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Background: In vivo testing of the lipid depletion hypothesis in human beings during lipid-modifying therapy has not been possible until recent developments in magnetic resonance imaging (MRI)., Trial Design: The Carotid Plaque Composition Study is a prospective, randomized study designed to test the lipid depletion hypothesis in vivo. One hundred twenty-three subjects with coronary artery disease (CAD) or carotid disease and with levels of apolipoprotein B > or = 120 mg/dL (low-density lipoprotein levels 100-190 mg/dL) were enrolled and randomized to (1) single therapy--atorvastatin alone, placebos for extended release (ER)-niacin and colesevelam; (2) double therapy--atorvastatin plus ER-niacin (2 g/d), and placebo for colesevelam; (3) triple therapy--atorvastatin, ER-niacin, plus colesevelam (3.8 g/d). All subjects will undergo MRI scans of bilateral carotid arteries at baseline and annually for 3 years for a total of 4 examinations while on active therapy. Among these 123 subjects with mean age of 55 years and mean body mass index of 30 kg/m2, 73% are male, 43% have a family history of premature cardiovascular disease, 37% have had a previous myocardial infarction, 80% have clinically established CAD, 52% are hypertensive, 12% have diabetes, 23% are current smokers, and 47% meet the criteria for metabolic syndrome. The baseline carotid disease is evaluated using a MRI-modified American Heart Association lesion type definition. Of the 123 enrolled subjects, 40% have type III lesions with small eccentric plaque, 52% have type IV to V lesions with a necrotic core, and only 4% have calcified plaque based on the most diseased carotid location., Conclusions: The Carotid Plaque Composition Study uses a state-of-the-art imaging technology and comprehensive lipid management to test the plaque lipid depletion hypothesis in CAD subjects.

Background and Objectives: Slower blood flow in the setting of acute myocardial infarction (MI) has been related to adverse outcomes, but the relationship of coronary blood flow after percutaneous transluminal coronary angioplasty (PTCA) in the setting of acute coronary syndromes to adverse outcomes and restenosis has not been well described. We sought to evaluate the correlates of pre- and post-PTCA coronary blood flow to shed light on potential modifiable determinants., Methods: The RESTORE trial (Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis) was a randomized, double-blind, placebo-controlled trial of tirofiban in patients undergoing balloon angioplasty or directional atherectomy within 72 hours of occurrence of either unstable angina pectoris or acute MI. Coronary blood flow was assessed with the corrected TIMI frame count (CTFC), and clinical outcomes were assessed at 30 days., Results: In addition to tighter and longer minimum lumen diameters (MLDs), the multivariate correlates of slower flow before PTCA also included the presence of thrombus, collaterals, left coronary artery lesion location, acute MI, and >8F catheter size. As well as the above variables, type C and D dissection grades were related to slower post-PTCA CTFC. Death, or the composite of death/MI/coronary artery bypass graft at 30 days, was more frequent among patients with slower post-PTCA CTFCs and those with post-PTCA thrombus. In a multivariate model correcting for reference segment diameter and MLD, the post-PTCA CTFC was an independent predictor of late lumen loss and the follow-up MLD at 6 months. As a single index that integrates functional and anatomical aspects of the post-PTCA results, the ratio of CTFC/MLD was associated with death/MI by 30 days., Conclusions: In addition to MLD, variables such as the presence of thrombus, left coronary artery lesion location, and dissection grade also are associated with slower coronary blood flow after PTCA. In turn, post-PTCA CTFCs were an independent predictor of late lumen loss and follow-up MLDs. Furthermore, patients who die or who sustain other adverse cardiac events have slower coronary blood flow and greater thrombus burden after PTCA.

