Intravenous administration of 80 mg of recombinant tissue plasminogen activator (rt-PA, 40, 20, and 20 mg in successive hours) and streptokinase (SK, 1.5 million units over 1 hr) was compared in a double-blind, randomized trial in 290 patients with evolving acute myocardial infarction. These patients entered the trial within 7 hr of the onset of symptoms and underwent baseline coronary arteriography before thrombolytic therapy was instituted. Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001). Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy. Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK. The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001). The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups. Thus, in patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.
Are newer types of antihypertensive agents, which are currently more costly to purchase on average, as good or better than diuretics in reducing coronary heart disease incidence and progression? Will lowering LDL cholesterol in moderately hypercholesterolemic older individuals reduce the incidence of cardiovascular disease and total mortality? These important medical practice and public health questions are to be addressed by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind trial in 40,000 high-risk hypertensive patients. ALLHAT is designed to determine whether the combined incidence of fatal coronary heart disease (CHD) and nonfatal myocardial infarction differs between persons randomized to diuretic (chlorthalidone) treatment and each of three alternative treatments--a calcium antagonist (amlodipine), an angiotensin converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). ALLHAT also contains a randomized, open-label, lipid-lowering trial designed to determine whether lowering LDL cholesterol in 20,000 moderately hypercholesterolemic patients (a subset of the 40,000) with a 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor, pravastatin, will reduce all-cause mortality compared to a control group receiving "usual care." ALLHAT's main eligibility criteria are: 1) age 55 or older; 2) systolic or diastolic hypertension; and 3) one or more additional risk factors for heart attack (eg, evidence of atherosclerotic disease or type II diabetes). For the lipid-lowering trial, participants must have an LDL cholesterol of 120 to 189 mg/dL (100 to 129 mg/dL for those with known CHD) and a triglyceride level below 350 mg/dL. The mean duration of treatment and follow-up is planned to be 6 years. Further features of the rationale, design, objectives, treatment program, and study organization of ALLHAT are described in this article.
Abstract-Only a fraction of the clinical complications of atherosclerosis are explained by known risk factors. Animal studies have shown that plasma sphingomyelin (SM) levels are closely related to the development of atherosclerosis. SM carried into the arterial wall on atherogenic lipoproteins may be locally hydrolyzed by sphingomyelinase, promoting lipoprotein aggregation and macrophage foam cell formation. A novel, high-throughput, enzymatic method to measure plasma SM levels has been developed. Plasma SM levels were related to the presence of coronary artery disease (CAD) in a biethnic angiographic case-control study (279 cases and 277 controls). Plasma SM levels were higher in CAD patients than in control subjects (60Ϯ29 versus 49Ϯ21 mg/dL, respectively; PϽ0.0001). Moreover, the ratio of SM to SMϩphosphatidylcholine (PC) was also significantly higher in cases than in controls (0.33Ϯ0.13 versus 0.29Ϯ0.10, respectively; PϽ0.0001). Similar relationships were observed in African Americans and whites. Plasma SM levels showed a significant correlation with remnant cholesterol levels (rϭ0. 51, PϽ0.0001). By use of multivariate logistic regression analysis, plasma SM levels and the SM/(SMϩPC) ratio were found to have independent predictive value for CAD after adjusting for other risk factors, including remnants. The odds ratio (OR) for CAD was significantly higher for the third and fourth quartiles of plasma SM levels (OR T he association of lipid abnormalities and coronary atherosclerosis is well established. Case-control and prospective epidemiological studies have shown a direct correlation between coronary artery disease (CAD) and serum levels of total cholesterol and LDL cholesterol (LDL-C) and an inverse relationship between CAD and HDL cholesterol (HDL-C) levels. 1 However, compared with plasma cholesterol measurements, very little attention has been given to the relationship between phospholipids and CAD. 2,3 Atherogenesis is initiated by the interaction of cholesterol-rich lipoproteins, such as LDL, with the arterial wall. 4,5 The uptake of lipoprotein cholesterol by macrophages, leading to foam cell formation, is a central event in the initiation and progression of atherosclerosis. 6 However, native LDL is incapable of generating foam cells from macrophages. Thus, it is thought that LDL is modified in the arterial wall by processes such as oxidation, leading to macrophage chemotaxis and the uptake of modified LDL by macrophage foam cells. 7 Retention of lipoproteins on the subendothelial matrix, followed by aggregation, has also emerged as a central pathogenic process in macrophage foam cell formation and atherogenesis. 8 Lipoprotein aggregation in the vessel wall may result from enzymatic modification of LDL, induced by locally produced sphingomyelinase (SMase). 9 It has long been known that sphingomyelin (SM) accumulates in human and animal atheroma and that the major source is plasma lipoproteins. 10 Plasma SM levels are increased in human familial hyperlipidemias, especially in familial hypercholester...
Abstract-Elevated levels of lipoprotein(a) [Lp(a)] and the presence of small isoforms of apolipoprotein(a) [apo(a)] have been associated with coronary artery disease (CAD) in whites but not in African Americans. Because of marked race/ethnicity differences in the distribution of Lp(a) levels across apo(a) sizes, we tested the hypothesis that apo(a) isoform size determines the association between Lp(a) and CAD. We related Lp(a) levels, apo(a) isoforms, and the levels of Lp(a) associated with different apo(a) isoforms to the presence of CAD (Ն50% stenosis) in 576 white and African American men and women. Only in white men were Lp(a) levels significantly higher among patients with CAD than in those without CAD (28.4 versus 16.5 mg/dL, respectively; Pϭ0.004), and only in this group was the presence of small apo(a) isoforms (Ͻ22 kringle 4 repeats) associated with CAD (Pϭ0.043). Elevated Lp(a) levels (Ն30 mg/dL) were found in 26% of whites and 68% of African Americans, and of those, 80% of whites but only 26% of African Americans had a small apo(a) isoform. Elevated Lp(a) levels with small apo(a) isoforms were significantly associated with CAD (PϽ0.01) in African American and white men but not in women. This association remained significant after adjusting for age, diabetes mellitus, smoking, hypertension, HDL cholesterol, LDL cholesterol, and triglycerides. We conclude that elevated levels of Lp(a) with small apo(a) isoforms independently predict risk for CAD in African American and white men. Our study, by determining the predictive power of Lp(a) levels combined with apo(a) isoform size, provides an explanation for the apparent lack of association of either measure alone with CAD in African Americans. Furthermore, our results suggest that small apo(a) size confers atherogenicity to Lp(a) for cardiovascular disease. [1][2][3] In numerous, but not all, prospective studies, mainly in white populations, elevations of plasma Lp(a) levels, usually defined as Ն30 mg/dL, were significantly correlated with coronary artery disease (CAD). 4 -13 Curiously, although mean Lp(a) levels are twice as high in African Americans compared with whites, studies to date have failed to establish a significant association between elevated Lp(a) levels (Ն30 mg/dL) and CAD among African Americans. 1,14 -16 The lack of understanding of this racial difference has made it difficult to conclude with full confidence that Lp(a) is a risk factor for CAD..In addition to high Lp(a) levels, the presence of small apo(a) isoforms has been associated with CAD in whites. [17][18][19][20][21][22][23][24] In the majority of studies using high-resolution sizing techniques, small apo(a) size has been defined as Ͻ22 kringle 4 (K4) repeats. 17,18,24 The majority of whites with high Lp(a) levels possesses at least 1 small apo(a) isoform; however, the majority of African Americans with high Lp(a) levels has no small apo(a) isoform. 25 The high degree of correlation between elevated levels of Lp(a) and small apo(a) isoforms in whites makes it difficult to ascerta...
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