Journal Article•
Atherosclerosis is an Inflammatory Disease
TL;DR: Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations, cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.
About: This article is published in Japanese Circulation Journal-english Edition.The article was published on 1998-02-28 and is currently open access. It has received 9749 citations till now. The article focuses on the topics: Disease.
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TL;DR: This integrating paradigm provides a new conceptual framework for future research and drug discovery in diabetes-specific microvascular disease and seems to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain.
Abstract: Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.
8,289 citations
6,810 citations
TL;DR: The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying persons at risk for cardiovascular events.
Abstract: Background Since inflammation is believed to have a role in the pathogenesis of cardiovascular events, measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events. Methods We conducted a prospective, nested case–control study among 28,263 apparently healthy postmenopausal women over a mean follow-up period of three years to assess the risk of cardiovascular events associated with base-line levels of markers of inflammation. The markers included high-sensitivity C-reactive protein (hs-CRP), serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type 1 (slCAM-1). We also studied homocysteine and several lipid and lipoprotein measurements. Cardiovascular events were defined as death from coronary heart disease, nonfatal myocardial infarction or stroke, or the need for coronay-revascularization procedures. Results Of the 12 markers measured, hs-CRP was the strongest univariate predictor of the risk of cardiovascular events; the relative risk of events for women in the highest as compared with the lowest quartile for this marker was 4.4 (95 percent confidence interval, 2.2 to 8.9). Other markers significantly associated with the risk of cardiovascular events were serum amyloid A (relative risk for the highest as compared with the lowest quartile, 3.0), slCAM-1 (2.6), interleukin-6 (2.2), homocysteine (2.0), total cholesterol (2.4), low-density lipoprotein (LDL) cholesterol (2.4), apolipoprotein B-100 (3.4), high-density lipoprotein (HDL) cholesterol (0.3), and the ratio of total cholesterol to HDL cholesterol (3.4). Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone (P<0.001). The levels of hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter (3.4 mmol per liter), the target for primary prevention established by the National Cholesterol Education Program. In multivariate analyses, the only plasma markers that independently predicted risk were hs-CRP (relative risk for the highest as compared with the lowest quartile, 1.5; 95 percent confidence interval, 1.1 to 2.1) and the ratio of total cholesterol to HDL cholesterol (relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.9). Conclusions The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying women at risk for cardiovascular events.
5,895 citations
TL;DR: The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated, and a proinflammatory state probably contributes to the metabolic syndrome.
5,810 citations
TL;DR: In this article, a lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk, whereas a higher ratio of omega-3 PUFA had no effect.
3,322 citations
References
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TL;DR: The ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.
Abstract: Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.
10,861 citations
TL;DR: Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of my Cardiac Infarction.
Abstract: BACKGROUND Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. METHODS We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. RESULTS Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051). CONCLUSIONS Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.
7,099 citations
TL;DR: The reduction associated with the use of aspirin in the risk of a first myocardial infarction appears to be directly related to the level of C-reactive protein, raising the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease.
Abstract: Background Inflammation may be important in the pathogenesis of atherothrombosis. We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk. Methods We measured plasma C-reactive protein, a marker for systemic inflammation, in 543 apparently healthy men participating in the Physicians' Health Study in whom myocardial infarction, stroke, or venous thrombosis subsequently developed, and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years. Subjects were randomly assigned to receive aspirin or placebo at the beginning of the trial. Results Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infarction (1.51 vs. 1.13 mg per liter, P<0.001) or ischemic stroke (1.38 vs. 1.13 mg per liter, P = 0.02), but not venous thrombosis (1.26 vs. 1.13 mg per liter, P = 0.34), than among men without vascular events. The men in the quartile wit...
5,489 citations
TL;DR: A response-to-injury hypothesis of atherogenesis proposes that "injury" to the endothelium is the initiating event in atherosclerosis, and intimal smooth-muscle proliferation as the key event in the development of the advanced lesions of Atherosclerosis.
Abstract: CARDIOVASCULAR disease remains the chief cause of death in the United States and Western Europe, and atherosclerosis, the principal cause of myocardial and cerebral infarction, accounts for the majority of these deaths.1 This review, like its predecessor,2 will not attempt to cover all literature on atherosclerosis. In a previous review of the pathogenesis of atherosclerosis,2 Glomset and I discussed various hypotheses of atherogenesis2 3 4 5 6 7 and emphasized the importance of intimal smooth-muscle proliferation as the key event in the development of the advanced lesions of atherosclerosis. The response-to-injury hypothesis of atherogenesis2 3 4 5 6 proposes that "injury" to the endothelium is the initiating event in . . .
4,835 citations
TL;DR: It is concluded that human coronary arteries enlarge in relation to plaque area and that functionally important lumen stenosis may be delayed until the lesion occupies 40 percent of the internal elastic lamina area.
Abstract: Whether human coronary arteries undergo compensatory enlargement in the presence of coronary disease has not been clarified. We studied histologic sections of the left main coronary artery in 136 hearts obtained at autopsy to determine whether atherosclerotic human coronary arteries enlarge in relation to plaque (lesion) area and to assess whether such enlargement preserves the cross-sectional area of the lumen. The area circumscribed by the internal elastic lamina (internal elastic lamina area) was taken as a measure of the area of the arterial lumen if no plaque had been present. The internal elastic lamina area correlated directly with the area of the lesion (r = 0.44, P less than 0.001), suggesting that coronary arteries enlarge as lesion area increases. Regression analysis yielded the following equation: Internal elastic lamina area = 9.26 + 0.88 (lesion area) + 0.026 (age) + 0.005 (heart weight). The correlation coefficient for the lesion area was significant (P less than 0.001), whereas the correlation coefficients for age and heart weight were not. The lumen area did not decrease in relation to the percentage of stenosis (lesion area/internal elastic lamina area X 100) for values between zero and 40 percent but did diminish markedly and in close relation to the percentage of stenosis for values above 40 percent (r = -0.73, P less than 0.001). We conclude that human coronary arteries enlarge in relation to plaque area and that functionally important lumen stenosis may be delayed until the lesion occupies 40 percent of the internal elastic lamina area. The preservation of a nearly normal lumen cross-sectional area despite the presence of a large plaque should be taken into account in evaluating atherosclerotic disease with use of coronary angiography.
3,631 citations