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D M Kramsch

Publications and source records attributed to D M Kramsch.

At least 19 recordsLinked to original sources
PubMed1997

Limits of lipid-lowering therapy: the potential benefits of amlodipine as an antiatherosclerotic agent.

Treatment of atherosclerosis has focused mainly on decreasing low-density lipoprotein cholesterol (LDL-C). However, recent coronary angiography trials have revealed that aggressive lowering of LDL-C below 100 mg/dl arrests atherosclerosis progression in only 50% to 60% of patients. Furthermore, with quantitative coronary angiography, significant regression occurred only in advanced fibrous-fatty plaques (> or = 50% stenosis) and not in the younger, more cell-proliferative lesions (< 50% stenosis). It is clear that lipid-lowering therapy has limited efficacy; therefore, other drugs, especially antiproliferative agents, may be useful for secondary and primary prevention. To test this hypothesis a new calcium antagonist, amlodipine, which has in vitro antiproliferative, cell membrane stabilizing, and antioxidative properties, was studied to determine whether it has antiatherogenic effects in nonhuman primates. Amlodipine normalized elevated levels of oxidized arterial cholesterol without reducing elevated total plasma cholesterol levels and significantly suppressed atherosclerosis progression in monkeys who had been fed an atherogenic diet. These data suggest that amlodipine may be an excellent candidate, in combination with lipid-lowering drugs, for dual therapy of atherosclerotic vascular disease, and also may be effective monotherapy, even when LDL-C is not lowered satisfactorily.

Amlodipine↗
PubMed1996

Quantitation and localization of regional body fat distribution--a comparison between magnetic resonance imaging and somatometry.

UNLABELLED: The emerging concept that various fat compartments are metabolically active and play separate and decisive roles in the pathogenesis of coronary atherosclerosis, hypertension, insulin resistance, diabetes and stroke, has given obesity research a new direction. Of particular interest is the relative amount of intra-abdominal fat thought to be responsible for the metabolic complications. We studied the precise fat distribution and its correlations with the metabolic parameters in 44 non-human primates (Macaca fascicularis). Intra-abdominal, subcutaneous, and total abdominal fat (IAF, SAF, TAF) were assessed by magnetic resonance imaging (MRI) and somatometry. Quantitative computer analyses of abdominal MRI scans revealed predominant IAF distribution. Box plot analysis of IAF and SAF revealed wide diversity in the amounts of fat, especially in monkeys with body mass index (BMI) < 30 kg/m2. Primates with similar BMI in each quartile revealed an extensive heterogeneity in IAF as well as SAF. Numerous significant correlations within site-specific somatometric measurements as well as within the MRI determinants of abdominal fat were seen. However, only body weight correlated with IAF and skinfolds could predict SAF. After adjusting for body weight, partial correlation analysis showed a significant correlation (P < 0.05) between total cholesterol and IAF. CONCLUSION: MRI revealed considerable heterogeneity of IAF, SAF and TAF in cohort of primates believed to be homogeneous by somatometric definition. Male cynomolgus monkeys appear to be a valuable model for a systematic evaluation of fat. Individuals with identical body weight and height may show a diverse pattern of fat distribution.

Abdomen↗
PubMed1996

Probucol suppresses oxidant stress in hypertensive arteries. Immunohistochemical evidence.

Oxy-free radicals may be involved in the pathogenesis of accelerated atherosclerosis in hypertension. We evaluated the direct antioxidant potential of probucol in hypertensive arteries by studying the spatial immunohistochemical distribution of three primary antioxidant enzymes (AEs). Nineteen normocholesterolemic New Zealand White rabbits were divided into two groups: normotensive controls (NT; n = 6) and 13 animals rendered hypertensive by surgical coarctation of abdominal aorta. The hypertensive group was subdivided into hypertensive alone (HT; n = 8) and hypertensive treated with 1% probucol (PO) for 9 weeks (HT-P; n = 5). Blood pressure rose significantly in both hypertensive groups (P < .005). At autopsy, both hypertensive groups showed similarly significant increases in mean arterial intima-media thickness (IMT) whether or not they were treated with probucol. However, only HT rabbits revealed significant increases in the intima-media depth penetration of glutathione peroxidase, superoxide dismutase, and catalase AEs. By contrast, in HT-P animals probucol produced significant reductions of immunostaining of all three AEs compared to the HT group (P < .05). Additionally, specific macrophage immunostaining revealed that the arterial wall of HT rabbits had numerous (10 to 12 per high power field) subintimal and medial macrophages as compared to the HT-P animals (1 to 2 per high power field). The blood pressure level correlated significantly with IMT in all three groups, but with depth penetration of the three AEs only in the NT and HT groups. Probucol, therefore, appears to act in concert with the native arterial antioxidant enzymes as a potent free radical scavenger to reduce oxidative stress and thus attenuate the macrophage invasive response in hypertensive arteries.

