Göran Walldius

PLASMINOGEN ACTIVATOR INHIBITOR IN PLASMA: RISK FACTOR FOR RECURRENT MYOCARDIAL INFARCTION

Measurements of haemostatic function and metabolic and angiographic indices of risk were included in a prospective cohort study of variables predictive of recurrences within 3 years in 109 unselected men with a first myocardial infarction (MI) before the age of 45. In the course of follow-up, 16 patients had at least one reinfarction (fatal recurrences in 9 and nonfatal in 7) and 1 died suddenly. High plasma concentrations of the fast-acting plasminogen activator inhibitor were independently related to reinfarction along with dyslipoproteinaemia involving VLDL and HDL, poor left ventricular performance, and multiple-vessel coronary artery disease. Besides being independently associated with reinfarction in the present population, high triglyceride levels were possibly connected with a predisposition to thrombosis through a coexisting high level of plasminogen activator inhibitor. The data indicate that reduced fibrinolytic capacity due to increased plasma levels of the plasminogen activator inhibitor predisposes to reinfarction in a complex interplay with atherogenic factors, multiple coronary lesions, and compromised left ventricular function.

High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study

BACKGROUND Apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) are thought to be better predictors of acute myocardial infarction than total cholesterol and LDL-cholesterol. We investigated whether apoB and apoA-I are predictors of risk of fatal myocardial infarction. We also aimed to establish whether apoB and apoA-I add further information about risk of fatal myocardial infarction to that obtained with total cholesterol, triglycerides, and LDL-cholesterol. METHODS We recruited 175553 individuals mainly from screening programmes. We measured concentrations of apoB, apoA-I, total cholesterol, and triglycerides, and calculated apoB/apoA-I ratio and concentrations of LDL-cholesterol and HDL-cholesterol. The relation between death from acute myocardial infarction and initial values for apoB, apoA-I, and the other lipids was examined. FINDINGS Mean follow-up was 66.8 months (SD 41.3) for 98722 men and 64.4 months (41.4) for 76831 women. 864 men and 359 women had fatal myocardial infarction. In univariate analyses adjusted for age and in multivariate analyses adjusted for age, total cholesterol, and triglycerides, the values for apoB and apoB/apoA-I ratio were strongly and positively related to increased risk of fatal myocardial infarction in men and in women. ApoA-I was noted to be protective. In multivariate analysis, apoB was a stronger predictor of risk than LDL-cholesterol in both sexes. INTERPRETATION Although LDL-cholesterol and HDL-cholesterol are known risk factors, we suggest that apoB, apoB/apoA-I, and apoA-I should also be regarded as highly predictive in evaluation of cardiac risk. Although increased throughout the range of values of LDL-cholesterol, apoB and apoA-I might be of greatest value in diagnosis and treatment in men and women who have common lipid abnormalities, but have normal or low concentrations of LDL-cholesterol.

Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment

More Nobel prizes have been awarded for the study of cholesterol than for any other molecule. Presently, concentration of LDL cholesterol is the fundamental index of risk of vascular disease. It is an estimate of the mass of cholesterol in the LDL fraction in plasma. By contrast, the value for apolipoprotein B is a measurement of the total number of atherogenic particles. Results of many studies show that apolipoprotein B is a better marker of risk of vascular disease and a better guide to the adequacy of statin treatment than any cholesterol index. Moreover, the ratio of apolipoprotein B/apolipoprotein A-1 seems superior to the ratio of total cholesterol/HDL cholesterol as an overall index of the risk of vascular disease. We review this evidence and include observations that were not previously published. The pathophysiological bases for the superiority of apolipoprotein B to cholesterol as a predictor of risk are reported elsewhere. 1

The apoB/apoA-I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy--a review of the evidence.

During the last several years interest has focused on the importance of the lipid‐transporting apolipoproteins – apoB transports all potentially atherogenic very low‐density lipoprotein (VLDL), intermediate‐density lipoprotein (IDL) and LDL particles, and apoA‐I transports and acts as the major antiatherogenic protein in the HDL particles. The evidence for the apoB/apoA‐I ratio being a strong, new risk factor for cardiovascular (CV) disease and a target for lipid‐lowering therapy is reviewed. Results from clinical prospective studies and lipid‐lowering trials in healthy subjects and in patients with different clinical manifestations of atherosclerosis are reported. Risk of nonfatal and fatal myocardial infarction and stroke, and manifestations of atherosclerosis documented by angiographic, ultrasound and other techniques has been related to conventional lipids and apolipoproteins (apo). The cholesterol balance determined as the apoB/apoA‐I ratio has repeatedly been shown to be a better marker than lipids, lipoproteins and lipid ratios. The results indicate that the apoB/apoA‐I ratio is a simple, accurate and new risk factor for CV disease – the lower the apoB/apoA‐I ratio, the lower is the risk. Guidelines should be developed in order to recognize the important clinical risk information embedded in the apoB/apoA‐I ratio.

