Richard M. Fleming

A tête-à-tête comparison of ejection fraction and regional wall motion abnormalities as measured by echocardiography and gated sestamibi SPECT

Determination of ejection fraction and regional wall motion abnormalities (RWMAs) consistent with stunned, hibernating, or infarcted myocardium can be noninvasively determined by both echocardiography and nuclear cardiac imaging. Prior comparisons between the 2 methods have been limited to Tc 99m pertechnetate or to stress images with attention to RWMAs only. To determine the relationship between results seen with echocardiography and gated single photon emission computed tomography (SPECT) using sestamibi, 26 individuals with varying degrees of coronary artery disease were prospectively studied with both techniques. Five indi viduals had single-vessel disease, 10 had 2-vessel disease, and 11 had triple-vessel disease. Each individual underwent 2-D, M-mode, and Doppler echocardiography (echo) as well as gated SPECT imaging using rest and stress (high-dose dipyridamole/HDD) sestamibi imaging. The results were statistically different when ejection fractions (EFs) and RWMAs were compared. There were no statistical differences between EFs determined at rest when either echo or nuclear imaging was used. However, patients with EFs <70-80% were overestimated by echo, with echo underestimating EFs > 70-80% (p = 0.001). There was a high correlation (r = 0.76) between resting echocardiographic EFs and SPECT resting gated sestamibi images in patients with single-vessel disease, and a moderate correlation (r=0.68 and r=0.68) in patients with 2- and 3-vessel disease, respectively. Differences in the detection of RWMAs were statistically different for patients with 2-vessel disease (p = 0.04) and approached significance in 3-vessel disease (p = 0.56) with more RWMA being detected by resting gated SPECT imaging than by echo. Greater differences in RWMAs were seen in patients with 1-, 2-, and 3-vessel disease when resting echo was compared with HDD gated SPECT sestamibi imaging. These differ ences were statistically greater in 2- (p=0.0027) and 3- (p=0.0003) vessel disease. Differences between stress and resting images are expected in individuals with severe coronary artery disease. Comparison of noninvasive assessment of EFs and RWMAs by gated SPECT sestamibi and echocardiography showed different results when looking at EFs, with echo reporting greater EFs for people with EFs < 70-80%. Patients with two and 3-vessel disease were statis tically more likely to have RWMAs detected by gated SPECT sestamibi than by echo.

Comparing a High-Dose Dipyridamole SPECT Imaging Protocol with Dobutamine and Exercise Stress Testing Protocols

Objective. To determine the safety, sensitivity, specificity, and accuracy of high-dose dipyridamole compared with treadmill and dobutamine stress imaging protocols. Background. Nuclear imaging studies using standard dose dipyridamole provide similar results to those obtained when treadmill stress is used. Recently dobutamine tomography and planar imaging with high-dose dipyridamole have been shown to improve nuclear imaging results. Methods. One hundred fifty-nine patients were imaged with thallium, teboroxime, or sestamibi per standard single photon emission computed tomography (SPECT) protocols. Pharmacologic stress was performed in 85 people with the remainder under going exercise testing by Bruce protocol. In this study, 0.852 mg dipyridamole was used per kilogram body weight and was infused over a four-minute period. Results from nuclear imaging were compared with those from coronary arteriograms. Results. The sensitivity and specificity of high-dose dipyridamole was 100% and 88.9%, respectively, which is statistically greater (P < 0.005) than that achieved when patients were stressed by treadmill. Side effects with the higher dose of dipyridamole were easily reversed with aminophylline. The sensitivity and specificity of intravenous dobutamine was 100%, but it was used in a limited number of subjects. When patients were stressed by Bruce protocol the sensitivity was 92.5% and specificity was 42.8%. The differences were not attributable to inadequate exercise duration. Conclusions. High-dose dipyridamole is safe and easily reversed with intravenous aminophylline. The sensitivity and specificity of dipyridamole and dobutamine stress testing were statistically more accurate than results obtained with treadmill protocols when SPECT is used to image the heart. High-dose dipyridamole resulted in greater changes in heart rate and blood pressure response than seen with standard-dose dipyridamole. Associated side effects can be easily reversed with the administration of intravenous aminophylline without significant complications. The sensitivity, specificity, and accuracy of single photon emission computed tomography using high-dose dipyridamole are 100%, 88.9%, and 97.9%, respectively, for the overall presence or absence of disease when compared with coronary arteriography. This is significantly (P < 0.005) greater than that obtained by treadmill nuclear imaging protocols, independent of imaging agent.