Animals↗
PubMed1995

Limits of lipid-lowering therapy: the benefits of amlodipine as an anti-atherosclerotic agent.

Treatment of atherosclerosis has mainly focused on decreasing low-density lipoprotein cholesterol (LDL-C). However, recent coronary angiographic trials revealed that aggressive lowering of LDL-C below 100 mg/dl arrests atherosclerosis progression in only 50-60% of patients. Furthermore, quantitative coronary angiography in these trials showed significant regression only in advanced fibrous-fatty plaques (> or = 50% stenosis) and not in the younger, more cell-proliferative lesions (< 50% stenosis). It is clear that lipid-lowering therapy has limited efficacy and there is therefore a need for other drugs, especially anti-proliferative agents, for secondary and primary prevention. To test this hypothesis, a new calcium antagonist, amlodipine, was studied for its anti-atherogenicity in non-human primates because of its known in vitro anti-cell proliferant, cell membrane stabilising and anti-oxidant properties. Amlodipine was found to normalise elevated plasma levels of oxidised LDL without reducing elevated total LDL-C levels in monkeys fed an atherogenic diet which, however, significantly suppressed atherosclerosis progression. These data suggest that amlodipine may be an excellent candidate, in combination with lipid-lowering drugs, for dual therapy of atherosclerotic vascular disease and may also be effective as monotherapy even when LDL-C is not lowered satisfactorily.

Amlodipine↗
PubMed1994

Effects of lovastatin on ApoA- and ApoB-containing lipoproteins. Families in a subpopulation of patients participating in the Monitored Atherosclerosis Regression Study (MARS).

To establish whether lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, exhibits a specific effect on apolipoprotein (apo) A- and apoB-containing lipoproteins, 63 subjects, a subset of the 270 Monitored Atherosclerosis Regression Study (MARS) patients with hypercholesterolemia (190 to 295 mg/dL) and documented coronary artery disease, were randomized into either lovastatin 40 mg twice daily or matching placebo tablets twice daily. Both groups consumed a diet containing 27% calories as fat (polyunsaturated fat/saturated fat ratio, 2.85) and a daily cholesterol intake of less than 250 mg. The plasma lipid and apolipoprotein profiles were determined at the time of randomization and after 2 years of treatment, and the levels of apoA- and apoB-containing lipoprotein families were measured after 2 years of treatment. After this treatment period, the drug group was characterized in comparison with the placebo group by significantly reduced levels of total cholesterol (33%), triglycerides (30%), very-low-density lipoprotein cholesterol (36%), low-density lipoprotein cholesterol (43%), apoB (36%), apoC-III (18%), and apoE (17%) and slightly but insignificantly increased levels of high-density lipoprotein cholesterol (6%) and apoA-I (1%). The 2-year levels of lipoprotein containing apoA-I but no apoA-II (LpA-I) and lipoprotein containing both apoA-I and apoA-II (LpA-I/A-II) particles separated by immunoaffinity chromatography on an anti-apoA-II immunosorber did not differ between the two treatment groups. However, the apoB-containing lipoprotein (Lp) families defined by apolipoprotein composition and separated by immunoaffinity chromatography on anti-apoA-II and anti-apoC-III immunosorbers were affected in a selective manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin.