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein‐related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid‐lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL−1 in high‐risk patients should be reassessed in the light of the new clinical trial results and a new ultra‐low target of <80 mg dL−1 be considered. The evidence also indicates that the apo B/apo A‐I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein‐related risk of vascular disease.

Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-modifying therapy

Although LDL cholesterol (LDL‐C) is associated with an increased risk of coronary heart disease, other lipoproteins and their constituents, apolipoproteins, may play an important role in atherosclerosis. Elevated levels of apolipoprotein (apo) B, a constituent of atherogenic lipoproteins, and reduced levels of apo A‐I, a component of anti‐atherogenic HDL, are associated with increased cardiac events. Apo B, apo A‐I and the apo B/apo A‐I ratio have been reported as better predictors of cardiovascular events than LDL‐C and they even retain their predictive power in patients receiving lipid‐modifying therapy. Measurement of these apolipoproteins could improve cardiovascular risk prediction.

The effect of probucol on femoral atherosclerosis: the Probucol Quantitative Regression Swedish Trial (PQRST).

The Probucol Quantitative Regression Swedish Trial tested whether treatment of hypercholesterolemic persons with probucol for 3 years affected femoral atherosclerosis. The primary end point was the change in atheroma volume estimated as change in lumen volume of the femoral artery assessed by quantitative arteriography. Three hundred three patients with visible atherosclerosis were randomized to probucol 0.5 g, twice daily, or to placebo. All patients were given diet and cholestyramine, 8 to 16 g/day. Twenty-nine patients were excluded because of inadequate primary end point measurements. The mean age of the remaining 274 subjects (158 were men) was 55 years. Seventeen percent had intermittent claudication and 24% had angina pectoris. After 3 years, the probucol-treated patients had 17% lower serum cholesterol, 12% lower low-density lipoprotein cholesterol, 24% lower total high-density lipoprotein cholesterol, and 34% lower high-density lipoprotein2 cholesterol levels than control subjects. All lipoprotein differences between the treatment groups remained highly significant during the trial. There was no statistically significant change in lumen volume between the probucol and the control group. Furthermore, there was no difference between the treatment groups with regard to change in arterial edge roughness or amount of aorto-femoral atherosclerosis; neither were there any differences between the treatment groups with regard to change in ST-segment depressions on exercise tests or ankle/arm blood pressure (secondary end points). In the control group, lumen volume increased (p < 0.001) and roughness of the femoral artery decreased (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The apoB/apoA-I ratio is better than the cholesterol ratios to estimate the balance between plasma proatherogenic and antiatherogenic lipoproteins and to predict coronary risk

Abstract Background: The apolipoprotein B (apoB)/apoA-I ratio represents the balance of proatherogenic and antiatherogenic lipoproteins. The purpose of this study was to determine whether the apoB/apoA-I ratio was superior to any of the cholesterol ratios – total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C), low-density lipoprotein cholesterol (LDL-C)/HDL-C and non-HDL-C/HDL-C – in predicting the risk of coronary disease. Moreover, we examined whether any lipids, lipoproteins or cholesterol ratios add significant predictive information beyond that provided by the apoB/apoA-I ratio. Methods: Plasma lipids, lipoproteins, apoB, and apoA-I were measured in 69,030 men and 57,168 women above 40years of age. After a mean follow-up of 98months, 1183 men and 560 women had died from a myocardial infarction in this prospective apolipoprotein-related mortality risk (AMORIS) study. Results: High apoB and a high apoB/apoA-I ratio were strongly related to increased coronary risk, while high apoA-I was inversely related to risk. The apoB/apoA-I ratio was superior to any of the cholesterol ratios in predicting risk. This advantage was most pronounced in subjects with LDL-C levels <3.6mmol/l. Addition of lipids, lipoproteins or any cholesterol ratio to apoB/apoA-I in risk models did not further improve the strong predictive value of apoB/apoA-I. Conclusions: These results indicate that the apoB/apoA-I ratio is at present the best single lipoprotein-related variable to quantitate coronary risk. Given the additional advantages apolipoproteins possess – fasting samples are not required, apoB/apoA-I is a better index of the adequacy of statin therapy than LDL-C, and the measurement of apoB and apoA-I are standardized, whereas LDL-C and HDL-C are not – there would appear to be considerable advantage to integrating apolipoproteins into clinical practice.

