Clemens von Schacky

The Effect of Dietary ω-3 Fatty Acids on Coronary Atherosclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial

Ingestion of fish or other sources of -3 fatty acids has been called a comprehensive strategy toward the prevention of atherosclerosis (1). Hundreds of epidemiologic studies, studies of mechanisms of action, and studies in experimental animals have shown that dietary intake of -3 fatty acids has antiatherosclerotic potential (1-9). However, few clinical trials have shown that -3 fatty acids have cardiovascular benefit in humans. The Diet and Reinfarction Trial (DART) (10) showed a 29% reduction in overall mortality rates in survivors of a first myocardial infarction who consumed fish rich in -3 fatty acids at least twice weekly for 2 years. Dietary -3 fatty acids do not prevent restenosis after percutaneous coronary angioplasty (11-13). One study (14) showed that fewer aortocoronary venous bypass grafts were occluded after ingestion of a fish oil concentrate, 4 g/d, for 1 year. Dietary intake of -3 fatty acids or olive oil, 6 g/d, did not affect the course of coronary atherosclerosis in another study totaling 59 patients (15). To test the hypothesis that consuming -3 fatty acids for 2 years leads to less progression and more regression of coronary atherosclerosis, as assessed by coronary angiography, we conducted a randomized, double-blind, placebo-controlled study in patients with coronary atherosclerosis. Methods Patients Patients who were hospitalized for diagnostic coronary angiography at our institution between 1 September 1992 and 19 May 1994 were asked to participate in our study if they fulfilled the entry criteria: 1) stenosis greater than 20% in at least one vessel and 2) revascularization (percutaneous transluminal coronary angioplasty [PTCA] or coronary bypass surgery) planned or performed in the previous 6 months in no more than one vessel. Exclusion criteria were history of cardiac transplantation, age younger than 18 years or older than 75 years, hemodynamically relevant left main stenosis or proximal stenosis in all three main vessels, biplane left ventricular ejection fraction less than 35%, ventricular tachycardias ( 3 QRS complexes), hemodynamically relevant cardiac valve disease, a prognosis severely limited by noncardiac disease, bleeding tendency (for example, due to thrombocytopenia or anticoagulation), diabetes, or other evidence of increased risk. Patients were not asked to participate if they were participating in another study, had psychiatric disease, had a history of noncompliance, lived too far away, had an initial coronary angiogram of poor quality, or had a history of allergic reaction to contrast material. Patients who agreed to participate gave written, informed consent that included consent for follow-up coronary angiography. One of the authors determined clinical status and decided whether to include patients in the study. Case report forms were filled out with data on predefined criteria relevant to history and clinical examination. A laboratory blood work-up (which included investigation of 38 routine variables plus erythrocyte phospholipid fatty acid composition), resting electrocardiography, and exercise stress test were done. Overweight patients (body mass index>25 kg/m2) were advised to restrict caloric intake, and all patients were advised to avoid eating cholesterol-rich foods; no other dietary advice was given. Our study was approved by the Ethics Committee of the Faculty of Medicine of the Ludwig Maximilians-University of Munich and was conducted according to the Good Clinical Practice Guidelines of the European Community. These guidelines require, among an exhaustive list of prerequisites, that studies be monitored regularly by external personnel. Study Design This Study on Prevention of Coronary Atherosclerosis by Intervention with Marine Omega-3 fatty acids (SCIMO) was a randomized, double-blind, stratified, single-center trial. It was designed to compare the effect of placebo with that of fish oil concentrate on changes on coronary angiography at 2 years, as assessed by an expert panel (the predefined primary end point) according to intention-to-treat principles. Predefined secondary end points were assessment of these changes with quantitative coronary angiography and cardiovascular events. Before randomization, patients were stratified according to three criteria: 1) PTCA done less than 6 months before randomization, 2) current therapy with a lipid-lowering agent, and 3) the presence of more than two of four risk factorsa low-density lipoprotein (LDL) cholesterol level greater than 3.88 mmol/L (150 mg/dL), current smoking, history of myocardial infarction in a first-degree relative younger than 60 years of age, and hypertension. For the resulting nine strata, a random sequence of study group assignments was computer-generated by the trial monitor in Norway. Strata were balanced every four patients and numbered consecutively. Each patient received the next consecutive number in his or her stratum. For each number, an envelope containing the randomization result was prepared and sealed by the monitor in Norway. In Munich, these sealed envelopes (the only location of the study group assignments) were kept accessible for safety, but no seals were broken. All patients and personnel were blinded to study group assignments. To ensure blindness, patients were told that the capsules differed in composition but not in taste. At the end of the study, patients were asked what they thought the capsules contained. Interventions and Measurements The placebo capsules and the fish oil capsules looked identical and were made of opaque soft gelatin, and each contained 1 g of a fatty acid mixture. The fatty acid mixture in the placebo capsules was 26.0% C16:0, 4.6% C18:0, 35.8% C18:1-9, 16.7% C18:2-6, 2.1% C18:3-3, 0% C20:4-6, and 14.8% other compounds and contained no marine -3 fatty acids; this reflects the fatty acid composition of the average European diet (16). The fatty acid mixture in the fish oil capsules