G.J.H. Uijen

LDL-apheresis atherosclerosis regression study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis

BACKGROUND Intensive lipid lowering may retard the progression of coronary atherosclerosis. LDL-apheresis has the potential to decrease LDL cholesterol to very low levels. To assess the effect of more aggressive lipid lowering with LDL-apheresis, we set up a randomized study in men with hypercholesterolemia and severe coronary atherosclerosis. METHODS AND RESULTS For 2 years, 42 men were treated with either biweekly LDL-apheresis plus medication or medication alone. In both groups a dose of simvistatin of 40 mg per day was administered. Baseline (mean+/-SD) LDL cholesterol was 7.8+/-1.9 mmol x L(-1) and 7.9+/-2.3 mmol x L(-1) in the apheresis and medication groups, respectively. The mean reduction in LDL cholesterol was 63% (to 3.0 mmol x L(-1)) and 47% (to 4.1 mmol x L(-1)), respectively. Primary quantitative coronary angiographic end points were changes in average mean segment diameter and minimal obstruction diameter. No differences between the apheresis and medication groups were found in mean segment diameter (-0.01+/-0.16 mm versus 0.03+/-0.16 mm, respectively) or in minimal obstruction diameter (0.01+/-0.13 mm versus 0.01+/-0.11 mm, respectively), expressed as means per patient. On the basis of coronary segment, mean percent stenosis of all lesions showed a tendency to decrease; only in the apheresis group more minor lesions disappeared in comparison to the medication group. On bicycle exercise tests, the time to 0.1 mV ST-segment depression increased significantly by 39% and the maximum level of ST depression decreased significantly by 0.07 mV in the apheresis group versus no changes in the medication group. CONCLUSIONS Two years of lipid lowering both with medication alone or LDL-apheresis with medication showed angiographic arrest of the progression of coronary artery disease. However, more aggressive treatment induced functional improvement, which may precede anatomic changes.

Aspirin Plus Coumarin Versus Aspirin Alone in the Prevention of Reocclusion After Fibrinolysis for Acute Myocardial Infarction Results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial

Background—Despite the use of aspirin, reocclusion of the infarct-related artery occurs in ≈30% of patients within the first year after successful fibrinolysis, with impaired clinical outcome. This study sought to assess the impact of a prolonged anticoagulation regimen as adjunctive to aspirin in the prevention of reocclusion and recurrent ischemic events after fibrinolysis for ST-elevation myocardial infarction. Methods and Results—At coronary angiography <48 hours after fibrinolytic therapy, 308 patients receiving aspirin and intravenous heparin had a patent infarct-related artery (Thrombolysis In Myocardial Infarction [TIMI] grade 3 flow). They were randomly assigned to standard heparinization and continuation of aspirin alone or to a 3-month combination of aspirin with moderate-intensity coumarin, including continued heparinization until a target international normalized ratio (INR) of 2.0 to 3.0. Angiographic and clinical follow-up were assessed at 3 months. Median INR was 2.6 (25 to 75th percentiles 2.1 to 3.1). Reocclusion (≤TIMI grade 2 flow) was observed in 15% of patients receiving aspirin and coumarin compared with 28% in those receiving aspirin alone (relative risk [RR], 0.55; 95% CI 0.33 to 0.90;P <0.02). TIMI grade 0 to 1 flow rates were 9% and 20%, respectively (RR, 0.46; 95% CI, 0.24 to 0.89;P <0.02). Survival rates free from reinfarction and revascularization were 86% and 66%, respectively (P <0.01). Bleeding (TIMI major and minor) was infrequent: 5% versus 3% (P =NS). Conclusions—As adjunctive to aspirin, a 3-month-regimen of moderate-intensity coumarin, including heparinization until the target INR is reached, markedly reduces reocclusion and recurrent events after successful fibrinolysis. This conceptual study provides a mechanistic rationale to further investigate the role of prolonged anticoagulation after fibrinolytic therapy.

Geometrical aspects of the interindividual variability of multilead ECG recordings

The ECG as measured from healthy subjects shows a considerable interindividual variability. This variability is caused by geometrical as well as by physiological factors. In this study, the relative contribution of the geometrical factors is estimated. In addition a method aimed at correcting for these factors is described. First, a measure (RV) for quantifying the overall variability is presented, and for healthy individuals its value is estimated as 0.52. Next, based on a simulation study using the individual (heart-lung-torso) geometry of 25 subjects, the variability caused by geometrical factors is estimated as 0.40, indicating that in healthy subjects the RV for healthy individuals resulting from electrophysiology is of the order of 0.33. In an evaluation of the correction procedure, applied to realistic, simulated body surface potentials, it is shown that RV caused by geometrical factors can be reduced from 0.40 to 0.06. When applying the correction procedure to measured ECG data no reduction of the RV value could be demonstrated. These results indicate that the involved procedure of the inverse computation of a cardiac equivalent source, at the present time, is of insufficient quality to cash in on the substantial reduction of RV values from 0.52 down to 0.33 that might be obtainable.