BACKGROUND: The Monitored Atherosclerosis Regression Study, a randomized, double-blind, placebo-controlled, 2-year trial of lovastatin monotherapy, found that coronary lesions < 50% diameter stenosis (%S) and coronary lesions > or = 50% S at baseline had different responses to therapy. We now report on clinical, lipid, and nonlipid risk factors of treatment response in these lesion subsets. METHODS AND RESULTS: Two hundred seventy subjects, 37 to 67 years old, with plasma total cholesterol (TC) 190 to 295 mg/dL (4.91 to 7.63 mmol/L) and total triglyceride < 500 mg/dL (5.65 mmol/L) were randomized to low-fat, low-cholesterol diet and either lovastatin 80 mg/d or placebo. Logistic regression was used to model the association between risk factors and coronary lesion progression in mild/moderate (< 50% S) and severe (> or = 50% S) lesions in 220 angiogram pairs analyzed by computer quantitative coronary angiography. In the placebo group, risk factors (P < .05) for the progression of mild/moderate lesions were triglycerides and TC/high-density lipoprotein cholesterol (HDL-C). Risk factors for the progression of severe lesions were HDL-C (negative), low-density lipoprotein cholesterol (LDL-C)/HDL-C, and TC/HDL-C. TC/HDL-C was the predominant risk factor for both mild/moderate and severe lesions in the multivariate analysis. In the lovastatin group, with aggressive lowering of LDL-C and TC below 85 mg/dL and 156 mg/dL, respectively, risk factors for mild/moderate lesions included triglycerides and very-low-density lipoprotein-LDL-associated apolipoprotein C-III (apo C-III-heparin precipitate), a marker of triglyceride-rich lipoprotein particles. Apo C-III-heparin precipitate was the predominant risk factor in the multivariate analysis. Risk factors for severe lesions were LDL-C, LDL-C/HDL-C, TC/HDL-C, and apo B; LDL-C/HDL-C was the predominant risk factor. CONCLUSIONS: These results indicate that triglyceride-rich lipoproteins and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression, respectively. These results add to the growing evidence of the importance of triglyceride-rich lipoproteins as a risk factor for coronary artery disease and the need for treatment in the progression of atherosclerosis.

Adult↗
PubMed1994

Biochemical and cytotoxic characteristics of an in vivo circulating oxidized low density lipoprotein (LDL-).

Using ion exchange high pressure liquid chromatography, total plasma low density lipoprotein (LDL) from 30 hypercholesterolemic and 10 normocholesterolemic cynomolgus monkeys was subfractionated into unmodified LDL (n-LDL) and more negatively charged LDL (LDL-). In hypercholesterolemic monkeys, the absolute LDL-cholesterol level was 16.54 +/- 2.82 mg/dl (mean +/- SE) whereas in normocholesterolemic monkeys it was 2.39 +/- 0.12 mg/dl (P < 0.0001); the percentage of LDL- was 5.2 +/- 0.71% and 4.9 +/- 0.19% of the total LDL for hypercholesterolemic versus normocholesterolemic monkeys, respectively. LDL- averaged 5% and n-LDL 95% of the total plasma LDL cholesterol. To confirm and further elucidate the oxidative nature of LDL-, cholesterol and cholesterol oxide contents of LDL- and n-LDL were determined by capillary gas chromatography; 53.98 +/- 2.24% (mean +/- SE) of the LDL- cholesterol was oxidized whereas in n-LDL only 10.70 +/- 1.06% of the cholesterol was oxidized (P < 0.00001). The spectrum of oxysterols identified, which was similar for LDL- and n-LDL, suggested a free radical-mediated process for cholesterol oxidation. The principal oxysterols identified were: cholest-5-ene-3 beta, 7 alpha-diol, cholesta-3,5-diene-7-one, cholest-5-ene-3 beta, 7 beta-diol, 5,6 beta-epoxy-5 beta-cholestan-3 beta-ol, 5,6 alpha-epoxy-5 alpha-cholestan-3 beta-ol, 5 alpha-cholestan-3 beta,5,6 beta-triol, 3 beta-hydroxycholest-5-ene-7-one, and cholest-5-ene-3 beta,25-diol. To model one of the steps in the possible mechanism of atherogenesis, the cytotoxicity of LDL- was demonstrated to be greater against subconfluent than confluent aortic endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS).