was 0.9% C16:0, 6.0% C18:0, 4.5% C18:1-9, 0% C18:2-6, 0.6% C18:3-3, 1.4% C20:4-6, 35.4% C20:5-3, 9.7% C22:5-3, 21.5% C22:6-3, and 20.0% other compounds. The peroxide values were 0.5 in the placebo capsules and 0.6 in the fish oil capsules. All capsules contained 4 mg of tocopherol- as an antioxidant. Identical screw-top plastic containers each contained 90 capsules. The trial monitor in Norway labeled each container with identical information plus a unique randomization number. In the first 3 months of the study, six capsules per day were recommended; in the next 21 months, three capsules per day were recommended. Patients were seen as outpatients at months 1, 6, 12, and 18. At each visit, a history was taken, clinical status was evaluated, and a laboratory work-up (including measurement of erythrocyte phospholipid fatty acid composition) was done. At month 24, all investigations were repeated, including coronary angiography (done during a 2-day hospital stay). At months 0 and 24, but not at months 1, 6, 12, and 18, blood was taken from patients after an overnight fast. Levels of LDL cholesterol were calculated according to the Friedewald formula from measurements obtained in an automated Hitachi 917 or 717 serum analyzer (Boehringer Mannheim, Germany). Coronary angiography with highly standardized angulations was done as described elsewhere (17, 18) and included at least three biplane projections, identically repeated during follow-up angiography. Nitroglycerin, 0.8 mg, was given sublingually for maximal dilatation at the start of the procedure. An expert panel of three experienced invasive cardiologists, who were blinded to all aspects of randomization (such as the temporal order of films) and all patient characteristics (such as name or randomization status), simultaneously assessed changes on coronary angiograms. The same three experts evaluated all pairs of films. Pairs of films (one film taken at baseline and one taken at 2 years) were randomly assigned to two 35-mm angiographic projectors projecting in parallel. Ventriculograms were not reviewed. If PTCA had been done in one of the three coronary vessels in the 6 months before the start of the study or during the study period, the vesselbut not the patientwas excluded from primary analysis (19). Frames in identical angulations were compared in end-diastole. Lesions were identified and were then sought on the corresponding segment on the other film in the pair. With methods described elsewhere (20), angiographically detectable changes on one film were graded relative to the other film in the pair on a scale from 3 to +3. On this scale, 0 indicates no difference, 1 indicates a definitely discernible but small difference, 2 indicates an intermediate difference, and 3 indicates an extreme difference. This score was applied to global assessment of the pairs as well as to each segment of the coronary tree (primary end point). A moderator (who was blinded like the members of the expert panel) documented the results of the expert panel sessions, which were obtained after all three experts had agreed on the results. Agreement was always reached, sometimes after a short discussion. After an expert panel session, the moderator (but not the experts) was unblinded only to the sequence of films just evaluated. This was done to minimize errors. This information was added to the document generated at each session. Quantitative coronary angiography was done with two Arripro projectors coupled with a Qansad system, version V3.2, with periodic updates (ARRI, Munich, Germany). This system is equivalent to other second-generation systems (21). Pairs of angiograms on which at least one change in a coronary segment was identified by the expert panel were analyzed according to the system manual and current algorithms (17, 18). Cardiovascular events were predefined as sudden death, fatal or nonfatal myocardial infarction, congestive heart failure, and neurologic deficits (ischemic or hemorrhagic) according to World Health Organization dBACKGROUND Epidemiologic studies, studies of mechanisms of action, and many animal studies indicate that dietary intake of omega-3 fatty acids has antiatherosclerotic potential. Few trials in humans have examined this potential. OBJECTIVE To determine the effect of dietary intake of omega-3 fatty acids on the course of coronary artery atherosclerosis in humans. DESIGN Randomized, double-blind, placebo-controlled, clinically controlled trial. SETTING University preventive cardiology unit. PATIENTS 223 patients with angiographically proven coronary artery disease. INTERVENTION Fish oil concentrate (55% eicosapentaenoic and docosahexaenoic acids) or a placebo with a fatty acid composition resembling that of the average European diet, 6 g/d for 3 months and then 3 g/d for 21 months. MEASUREMENTS The results of standardized coronary angiography, done before and after 2 years of treatment, were evaluated by an expert panel (primary end point) and by quantitative coronary angiography. Patients were followed for clinical and laboratory status. RESULTS Pairs of angiograms (one taken at baseline and one taken at 2 years) were evaluated for 80 of 112 placebo recipients and 82 of 111 fish oil recipients. At the end of treatment, 48 coronary segments in the placebo group showed changes (36 showed mild progression, 5 showed moderate progression, and 7 showed mild regression) and 55 coronary segments in the fish oil group showed changes (35 showed mild progression, 4 showed moderate progression, 14 showed mild regression, and 2 showed moderate regression) (P = 0.041). Loss in minimal luminal diameter, as assessed by quantitative coronary angiography, was somewhat less in the fish oil group (P > 0.1). Fish oil recipients had fewer cardiovascular events (P = 0.10); other clinical variables did not differ between the study groups. Low-density lipoprotein cholesterol levels tended to be greater in the fish oil group. CONCLUSION Dietary intake of omega-3 fatty acids modestly mitigates the course of coronary atherosclerosis in humans.