Relationship of angiographically defined coronary artery disease to serum lipoproteins and apolipoproteins in young survivors of myocardial infarction.

The relationship of serum lipoprotein and apolipoprotein concentrations to angiographically determined coronary artery disease was investigated in 105 consecutive male survivors of myocardial infarction under the age of 45. Concentrations and composition of lipoproteins, lipid indexes, and nonlipid risk factors (tobacco consumption, hypertension, reduced glucose tolerance, and obesity) were related to a recently developed scoring system for semiquantitative estimation of diffuse coronary atheromatosis, as well as to the number and severity of significant coronary artery stenoses. The concentrations of cholesterol in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), in combination with serum triglyceride or VLDL triglyceride level, comprised the best set of independent discriminatory lipid variables between patients and control subjects. In the patients, LDL cholesterol and apolipoprotein B levels showed strong relationships to the extent and severity of coronary atheromatosis but not to the number and severity of distinct coronary stenoses. HDL2 cholesterol concentration correlated inversely with the coronary atheromatosis score, whereas other variables reflecting HDL concentration and composition or VLDL lipids were not independently related to any of the coronary scores. The LDL triglyceride level, an index of intermediate-density lipoprotein (IDL) accumulation, was significantly correlated to the coronary atheromatosis score in univariate analysis. Nonlipid risk factors were correlated neither to coronary atheromatosis nor to severity of stenoses. Stepwise multiple regression analyses of data adjusted for age, cumulative tobacco consumption, and weight indicated that 18% of the variation in the coronary atheromatosis score could be accounted for by levels of apolipoprotein B. Addition of other lipoprotein variables or the nonlipid variables hypertension and glucose tolerance did not significantly increase the value of R2. When ratios of lipoprotein lipids and apolipoproteins were included in the regression model, the highest multiple correlation coefficient was obtained with the LDL/HDL cholesterol ratio alone (R2 = .22). The present data demonstrate the importance of elevated LDL cholesterol and apolipoprotein B concentrations for the development of coronary atheromatosis in young male survivors of myocardial infarction. The lack of correlations between the levels of lipoprotein lipids and serum apolipoproteins and the severity of coronary stenoses suggests that mechanisms other than disturbances of lipoprotein metabolism may be involved in the progression of more advanced coronary lesions.

RISK FACTORS FOR ISCHÆMIC HEART-DISEASE IN NORMAL MEN AGED 40: Edinburgh—Stockholm Study

Abstract 107 healthy men in Edinburgh and 82 in Stockholm, all aged 40 and selected at random, took part in a study aimed at identifying factors which might explain why, in men of this age, the mortality-rates from ischaemic heart disease are three times greater in Edinburgh men. Clinical measurements and electrocardiographic procedures were standardised, and steps taken to eliminate interlaboratory differences. Edinburgh men were shorter and fatter; had higher systolic and diastolic blood-pressures; smoked more cigarettes (but the number of cigarette smokers in the two groups was similar); drank more alcohol; had more E.C.G. abnormalities and lower exercise tolerance. They had higher levels of total serum-triglycerides and triglycerides in very low (V.L.D.L.), low (L.D.L.), and high (H.D.L.) density lipoproteins. Triglyceride clearance (assessed by an intravenous fat-tolerance test) was similar. Serum-cholesterol and L.D.L.-cholesterol concentrations were similar in both cities but cholesterol in V.L.D.L. was higher, and cholesterol in H.D.L. was lower, in Edinburgh men. The relative linoleic-acid content of plasma-triglycerides and of plasma-cholesterol esters were lower in Edinburgh men, and their subcutaneous adipose tissue glycerides had a lower polyunsaturated/ saturated fatty-acid ratio and a strikingly lower relative linoleic acid content. Edinburgh men had a greater total plasma-insulin response to a standardised glucose-tolerance test. The glucose response was the same in both cities. Plasma free fatty-acids and free glycerol were reduced by a lesser extent in Edinburgh men in response to a glucose load. Although the high incidence of ischaemic heart-disease in Scotland may be due to many factors, some of which are well established, this study points out metabolic factors which may provide new information on the pathogenesis of ischaemic heart-disease.