Quantitative Coronary Arteriography and Its Assessment of Atherosclerosis: Part I. Examining the Independent Variables

Background. Previous work has demonstrated that quantitative coronary arteriography (QCA) can accurately measure phantom images to within ±0.1 mm and has been accepted as a reliable and reproducible method of measuring human coronary artery disease (CAD). Assessment of CAD by QCA involves the measurement of numerous variables, which are currently required to calculate stenosis flow reserve (SFR). Methods and Results. In this study 1040 stenotic lesions were analyzed by two well- accepted methods with demonstrated accuracy and reproducibility. These methods measure percent diameter stenosis (%DS), absolute diameter, percent area stenosis, length, as well as entry and exit angles to and from a stenotic coronary artery lesion respectively Based upon these results, the mean ± standard deviations and range seen in CAD were determined for each of these independent variables. This study demonstrated that atherosclerotic coronary artery lesions do not appear to exceed an entry angle of -39°, an exit angle of +35°, or an absolute length of 4.84 cm when accurately measured by QCA. It was also noted that, once percent diameter stenosis exceeded 89% (regardless (continued on next page) of the visual estimate) or percent area stenosis exceeds 99%, coronary arteries become completely occluded as measured by QCA. Conclusions. While previously suspected that once certain critical limits are exceeded in the deposit of cholesterol and calcium within the coronary artery, the artery will close, this study demonstrated by QCA what the limitations in human coronary arteries appear to be. These limits may be in part due to turbulent factors resulting in platelet activation or local mediators from endothelium of the coronary artery. ABSTRACT Contemporary quantitative coronary arteriography (QCA) was used to measure the different variables present in atherosclerotic coronary arteries. While the interaction of each of the independent variables undoubtedly plays a role in the determination of coronary artery blood flow and closure, the limitations of each of these variables have not yet been defined in humans. This study, based on the results of human coronary arteri ograms as analyzed by QCA, demonstrates the limitations of each of these variables, after which coronary arteries close and blood flow equals zero.

Quantitative Coronary Arteriography and Its Assessment of Atherosclerosis Part II. Calculating Stenosis Flow Reserve from Percent Diameter Stenosis

Background. Assessment of coronary artery disease by quantitative coronary arteriog raphy (QCA), while highly accurate, is more expensive than visual estimates of disease and involves the measurement of numerous variables requiring specialized equipment and personnel, thereby reducing its clinical applicability. In part 1 of this paper, the indepen dent variables that influence flow of 1040 coronary artery segments were analyzed. Methods and Results. Using the information previously reported in part 1 of this paper, we set out to determine the importance of each of the independent variables (percent diameter and area stenosis, length, absolute diameter, entry and exit angles) in the prediction of stenosis flow reserve (SFR). Analysis of variance (ANOVA) was used to determine the importance of each of these variables, as well as their interactions, on the determination of SFR. Only percent diameter stenosis (%DS) demonstrated statis tical significance (P < 0.001) in determining stenosis flow reserve. When the results of SFR were plotted against %DS, a quadratic relationship was demonstrated with an R2 value of 0.903 (r = 0.95). To verify the quadratic equation, the %DS of 100 different arterial stenoses was measured and used to calculate an SFR by the quadratic formula. The QCA and quadratic (calculated) determined SFRs compared favorably, with a correlation of 0.97. (continued on next page) Conclusions. The ability to calculate SFR directly from measured %DS allows the incor poration of calculated SFR into the clinical setting, where cardiologists can interpret lesion severity both anatomically and hemodynamically. This incorporation can be done without additional cost to the physician, hospital, patient, or third-party payers. ABSTRACT Contemporary quantitative coronary arteriography (QCA) methods accurately measure stenosis flow reserve (SFR) under conditions of coronary artery disease but are too expensive for practical clinical use. A simple laminar flow (Poiseuille) model was fitted to 1040 stenotic lesions and cross-validated on an independent sample of 100 lesions. This simple model was found adequate for practical use with a cross-validated correlation of 0.97 with QCA measurement. Turbulence and other known complexities had no practical effect.

