The Fleming Unified Theory of Vascular Disease: a link between atherosclerosis, inflammation, and bacterially aggravated atherosclerosis (BAA)
Explore the source record for details and available documents.
Arteriosclerosis↗
Biomedical subjects
R M Fleming
Publications and source records attributed to R M Fleming.
The effect of high-protein diets on coronary blood flow.
Recent research has demonstrated that successful simultaneous treatment of multiple risk factors including cholesterol, triglycerides, homocysteine, lipoprotein (a) [Lp(a)], fibrinogen, antioxidants, endothelial dysfunction, inflammation, infection, and dietary factors can lead to the regression of coronary artery disease and the recovery of viable myocardium. However, preliminary work revealed that a number of individuals enrolled in the original study went on popular high-protein diets in an effort to lose weight. Despite increasing numbers of individuals following high-protein diets, little or no information is currently available regarding the effect of these diets on coronary artery disease and coronary blood flow. Twenty-six people were studied for 1 year by using myocardial perfusion imaging (MPI), echocardiography (ECHO), and serial blood work to evaluate the extent of changes in regional coronary blood flow, regional wall motion abnormalities, and several independent variables known to be important in the development and progression of coronary artery disease. Treatment was based on homocysteine, Lp (a), C-reactive protein (C-RP), triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and fibrinogen levels. Each variable was independently treated as previously reported. MPI and ECHO were performed at the beginning and end of the study for each individual. The 16 people (treatment group/TG) studied modified their dietary intake as instructed. Ten additional individuals elected a different dietary regimen consisting of a "high-protein" (high protein group/HPG) diet, which they believed would "improve" their overall health. Patients in the TG demonstrated a reduction in each of the independent variables studied with regression in both the extent and severity of coronary artery disease (CAD) as quantitatively measured by MPI. Recovery of viable myocardium was seen in 43.75% of myocardial segments in these patients, documented with both MPI and ECHO evaluations. Individuals in the HPG showed worsening of their independent variables. Most notably, fibrinogen, Lp (a), and C-RP increased by an average of 14%, 106%, and 61% respectively. Progression of the extent and severity of CAD was documented in each of the vascular territories with an overall cumulative progression of 39.7%. The differences between progression and extension of disease in the HPG and the regression of disease in the TG were statistically (p<0.001) significant. Patients following recommended treatment for each of the independent variables were able to regress both the extent and severity of their coronary artery disease (CAD), as well as improve their myocardial wall motion (function) while following the prescribed medical and dietary guidelines. However, individuals receiving the same medical treatment but following a high-protein diet showed a worsening of independent risk factors, in addition to progression of CAD. These results would suggest that high-protein diets may precipitate progression of CAI) through increases in lipid deposition and inflammatory and coagulation pathways.
Adult↗
Shortcomings of coronary angiography.
Explore the source record for details and available documents.
Coronary Angiography↗
Reversing heart disease in the new millennium--the Fleming unified theory.
Nineteen people without prior history of documented heart disease were studied for 8 months to determine the effect of treatment based on an immunologic unified theory of vascular disease. Subjects underwent myocardial perfusion imaging to quantify the extent and severity of coronary artery disease, along with assessment of wall motion abnormalities and ejection fraction by both nuclear and echocardiographic methods. These tests were repeated at the end of the study. Treatment consisted of dietary changes, treatment of cholesterol, triglycerides, homocysteine, lipoprotein (a), fibrinogen, C-reactive protein, and infection. Patients who followed the dietary recommendations demonstrated statistically reduced disease in all three major coronary arteries, whereas those individuals who followed high-protein diets demonstrated statistically greater levels of disease.
Blood Flow Velocity↗
Training physicians and health care providers to accurately read coronary arteriograms. A training program.
UNLABELLED: Patterns in visual interpretation of coronary arteriograms (CAs) frequently cause incorrect assessment of percent diameter stenosis (%DS). These errors result in overestimating the results of angioplasty as well as of the number of arteries significantly affected by coronary artery (CAD) disease. METHODS: Forty-one physicians, nurses, and students participated in the standardization of 45 Kodachromes (39 arteries, 6 phantoms) and 5 photographic reproductions. Eleven of the 41 participated in a three-part training program designed to eliminate errors and improve accuracy of interpreting %DS from CAs. RESULTS: Improvement in reading %DS was seen in 69% of CAs with statistical (P < or = 0.05) improvement in one third of these cases, whose narrowings ranged from 4% to 84%DS. Variability of reporting was reduced in 26% of the cases. Skewing, representing an overestimation of "severe" disease and underestimation of "less severe" disease, was reduced with statistical improvement (P < or = 0.05) in reported %DS noted after training. Similar improvement was seen with phantoms but not in photographic images where the arterial edges were outlined. CONCLUSION: The outcomes of clinical management, invasive and interventional (mechanical, thrombolytic) procedures, as well as research studies depend in part upon the accuracy of reading %DS from CAs. Most studies to date have completed using extremely unreliable estimates of %DS with resultant problems in data interpretation. The use of this standardized training program has led to significant improvement in accurately assessing CAD.