OBJECTIVE: To assess the effects of lipid-lowering therapy with lovastatin on coronary angiographic findings in patients with coronary artery disease and to compare the findings with those of two lipid-lowering angiographic trials using similar end points. DESIGN: Randomized, double-blind, placebo-controlled, multicenter coronary angiographic trial. SETTING: Community- and university-based cardiac catheterization laboratories. PARTICIPANTS: A total of 270 patients, 37 to 67 years old, with total cholesterol ranging from 4.92 to 7.64 mmol/L (190 to 295 mg/dL) and angiographically defined coronary artery disease. INTERVENTION: A cholesterol-lowering diet and either lovastatin, 80 mg/day, or placebo. OUTCOME: Per-patient change in percent diameter stenosis as determined by quantitative coronary angiography (primary end point). Global change score, based on the consensus of blinded expert readers regarding angiographic change (secondary endpoint). RESULTS: Lovastatin lowered total cholesterol level by 32%, low-density lipoprotein cholesterol by 38%, and the apolipoprotein B by 26% and raised the high-density lipoprotein cholesterol by 8.5% (P < 0.001). Average percent diameter stenosis increased 2.2% in placebo recipients and 1.6% in lovastatin recipients (P > 0.20). For lesions 50% or greater, average percent diameter stenosis increased 0.9% in placebo recipients and decreased 4.1% in lovastatin recipients (P = 0.005). The mean global change score was +0.9 (indicating progression) in the placebo group and +0.4 in the lovastatin group (P = 0.002); 13 placebo recipients and 28 lovastatin recipients had global change scores indicating regression (P < 0.02). CONCLUSION: Treatment with lovastatin plus diet slows the rate of progression and increases the frequency of regression in coronary artery lesions (by global change score), especially in more severe lesions (by quantitative angiography). This is the third lipid-lowering trial to show a benefit using the global change score, an end point predictive of clinical coronary events. Differences between two of these trials, using quantitative coronary angiographic end points, may have theoretical bearing on the mechanisms by which lipid-lowering therapy operates at the level of the arterial wall.

Adult↗
PubMed1993

Body fat and fat distribution by anthropometry and the response to high-fat cholesterol-containing diet in monkeys.

Considerable variability exists among individuals in the response of plasma cholesterol to changes in dietary fat and cholesterol, and obesity is one variable reported to affect this response. This study was performed to determine the relationship between body fat and changes in plasma cholesterol in cynomolgus monkeys fed a high-fat cholesterol-containing diet for 12 months. The animals gained significant body weight (body mass index increased from 30.5 +/- 0.5 to 35.7 +/- 2.8 kg/m2) and skinfold parameters of body fat increased as well. Total cholesterol increased from 109 +/- 4 to 390 +/- 25 mg/dl (P < 0.001), and there were also significant increases in LDL- and HDL-cholesterol and triglyceride. While there was very little relationship between body fat and plasma lipids before the diet, after 12 months, there were significant negative correlations between total and LDL-cholesterol and anthropometric measures of body fat (r ranged from -0.37 to -0.55, P < 0.01). The correlations were not affected when the effects of baseline body mass index and serum cholesterol and total food intake were controlled by partial correlation analysis. In this sample of animals, the acquisition of greater body fat appeared to protect against rises in cholesterol in response to consumption of a high-fat cholesterol-containing diet.

Adipose Tissue↗
PubMed1992

The Monitored Atherosclerosis Regression Study (MARS). Design, methods and baseline results.