Effect of oral postmenopausal hormone replacement on progression of atherosclerosis : A randomized, controlled trial

Abstract —Postmenopausal hormone replacement therapy (HRT) is associated with low cardiovascular morbidity and mortality in epidemiological studies. Yet, no randomized trial has examined whether HRT is effective for prevention of coronary heart disease (CHD) in women with increased risk. The objective of this study was to determine whether HRT can slow progression of atherosclerosis, measured as intima-media thickness (IMT) in carotid arteries. Carotid IMT is an appropriate intermediate end point to investigate clinically relevant effects on atherogenesis. This randomized, controlled, observer-blind, clinical, single-center trial enrolled 321 healthy postmenopausal women with increased IMT in ≥1 segment of the carotid arteries. For a period of 48 weeks, subjects received either 1 mg/d 17&bgr;-estradiol continuously plus 0.025 mg gestodene for 12 days every month (standard-progestin group), or 1 mg 17&bgr;-estradiol plus 0.025 mg gestodene for 12 days every third month (low-progestin group), or no HRT. Maximum IMT in 6 carotid artery segments (common, bifurcation, and internal, both sides) was measured by B-mode ultrasound before and after intervention. HRT did not slow IMT progression in carotid arteries. Mean maximum IMT in the carotid arteries increased by 0.02±0.05 mm in the no HRT group and by 0.03±0.05 and 0.03±0.05 mm, respectively, in the HRT groups (P >0.2). HRT significantly decreased LDL cholesterol, fibrinogen, and follicle-stimulating hormone. In conclusion, 1 year of HRT was not effective in slowing progression of subclinical atherosclerosis in postmenopausal women at increased risk.