It is unclear how agents designed to promote angiogenesis in the human heart affect the arteriographic appearance of the collateral circulation. Possible changes in collateral vessels include new collateral vessels arising from epicardial arteries, new branches emanating from existing collateral vessels, wider or longer collateral vessels, and higher dye transit rates that result in improved recipient vessel filling. Given the multiple mechanisms by which these new agents may improve myocardial perfusion, a rigorous, systematic, and comprehensive analysis of coronary arteriograms is required to discern the true mechanism of benefit. The method of analysis must account for potential changes in collateral blood flow, number, branching pattern, and length as well as changes in recipient vessel filling. The ability to detect differences between intricate networks of vessels in an angiographic study is dependent on maintaining consistency in cinefilming as well as the core laboratory methods between time points. In this report, we describe the methodology our angiographic core laboratory has found to be most effective to evaluate these very complex angiograms and attempt to capture all the possible modalities of angiogenesis.

A mechanical injection was used to determine the impact of injection rate on the TIMI frame count. The 1.0-ml/s increase in hand injection rates from the 10th to 90th percentiles for angiographers is associated with a minor decrease of <2 frames that is <7% of the corrected TIMI frame count.

To date, there have been no quantitative in vivo assessments of contrast volumes and injection rates using modern high flow catheters during coronary angiography. Contrast volumes (n = 554), injection durations (n = 563), and injection rates (n = 498) were collected during 88 cardiac catheterizations. With increasing cathetersize (6, 7, and 8 French), injection volume increased (P < 0.0001), duration decreased (P < 0.0001), and rate increased (P < 0.0001). Compared with injections into the right coronary artery, left coronary artery injections were larger (7.1 +/- 0.1 cc vs. 4.8 +/- 0.1 cc, p < 0.0001), longer (3.6 +/- 0.05 sec vs 3.0 +/- 0.07 sec, P < 0.0001) and faster (2.1 +/- 0.04 cc/sec vs. 1.7 +/- 0.06 cc/sec, P < 0.0001). Patients with a significant stenosis in the left main or proximal right coronary artery received less contrast (P < 0.0001) more slowly (P < 0.0001) over a similar duration of injection (P = NS). When collaterals arose from the injected artery, angiographers injected more contrast (P < 0.001) over a longer period (P < 0.0001) more slowly (P < 0.0001). Catheter size and the injected vessel's location and anatomy significantly affect coronary catheterization injection technique.

The survival benefit following a reperfusion strategy, be it pharmacologic or mechanical, appears to be due to both full and early reperfusion. While the TIMI Flow Grade classification scheme has been a useful tool to assess coronary blood flow in acute syndromes, it has several limitations. A newer method of assessing coronary blood flow called the Corrected TIMI Frame Count method has the following advantages: (1) it is a continuous quantitative variable rather than a categorical qualitative variable; (2) the flow in the non-culprit artery is not assumed to be normal as it is in the assessment of TIMI Grade 3 Flow; (3) there is simplified reporting of reperfusion efficacy through the use of a single number instead of expressing the data in 2 to 4 categories; (4) because a single number rather than 4 categories is used to report the data, there is more efficient use of the dataset by increasing the statistical power; and finally (5) coronary flow can be expressed in intuitive terms (e.g. time or cm/sec for strategy A versus time or cm/sec for strategy B). This paper reviews the history of the open artery hypothesis and recent advances in the field.

Background: Although the Thrombolysis in Myocardial Infarction flow grade system is a widely used index of coronary blood flow, it has important limitations. We recently described a new continuous measure of blood flow in native coronary arteries, the Thrombolysis in Myocardial Infarction frame count (TFC), and sought to extend this method to coronary artery bypass grafts., Methods: We retrospectively analyzed cinefilms of patients' status after coronary artery bypass grafting, excluding patients with recent myocardial infarction and grafts with stenoses in the graft or native vessel. We counted the cineframes required for dye to travel from the ostium of the graft to the graft anastomotic site (TFCg) and to a standardized distal coronary landmark (TFC)., Results: For all vein grafts combined, TFCg was 19.2+/-5.7 frames (mean+/-SD, n = 93) and the TFC was 33.9+/-8.0 frames (n = 67). The upper limits for "normal" flow, calculated from the 95% confidence intervals, were 31 frames for TFCg and 50 frames for TFC., Conclusions: The Thrombolysis in Myocardial Infarction frame counting method has now been extended to normal saphenous vein grafts, and normal reference values are provided.