Mean transit time for the assessment of myocardial perfusion by videodensitometry.

The intrinsic limitations of coronary arteriography to predict the physiological effects of coronary obstructions are well known. Therefore, more direct assessments of the functional significance of coronary stenoses are becoming increasingly important. Study of contrast passage by electrocardiogram-triggered digital radiography has been proposed as a way of assessing changes in myocardial perfusion. The main problems in this approach are the limited time for motionless image acquisition, the potential alteration of vascular volume between different states, and the changing flow pattern induced by contrast agents. This has led to empiric substitution of mean transit time (Tmn) by other time parameters and to representation of vascular volume by maximal contrast intensity (Dmax). To avoid these problems, intact dogs were studied during almost motionless image acquisition of 20-25 consecutive paced heart beats obtained with synchronous radiographic pulses. In this way, unequivocal and reproducible determination of Tmn was possible. Constant and maximal vascular volume was created by continuous infusion of dipyridamole, and it was proved that coronary flow in this model was not influenced by contrast injections. Flow in the circumflex artery was measured by a ring mounted and calibrated Doppler probe. In each dog, flow in the circumflex artery was varied by a balloon occluder in 12 small steps (range, 0-174 +/- 42 ml/min). Inverse appearance time (1/Tapp), Dmax, Dmax/Tapp, inverse time of maximal intensity (1/Tmax), and 1/Tmn were calculated and the relations of these parameters to measured flow were investigated. Tmn proved to be the most reliable parameter for this purpose (r = 0.97 +/- 0.02; mean +/- SD), followed by Tmax (r = 0.93 +/- 0.04). Dmax failed to represent vascular volume but, in fact, showed a moderate correlation with flow (r = 0.78 +/- 0.22), as did Tapp (r = 0.64 +/- 0.18, 0.75 +/- 0.27, and 0.59 +/- 0.26 for the three definitions of Tapp used in this study). Dmax/Tapp correlated better with flow than either component separately. Our results indicate that the mean transit time calculated by videodensitometry can be used to accurately assess changes in myocardial perfusion strictly according to the original principles of indicator dilution theory.

Solution Methods of Electrical Field Problems in Physiology

The forward problem in electrophysiology¿the computation of the potential distribution due to a known electrical source in a known volume conductor¿is discussed. Three methods of solution are considered: 1) the finite difference method 2) a discretized integral equation method 3) the analytic method.

Low Density Lipoprotein Apheresis Improves Regional Myocardial Perfusion in Patients With Hypercholesterolemia and Extensive Coronary Artery Disease : The LDL-Apheresis Atherosclerosis Regression Study (LAARS)

OBJECTIVES In a randomized study we evaluated the effect of biweekly low density lipoprotein (LDL) apheresis plus simvastatin versus medication alone on regional myocardial perfusion. BACKGROUND In patients with severe hypercholesterolemia, diet and lipid-lowering drugs are often insufficient to achieve optimal LDL cholesterol values. Low density lipoprotein apheresis is a very effective lipid-lowering therapy. Assessment of regional myocardial perfusion enables evaluation of the functional state of the coronary circulation. METHODS We studied 42 patients with severe hypercholesterolemia and extensive coronary artery disease who were randomized to diet and simvastatin with or without biweekly LDL apheresis. Regional myocardial perfusion was assessed by digital subtraction angiography with videodensitometric calculation of hyperemic mean transit time (HMTT) of contrast medium at baseline and after 2 years of therapy. RESULTS Low density lipoprotein cholesterol decreased by 63% (to 3.0 mmol/liter) in the LDL apheresis group and by 47% (to 4.1 mmol/liter) in the medication group. Paired HMTT measurements were assessed in 43 regions in the LDL apheresis group and 35 regions in the medication group. In the LDL apheresis group, regional HMTT decreased over 2 years from 3.35 +/- 1.18 (mean +/- SD) to 2.87 +/- 0.82 s (-14%, p = 0.001), whereas no change in the medication group was observed: 2.95 +/- 1.06 to 2.96 +/- 0.90 s (p = NS). In the patient-based comparison, the mean change in HMTT was -0.45 s (-14%, p = 0.01) in the LDL apheresis group and -0.05 s (-2%, p = NS) in the medication group, respectively. Only exercise-induced ischemia improved in the LDL apheresis group. CONCLUSIONS Biweekly LDL apheresis plus simvastatin decreased time-averaged LDL cholesterol levels by an additional 31% (1.1 mmol/liter) compared with medication alone. After 2 years of therapy, regional myocardial perfusion improved in the LDL apheresis group and remained unchanged in the medication group. Thus, aggressive reduction of LDL cholesterol has a favorable effect on regional myocardial perfusion and alleviates ischemia.

On selecting a body surface mapping procedure.