Carotid Artery Plaque Burden, Stiffness, and Mortality Risk in Elderly Men A Prospective, Population-Based Cohort Study

Background—Indicators of carotid atherosclerosis may confer additional prognostic value and guide clinicians in cardiovascular risk assessment. Carotid artery morphology (plaque burden) and function (stiffness indexes) as predictors of all-cause and cardiovascular mortality were prospectively evaluated in elderly men. Methods and Results—Cardiovascular risk profile was measured in 367 independently living men (mean±SD age, 78±4 years). The number of carotid plaques was assessed by B-mode ultrasound, and arterial stiffness was quantified with a wall tracker system. During 48 months of follow-up, 70 deaths (28 cardiovascular) occurred. The total number of carotid plaques was the parameter most closely related to prognosis. In the age-adjusted multivariate Cox model, all-cause mortality was predicted by number of plaques (hazard ratio [HR] per 1-unit increase, 1.35; 95% confidence interval [CI], 1.12 to 1.64). Predictors of cardiovascular mortality in the respective model were number of plaques (HR, 1.18; 95% CI, 1.04 to 1.33) and Young’s elastic modulus (HR, 1.68; 95% CI, 1.26 to 2.26). Number of plaques improved the prognostic utility in any prognosis model when added to commonly available cardiovascular risk information. In contrast, stiffness indexes offered no consistent additive value. Conclusions—In elderly men, carotid artery plaque burden is a strong independent predictor of all-cause and cardiovascular mortality in the years to come. The additional value of carotid artery stiffness measurements as a pathophysiologically related entity appears to be limited in this age group and, if anything, confined to cardiovascular mortality risk.

Incorporation of EPA and DHA into plasma phospholipids in response to different omega-3 fatty acid formulations--a comparative bioavailability study of fish oil vs. krill oil.

BackgroundBioavailability of omega-3 fatty acids (FA) depends on their chemical form. Superior bioavailability has been suggested for phospholipid (PL) bound omega-3 FA in krill oil, but identical doses of different chemical forms have not been compared.MethodsIn a double-blinded crossover trial, we compared the uptake of three EPA+DHA formulations derived from fish oil (re-esterified triacylglycerides [rTAG], ethyl-esters [EE]) and krill oil (mainly PL). Changes of the FA compositions in plasma PL were used as a proxy for bioavailability. Twelve healthy young men (mean age 31 y) were randomized to 1680 mg EPA+DHA given either as rTAG, EE or krill oil. FA levels in plasma PL were analyzed pre-dose and 2, 4, 6, 8, 24, 48, and 72 h after capsule ingestion. Additionally, the proportion of free EPA and DHA in the applied supplements was analyzed.ResultsThe highest incorporation of EPA+DHA into plasma PL was provoked by krill oil (mean AUC0-72 h: 80.03 ± 34.71%*h), followed by fish oil rTAG (mean AUC0-72 h: 59.78 ± 36.75%*h) and EE (mean AUC0-72 h: 47.53 ± 38.42%*h). Due to high standard deviation values, there were no significant differences for DHA and the sum of EPA+DHA levels between the three treatments. However, a trend (p = 0.057) was observed for the differences in EPA bioavailability. Statistical pair-wise group comparisons revealed a trend (p = 0.086) between rTAG and krill oil. FA analysis of the supplements showed that the krill oil sample contained 22% of the total EPA amount as free EPA and 21% of the total DHA amount as free DHA, while the two fish oil samples did not contain any free FA.ConclusionFurther studies with a larger sample size carried out over a longer period are needed to substantiate our findings and to determine differences in EPA+DHA bioavailability between three common chemical forms of LC n-3 FA (rTAG, EE and krill oil). The unexpected high content of free EPA and DHA in krill oil, which might have a significant influence on the availability of EPA+DHA from krill oil, should be investigated in more depth and taken into consideration in future trials.

n−3 Fatty acids and the prevention of coronary atherosclerosis

Epidemiologic studies have shown an inverse correlation between consumption of fish or other sources of dietary n-3 fatty acids and cardiovascular events. Numerous mechanisms of action for the favorable effect of dietary n-3 fatty acids on factors implicated in the pathogenesis of atherosclerosis have been described. Studies in dogs, swine, and nonhuman primates have consistently shown beneficial effects in various models of vasoocclusive diseases. Studies published currently do not indicate that dietary n-3 fatty acids prevent restenosis after percutaneous coronary angioplasty or induce regression of coronary atherosclerosis. However, in a recent study, occlusion of aortocoronary venous bypass grafts was reduced after 1 y by daily ingestion of 4 g fish-oil concentrate. In the Diet and Reinfarction Trial, 2-y overall mortality was reduced by 29% in survivors of a first myocardial infarction after consumption of n-3 fatty acid-rich fatty fish at least twice a week had been advised (Lancet 1989;2:757-61). When n-3 fatty acids were integrated into a diet resembling a traditional Mediterranean diet, 5-y cardiovascular mortality after a first myocardial infarction was reduced by 70% (Lancet 1994; 343:1454-9). Preliminary studies indicate that cardiac transplant patients could be an interesting focus of investigation. Currently, food sources rich in n-3 fatty acids are thought to be beneficial in secondary prophylaxis after a myocardial infarction. Large-scale clinical studies with endpoints such as morbidity and mortality are needed to more precisely define the role of n-3 fatty acids in primary and secondary prophylaxis of coronary atherosclerosis.