OBJECTIVE: The Monitored Atherosclerosis Regression Study (MARS) was designed to evaluate the effect of cholesterol lowering by monotherapy with an HMG-CoA reductase inhibitor on progression/regression of atherosclerosis in subjects with angiographically documented coronary artery disease. The purpose of this paper is to present the design, methods, and baseline results of MARS. DESIGN: MARS is a prospective, randomized, double-blind, placebo-controlled trial with baseline, 2-year, and 4-year coronary angiography as well as carotid, brachial, and popliteal ultrasonography. SETTING: Outpatient clinics at the University of Southern California School of Medicine and the University of Wisconsin School of Medicine. SUBJECTS: Two hundred seventy participants of both sexes were recruited directly from the cardiac catheterization laboratory or by chart review of patients having undergone cardiac catheterization in the past. Subjects were considered eligible if they had angiographically demonstrable atherosclerosis in 2 or more coronary artery segments, unaltered by angioplasty, with at least 1 lesion > or = 50% but < 100% diameter stenosis (%S). The inclusion range for total cholesterol (TC) was between 190 and 295 mg/dL. Exclusion factors were: triglycerides > or = 500 mg/dL; premenopausal females; uncontrolled hypertension; diabetes mellitus; untreated thyroid disease; liver dysfunction; renal insufficiency; congestive heart failure; major arrhythmia; left ventricular conduction defects; or any life-threatening disease. INTERVENTION: Subjects were placed on a low-fat, low-cholesterol diet and either 40 mg b.i.d. lovastatin (Mevacor) or placebo. Randomization was stratified by sex, smoking status, and TC. MAIN OUTCOME MEASURES: Per-subject average change in %S as determined by quantitative coronary angiography (QCA) is the primary angiographic endpoint. Secondary endpoints are: categorical analyses of the proportion of subjects with progression; human panel reading of coronary angiograms; and change in minimum lumen diameter (MLD) in mm by QCA. Carotid, brachial, and popliteal ultrasonography is also being performed. RESULTS: The subjects randomized into MARS are 91.5% male with an age range of 37 to 67 years (mean age 57.9 years). For the cohort, baseline lipids are (mean +/- SD): TC, 231 +/- 24 mg/dL; low-density lipoprotein cholesterol (LDL-C) by ultracentrifugation, 153 +/- 24 mg/dL; LDL-C, by calculation, 157 +/- 23 mg/dL; high-density lipoprotein cholesterol (HDL-C), 43 +/- 10 mg/dL; and triglycerides, 160 +/- 73 mg/dL. There were no significant differences between treatment groups in baseline lipid levels or baseline angiographic characteristics. CONCLUSIONS: MARS baseline data show adequacy of randomization with comparability of lovastatin and placebo groups in demographic, lipid, and angiographic characteristics.

Adult↗
PubMed1992

Immunolocalization of native antioxidant scavenger enzymes in early hypertensive and atherosclerotic arteries. Role of oxygen free radicals.

To elucidate the role of oxygen free radicals and lipid peroxidation in the pathogenesis of early hypertension and atherosclerosis, we studied the native distribution of three primary arterial antioxidant enzymes (AEs). Specific immunohistochemical localization of superoxide dismutase (Cu-Zn SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) was examined in the arterial wall of New Zealand White rabbits: six sham-operated normotensive/normolipidemics (NT/NL), seven coarctation-induced hypertensive/normolipidemics (HT/NL), eight normotensive diet-induced hyperlipidemics (NT/HL), and six hypertensive/hyperlipidemics (HT/HL). All three AEs were confined primarily to the endothelium in NT/NL rabbit aortas. However, in HT and HL rabbits a greater proportion of the arterial wall, including the endothelium, inner media, and middle media, displayed immunolocalization of three AEs. Multiple linear-regression analysis revealed that more than 70% of the total variability in the depth of immunolocalization of arterial AEs could be explained by changes in blood pressure and/or total cholesterol. Also, levels of plasma and arterial cholesterol oxides were significantly different (p less than 0.05) in HT and HL rabbits compared with controls, with twofold increases in NT/HLs, threefold increases in HT/NLs, and fourfold increases in HT/HLs. We conclude that intense free-radical activity in the arterial wall of HT and HL animals is one possibility and that this occurs despite the presence of abundant AEs.

Animals↗
PubMed1992

Regression of atherosclerosis: which components regress and what influences their reversal.