Cardiology↗
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 counseling. 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 counseling. When dietary counseling and hypolipidemic medications are used together, reductions 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.
Cardiology↗
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 no 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 undergoing 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 imaging agent.
Aged↗
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 hyperlipidemic medication(s) for eighteen months. RESULTS: Subjects in group 1 demonstrated a statistical increase in TC (P < or = 0.001) during the study. Patients in groups 2 (P < or = 0.001) and 3 (P < or = 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 significant (P < or = 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 hyperlipidemic medications.
Aged↗
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 degrees, and exit angle of +35 degrees, 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 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.
Coronary Angiography↗
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 arteriography (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 independent 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 statistical 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. CONCLUSIONS: The ability to calculate SFR directly from measured %DS allows the incorporation 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.
Analysis of Variance↗
Patterns in visual interpretation of coronary arteriograms as detected by quantitative coronary arteriography.
In part 1 of a three-part study, 14 novice readers and 6 experienced cardiologists interpreted phantom images of known stenosis severity. No difference between the interpretations of experienced and novice readers was detectable. Visual estimates of "moderately" severe stenosis were 30% higher than actual percent diameter stenosis. In part 2 of the study, visual interpretation of percent diameter stenosis from 212 stenoses on 241 arteriograms was compared with quantitative coronary arteriographic assessment. The visual analysis overestimated disease severity in arteries with greater than or equal to 50% diameter stenosis (except for right coronary lesions) and underestimated severity in all arteries with less than 50% diameter stenosis. Of the 241 arteriograms, 40 had quantitative and visual analysis of all three coronary arteries for assessment of significant disease. In only 62% of the cases did visual and quantitative methods agree on the presence of severe disease; visual estimates diagnosed significantly (p less than 0.05) more three-vessel disease. In part 3 of the study, comparison of percent diameter stenosis by visual estimate with quantitative coronary arteriographic assessment before and after balloon angioplasty of 38 stenoses showed that visual interpretation significantly (p less than 0.001) overestimated initial lesion severity and underestimated stenosis severity after angioplasty.
Angiography↗
Comparison of technetium-99m teboroxime tomography with automated quantitative coronary arteriography and thallium-201 tomographic imaging.
Technetium-99m (Tc-99m) teboroxime is a new perfusion tracer that is highly extracted and rapidly cleared by the myocardium. To determine the feasibility of Tc-99m teboroxime imaging in the diagnosis of patients with suspected coronary artery disease, 30 patients underwent single photon emission computed tomography imaging with Tc-99m teboroxime (25.2 +/- 1 mCi) at peak exercise and again 60 min later at rest. All patients underwent either a thallium stress test (n = 26) or automated quantitative coronary arteriography (n = 25), or both, without intervening revascularization or infarction. Images were reviewed by two investigators who had no knowledge of clinical data. Coronary lesions with greater than or equal to 50% diameter narrowing by quantitative coronary arteriography were considered significant. Both thallium and Tc-99m teboroxime detected disease in all patients with two or three vessel disease. One vessel disease was detected with Tc-99m teboroxime in 9 of 10 patients and with thallium in 8 of 10 (p = NS). In patients without angiographically significant disease. Tc-99m teboroxime demonstrated normal perfusion in six of eight patients and thallium in three of five (p = NS). Overall, when presence or absence of disease detected by Tc-99m teboroxime or thallium was compared with quantitative coronary arteriography, there was no difference between Tc-99m teboroxime and thallium. These results suggest that Tc-99m teboroxime is comparable to thallium as an imaging agent. The rapid biologic half-life, 5.3 min, allows studies to be completed in 60 to 90 min.
Angiography↗
Nuclear imaging analysis of human low-density lipoprotein biodistribution in rabbits and monkeys.
We have evaluated the biodistribution of human low-density lipoprotein (LDL) radiolabeled with 99mTc or with 123I-tyramine cellobiose in rabbits and in rhesus monkeys. Biodistribution was assessed after intravenous injection of radiolabeled LDL by quantitative analysis of scintigrams, counting of excreta, and counting of tissues at necropsy. Both rabbits and monkeys showed lower renal uptake (123I:99mTc approximately 1:3, as regional percent injected activity corrected for physical decay) and excretion (1:2 to 1:4), but higher hepatic (1.5:1 to 2:1) and cardiac (1.7:1 to 4:1) uptake of 123I than of 99mTc. Adrenals were visualized in normolipemic animals with 123I-tyramine cellobiose-LDL but not with 99mTc-LDL. Hyperlipemic animals showed increased cardiac (up to six-fold) and decreased hepatic activity (by 50%-60%) of both radionuclides. We conclude that 123I-tyramine cellobiose-LDL is better suited than 99mTc-LDL for dynamic studies of LDL metabolism in vivo.