The Thrombolysis In Myocardial Infarction (TIMI) frame count is a relative index of coronary flow that measures time by counting the number of frames required for dye to travel from the ostium to a standardized coronary landmark in a cineangiogram filmed at a known speed (frames/s). We describe a new method to measure distance along arteries so that absolute velocity (length divided by time) and absolute flow (area x velocity) may be calculated in patients undergoing percutaneous transluminal coronary angiography (PTCA). After PTCA, the guidewire tip is placed at the coronary landmark and a Kelly clamp is placed on the guidewire where it exits the Y-adapter. The guidewire tip is then withdrawn to the catheter tip and a second Kelly clamp is placed on the wire where it exits the Y-adapter. The distance between the 2 Kelly clamps outside the body is the distance between the catheter tip and the anatomic landmark inside the body. Velocity (cm/s) may be calculated as this distance (cm) divided by TIMI frame count (frames) x film frame speed (frames/s). Flow (ml/s) may be calculated by multiplying this velocity (cm/s) and the mean cross-sectional lumen area (cm2) along the length of the artery to the TIMI landmark. In 30 patients, velocity increased from 13.9 +/- 8.5 cm/s before to 22.8 +/- 9.3 cm/s after PTCA (p <0.001). Despite TIMI grade 3 flow both before and after PTCA in 18 patients, velocity actually increased 38%, from 17.0 +/- 5.4 to 23.5 +/- 9.0 cm/s (p = 0.01). For all 30 patients, flow doubled from 0.6 +/- 0.4 ml/s before to 1.2 +/- 0.6 ml/s after PTCA (p <0.001). In the 18 patients with TIMI grade 3 flow both before and after PTCA, flow increased 86%, from 0.7 +/- 0.3 to 1.3 +/- 0.6 ml/s (p = 0.001). Distance along coronary arteries (length) can be simply measured using a PTCA guidewire. This length may be combined with the TIMI frame count to calculate measures of absolute velocity and flow that are sensitive to changes in perfusion. TIMI grade 3 flow is composed of a range of velocities and flows.

Background: Although the Thrombolysis in Myocardial Infarction (TIMI) flow grade is valuable and widely used qualitative measure in angiographic trials, it is limited by its subjective and categorical nature., Methods and Results: In normal patients and patients with acute myocardial infarction (MI) (TIMI 4), the number of cineframes needed for dye to reach standardized distal landmarks was counted to objectively assess an index of coronary blood flow as a continuous variable. The TIMI frame-counting method was reproducible (mean absolute difference between two injections, 4.7 +/- 3.9 frames, n=85). In 78 consecutive normal arteries, the left anterior descending coronary artery (LAD) TIMI frame count (36.2 +/- 2.6 frames) was 1.7 times longer than the mean of the right coronary artery (20.4 +/- 3.0) and circumflex counts (22.2 +/- 4.1, P < .001 for either versus LAD). Therefore, the longer LAD frame counts were corrected by dividing by 1.7 to derive the corrected TIMI frame count (CTFC). The mean CTFC in culprit arteries 90 minutes after thrombolytic administration followed a continuous unimodal distribution (there were not subpopulations of slow and fast flow) with a mean value of 39.2 +/- 20.0 frames, which improved to 31.7 +/- 12.9 frames by 18 to 36 hours (P < .001). No correlation existed between improvements in CTFCs and changes in minimum lumen diameter (r=-.05, P=.59). The mean 90-minute CTFC among nonculprit arteries (25.5 +/- 9.8) was significantly higher (flow was slower) compared with arteries with normal flow in the absence of acute MI (21.0 +/- 3.1, P < .001) but improved to that of normal arteries by 1 day after thrombolysis (21.7 +/- 7.1, P=NS)., Conclusions: The CTFC is a simple, reproducible, objective and quantitative index of coronary flow that allows standardization of TIMI flow grades and facilitates comparisons of angiographic end points between trials. Disordered resistance vessel function may account in part for reductions in flow in the early hours after thrombolysis.