Throughout the world, various procedures related to body surface mapping have evolved. The large differences in these procedures make multicenter studies difficult. This paper discusses the problems involved in selecting the number of leads, lead placement, and map format. Methods are highlighted that have been developed for pooling of the data as obtained by different centers. Recommendations are included to newcomers in the field. (The work stems from an international study, the Noninvasive Evaluation of the Myocardium, a study group sponsored by the European Commission, which has as one of its objectives the standardization of body surface mapping procedures.)

Concept of maximal flow ratio for immediate evaluation of percutaneous transluminal coronary angioplasty result by videodensitometry.

BackgroundIn the setting of percutaneous transluminal coronary angioplasty (PTCA), immediate information about the result of the intervention is important, whereas morphological parameters are often less reliable than in diagnostic coronary arteriography. Recently, a new videodensitometric method was introduced and validated in animal experiments, which allows accurate comparison of maximal myocardial perfusion between situations with different degrees of stenosis. This method uses mean transit time (Tmn) of the contrast agent at maximal hyperemia as a parameter for maximal flow and is strictly in accordance with indicated dilation theory. Methods and ResultsIn 40 patients with angina pectoris, single-vessel disease, and a positive exercise test at the time of acceptance for PTCA, this approach was applied for evaluation of the improvement of maximal flow achieved by the PTCA. Maximal vasodilation was induced immediately before and 15 minutes after PTCA by intracoronary administration of papaverine, and digital angiographic studies were performed. By special breath-holding instruction, almost motionless, triggered image acquisition was possible during 15-20 heartbeats. Excellent subtraction images could be obtained, and reliable determination of Tm, at maximal hyperemia was possible in 33 patients both before and after PTCA. The ratio between maximal flow after and before PTCA, called maximal flow ratio (MFR), was represented by the ratio between Tm, before and after the intervention and compared with the results of exercise testing 24-48 hours before and 7-10 days after the procedure. After correction for pressure changes, MFR was 2.2 ± 1.5 for the 33 dilated vessels and 1.0 ± 0.2 for 25 normal vessels serving as a control. In 94% of all patients, an MFR value of more than 1.6 or less than 1.6 discriminated between presence or absence of reversal of exercise test result from positive to negative. If on-line judgment of success was based upon angiographic parameters or measurement of trans-stenotic pressure gradient, the relation with noninvasive functional improvement was present only in 66% and 74% of all patients, respectively. A definite range of what can be called normal Tmn at maximal hyperemia could be distinguished, and post-PTCA values for successfully dilated arteries returned completely to this normal range. ConclusionsAccurate comparison of maximal myocardial perfusion before and after PTCA is possible in man, improvement of maximal flow is highly related to functional improvement as indicated by exercise test results, and, therefore, this method provides a straightforward way for on-line evaluation of the result of the intervention. (Circulation 1991;83:854–865)

Accuracy of QRS detection in relation to the analysis of high-frequency components in the electrocardiogram

The detection of high-frequency components in the QRS complex by means of coherent signal averaging is affected by inaccuracy in the time reference. Jitter of the time reference or trigger, which is derived from the low-frequency QRS complex, will be caused by the noise in the QRS complex. A theory is developed by which the trigger jitter can be predicted from the properties of signal and noise for a system consisting of a filter and a single-level, dual-level or peak detector. The theory is applicable when the noise is additive and, under certain conditions, also when the noise is multiplicative. Using this theory the trigger jitter of a given filter-level detection system is compared with that of an optimal detection system consisting of a matched filter and peak detector. The theoretical trigger jitter of the above-mentioned detectors has been computer for e.c.g. recordings of 23 individuals, as a function of different filter settings and and with the assumption that the noise was additive. This resulted in an average trigger jitter of 0·2±0·1 ms for the optimal system, while for the peak detector and the dual level detector the jitter was slightly higher provided that the QRS complexes were symmetrical after filtering. With the effects of ventilation taken into account (multiplicative noise) it is shown that dual-level detection is considerably more accurate than single-level detection. A description of the dual-level detector is also presented.

Interindividual variability of multilead electrocardiographic recordings: influence of heart position.

The electrocardiogram (ECG) of normal, healthy subjects shows a large interindividual variability. Part of this variability is due to the heart position and orientation relative to the electrodes. In this report, the interindividual variability is quantified using the relative variability measure, computed as the averaged standard deviation in the ECGs, scaled by the average root mean square of the ECGs. The relative variability in the QRS complex is estimated as 0.52. The heart position and orientation relative to the lead positions is documented in 25 normal subjects. The long axis angle varies considerably among the subjects (27.1+/-8.8 degrees to the transversal plane and 38 degrees +/-5 degrees to the frontal plane). Moving the electrodes in the frontal plane to a position relative to a common reference point at the base of the heart (shift: 0.8+/-0.7 cm leftward and 2.4+/-2.3 cm downward) did not reduce the interindividual variability.