Two major features of atherosclerosis may be distinguished: (a) atherosis caused by lipid infiltration in cells and extracellularly and (b) sclerosis caused by connective tissue deposition and by functional disturbance of the endothelium, leading to impairment of endothelium-derived relaxing factor (EDRF)-release and reduced arterial compliance. Atherosis generally rarely causes clinical symptoms and, furthermore, is reversible by lowering of LDL-C. However, the clinically significant human lesion is the fibrous atheromatous plaque. Regression of established fibrous lesions by maximal lowering of LDL-C is slow in native coronary arteries and nonexistent in bypass grafts. However, there is good evidence from recent clinical trials that even in arteries with significant fibrous plaques, functional improvement of sclerosis (increased compliance) can be achieved by reducing maximally LDL-C in spite of remaining structural connective tissue abnormalities, presumably through normalization of EDRF. Atherosclerosis, therefore, appears to be best influenced by lipid lowering when it is in its atherosis phase. In the plaques of advanced atherosclerosis, when connective tissue sclerosis is present, agents working through mechanisms other than lipid lowering appear to be required for plaque reversal.

Animals↗
PubMed1989

Reversal of atherosis and sclerosis. The two components of atherosclerosis.

In 1904, Marchand recognized the consistent association of fatty degeneration and vessel stiffening and introduced the term "atherosclerosis" to indicate this combination. Current research is focused principally on the lipid component, but there is evidence that both aspects are reversible. Atheromatous lipids add significantly to the volume of lesions and thus contribute to vascular obstruction and end-organ damage. Reversal of atherosis has been observed in all the major species used in atherosclerosis research; rabbits, swine, dogs, chicks, pigeons, and subhuman primates. Direct evidence for reversal in humans is based on angiographic trials and is less extensive. One femoral artery and one coronary artery trial indicate that the lesions can be stabilized. CLAS, the largest angiographic trial to date, indicates that coronary lesion reversal is possible. Clinical effects of sclerosis are more subtle, and there is little evidence that sclerosis alone leads to end-organ damage. However, it should be noted that atherosclerotic lesions producing end-organ damage invariably have a major fibrous component. Sclerotic vessels have reduced systolic expansion and abnormally rapid pulse wave propagation, which can be measured noninvasively. Primate studies indicate that sclerosis is induced by hypercholesterolemic diets and is reversible when these diets are withdrawn. Changes in sclerosis may be another useful indicator of the formation and reversal of lesions and may involve changes in EDRF. Future studies of atherosclerosis reversal should use a combination of measures to evaluate both atherosis and sclerosis.

Angiography↗
PubMed1988

The oxygen environment of the arterial media in early rabbit hypertension.

Hypertensive stimuli in experimental animals appear to cause early arterial wall hypermetabolism before hypertension is established and before histomorphic changes are marked. Hypermetabolism and the large diffusion distances for oxygen characteristic of large arteries imply that mural hypoxia could occur early in the disease but this has not been studied. Therefore, we measured aortic wall tissue oxygen distributions in male New Zealand White rabbits 2 weeks (1) after production of upper body hypertension by coarctation of the abdominal aorta, (2) after sham operation, and (3) in normal controls. As compared to normal and sham operated animals, blood pressure in the coarctation animals was significantly elevated from control levels, and the oxygen partial pressures were significantly reduced throughout the media. However, the hypoxic mural oxygen tensions in this relatively thin wall were not low enough to terminate classical respiration. At the time of measurement, moderate microscopic pathology was already present, including increased connective tissue production. The accompanying histomorphic changes are compatible with reports of extrarespiratory oxygen sensitivity of connective tissue metabolism.

Animals↗
PubMed1984

Tolerance and safety of enalapril.

Enalapril is the result of a targeted research programme to develop a non-mercapto converting enzyme inhibitor with a long duration of action and an improved safety profile for use in the therapy of hypertension and congestive heart failure. Over 3500 patients world-wide have received enalapril or enalaprilat. Long-term experience at present includes over 2500 patients. While enalapril and captopril produce similar efficacy, enalapril is better tolerated and appears not to be associated with occurrence of captopril-type side-effects, particularly the skin rash, taste loss, leukopenia and proteinuria. Enalapril and other converting enzyme inhibitors may be associated with renal insufficiency when given to patients with bilateral renovascular hypertension.

Captopril↗