Background: Precise knowledge of the expected "normal" lumen diameter at a given coronary anatomic location is a first step toward developing a quantitative estimate of coronary disease severity that could be more useful than the traditional "percent stenosis.", Methods and Results: Eighty-three arteriograms were carefully selected from among 9,160 consecutive studies for their smooth lumen borders indicating freedom from atherosclerotic disease. Of these, 60 men and 10 women had no abnormalities of cardiac function, seven men had idiopathic dilated cardiomyopathy, and six men had left ventricular hypertrophy associated with significant aortic stenosis. Lumen diameter was measured at 96 points in 32 defined coronary segments or major branches. Measurements were scaled to the catheter, corrected for imaging distortion, and had a mean repeat measurement error of 0.12 mm. When sex, anatomic dominance, and branch length were accounted for, normal lumen diameter at each of the standard anatomic points could usually be specified with a population variance of +/- 0.6 mm or less (SD) and coefficient of variation of less than 0.25 (SD/mean). For example, the left main artery measured 4.5 +/- 0.5 mm, the proximal left anterior descending coronary artery (LAD) 3.7 +/- 0.4 mm, and the distal LAD 1.9 +/- 0.4 mm. For the LAD, lumen diameter was not affected by anatomic dominance (right versus left), but for the right coronary artery, proximal diameter varied between 3.9 +/- 0.6 and 2.8 +/- 0.5 mm (p less than 0.01) and for the left circumflex, between 3.4 +/- 0.5 and 4.2 +/- 0.6 mm (p less than 0.01). Women had smaller epicardial arterial diameter than men (-9%; p less than 0.001), even after normalization for body surface area (p less than 0.01). Branch artery caliber was unaffected by the anatomic dominance but increased with branch length, expressed as a fraction of the origin-to-apex distance (p less than 0.001). Lumen diameter was not affected by age or by vessel tortuosity but was significantly increased among men with left ventricular hypertrophy (+ 17%; p less than 0.001) or dilated cardiomyopathy (+ 12%; p less than 0.001)., Conclusions: This is a reference normal data set against which to compare lumen dimensions in various pathological states. It should be of particular value in the investigation of diffuse atherosclerotic disease.

The clinically important coronary segmental anatomy has been described in a format useful for quantitative analysis and standardized display. We have determined the intrathoracic location and course of each of the 23 coronary artery segments and branches commonly used for clinical description of disease. Measurements were averaged from perpendicular angiographic view-pairs in 37 patients with normal-sized hearts. Each segment or branch is described by several points along its course; each point is specified in polar coordinates as the radial distance from the principal coronary ostium and by angles about the patient, corresponding to those describing rotation in c-arm radiographic systems. This computer-assisted measurement method is accurate to within +/- 0.2 cm (SD) and +/- 2 degrees in phantom studies. Coronary segment location among a group of normal-sized hearts can be specified to within +/- 1.0 cm (SD). For example, the left anterior descending coronary artery segment at the apex of the heart is 12.2 +/- 1.0 cm from the left coronary ostium, 32 +/- 4 degrees to the left of the anterioposterior axis, and at 46 +/- 7 degrees of caudal angulation. There are several clinically important applications of this new knowledge. First, this anatomic format provides the basis for estimating regional myocardial contraction and the relative size of the myocardial region at risk from a given arterial occlusion. Second, precise knowledge of "normal" segment location greatly simplifies the computation of dimensional correction factors for quantitative arteriography. Third, viewing angles most appropriate for videodensitometric assessment of lesion lumen area may be computed from these data. The theoretical basis and numerical values needed for most of the above estimates are provided. Finally, a computer program has been written to generate a three-dimensional tree-branch vascular model from these anatomic locations. This easily used interactive program aids in teaching coronary angiographic anatomy and, of importance, permits selection of viewing angles that "best" visualize the traditionally difficult parts of the coronary tree.