The Longitudinal Effects of Fenfluramine-Phentermine Use

The use of previous anorectic medications and the combined use of the anorectic medications fenfluramine and phentermine (Fen-Phen) have been associated with varying degrees of valvular regurgitation and pulmonary hypertension. More recent reports have suggested a lower incidence of both than was previously reported. Comparisons of patients with similar body mass index (BMI) have been missing as well as information regarding chamber dimensions and pressures. Using transthoracic 2D, M-mode, and Doppler echocardiography, 57 men and women (30 Fen-Phen and 27 BMI-matched individuals/BMIMCG) were studied to determine their chamber dimensions, wall motion, diastolic function, valvular abnormalities, left ventricular ejection fractions (LVEFs), and pulmonary artery pressures (pAPs). The 30 Fen-Phen subjects were studied shortly after discontinuing the medications and again 6 to 12 months later. The results in these subjects were then compared with the valvular findings of 660 randomly selected cardiac patients with non-Fen-Phen-induced heart disease (NFPHD). Valvular regurgitation was greatest among patients who had recently discontinued the use of Fen-Phen (EFP) with 57% of all valves having regurgitation, 87.5% of which were “mild.” These same individuals also had the largest left ventricles at end (LVEDD) diastole (5.03 ±0.22 cm) and systole (LVESD). The LVESDs were statistically larger (p ≤ 0.05) than that seen in the other groups, while at the same time their LVEFs were statistically (p ≤ 0.01) lower (53.44 ±9.48%). These same patients had statistically (p ≤ 0.05) greater PAPs (29.21 ±10.52 mm Hg), which were associated with a lower incidence rate (14%) of pulmonic regurgitation (PR). The number of people with aortic regurgitation (AR), statistically (p ≤ 0.05) decreased (40%) as the duration of time since discontinuing Fen-Phen increased (late Fen-Phen/LFP). However, for those individuals who continued to have AR, there was an increase in the number of people who progressed from mild to moderate AR, with an associated increase in LVEDD (5.41 ±0.55 cm), LVESD (3.51 ± 0.84 cm), and LVEF (63.45 ±15.25%). The LFP studies showed a statistical (p ≤ 0.001) increase in PR with a subsequent drop in PAPs from 29.21 ±10.52 mm Hg in the early (EFP) studies to 14.02 ±1.35 mm Hg, which was augmented with weight-bearing and Valsalva maneuvers. The reduction in the percentage of individuals with valvular regurgitation and pulmonary hypertension appears to be due to changes in the heart valves, pressures, and chamber size. The incidence of tricuspid and mitral regurgitation decreased with time, while pulmonic and aortic regurgitation tended to increase or become more severe when present.

High-Dose Dipyridamole and Gated Sestamibi SPECT Imaging Provide Diagnostic Resting and Stress Ejection Fractions Useful for Predicting Extent of Coronary Artery Disease

A decline in ejection fraction at stress compared with rest images has been associated with increased severity of coronary artery disease (CAD) and suggests a poorer prognosis. Myocardial perfusion imaging (MPI) using high-dose dipyridamole (HDD) has been shown to more accurately detect CAD than either standard dose dipyridamole (SDD) or exercise-induced stress (EST), but has not been looked at to determine its usefulness in detecting changes in stress and rest ejection fractions. To determine the relationship between changes in left ventricular ejection fraction (LVEF) and the severity of CAD, 36 individuals underwent gated single photon emission computed tomography (SPECT) MPI using HDD. In each case resting and stress LVEFs were determined along with MPI results. Subjects with single-vessel CAD demonstrated an increase in LVEF from 77.8% (sd ±8.8%) to 85.6% (sd ±8.4%) resulting in a statistically significant increase in LVEF of 7.8% (p = 0.009). Patients with two-vessel disease showed a smaller increase from 73.2% (sd + 8.3%) to 79.8% (sd + 9.8%) following HDD stress. This increase was statistically (p=0.008) significant. Patients with triple-vessel CAD showed a reduction in LVEF from 67.4% (sd ± 14.07) to 65.1 % (sd ± 16.5%) which represented a decrease in LVEF of 2.7% and approached (p=0.25) but did not reach statistical significance. Both the resting and stress LVEFs were statistically lower (p<0.05) in patients with triple- vessel CAD. Changes in resting LVEF (REF) and HDD pharmacologically induced stress LVEF (SEF) provide a valuable diagnostic marker as to the number of significantly diseased coronary arteries and can be acquired from gated SPECT sestamibi images.

