Ticagrelor, a P2Y12 antagonist, is approved for the prevention of thromboembolic events. However, antiplatelet therapies carry a risk of bleeding. Objective To explore the hemostatic effects of MEDI2452, an antidote for ticagrelor. Methods Pigs, pre-treated with aspirin, were given an intravenous infusion of ticagrelor or vehicle. At the end of the infusion, a piece of a liver lobe was cut off and a bolus of MEDI2452 or vehicle was administered intravenously. Blood was collected to monitor blood loss, mean arterial blood pressure (MAP) was recorded and survival time was observed over 4 h. Blood samples for drug plasma exposures and platelet aggregation were collected. Results MEDI2452 eliminated the free concentrations of ticagrelor and its active metabolite AR-C124910XX within 5 min. ADP-induced platelet aggregation was close to normal at 60 min, which was not significantly different from aspirin alone. MEDI2452 numerically reduced ticagrelor-mediated effects: body-weight-adjusted blood loss in the 15- to 90-min interval, 12 (confidence interval [CI] 95% 7-28] vs. 17 (CI 95% 5-31) (ticagrelor and aspirin) vs. 5 (CI 95% 3-9) mL kg-1 (aspirin alone), survival 70% (CI 95% 47-100) vs. 45% (CI 95% 21-92) (ticagrelor and aspirin) vs. 100% (CI 95% 100-100) (aspirin alone), and median survival time, 240 (CI 95% 180-240) vs. 169 (CI 95% 64-240) (ticagrelor and aspirin) vs. 240 (CI 95% 240-240) min (aspirin alone). Finally, MEDI2452 significantly attenuated the decline in MAP, 0.08 (CI 95% 0.07-0.09) vs. 0.141 (CI 95% 0.135-0.148) (ticagrelor and aspirin) vs. 0.04 (CI 95% 0.03-0.05) mmHg per min (aspirin alone) and maintained MAP at a significantly higher level, 73 (CI 95% 51-95) vs. 48 (CI 95% 25-70) (ticagrelor and aspirin) vs. 115 (CI 95% 94-136) mmHg (aspirin alone). Conclusion MEDI2452 eliminated free ticagrelor and AR-C124910XX within 5 min. This translated into a gradual normalization of ADP-induced platelet aggregation and significant improvement in blood pressure and numerical but non-significant improvements in blood-loss and survival.

Unraveling the pharmacokinetic interaction of ticagrelor and MEDI2452 (Ticagrelor antidote) by mathematical modeling.

The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence.

Note: pneumatically modulated liquid delivery with feedback control.

We present the design and characterization of a pneumatically driven liquid delivery system using an embedded microcontroller with feedback control capable of maintaining a stable, constant flow rate over several hours of operation. Flow rates with relative standard deviations less than 1% were achieved and compared to a typical laboratory syringe pump.

Evaluation of AR-H067637, the active metabolite of the new direct thrombin inhibitor AZD0837, in models of venous and arterial thrombosis and bleeding in anaesthetised rats.

AZD0837, currently in clinical development, is a once-daily oral anticoagulant that is bioconverted to AR-H067637, a selective, reversible direct thrombin inhibitor (DTI). When developing a new DTI, the antithrombotic effects are commonly investigated in in vivo animal models; this report shows the effect of AR-H067637 in venous and arterial thrombosis and bleeding models in anaesthetised rats. Thrombus formation was induced by topical application of ferric chloride to the carotid artery or to the caval vein with partial stasis. Cutaneous incision bleeding time and muscle transection blood loss were assessed, with or without acetylsalicylic acid (ASA). Activated partial thromboplastin time (APTT), ecarin coagulation time (ECT) and thrombin coagulation time (TCT) were used as plasma biomarkers of anticoagulant effect. Dalteparin was used as a reference compound. AR-H067637, given by continuous infusion, displayed a dose-dependent antithrombotic effect, with 50% inhibition (IC50) of thrombus size in venous and arterial thrombosis models obtained at plasma concentrations of 0.13 µM and 0.55 µM, respectively, without increased bleeding. Dose-dependent increased bleeding and blood loss were seen at plasma concentrations ≥1 µM AR-H067637. At the highest AR-H067637 plasma concentration tested, bleeding time and blood loss increased two and four times the vehicle group. Addition of ASA moderately potentiated bleeding time and blood loss. APTT, ECT and TCT were dose-dependently prolonged. These studies demonstrate that the DTI AR-H067637 inhibits thrombus formation in rat venous and arterial thrombosis models with no or minor increases in bleeding.