Dietary ω-3, ω-6, and ω-9 Unsaturated Fatty Acids and Growth Factor and Cytokine Gene Expression in Unstimulated and Stimulated Monocytes A Randomized Volunteer Study

Abstract —Dietary ω-3 fatty acids retard coronary atherosclerosis. Previously, we demonstrated that dietary ω-3 fatty acids reduce platelet-derived growth factor (PDGF)-A and PDGF-B mRNA levels in unstimulated, human mononuclear cells (MNCs). In a randomized, investigator-blinded intervention trial, we have now compared the effect of ingestion of 7 g/d ω-3, ω-6, or ω-9 fatty acids for 4 weeks versus no dietary intervention on PDGF-A, PDGF-B, heparin-bound epidermal growth factor (HB-EGF), monocyte chemoattractant protein-1 (MCP-1), and interleukin-10 gene expression in unstimulated MNCs and in monocytes that were adherence-activated ex vivo in a total of 28 volunteers. In unstimulated MNCs, mRNA steady-state levels of PDGF-A, PDGF-B, and MCP-1 were reduced by 25±10%, 31±13%, and 40±14%, respectively, after ω-3 fatty acid ingestion, as assessed by quantitative polymerase chain reaction (all P <0.05). In monocytes that were adherence-activated ex vivo for 4 and 20 hours, mRNA steady-state levels of PDGF-A, PDGF-B, and MCP-1 were reduced by 25±13%, 20±15%, and 30±8%, respectively (all P <0.05). Interleukin-10 and HB-EGF mRNA steady-state levels were not influenced by ω-3 fatty acid ingestion. Expression of all respective mRNAs in control volunteers or in those ingesting ω-6 or ω-9 fatty acids were not altered. We conclude that human gene expression for PDGF-A, PDGF-B, and MCP-1, factors thought relevant to atherosclerosis, is constitutive, is constant, and can be reduced only by dietary ω-3 fatty acids in unstimulated and adherence-activated monocytes.

The effect of 17β-estradiol on endothelial and inflammatory markers in postmenopausal women: a randomized, controlled trial

Abstract Background: Intervention trials in postmenopausal women with coronary artery disease have failed to demonstrate beneficial effects of hormone replacement therapy (HRT) on the course of disease, potentially due to pro-inflammatory effects of conjugated equine estrogens. We characterized the effects of 48 weeks treatment with two estradiol-based HRT regimens on nonspecific (high sensitivity C-reactive protein [hs-CRP], blood sedimentation rate [BSR], fibrinogen) and specific endothelial markers (cell adhesion molecules: ICAM-1, VCAM-1, E-selectin). Method and Results: Postmenopausal women randomly received either 1 mg 17β-estradiol daily plus 25 μg gestodene for the last 12 days of each 28 day cycle (=standard dose progestin; n =65), or gestodene added each third cycle only (=low dose progestin; n =65), or no HRT ( n =73). Both HRT regimens reduced levels of ICAM-1 (−9%), VCAM-1 (−9%), E-selectin (−11%), fibrinogen (−12%), BSR (−5%). No effect was observed on hs-CRP levels in any group. In smokers, E-selectin remained unchanged whereas ICAM-1 and VCAM-1 were lowered. Subjects on antihypertensive or lipid lowering medication showed effects comparable to the whole cohort. Effects of low and standard dose progestin were not different. Conclusion: We conclude that a combination therapy with 1 mg 17β-estradiol favourably affects the vascular inflammation processes as indicated by a neutral effect on hs-CRP and reduction of cell adhesion molecules.