Treating Hyperlipidemia in the Elderly

Background: Determination of the effects of dietary modification and hyperlipidemic medications in the elderly (> sixty-five years of age) patient has not been significantly investigated to date despite knowledge that elevated cholesterol (TC) and triglyceride (TG) levels increase the risk of coronary artery disease (CAD). Methods: Twenty-seven individuals were placed into one of three treatment groups and longitudinally followed up to examine the effects of diet and hyperlipidemic medications on TC and TG levels. Group 1 (n = 14) received neither dietary nor drug therapy. Group 2 (n = 9) received dietary counseling without concomitant hyperlipidemic medications. Subjects in group 3 (n = 4) underwent dietary instruction for six months and hyperlipi demic medication(s) for eighteen months. Results: Subjects in group 1 demonstrated a statistical increase in TC (P ≤ 0.001) during the study. Patients in groups 2 (P ≤ 0.001) and 3 (P ≤ 0.05) demonstrated statistical improvement in TC reduction during dietary counseling. The effect on TC was blunted in group 3 after dietary counseling was discontinued. Reductions in TG levels were signifi cant (P ≤ 0.001) only for patients in group 2. Conclusion: Elderly individuals were able to significantly reduce both TC and TG levels by dietary modification alone. Minimal improvement was seen with the addition of hyper lipidemic medications.

The Fleming Unified Theory of Vascular Disease: A Link Between Atherosclerosis, Inflammation, and Bacterially Aggravated Atherosclerosis (BAA)

women dying from heart disease than men. Second, approximately 70% of all heart attacks occur in coronary arteries that are viewed to be relatively disease free ( < 50% diameter stenosis) by angiography (cardiac catheterization). This means that the detection of disease requires the use of more sophisticated and accurate tests including nuclear cardiac imaging (PET, SPECT), endothelial function, and electron beam (calcium) testing. Finally, despite our understanding of coronary artery disease, our evaluation and treatment of risk factors is sad. Patients and physicians alike are more confused about what constitutes an elevated cholesterol concentration

Assessing the Independent Effect of Dietary Counseling and Hypolipidemic Medications on Serum Lipids

Determination of changes in total cholesterol (TC) and triglyceride (TG) levels has focused primarily on hypolipidemic drug effects. Changes resulting from dietary effect alone versus diet and drug effect have not yet been fully established. Seventy subjects were enrolled into four treatment groups to determine the impact of diet and drug effect upon TC and TG. Group 1 (n = 28) served as the control group and received no dietary counseling or drug therapy. Group 2 (n = 22) received dietary coun seling. Group 3 (n = 7) underwent dietary counseling for six months and drug therapy for eighteen months. Subjects in groups 1-3 were monitored for eighteen months. Patients in group 4 (n = 13) were followed up for thirty-six months. No intervention occurred during the first eighteen months, and hypolipidemic medications were used during the second eighteen-month period. Subjects in groups 1 and 4 received no specific dietary counseling and demonstrated no significant improvement over the course of the study. Patients in groups 2 and 3 showed significant reductions in both TC and TG. The improvement in TC seen for patients in group 3 was reduced after dietary counseling ceased. Dietary intervention is necessary if patients are to statistically significantly reduce TC and TG levels. Drug therapy demonstrated the expected reductions in both TC and TG but did not statistically significantly lower lipid levels without concomitant dietary coun seling. When dietary counseling and hypolipidemic medications are used together, reduc tions in TC and TG values are even greater than those seen with dietary effect alone. Diet control alone appears to significantly reduce TC and TG levels, resulting in reduced need for antianginal medications.

The Clinical Importance of Risk Factor Modification: Looking at Both Myocardial Viability (MV) and Myocardial Perfusion Imaging (MPI).

Determination of changes in coronary artery disease (CAD) following risk factor modification (lipid lowering and stress reduction) have focused only on changes in myocardial blood flow (Q)/myocardial perfusion imaging (MPI) and not myocardial viability (MV). To determine the outcome of each and to determine if there are differences in myocardial viability versus coronary blood flow, 31 people were studied for 1 year with comparison of baseline and 1-year PET results. One subject underwent an additional 2-year follow-up study, providing a total of 32 comparisons. A total of 224 myocardial segments were compared with improvement in MPI seen in 58 of 224 segments (25.9%), stabilization in 111 of 224 (49.6%) segments, and progression of disease in 55 of 224 (24.6%) segments. MV improved in 82 of 224 segments (36.6%), showed stabilization in 83 of 224 (37.0%) of the segments, and worsening in 59 (26.3%) of 224 segments. When improvement in either MPI or MV were added together, improvement was seen in 50.9% (p≤0.001) of the segments and stabilization was seen in 30.4% (p≤0.001). Despite RFM as defined above, progression of CAD and loss of myocardial viability was noted in 15% of the myocardial segments studied. This study demonstrated that regardless of whether one looks at MPI alone or a combination of MPI and MV, reduction of serum lipids and stress reduction alone cannot guarantee stabilization or regression of atherosclerosis. Clearly there are additional factors involved which play an important role in reveral of CAD which must be addressed in future studies.