Cancer risk of patients with ischaemic syndromes.

INTRODUCTION: Angiogenesis constitutes the regulation of collateral formation in subjects with ischaemic syndromes and is also a prerequisite for cancer progression. Patients with severe symptomatic ischaemic syndromes may have a reduced ability for angiogenesis and thus a lower risk to develop cancer. SUBJECTS AND METHODS: Patients below 80 years and treated for acute myocardial infarction (AMI), angina pectoris (AP), intermittent claudication (IC) or undergoing revascularization during 1972-1991 in Stockholm county (n=63 921) were followed regarding cancer incidence 1972-2000. Cancer incidence was compared with that of the general population of Stockholm County by standardized incidence ratios (SIR). RESULTS: An increased incidence of cancer overall compared with the general population was seen in patients treated for AMI [SIR men 1.08 (95% Confidence Interval 1.04-1.11) and women 1.15 (1.09-1.21)], AP [men 1.16 (1.11-1.21) and women 1.06 (1.00-1.12)] and IC [men 1.48 (1.31-1.64) and women 1.43 (1.17-1.68)]. This increase was mainly due to an increased incidence of tobacco-related cancer. In patients undergoing revascularization no increase in incidence was seen [SIR men 0.97 (0.91-1.03) and women 1.06 (0.91-1.20)]. CONCLUSION: Patients with mild to moderate symptomatic ischaemic syndromes are, as expected, at increased risk of subsequently develop tobacco-related cancer. A lack of increased cancer risk in patients undergoing revascularization could be due to a reduced ability for angiogenesis in patients with severe atherosclerotic disease but may also be related to lifestyle changes.

Early results of a new mechanical tri-leaflet heart valve prosthesis--"Tricusp": an animal study.

OBJECTIVE: A new tri-leaflet mechanical heart valve made of titanium was inserted in the mitral position to evaluate early results. METHODS AND RESULTS: Five sheep were followed between 3 and 6 months (mean 4.7 months) and performed very well clinically during the follow-up period. In three of five animals a minor para-valvular leakage without hemodynamic importance was observed. The invasive pressure measurements at the end of follow-up revealed only minor transvalvular pressure differences between 1 and 4 mmHg (mean 2.4 mmHg). Similar results were obtained by echo-Doppler technique. Histological examination of the tissue around the valve showed no signs of foreign body reaction or chronic inflammatory reaction. CONCLUSION: This new tri-leaflet heart valve has shown an excellent hemodynamic performance and good tissue compatibility, and therefore may be an alternative to other currently used valve prostheses.

Determination of cardiac involvement in sarcoidosis by magnetic resonance imaging and Doppler echocardiography.

OBJECTIVES: To elucidate whether cardiac magnetic resonance imaging (MRI) could be useful in disclosing structural changes in the myocardium in sarcoidosis patients and to relate echo-Doppler derived indices of left ventricular function to electrocardiogram (ECG) findings. DESIGN: The MRI was performed in 18 consecutive patients with sarcoidosis. Left ventricular ejection fraction (LVEF), i.e. systolic function, was estimated echocardiographically by Simpson's two-dimensional method (n = 16). Diastolic function was estimated by age-corrected Doppler-derived indices: isovolumetric relaxation time (IVRT), deceleration time (DT) and early filling/atrial contraction ratio (E/A ratio). RESULTS: Eleven patients had conduction defects or dysrhythmias (ECG+) whilst seven patients had a normal ECG (ECG-). In two patients, high signalling, contrast-enhanced, isolated regions, suggestive of deposits, were seen in the left ventricular myocardium on MRI. Both these patients had abnormal ECGs and signs of systolic and/or diastolic dysfunction on echocardiography. LVEF was subnormal in seven of 10 of the ECG+ patients and in two of six of the ECG-. Signs of diastolic dysfunction were found in 59% and 56% of the measurements in the ECG+ and ECG- patients, respectively. CONCLUSION: We conclude (i) that myocardial deposits on MRI in sarcoidosis patients have a high specificity for cardiac involvement but a rather low sensitivity; (ii) that a substantial proportion of sarcoidosis patients with abnormal ECGs have echocardiographic signs of systolic and/or diastolic dysfunction.