The effect of 17β-estradiol on MCP-1 serum levels in postmenopausal women

Objective: Monocyte chemoattractant protein-1 (MCP-1) is considered a propagator of atherosclerosis and a key modulator of monocyte activity. Hormone replacement therapy (HRT) is currently being investigated as a means towards prevention of atherosclerosis. We aimed to assess (1) the range of circulating MCP-1 levels in postmenopausal women, (2) the correlation between MCP-1 and atherosclerotic burden, and (3) the effects of commencement and discontinuation of HRT on MCP-1 serum levels. Methods: This clinical prospective trial investigated 51 postmenopausal women at increased risk for cardiovascular events who were randomized to receive either no HRT or 1 mg 17β-estradiol continuously plus sequential progestagen over 1 year. Intima-media thickness (IMT) of carotid and femoral arteries was measured by ultrasound. Serum levels of MCP-1 and cellular adhesion molecules were measured by ELISA. Results: At baseline, MCP-1 levels and overall mean maximum IMT correlated ( r =0.589; P <0.0001, Pearsons coefficient). MCP-1 levels in serum gradually decreased after 3, 6, and 12 months of HRT by 16.8±15.7% at 12 months ( P <0.0001, MANOVA). Similarly, all cellular adhesion molecules decreased significantly by 6–12%. After 12 months, women decided whether to continue or discontinue treatment. At 18 months, in women discontinuing HRT ( n =17), MCP-1 levels rose by 21±20% ( P =0.003), but remained lowered in women continuing HRT. Conclusion: Our observations indicate that 17β-estradiol may have an antiatherosclerotic effect by reducing MCP-1 serum levels and cell adhesion molecules.

Effect of dietary supplementation with ω-3 fatty acids on progression of atherosclerosis in carotid arteries

OBJECTIVE Omega-3 polyunsaturated fatty acids (omega-3 PUFA) from fish oil slow atherosclerosis progression in coronary arteries, as we showed in a randomized double-blind placebo-controlled clinical trial. Embedded in this trial, the present study examined the influence of 2 years of dietary supplementation with 1.65 g omega-3 PUFA per day on progression of carotid atherosclerosis in 223 patients with coronary artery disease. METHODS Coronary angiography, a comprehensive clinical examination, and intima-media thickness measurement by B-mode ultrasound of the carotid arteries (common, internal and bifurcation), were performed at the study start and study end. An expert panel visually evaluated the global change of carotid atherosclerosis on a semiquantitative scale. A second outcome measure was the change of overall mean maximum intima-media thickness. RESULTS One hundred and seventy-one patients completed the study. In the global change score, 38% of the patients in the fish oil group and 35% in the placebo group showed progression. Global change was not different between intervention groups. Mean maximum intima-media thickness increased by 0.07+/-0.13 mm and 0.05+/-0.11 mm in the fish oil and placebo group, respectively (mean+/-S.D., P=0.24). No correlation was found between the change in carotid and coronary arteries. CONCLUSIONS In this group of selected patients with documented coronary artery disease omega-3 PUFA given for 2 years did not demonstrate an effect on slowing progression of atherosclerosis in carotid arteries as measured by ultrasound.

Omega-3 Index and Cardiovascular Health

Recent large trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the cardiovascular field did not demonstrate a beneficial effect in terms of reductions of clinical endpoints like total mortality, sudden cardiac arrest or other major adverse cardiac events. Pertinent guidelines do not uniformly recommend EPA + DHA for cardiac patients. In contrast, in epidemiologic findings, higher blood levels of EPA + DHA were consistently associated with a lower risk for the endpoints mentioned. Because of low biological and analytical variability, a standardized analytical procedure, a large database and for other reasons, blood levels of EPA + DHA are frequently assessed in erythrocytes, using the HS-Omega-3 Index® methodology. A low Omega-3 Index fulfills the current criteria for a novel cardiovascular risk factor. Neutral results of intervention trials can be explained by issues of bioavailability and trial design that surfaced after the trials were initiated. In the future, incorporating the Omega-3 Index into trial designs by recruiting participants with a low Omega-3 Index and treating them within a pre-specified target range (e.g., 8%–11%), will make more efficient trials possible and provide clearer answers to the questions asked than previously possible.