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In 1908, Alexander I. Ignatowski (1875-1955) published his pioneering work that first revealed a relationship between cholesterol-rich food and experimental atherosclerosis. This early experimental work paved a way to the metabolic study of the mechanism of atherosclerosis. Herein, we present a brief account of Ignatowski's work and life.

Research articles on atherosclerosis have been well represented in The American Journal of Pathology (AJP), with more than 500 articles published since 1925. An initial focus on descriptive studies led to the proposal that atherosclerosis occurs as a response to vascular injury. With time, this view was modified by a greater understanding of the roles played by lipids and integrity of the vessel wall's constituent cells and matrix. AJP has been a major contributor to the field, publishing numerous seminal research papers and review articles on the latest advances in atherosclerosis. This Centennial Review highlights these myriad contributions., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to determine whether ancient Egyptians had atherosclerosis., Background: The worldwide burden of atherosclerotic disease continues to rise and parallels the spread of diet, lifestyles, and environmental risk factors associated with the developed world. It is tempting to conclude that atherosclerotic cardiovascular disease is exclusively a disease of modern society and did not affect our ancient ancestors., Methods: We performed whole body, multislice computed tomography scanning on 52 ancient Egyptian mummies from the Middle Kingdom to the Greco-Roman period to identify cardiovascular structures and arterial calcifications. We interpreted images by consensus reading of 7 imaging physicians, and collected demographic data from historical and museum records. We estimated age at the time of death from the computed tomography skeletal evaluation., Results: Forty-four of 52 mummies had identifiable cardiovascular (CV) structures, and 20 of these had either definite atherosclerosis (defined as calcification within the wall of an identifiable artery, n = 12) or probable atherosclerosis (defined as calcifications along the expected course of an artery, n = 8). Calcifications were found in the aorta as well as the coronary, carotid, iliac, femoral, and peripheral leg arteries. The 20 mummies with definite or probable atherosclerosis were older at time of death (mean age 45.1 ± 9.2 years) than the mummies with CV tissue but no atherosclerosis (mean age 34.5 ± 11.8 years, p < 0.002). Two mummies had evidence of severe arterial atherosclerosis with calcifications in virtually every arterial bed. Definite coronary atherosclerosis was present in 2 mummies, including a princess who lived between 1550 and 1580 BCE. This finding represents the earliest documentation of coronary atherosclerosis in a human. Definite or probable atherosclerosis was present in mummies who lived during virtually every era of ancient Egypt represented in this study, a time span of >2,000 years., Conclusions: Atherosclerosis is commonplace in mummified ancient Egyptians., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This paper describes early INCAP studies showing that cholesterol and lipoprotein levels were much lower in the low-income populations of Central America than values that were just beginning to emerge from industrialized countries. These led to the collection of aortas and coronary vessels from 14,610 males and 7,906 females from serial autopsies from 12 public general hospitals in developing countries, mostly in Latin America and in New Orleans and Oslo. The severity of atherosclerotic lesions in the samples was evaluated independently by four pathologists after the samples were randomized, who determined that the severity of atherosclerosis progressed so slowly in the developing country samples that it rarely became clinically significant. The strongest correlation with the severity of lesions was the fat content of the diet.

Karl Rokitansky (1804-1878) was the first to put forward a theory on pathogenesis of atherosclerosis. His "thrombogenic" theory is included in his famous three-volume Manual of Pathological Anatomy. In its first edition issued in 1844 he describes the disease under the heading Excessive formation of plaques on the interior of vessels. He does not use the term "atherosclerosis", speaking simply about a process. The description is merely macroscopic, based predominantly on lesions of the aorta. The process starts as thickening--hypertrophy and plaque formation of the vascular inner layer. The apposed pseudomembrane is composed of foreign substance of blood origin--fibrin. The pseudomembrane eventually develops into either an atheromatous process or ossification. Rokitansky accurately describes an atheromatous plaque with its lipid-rich interior, including its complications, however, he misregards plaque calcification for ossification. Although Rokitansky is aware that the disease may cause both narrowing and dilatation of a vessel, he claims that outcomes of the disease are unknown. In the third edition of Rokitansky's textbook issued 12 years later there are already included histological drawings of the aortic intimal and medial lesions.