ECG-abnormalities in Japanese and Swedish patients with sarcoidosis. A comparison.

BACKGROUND AND AIM OF THE WORK: ECG abnormalities are more common in patients with sarcoidosis than in controls. The incidence of cardiac sarcoid granulomas in the Japanese population has been found to be higher than that seen in Caucasians. We compared the prevalence of ECG abnormalities in Japanese and Swedish patients with sarcoidosis. METHODS: Twelve-lead routine ECG's were compared between consecutive patients (134 Japanese and 149 Swedish) of similar age with histologically verified sarcoidosis or a high clinical probability of the disease and a history of no more than 12 months before the ECG. RESULTS: There was no statistically significant difference in the prevalence of first degree AV block, ST-T-segment abnormalities, right bundle branch block (RBBB) and left anterior block (LAH) in Japanese and Swedish patients. Among the Swedes, the results were compared with those of a smaller group (n = 29) of older patients with a longer disease course. In these few patients LAH and RBBB occurred more frequently than in patients with a recent diagnosis. CONCLUSIONS: ECG abnormalities in patients with sarcoidosis seem to be of similar frequency in Japan and Sweden. ST-T changes and first degree AV block would appear early in the course of the disease, whereas more pronounced conduction defects may appear later.

Chronic cobalt exposure affects antioxidants and ATP production in rat myocardium.

Chronic cobalt exposure is characterized by severe cardiac insufficiency. Since the mechanisms of cobalt toxicity are not yet clear, we analysed the effects of chronic cobalt exposure on antioxidant enzyme activities and myocardial mitochondrial ATP production rate in a rat model. One group of rats was fed a conventional diet and another a cobalt supplemented diet for 24 weeks. The manganese-superoxide dismutase activity was markedly reduced in the cobalt rats (18+/-4.7 U/mg protein) compared to the control rats (100+/-22 U/mg protein; p <0.001). Activity in the respiratory chain enzymes succinate-cytochrome c reductase, NADH-cytochrome c reductase and cytochrome c oxidase was also reduced in the cobalt rats (p<0.01). Glutamate dehydrogenase activity, located in the mitochondrial matrix, was unchanged. The mitochondrial ATP production rate in relation to myocardial mass was lower in the cobalt rats for all substrates tested except palmitoyl-l-carnitine + malate. In conclusion, 24 weeks of chronic cobalt exposure induces a marked decrease in manganese-superoxide dismutase activity, a moderate decrease in mitochondrial ATP production rate and a general reduction in the capacity of the respiratory chain. The impairment in mitochondrial ATP production might be secondary to the decreased manganese-superoxide dismutase activity, causing inactivation of mitochondrial factors susceptible to superoxide radicals.

Monotherapy with amlodipine or atenolol versus their combination in stable angina pectoris.

BACKGROUND: The basic cause of angina pectoris is imbalance between the metabolic needs of the myocardium and the capacity of the coronary circulation to deliver sufficient oxygenated blood to satisfy these needs. HYPOTHESIS: The study was undertaken to evaluate whether the effect of combined amlodipine and atenolol therapy on patients with stable angina pectoris and with ST-depression during exercise testing and 48-h ambulatory electrocardiographic monitoring is superior to that of either agent given alone. METHODS: Patients with stable angina pectoris and ST depression during exercise and ambulatory monitoring were randomized to receive amlodipine (n = 116) or atenolol (n = 116), or both (n = 119). All patients were also treated with short- and long-acting nitrates. The design was a double-blind, randomized, triple-arm parallel group study with 10 weeks of administration of the test medication. RESULTS: In terms of time to onset of ST depression > 1 mm, time to onset of angina, total exercise time, maximum achieved workload, and peak intensity of angina, amlodipine and atenolol alone were as effective as their combination. During ambulatory monitoring, atenolol was more effective than amlodipine regarding total time and number of ST-depression episodes, and as effective as the combined drugs. CONCLUSION: For individual patients with stable angina pectoris, combination of a beta blocker with a calcium antagonist is not necessarily more effective than either drug given alone.

