J. Larry Klein

Beneficial Effects of Cholesterol-Lowering Therapy on the Coronary Endothelium in Patients with Coronary Artery Disease

BACKGROUND Impaired endothelium-mediated relaxation contributes to vasospasm and myocardial ischemia in patients with coronary artery disease. We hypothesized that cholesterol-lowering therapy with the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin could improve endothelium-mediated responses in patients with coronary atherosclerosis. METHODS In a randomized, double-blind, placebo-controlled trial, we studied coronary endothelial responses in 23 patients randomly assigned to either lovastatin (40 mg twice daily; 11 patients) or placebo (12 patients) plus a lipid-lowering diet (American Heart Association Step 1 diet). Patients were studied 12 days after randomization and again at 5 1/2 months. These patients had total cholesterol levels ranging from 160 to 300 mg per deciliter (4.1 to 7.8 mmol per liter) and were undergoing coronary angioplasty. At the initial and follow-up studies, patients received serial intracoronary infusions (in a coronary artery not undergoing angioplasty) of acetylcholine to assess endothelium-mediated vasodilatation. The responses of the coronary vessels were analyzed with quantitative angiography. RESULTS The patients in the placebo and lovastatin groups had similar responses to acetylcholine at a mean of 12 days of therapy (expressed as the percentage of change in diameter in response to acetylcholine doses of 10(-9) M, 10(-8) M, 10(-7) M, and 10(-6) M). In the placebo group, the respective mean (+/- SE) changes were 1 +/- 2, 0 +/- 2, -2 +/- 4, and -19 +/- 4 percent; in the lovastatin group, they were -2 +/- 2, -4 +/- 4, -12 +/- 5, and -16 +/- 7 percent (P = 0.32). (Coronary-artery constriction is reflected by negative numbers). The responses to acetylcholine in the placebo group after a mean of 5.5 months of therapy were -3 +/- 3, -1 +/- 2, -8 +/- 4, and -18 +/- 5 percent, respectively; there was significant improvement in the lovastatin group, which had responses of 3 +/- 3, 3 +/- 3, 0 +/- 2, and 0 +/- 3 percent (P = 0.004). CONCLUSIONS Cholesterol lowering with lovastatin significantly improved endothelium-mediated responses in the coronary arteries of patients with atherosclerosis. Such improvement in the local regulation of coronary arterial tone could potentially relieve ischemic symptoms and signal the stabilization of the atherosclerotic plaque.

Endovascular β-Radiation to Reduce Restenosis After Coronary Balloon Angioplasty Results of the Beta Energy Restenosis Trial (BERT)

BACKGROUND In the porcine overstretch injury model of restenosis, endovascular beta-radiation reduces neointima formation. To determine whether this therapy could be applied to patients with coronary artery disease, a special device was developed to allow delivery of 12 encapsulated 90Sr/Y sources, measuring a total of 30 mm, to various sites within the coronary arterial tree. This study was designed to evaluate the feasibility of the delivery of 12, 14, or 16 Gy at 2 mm after balloon angioplasty of stenoses of native coronary vessels. METHODS AND RESULTS Delivery of beta-radiation was attempted in 23 patients after successful balloon angioplasty. Source delivery was successful in 21 of the 23 patients (91%). There was no in-hospital or 30-day morbidity or mortality. Follow-up quantitative coronary arteriography in 20 patients demonstrated a late loss of 0.05 mm, a late loss index of 4%, and a restenosis rate of 15%. The use of the beta-emitter 90Sr/Y significantly reduced treatment time and operator exposure compared with previous trials with the gamma-emitter 192Ir. CONCLUSIONS In this study, the administration of endovascular beta-radiation after angioplasty was safe and feasible and substantially altered the postangioplasty late lumen loss, resulting in a lower-than-expected rate of restenosis. On the basis of these encouraging results, a multicenter, randomized trial with operators and patients blinded to treatment assignment is planned.

Lack of Effect of Lovastatin on Restenosis after Coronary Angioplasty

BACKGROUND Experimental and clinical observations suggest that lowering serum lipid levels may reduce the risk of restenosis after coronary angioplasty. We report the results of a prospective, randomized, double-blind trial evaluating whether lowering lipid levels with lovastatin can prevent or delay restenosis after angioplasty. METHODS Seven to 10 days before angioplasty, we randomly assigned eligible patients to receive lovastatin (40 mg orally twice daily) or placebo. Patients who underwent successful, complication-free, first-time angioplasty of a native vessel (the index lesion) continued to receive therapy for six months, when a second coronary angiogram was obtained. The primary end point was the extent of restenosis of the index lesion, as assessed by quantitative coronary arteriography. Of 404 patients randomly assigned to study groups, 384 underwent angioplasty; 354 of the procedures were successful, and 321 patients underwent angiographic restudy at six months. RESULTS At base line, the patients in the lovastatin group (n = 203) and the placebo group (n = 201) were similar with respect to demographic clinical, angiographic, and laboratory characteristics. At base line the mean (+/- SD) degree of stenosis, expressed as a percentage of the diameter of the vessel, was 64 +/- 11 percent in the lovastatin group, as compared with 63 +/- 11 percent in the placebo group (P = 0.22). Despite a 42 percent reduction in the serum level of low-density lipoprotein cholesterol in the lovastatin group, after six months of treatment the amount of stenosis seen in the second angiogram was 46 +/- 20 percent in the placebo group, as compared with 44 +/- 21 percent in the lovastatin group (P = 0.50). Similarly, there were no significant differences in minimal luminal diameter or other measures of restenosis. A trend was noted toward more myocardial infarctions in the lovastatin group, as a result of acute vessel closure or restenosis at the site of angioplasty, but there were no other important differences between the two groups in the frequency of fatal or nonfatal events at six months. CONCLUSIONS Treatment with high-dose lovastatin initiated before coronary angioplasty does not prevent or delay the process of restenosis in the first six months after the procedure.