Already at the beginning of the 20th century, a potential role for microbes in vascular diseases was suggested. However, until the late '70 of that century, not much attention has been paid to this infection hypothesis. Then, predominantly based on the pioneering work of Fabricant et al., evidence for a contributing or even initiating role for microbes in atherosclerosis, as well as other vascular diseases, was accumulating. Also, the seminal paper by Saikku and co-workers, demonstrating serological evidence of an association of Chlamydia pneumoniae, an obligate intracellular respiratory gram-negative bacterium, with chronic coronary heart disease and acute myocardial infarction, significantly boosted the research on the infection hypothesis. Since then, numerous papers have been published demonstrating associations between a large variety of pathogens and atherosclerotic disease. Furthermore, many molecular mechanisms have been suggested by which microbes may affect atherogenesis. Nevertheless, in recent large randomised prospective trials, evaluating the efficacy of antibiotic treatment for the secondary prevention of coronary events, no reduction in the rate of cardiovascular events was observed, thereby seriously challenging the validity of the infection hypothesis. Nevertheless, the large body of supporting evidence, which has accumulate over the past decades, should not be ignored and maybe we should look at the hypothesis, and in particular the mechanisms by which microbes affect the disease, from a different angle.

Dom João VI's death occurred in adverse political conditions that led to the regicide hypothesis. The main aim of this paper is to mention life style and conditions of the death of the king by means of narrative review based on primary and secondary sources. Dom João VI died in the way of convulsions and gastrointestinal symptoms. This could be the result of the pathological chain of genetic determination, accentuated by the inappropriate life style, obesity and sedentary habits, and/or poisoning. The finding of arsenic in high doses in his viscera favors the last hypothesis as the basic cause of death, but one can not discard the atherosclerosis predisposing risk factors for a final stroke.

The full awareness that physical exercise represents a form of prevention and therapy for cardiovascular diseases is rather recent, considering that the discovery of blood circulation dates back to the 17th century and that the definition of major cardiovascular risk factors is an acquisition of the 20th century. In this paper a historical review has been undertaken so as to evidence major selected highlights of cardiovascular knowledge applied to physical activity from antiquity to the present day. Despite of the fact that the role of physical activity for the sake of a good body equilibrium is an ancient concept, as documented by the recurrent term ''exercise'' in the works of Hippocrates, only about 70 years have passed from the time when, in the '30s, myocardial infarction patients were strictly advised to observe a period of bed rest of at least 6 weeks; less than a century has passed since the so-called ''chair therapy'' constituted the cornerstone of the therapy of the cardiovascular patient. In the '40s and the '50s a certain amount of attentive mobilization proved to be beneficial, given that it was associated with a remarkable reduction of thromboembolic risk. In the '70s an increasing amount of clinical literature documented that even healthy subjects, remaining in bed for a long period, showed relatively rapidly signs of de-conditioning. In 1973 Kavanagh et al. demonstrated that the patients included in cardiac rehabilitation showed an improvement in their physical work capacity, an increase in their global cardiovascular function and went back more quickly and safely to their work environment, as compared with cardiac patients not performing rehabilitative physical exercise. The studies performed in the '70s provided the bases of modern cardiovascular rehabilitation, a multidimensional and integrated approach, one of whose pillars is structured physical activity.

Thirty years ago, Kurt Oster promulgated the avant-garde theory that bovine xanthine oxidase, absorbed intact from homogenized milk, promoted atherogenesis by oxidatively damaging membrane plasmalogens. Under the mistaken impression that folic acid is a xanthine oxidase inhibitor, he administered high-dose folate (80 mg daily) to hundreds of patients afflicted with symptomatic atherosclerosis, and reported marked improvements in angina, intermittent claudication, and wound healing; he also suspected that this regimen was decreasing heart attack risk. The xanthine oxidase theory has since fallen by the wayside, but there is now evidence that folic acid can lessen endothelial oxidative stress by improving the function of "uncoupled" nitric oxide synthase deficient in tetrahydrobiopterin. In light of these new findings, a properly controlled assessment of Oster's mega-dose folate therapy is warranted.

The history of atherosclerosis represents a very interesting and intriguing charter of the history of medicine. Atherosclerosis was present even in the old age, as demonstrated by paleopathological studies. Starting from these observations, recent evidences highlighted the crucial role of inflammation in the genesis of atherosclerosis.

The first four reviews in this series (Steinberg, D. 2004. J. Lipid Res. 45: 1583-1593; Steinberg, D. 2005. J. Lipid Res. 46: 179-190; Steinberg, D. 2005. J. Lipid Res. 46: 2037-2051; Steinberg, D. 2006. J. Lipid Res. 47: 1-14) traced the gradual accumulation of evidence, evidence of several different kinds, supporting the lipid hypothesis. They tracked the history from Anitschkow's 1913 classic work on the cholesterol-fed rabbit model to the breakthrough 1984 Coronary Primary Prevention Trial, the first large, randomized, double-blind primary intervention trial showing that decreasing blood cholesterol (using cholestyramine) significantly reduces coronary heart disease events. At that point, for the first time, decreasing blood cholesterol levels became an official national public health goal. Still, only a small fraction of patients at high risk were getting appropriate cholesterol-lowering treatment, and a number of important clinical questions remained unanswered. This final review in the series traces the early studies that led to the discovery of the statins and briefly reviews the now familiar large-scale clinical trials demonstrating their safety and their remarkable effectiveness in reducing coronary heart disease morbidity and mortality.