Myocardial morphology and cardiac function in rats with renal failure.

The effects of chronic renal failure on cardiac performance and myocardial morphology were studied in rats: 17 with 5/6 nephrectomy (CRF rats) and 12 with sham operation (controls). Cardiac function was assessed 8 weeks postoperatively, using the Langendorff technique for an isolated working heart model. After the hemodynamic study the hearts were fixed for electron and light microscopy. In the CRF rats left ventricular systolic pressure was significantly higher at all preloads (10-20 cmH2O) and afterloads (70-90 cmH2O), and left ventricular stroke work was significantly increased at preload 20 cmH2O with afterloads 70 or 90 cmH2O. Light microscopy revealed fibronecrotic lesions consisting of fibroblastic proliferation with newly formed collagen interposed between or entrapping degenerative myocytes. The changes were focally distributed, with perivascular accentuation and were most frequent in the basal half of the ventricular wall. Electron microscopy of non-necrotic myocytes showed intact myocytes, with mitochondria morphometrically similar in the 2 groups, but a significantly lower incidence of mitochondrial granules in the CRF rats. Thus 8 weeks of CRF showed no cardiac dysfunction associated with the focally distributed fibronecrotic myocardial lesions and decrease in mitochondrial granules. The precise mechanism of the discrepancy between the morphological change and the cardiac function is unclear. One possible explanation may be that because the pathological changes in the myocardium were focal or mild to moderate, some compensation mechanism may be involved or it may be the turning point of functional change from acute renal failure to the chronic state.

Improved probabilistic neural network algorithm for chemical sensor array pattern recognition.

An improved probabilistic neural network (IPNN) algorithm for use in chemical sensor array pattern recognition applications is described. The IPNN is based on a modified probabilistic neural network (PNN) with three innovations designed to reduce the computational and memory requirements, to speed training, and to decrease the false alarm rate. The utility of this new approach is illustrated with the use of four data sets extracted from simulated and laboratory-collected surface acoustic wave sensor array data. A competitive learning strategy, based on a learning vector quantization neural network, is shown to reduce the storage and computation requirements. The IPNN hidden layer requires only a fraction of the storage space of a conventional PNN. A simple distance-based calculation is reported to approximate the optimal kernel width of a PNN. This calculation is found to decrease the training time and requires no user input. A general procedure for selecting the optimal rejection threshold for a PNN-based algorithm using Monte Carlo simulations is also demonstrated. This outlier rejection strategy is implemented for an IPNN classifier and found to reject ambiguous patterns, thereby decreasing the potential for false alarms.

Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes.

Melagatran, a new, competitive and rapid inhibitor of thrombin with a molecular mass of 429 Da is described. Melagatran is well tolerated when administered in very high doses, and the oral bioavailability in the dog is relatively high. The aim of the study was to determine, in the preclinical setting, the degree of selectivity against the fibrinolytic system required for entering the clinical development phase. Melagatran was compared with two structurally similar thrombin inhibitors, inogatran and H 317/86. The potent inhibition of thrombin by melagatran was demonstrated by a low inhibition constant (Ki) for thrombin (0.002 micromol/l) and prolongation of clotting time to twice the control value in coagulation assays at low concentrations (0.010, 0.59 and 2.2 micromol/l for thrombin time, activated partial thromboplastin time and prothrombin time, respectively). Furthermore, thrombin-induced platelet aggregation was inhibited at the same concentration (IC50-value 0.002 micromol/l) as the Ki-value for thrombin. In two assays of global fibrinolysis, inhibition was observed at a concentration of 1.1 micromol/l in a euglobulin plasma fraction model, while no inhibition was observed at a concentration of < or = 10 micromol/l in a plasma model. In an in vivo model of endogenous fibrinolysis in the rat, inhibition of fibrinolysis was observed at > or = 1.0 micromol/l. In all assays, except the Ki-ratio determinations, the compounds could be graded with regard to selectivity against the fibrinolytic system: inogatran > melagatran > H 317/86. For melagatran, inhibition of fibrinolysis was not observed at concentrations below the upper limit of the proposed therapeutic plasma concentration interval (< 0.5 micromol/l). Thus, melagatran seems to have a sufficient selectivity against the fibrinolytic system, while H 317/86 was considered to be insufficient for clinical development.