Effect of Cholesterol-Lowering Therapy on Coronary Endothelial Vasomotor Function in Patients With Coronary Artery Disease

BACKGROUND Improved endothelial function may contribute to the beneficial effects of cholesterol-lowering therapy. METHODS AND RESULTS In this randomized, double-blind study, we compared the effect of 6 months of simvastatin (40 mg/d) treatment with that of placebo on coronary endothelial vasomotor function in 60 patients with coronary artery disease. Simvastatin lowered LDL-cholesterol by 40+/-12% from 130+/-28 mg/dL (P<0.001). Peak intracoronary acetylcholine infusion produced epicardial coronary constriction at baseline in both the simvastatin (-17+/-13%) and placebo (-24+/-16%) groups. After treatment, acetylcholine produced less constriction in both groups (-12+/-19% and -15+/-14%, respectively, P=0.97). The increase in coronary blood flow during infusion of the peak dose of substance P was blunted at baseline in both the simvastatin (42+/-50%) and placebo (55+/-71%) groups, reflecting impaired endothelium-dependent dilation of coronary microvessels. After treatment, the flow increase was 82+/-81% in the simvastatin group and 63+/-53% in the placebo group (P=0.16). CONCLUSIONS Six months of cholesterol-lowering therapy has no significant effect on coronary endothelial vasomotor function in the study population of patients with coronary artery disease and mildly elevated cholesterol levels. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.

A quantitative evaluation of the three dimensional reconstruction of patients' coronary arteries

Background: Through extensive training and experience angiographers learn to mentally reconstruct the three dimensional (3D) relationships of the coronary arterial branches. Graphic computer technology can assist angiographers to more quickly visualize the coronary 3D structure from limited initial views and then help to determine additional helpful views by predicting subsequent angiograms before they are obtained. Methods: A new computer method for facilitating 3D reconstruction and visualization of human coronary arteries was evaluated by reconstructing biplane left coronary angiograms from 30 patients. The accuracy of the reconstruction was assessed in two ways: 1) by comparing the vessels centerlines of the actual angiograms with the centerlines of a 2D projection of the 3D model projected into the exact angle of the actual angiogram; and 2) by comparing two 3D models generated by different simultaneous pairs on angiograms. The inter- and intraobserver variability of reconstruction were evaluated by mathematically comparing the 3D model centerlines of repeated reconstructions. Results: The average absolute corrected displacement of 14,662 vessel centerline points in 2D from 30 patients was 1.64 ± 2.26 mm. The average corrected absolute displacement of 3D models generated from different biplane pairs was 7.08 ± 3.21 mm. The intraobserver variability of absolute 3D corrected displacement was 5.22 ± 3.39 mm. The interobserver variability was 6.6 ± 3.1 mm. Conclusions: The centerline analyses show that the reconstruction algorithm is mathematically accurate and reproducible. The figures presented in this report put these measurement errors into clinical perspective showing that they yield an accurate representation of the clinically relevant information seen on the actual angiograms. These data show that this technique can be clinically useful by accurately displaying in three dimensions the complex relationships of the branches of the coronary arterial tree.

Transesophageal dobutamine stress echocardiography in the evaluation of coronary artery disease

OBJECTIVES The goal of this study was to determine the feasibility, safety, sensitivity and specificity of transesophageal dobutamine stress echocardiography for the detection of coronary artery disease. BACKGROUND Dobutamine stress echocardiography has been shown to be an extremely sensitive and specific noninvasive technique for the detection of myocardial ischemia. However, inadequate transthoracic images preclude the use of dobutamine stress echocardiography in a small but significant group of patients. Transesophageal echocardiography provides better resolution than that obtained with routine transthoracic imaging. METHODS Patients scheduled for routine cardiac catheterization underwent transesophageal dobutamine stress echocardiography. All patients underwent coronary arteriography within 48 h of the study, and lesion severity was determined by quantitative coronary angiography. Significant coronary obstruction was defined as stenosis > 50%. RESULTS Fifty-one male patients were enrolled in the study; six were excluded for technical reasons. There were no adverse outcomes or complications. Of 27 patients with significant coronary artery disease, 22 had positive study results (sensitivity 82%). Of 13 patients without significant obstructive coronary disease, 1 had a false positive study result (specificity 93%). In patients with a minimal lumen diameter < 1.25 mm, sensitivity was > 80%, and in patients with a minimal lumen diameter > 1.5 mm, sensitivity was < 70%, suggesting that lesions with a minimal lumen diameter < 1.25 mm are more likely to be physiologically significant. CONCLUSIONS Transesophageal dobutamine stress echocardiography is a feasible, safe and accurate technique for the detection of myocardial ischemia. There are inherent limitations to this technique in that transesophageal echocardiography must be performed. Transesophageal dobutamine stress echocardiography may allow extension of dobutamine stress testing to patients with inadequate transthoracic echocardiographic imaging and may provide an opportunity for further research applications.

