T. Van Der Werf

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.

Significance of smoking in patients receiving thrombolytic therapy for acute myocardial infarction. Experience gleaned from the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.

BackgroundDespite the fact that smoking is a well-established risk factor for the development of coronary artery disease, some investigators have noted that hospital mortality after acute myocardial infarction is lower in patients who smoke than in nonsmoking patients. To evaluate the association of smoking with mortality during hospitalization after thrombolytic therapy and 6 months afterward, we analyzed the results of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial. Methods and ResultsPatients were divided into three groups: nonsmokers (those who never smoked), ex-smokers, and active smokers. Multivariate and univariate comparisons were made with respect to baseline characteristics and clinical outcome. There were 2,366 nonsmokers, 2,244 ex-smokers, and 3,649 active smokers. The baseline characteristics of nonsmoking patients differed significantly from the ex-smokers and active smokers. The nonsmoking group included more women than the ex-smokers or active smokers (45% versus 10.6% and 17.6%, respectively), was older (67±10 years versus 64±10 years and 58±11 years), had a higher rate of diabetes mellitus (16.3% versus 11.1% and 7.5%), and had a worse Killip class at admission. Nonsmoking patients and ex-smokers experienced more in-hospital reinfarction than active smokers (4.7% and 5% versus 2.7%, p<0.0001, respectively). Nonsmokers experienced more in-hospital shock than the ex-smokers or active smokers (9.2% versus 6.4% and 5.8%, P<0.0001), stroke (1.9% versus 1.8% and 0.8%, p<0.0001), and bleeding (7.2% versus 6.5% and 4.4%, p<0.0001). They also experienced a higher in-hospital and 6-month mortality (12.8% and 17.6%) than ex-smokers (8.2% and 12.1%) or active smokers (5.4% and 7.8%) (p<0.0001). A multivariate analysis accounting for all baseline characteristics demonstrated a significant association between nonsmoking and increased hospital mortality, with an odds ratio of 1.42 (confidence limits, 1.15–1.72). Among active smokers, there was a nonsignificant trend for mortality rates to decrease with increasing numbers of cigarettes smoked per day. ConclusionsThis retrospective analysis indicates that smokers receiving thrombolytic therapy after acute myocardial infarction have significantly better hospital and 6-month outcome than nonsmokers or ex-smokers. However, smokers sustained their infarction at a significantly earlier age than nonsmokers, and strenuous efforts should continue to be made to decrease the incidence of new and continued smoking.

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.

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)

The vibratory innocent heart murmur in schoolchildren: difference in auscultatory findings between school medical officers and a pediatric cardiologist.

SummaryIn 810 schoolchildren heart auscultation was performed by both a school medical officer (SMO) and a pediatric cardiologist (PC). The prevalence for a grade 1, 2, or 3 vibratory innocent heart murmur (VIHM), a grade 2 or 3 VIHM, and a grade 3 VIHM heard by the PC was 41%, 13%, and 1%, respectively. The SMO noted such murmurs in 26%, 9%, and 1%, respectively. In 30% of the cases in which the PC had noted a grade 2 or 3 VIHM, the SMO agreed; in 30% of such cases the SMO did not hear any heart murmur. If the PC heard a grade 2 or 3 VIHM phonocardiography was performed in a case-control study in which the controls did not have a heart murmur (94 pairs). In four children with a grade 2 or 3 VIHM no heart murmur could be registered and in three other children the murmur did not have the typical diamond shape. In contrast, in three children without a heart murmur at school a VIHM was seen on the phonocardiogram. In 26 children with a phonocardiographically proven grade 2 or 3 VIHM the SMO did not hear any heart murmur. One child with a grade 3 VIHM (both by the PC and SMO) had a minor subvalvular aortic stenosis. There is quite a difference in auscultatory detection of a venous hum: 9% (PC) and 2% (SMO). The prevalence of the pulmonary ejection murmur is identical at 4%. The carotid bruit is heard in 4% (PC) and 2% (SMO). Pathologic murmurs were heard in 12 children by the PC, agreed by the SMO in two cases. Eight of the 12 pathologic murmurs were confirmed by further cardiologic examination and one was decided to be an innocent pulmonary ejection murmur. The auscultatory findings of 4 SMOs, who examined >100 children each, differ remarkably when compared separately to the results of the PC. Variation in intensity of the heart murmurs and difference in auscultatory skills explain the great difference in ausculatory findings between the PC and the SMO. Specialized training of SMO to recognize (pathological) heart murmurs is advocated.