It is now clear that inflammation plays a key role in atherogenesis. As a matter of fact, signs of inflammation of atherosclerotic plaques have been observed for centuries and also constituted the basis for a fierce controversy in the 19th century between the prominent Austrian pathologist Carl von Rokitansky and his German counterpart, Rudolf Virchow. While the former attributed a secondary role to these inflammatory arterial changes, Virchow considered them to be of primary importance. We had the unique opportunity to address this controversy by investigating atherosclerotic specimens from autopsies performed by Carl von Rokitansky up to 178 years ago. Twelve atherosclerotic arteries originally collected between the years 1827 to 1885 were selected from the Collection Rokitansky of the Federal Museum of Pathological Anatomy, Vienna Medical University. Using modern sophisticated immunohistochemical and immunofluorescence techniques, it was shown that various cellular intralesional components, as well as extracellular matrix proteins, were preserved in the historic atherosclerotic specimens. Most importantly, CD3 positive cells were abundant in early lesions, thus, rather supporting Virchows's view, that inflammation is an initiating factor in atherogenesis. Furthermore, we hope to have opened a new and intriguing possibility to study various pathological conditions using valuable historical specimens.

Atherosclerosis is an inflammatory process disease that involves the artery wall and that is characterized by the progressive accumulation of lipids. The term arteriosclerosis has been created by Lobstein in 1833. Subsequently, during the 19th century, the contribution of Rokitansky and Virchow was important to elucidate the pathogenesis of arteriosclerosis and the morphologic aspects of the plaque. In the beginning of the 20th century, Aschoff was a leading proponent who regarded the morphologically different intimal lipid deposits of children and adults as early and late stages of one disease and he called them atherosis and atherosclerosis, respectively. The first classification of atherosclerosis was made by the World Health Organization (WHO) in 1958 and it consisted of the following sequence: fatty streak, atheroma, fibrous plaque and complicated lesions. In 1990s, thanks to much more sensitive techniques, the American Heart Association (AHA) proposed a new morphological classification based on eight lesion types designated by Roman numerals which indicate the usual sequence of lesion progression. Finally, Virmani et al. (2000) described a classification with the add of a specific plaque type, not recognized by the AHA classification, called "thin fibrous cap atheroma" which is more likely to rupture. The atherosclerotic process is characterized by typical ultrastructural changes that mainly involve the endothelial and smooth muscle cells. The morphological alterations of the endothelium are associated with dysfunctions leading to a proinflammatory and prothrombotic phenotype. This process seems to be due to turbulent blood flow and low fluid shear stress that normally occurs in particular regions of the vascular tree. Inflammation has a key role in the pathogenesis of atherosclerosis and it is supported by numerous factors such as modified LDL, hypertension, diabetes mellitus, free radicals and, in particular, by infectious agents such as Chlamydia pneumoniae.

As of the early 1980s, despite the wealth of evidence from experimental animal models, the extensive epidemiologic evidence, the powerful genetic evidence, and the strongly suggestive clinical intervention trial results, most clinicians still remained unpersuaded regarding the relevance of the lipid hypothesis. What was needed was a well-designed, large-scale, long-term, double-blind study demonstrating a statistically significant impact of treatment on coronary heart disease events. The National Institutes of Health (NIH) had laid the groundwork for such a study as early as 1970, but the study was not completed and the results published until 1984. This study, the Coronary Primary Prevention Trial, showed that treatment with a bile acid binding resin reduced major coronary events in hypercholesterolemic men by 19%, with a P value of 0.05. The NIH followed this up with a national Consensus Development Conference on Lowering Blood Cholesterol to Prevent Heart Disease. For the first time, the NIH now went on record advocating screening for hypercholesterolemia and urging aggressive treatment for those at high risk. The Institute initiated a national cooperative program to that end, the National Cholesterol Education Program. For the first time, preventing coronary heart disease became a national public health goal.

Nikolai N. Anichkov (1885-1964) first demonstrated the role of cholesterol in the development of atherosclerosis. His classic experiments in 1913 paved the way to our current understanding of the role of cholesterol in cardiovascular disease. Anichkov's research is often cited among the greatest discoveries of the 20th century; however, little is known about Anichkov and his team. Herein, we give a detailed historical account of Anichkov's work, his personality, his research team, and their pioneering effort.