Performance standards and edge detection witk computerized quantitative coronary arteriography

Quantitative coronary angiography (QCA) has become an important tool for evaluating coronary angiograms. Many methodologic factors, such as the choice of frame to analyze, the selection of the “normal,” segment and the method of edge detection used may affect the results of QCA. The sequential steps in performing QCA, including a comparison of visual and automated edgedetection methodologies, were evaluated using 12 precision-drilled phantoms and 20 patient films. Normal diameter, minimal lumen diameter, and diameter stenosis were measured. In the phantom studies, the measurements from both visual and automated systems correlated well with the true measurements of the phantoms and between systems (all r values >0.92). To study the difference between methodologies on QCA results as influenced by the choice of frame and normal segment analyzed, the patient films were analyzed independently in 3 separate rounds of interpretation. In round 1, each systems operator individually chose frames and normal segments for analysis. In round 2, both systems analyzed the same preselected frames, but independently chose normal segments. In round 3, both systems analyzed the same preselected normal segments and frames. The intersystem correlations between visual and automatic systems for rounds 1, 2, and 3 were: normal diameter, r = 0.25, r = 0.37, and r = 0.75, respectively; minimal lumen diameter, r = 0.79, r = 0.86, and r =0.85, respectively; and diameter stenosis, r = 0.65, r =0.73, and r = 0.87, respectively. The manual edge-detection and automated edge-detection systems used in this study are reasonably accurate and consistent on phantom studies. In patient studies, the nonautomated processes (choice of frame and normal segment for analysis) produced significant differences in the QCA results, thus illustrating that operator-dependent factors other than edge detection are very important in QCA.

Superposición en tres dimensiones de las imágenes de perfusión miocárdica y de la coronariografía

Introduccion y objetivos Integrar la informacion anatomica y funcional en pacientes con cardiopatia isquemica es una tarea habitual en la practica diaria del cardiologo. El objetivo de este trabajo es presentar una metodologia de unificacion tridimensional de la informacion anatomica relativa a las coronarias epicardicas, proveniente de la coronariografia, con la informacion fisiologica de perfusion tisular procedente de la tomogammagrafia de perfusion miocardica. Metodos Se seleccionaron 3 pacientes programados, por criterios clinicos, para revascularizacion coronaria percutanea y con enfermedad de un solo vaso (descendente anterior, coronaria derecha y circunfleja). Las imagenes coronariograficas biplanares se obtuvieron antes y despues de la dilatacion. Durante la oclusion coronaria se administro una dosis de 99mTc-tetrofosmina y, una vez finalizada la dilatacion, se obtuvieron las imagenes de perfusion miocardica correspondientes a la oclusion. La tomogammagrafia de control en reposo se repitio dos dias despues. Mediante una metodologia propia se generaron los contornos epicardicos de las imagenes de perfusion miocardica y sobre ellos se superpuso el arbol coronario tridimensional proveniente de la coronariografia. Resultados Se logro una correcta reconstruccion tridimensional del contorno epicardico y del arbol coronario completo en los 3 pacientes. La imagen unificada en tres dimensiones presento una excelente concordancia entre la extension de los defectos de perfusion y la distribucion anatomica del vaso ocluido. Conclusiones La superposicion tridimensional de las imagenes de perfusion miocardica y de la coronariografia es tecnicamente posible. Ello permite integrar la informacion anatomica y funcional de cara a facilitar la toma de decisiones por parte del cardiologo y mejorar el manejo del paciente coronario.

Aggressive Lipid Lowering in Postcoronary Angioplasty Patients With Elevated Cholesterol (the Lovastatin Restenosis Trial)

A substudy of the Lovastatin Restenosis Trial in patients with elevated cholesterol (>200 mg/dl) showed no evidence of an effect of aggressive lipid lowering on restenosis, confirming the results of the main trial.

Registration of multimodal 3D cardiac information using the iterative closest-point approach

A new implementation of the iterative closest point method for automatic registration is introduced. It is designed to unify three-dimensional models of the coronary artery tree created from biplane angiograms with three-dimensional models of the left ventricular epicardial surface created from perfusion SPECT. The speed and efficacy of the technique is evaluated using simulations and five patient studies. The technique is shown to be fast and quantitatively accurate in the simulations; evaluations of the results in patients are also satisfactory.