The vibratory innocent heart murmur in schoolchildren: A case-control Doppler echocardiographic study

SummaryIn 810 schoolchildren (aged 5–14 years) the prevalence of a grade 1–3/6 vibratory innocent heart murmur (VIHM) is 41%. Restricted to a grade 2 or 3 VIHM, the prevalence is 14%, decreasing from 21% in the age-class 5–6 years to 8% for children 13–14 years of age. The prevalence of a grade 3 VIHM is 1%. Together with a matched control, 84 children with a grade 2 or 3 VIHM underwent further cardiologic examination including electrocardiography, phonocardiography, and Doppler echocardiography. A positive correlation was found between the presence of a VIHM and higher left ventricular voltages on the ECG, but within the normal range; lower heart rate; smaller diameter of the ascending aorta (AAO); and higher blood flow velocity and higher maximal acceleration of the blood flow in the LVOT and the AAO. In 40% of the children with a VIHM, a systolic aortic valve vibration was seen with a frequency ≥100 Hz and an amplitude ≥1 mm, whereas this type of vibration was present in only one case control. No significant difference was found concerning the prevalence of false tendons in the left ventricle, systolic and diastolic diameter of the left ventricle, systolic time intervals, and shortening fraction of the left ventricle. The VIHM is strongly associated with a smaller AAO, with higher velocity and acceleration of the blood flow in the LVOT and AAO, and with a vibratory phenomenon of the aortic valve, pointing towards the LVOT-aortic valve region as the site of origin of the VIHM.

Assessment of the opening angle of implanted Björk-Shiley prosthetic valves.

A method has been developed in which cineradiography is used for the assessment of the opening angle of implanted Bjork-Shiley prosthetic valves. The method is based on the fact that the ring and the disc, which are known to be circular, appear to be elliptical on x-ray films. The spatial position of the valve can be retrieved from the characteristics of these ellipses when vectoranalysis is applied. The methods accuracy does not depend on the position of the patient with respect to the direction of the x-ray beam. The accuracy of the method was demonstrated with the use of a phantom valve. The difference between the measured and the real opening angle was -0.7 +/- 1.8 degrees (mean +/- SD). Results were reproducible in patients to within -0.1 +/- 1.8 degrees. In 18 patients with normally functioning valves it could be demonstrated with frame-by-frame analysis (interval between frames 20 msec) that the valves opened very rapidly up to about 60 degrees. Closing patterns varied. In one of our patients with valvular thrombosis insufficient valvular opening could be demonstrated by our method before the patients complaints drew attention to the valvular dysfunction.

Feasibility of Cardiovascular Magnetic Resonance of Angiographically Diagnosed Congenital Solitary Coronary Artery Fistulas in Adults

OBJECTIVE To evaluate the use of cardiovascular magnetic resonance (CMR) to visualize angiographically-detected congenital coronary artery fistulas in adults. METHODS CMR techniques were used to study 13 patients, recruited from the Dutch Registry, with previously angiographically diagnosed fistulas. RESULTS Coronary fistulas were detected in 10 of 13 (77%) patients by CMR and, retrospectively, in two (92%) more. In 93% of these, it was possible to determine the origin and the outflow site of the fistulas. Cardiovascular magnetic resonance allowed demonstration of dilatation of the fistula-related coronary artery in all cases. Tortuosity of fistulas was detected in all visualized patients. Uni-or bilaterality of fistulas as seen on CAG was proven on CMR in all patients. Flow measurement could be performed in 8 patients. A fairly good correlation (r = 0.72) was found between angiographic (mean 6.2 mm, range 1-16) and cardiovascular magnetic resonance (mean 6.3 mm, range 3-15) measured fistulous diameters. CONCLUSIONS Cardiovascular magnetic resonance of congenital fistulas with clinical significant shunting is feasible and can provide additional physiological data complementary to the findings of conventional coronary angiography.

Is nonionic isotonic iohexol the contrast agent of choice for quantitative myocardial videodensitometry

SummaryAll currently used contrast media in coronary angiography induce a considerable hyperemic response interfering with the interpretation of circulation times derived from myocardial time-density curves. Aim of this study therefore, was to find a contrast agent with minimal hyperemic response. For this purpose 2, 4 and 6 ml of the nonionic isotonic low iodinated contrast agent iohexol (Omnipaque 140®) and 6 ml of a similarly low iodinated but still hypertonic solution of the ionic diatrizoate (Urographin 30%®) were administered into the left coronary artery of 8 anesthetized instrumented dogs. Heart rate was held constant by atrial pacing and left ventricular pressure, left ventricular dP/dt and mean and phasic coronary blood flow were recorded. To test the hypothesis that the hyperemic response to nonionic contrast media is partly due to an increase in inotropic state mediated by CA++ion influx, all measurements were repeated 30 minutes after intracoronary administration of 0.5 mg verapamil. For iohexol the increase in coronary blood flow was small but significant: 12±7%, 25±11% and 38±16% for the 2, 4 and 6 ml administrations, respectively (mean±s.d; p<0.01). For the diluted diatrizoate the increase in coronary blood flow was 65±23%. Increases for currently used contrast agents are on the order of 200–300%. After verapamil, the hyperemic response to iohexol decreased significantly to 9±5%, 20±8% and 29±12% for the 2, 4 and 6 ml administrations, respectively (p<0.01). The reaction to diatrizoate was not affected by verapamil. Moreover, there was a significant positive correlation between the increase in coronary blood flow and left ventricular dP/dt max under all conditions for all but one dog.We conclude that the isotonic, low iodinated nonionic contrast agent iohexol has only a moderate influence on coronary blood flow, which can be further attenuated by verapamil. By this approach, a more reliable assessment of circulation times from myocardial time-density curves obtained by digital subtraction angiography and videodensitometry becomes possible.