In vitro flow dynamics of a new mechanical cardiac valve prosthesis--"tricusp".

The hydrodynamic performance of a newly developed JCL-trileaflet mechanical heart valve prostheses (Tricusp) was measured and compared with some of the currently most used heart valve prostheses types. All experiments were performed in an electrohydraulic, computer-controlled pulse duplicator simulating the left side of the human circulatory system. Testing conditions were set according to a Food and Drugs Administration interlaboratory comparison protocol, with cardiac outputs 3.0, 4.5, 6.5 or 8.0 l/min and a constant heart rate of 70 beats/min. Mean systolic pressure differences, volume and energy losses, dimensionless pressure losses and energy loss coefficients were calculated from the recorded pressure, volume and flow tracings. The results with the Tricusp valve were found to be as good, or even better than those with the currently most used commercially available bileaflet valves.

Chemiluminescence detection of hydrazine vapor.

An efficient, real-time chemiluminescence detector for hydrazine vapor, N(2)H(4)(g), is described, capable of monitoring sub part-per-billion levels of hydrazine in air. The catalytic oxidation of hydrazine by colloidal platinum forms an intermediate, oxidizing agent (e.g. OH or OOH) which subsequently oxidizes luminol, generating a chemiluminescence signal that is proportional to the hydrazine concentration. Major components of the instrument include a photomultiplier tube (PMT), a short length of glass tubing coiled directly in front of the PMT cathode surface, a vacuum pump for sampling the air, and a peristaltic pump for circulating the liquid reagent. The liquid reagent, a basic solution (pH 13) of luminol and colloidal platinum, is continuously recycled. The detection sequence is initiated by pumping the hydrazine vapor through a short length of teflon tubing that is concurrently transporting the liquid reagent. The liquid is separated from the gas stream in an impinger and quickly pumped to the PMT. We have evaluated the effect of solution pH, luminol and platinum concentrations, and air and liquid flow rates on the analytical characteristics of this system. A linear, dynamic detection range for hydrazine has been obtained from 1 to 2000 ppb in air, with an instrument response that is fully reversible and achieves plateau response in less than 2 min.

Progressive decline in renal function induces a gradual decrease in total hemoglobin and exercise capacity.

We examined 58 patients (38 men, 20 women; mean age: 45 +/- 12 years; body mass index: 24 +/- 4 kg/m2) with a glomerular filtration rate (GFR) ranging from 3 to 32 ml/min, in order to determine the effects of a progressive decline in renal function on total hemoglobin (THb) and exercise capacity. The THb ranged from 185 to 759 g and the hemoglobin concentration ranged from 66 to 151 g/l. Maximal exercise capacity ranged from 50 to 260 W (40-143% of the expected norm). Nearly all the patients interrupted their exercise tests due to general fatigue, leg tiredness or a combination of these factors. There was a significant partial correlation between THb and GFR after sex and age had been accounted for (r = 0.39; p < 0.005). Maximal exercise capacity and THb showed a significant partial correlation after sex, age and GFR had been accounted for (r = 0.27; p < 0.05). Maximal exercise capacity showed a significant partial correlation with GFR after sex, age and THb had been accounted for (r = 0.30; P < 0.05). In conclusion, there is a gradual decline in THb and maximal exercise capacity as uremia progresses. Anemia appears to be a contributory cause responsible for the decrease in maximal exercise capacity along with other factors pertinent to uremia per se.

Acute cobalt exposure and oxygen radical scavengers in the rat myocardium.