Animals↗
Extraction of ceftazidime in bone.
The extraction of ceftazidime has been measured in bone by means of the outflow dilution technique following injection into the perfused nutrient artery of the canine tibia. The instantaneous extraction was found to be 0.71 +/- 0.18 and the net extraction was 0.55 +/- 0.25 (mean +/- S.D. n = 5). The extraction of this antibiotic is relatively high and this experiment demonstrates the fact that antibiotics leave capillaries in bone and pass into the fluid spaces where they can act on pathogenic organisms.
Animals↗
Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes.
Adenylate cyclase in plasma membranes was inhibited by micromolar concentrations of delta 8-tetrahydrocannabinol and delta 9-tetrahydrocannabinol and by levonantradol and desacetyllevonantradol. This inhibition was noncompetitive for stimulation of the enzyme at the prostanoid receptor by prostaglandin E1 or prostacyclin, or at the peptide receptor by secretin or vasoactive intestinal peptide. Forskolin-activated adenylate cyclase was also inhibited by cannabimimetic agents. Inhibition by cannabinoid compounds was neither synergistic nor additive with muscarinic or alpha-adrenergic agents when each was present at maximally inhibitory concentrations. Cannabinoid inhibition was not blocked by atropine, yohimbine, or naloxone, suggesting that muscarinic, alpha 2-adrenergic and certain opiate receptors may not be required for the response. The inhibition of adenylate cyclase was specific for psychoactive cannabinoids, since cannabinol and cannabidiol produced minimal or no response. Inhibition was also stereoselective, since dextronantradol did not produce the response. A biphasic log dose-response curve was observed for each of the cannabinoid drugs, such that reversal of the inhibition occurred at 3-10 microM. Possible mechanisms for the effects of cannabinoid drugs on adenylate cyclase activity are discussed.
Adenylyl Cyclase Inhibitors↗
Differences in characteristics preferred by college students for academic advisors, vocational counselors, and psychotherapists: a preliminary report.
144 college students rated an academic advisor, a vocational counselor, or a psychotherapist on 10 characteristics and subsequently rated each of the three types of counseling situations on how "personal" they perceived each to be. Sex of experimenter and sex of subject were varied systematically. Female subjects when tested by a male experiment preferred a psychotherapist be more religious than an academic advisor or vocational counselor. Subjects viewed psychotherapy as a more personal situation than academic advising or vocational counseling.
Adult↗
A new, highly sensitive and specific assay for chymotrypsin.
1. A simple, highly sensitive, specific fluorometric method for the determination of chymotrypsin is described. 2. The new substrate utilized in this assay, N-glutaryl-glycyl-glycyl-l-phenylalanine beta-naphthylamide (GGPNA), is readily soluble in water, stable and highly specific for chymotrypsin. It is not degraded by a large excess of carboxypeptidase B, elastase, thrombin or plasmin and is virtually resistant to trypsin. 3. GGPNA is extremely sensitive to the action of chymotrypsin and permits detection of enzyme concentrations as low as 1 ng/ml. Linearity between enzyme concentration and fluorescence produced is maintained up to at least 3000 ng/ml. 4. alpha2-Macroglobulin-bound chymotrypsin hydrolyzes GGPNA at a rate about 2/3 of that exhibited by the free enzyme. 5. Bile pigments in amounts normally found in duodenal juice or traces of blood do not interfere with the assay. 6. GG PNA which releases beta-naphthylamine upon hydrolysis is suitable also for colorimetric and histological determination of chymotrypsin.
Bilirubin↗
Effect of alpha2 macroglobulin on some kinetic parameters of trypsin.
1. Complex formation of trypsin with alpha2 macroglobulin results in marked changes of the Michaelis-Menten constant, pH optimum and sensitivity to ionic strength in a system using N-carbobenzoxy-glycylglycyl-L-arginine-2-naphthylamide as substrate. 2. In contrasts to the inhibition (50%) observed when alpha2 macroglobulin-bound trypsin is assayed under conditions optimal for the free enzyme, there is minimal reduction of activity when determinations are performed at a substrate concentration and pH optimal for the bound enzyme. 3. The changes in substrate concentration and ionic environment required for maximum activity of alpha2 macroglobulin-bound trypsin are similar to those observed with enzymes embedded in polyelectrolyte matrices and may reflect alterations in the microenvironment of the enzyme resulting from conformational changes of the macromolecule during interaction with trypsin. 4. Enzymatic activity of trypsin towards casein is greatly reduced by alpha2 macroglobulin, even under assay conditions optimal for the bound enzyme, confirming previous findings that access to the active center for high-molecular weight substrates is sterically hindered by alpha2 macroglobulin.
Arginine↗