Excessive amounts of cobalt are cardiotoxic, although the mechanism for this toxicity remains unclear. We studied the effects of acute cobalt exposure on the activities of free radical scavengers in the myocardium in 5 groups of rats. Six rats served as a control group and were given a daily subcutaneous injection of 1 ml saline for 8 days. The other 4 groups of rats received a daily injection subcutaneously of cobalt chloride in doses of 1 mg/kg bw, 5 mg/kg bw, 20 mg/kg bw and 50 mg/kg bw, respectively for 8 days. There was a marked and dose-dependent accumulation of cobalt in the myocardium of the cobalt exposed rats. Creatine kinase, copper-zinc superoxide dismutase (CuZn-SOD) and alpha-tocopherol content did not differ between the control and the cobalt exposed groups. The activity of glutathione peroxidase increased, while the activity of manganese-superoxide dismutase (Mn-SOD) was significantly reduced in the cobalt exposed groups. There was an inverse relationship (r = 0.60, P < 0.0001) between the cobalt content and Mn-SOD activity in the myocardium. These results suggest that acute cobalt cardiotoxicity may involve a reduction of intrinsic scavengers resulting in an increased vulnerability to oxygen free radical toxicity.

Effects of renal failure on skeletal muscle.

In this cross-sectional study, we examined biopsies from the vastus lateralis muscle of 13 predialytic uremic men (mean age 46 +/- 8 years). Their average glomerular filtration rate was 14 +/- 7 ml/min x 1.73 m2 and their maximal exercise capacity, measured by standardized exercise test on a bicycle ergometer, was 184 +/- 45 W (94% of the expected norm). The proportion of type I fibers (type I%) in the uremic group was similar to that of the reference group (42 +/- 11 vs. 41 +/- 8% NS). The proportion of type IIA fibers (type IIA%) in the uremic group was higher than in the reference group (44 +/- 10 compared to 35 +/- 9%, p < 0.05). The proportion of type IIB fibers (type IIB%) was lower than in the reference group (13 +/- 8 vs. 21 +/- 8%, p < 0.05). Type I fiber area was similar to that of the reference group (4,768 +/- 1,033 vs. 4,627 +/- 1,112 microns 2, NS). Type IIA and type IIB fiber areas tended to be smaller than those of the reference group (type IIA fiber area: 4,515 +/- 929 vs. 5,213 +/- 1,288 microns 2, NS; type IIB fiber area: 3,953 +/- 1,066 vs. 4,406 +/- 1,582 microns 2, NS) with a type IIA area/type I area ratio which was significantly lower than in the reference group. Citrate synthase activity was 0.48 +/- 0.08 mu kat/g in the uremic group and 0.50 +/- 0.08 mu kat/g in the reference group, NS.(ABSTRACT TRUNCATED AT 250 WORDS)

The hemodynamic importance of atrial systole: a function of the kinetic energy of blood flow?

The relative importance of atrial systole on left ventricular filling was investigated at rest and during exercise in 25 patients with dual chamber pacemakers. The mean blood flow velocity over the mitral valve, the velocities of the rapid filling phase (E), the active filling phase (A), and the E/A ratio were determined by pulsed Doppler-echocardiography. The patients were first examined at rest during AV sequential pacing (DVI) at 70 and 104 beats/min. The investigation was subsequently repeated during atrial synchronous pacing (VDD) at rest and during supine submaximal exercise at workloads adjusted to achieve heart rates corresponding to those during DVI pacing. The mean blood flow velocity at rest did not differ between DVI and VDD pacing at 70 beats/min (0.46 vs 0.49 m/sec). When the resting heart rate was increased to 104 beats/min (DVI) the mean blood flow velocity increased to 0.56 msec (P < 0.001). At a corresponding heart rate during exercise (VDD) the velocity increased to 0.70 msec (P < 0.001). At a resting heart rate of 70 beats/min the E/A ratio (n = 14) did not differ significantly between DVI and VDD pacing. With an increased resting heart rate (DVI) the E/A ratio decreased from 0.94 +/- 0.45 to 0.78 +/- 0.18; NS. When the heart rate increased during exercise (VDD) the E/A ratio increased from 0.75 +/- 0.14 to 0.97 +/- 0.16; P < 0.001. There was a positive correlation between the increase of the mean blood flow velocity and the increase of the E/A ratio during exercise (r = 0.69, P < 0.01). No such correlation was found when the heart rate was changed at rest. Thus, the importance of atrial systole on ventricular filling diminishes during exercise in accordance with increasing blood flow velocity, which by physical principles is related to the kinetic energy. The relative importance of atrial systole is hence inversely correlated to the kinetic energy of the blood flow.