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Insulin receptor (IR) was discovered in 1970. Shortcomings in IR transcribed signals were found pro-diabetic, which could also inter-relate obesity and atherosclerosis in a time-dependent manner. Low-density lipoprotein receptor (LDLR) was discovered in 1974. Later studies showed that insulin could modulate LDLR expression and activity. Repression of LDLR transcription in the absence or inactivity of insulin showed a direct cause of atherosclerosis. Leptin receptor (OB-R) was found in 1995 and its resistance became responsible for developing obesity. The three interlinked pathologies namely, diabetes, atherosclerosis, and obesity were later on marked as metabolic syndrome-X (MSX). In 2012, the IR-LDLR inter-association was identified. In 2019, the proficiency of signal transmission from this IR-LDLR receptor complex was reported. LDLR was found to mimic IR-generated signaling path when it remains bound to IR in IR-DLR interlocked state. This was the first time LDLR was found sending messages besides its LDL-clearing activity from blood vessels., (© 2021 Wiley Periodicals LLC.)

Animal models that closely resemble both human disease findings and their onset mechanism have contributed to the advancement of biomedical science. The Watanabe heritable hyperlipidemic (WHHL) rabbit and its advanced strains (the coronary atherosclerosis-prone and the myocardial infarction-prone WHHL rabbits) developed at Kobe University (Kobe, Japan), an animal model of human familial hypercholesterolemia, have greatly contributed to the elucidation of the pathophysiology of human lipoprotein metabolism, hypercholesterolemia, atherosclerosis, and coronary heart disease, as described below. 1) The main part of human lipoprotein metabolism has been elucidated, and the low-density lipoprotein (LDL) receptor pathway hypothesis derived from studies using fibroblasts was proven in vivo. 2) Oxidized LDL accumulates in the arterial wall, monocyte adhesion molecules are expressed on arterial endothelial cells, and monocyte-derived macrophages infiltrate the arterial intima, resulting in the formation and progression of atherosclerosis. 3) Coronary lesions differ from aortic lesions in lesion composition. 4) Factors involved in the development of atherosclerosis differ between the coronary arteries and aorta. 5) The rupture of coronary lesions requires secondary mechanical forces, such as spasm, in addition to vulnerable plaques. 6) Specific lipid molecules in the blood have been identified as markers of the progression of coronary lesions. At the end of the breeding of the WHHL rabbit family at Kobe University, this review summarizes the history of the development of the WHHL rabbit family and their contribution to biomedical science.

Atherosclerosis is an inflammatory, progressive, and chronic illness that involves several molecular and epigenetic factors. Despite treatment limitations, clinical and therapeutic approaches have undeniably changed radically in recent decades through better knowledge of the pathophysiological basis of the disease, which has considerably improved patients' survival and quality of life. Some of these advances are attributable to basic biomedical research that provides insights into a better understanding and identification of new molecular and cellular targets for atherosclerosis treatment. Although rodent models have contributed substantially to a better understanding of the development of atherosclerosis, the accuracy of these models remains controversial. Research that utilizes genetic rodent models is well established, but the use of specific diets that are associated with other risk factors (e.g., hypertension, hormone deprivation, and pharmacological tools) is still debatable. The present review provides an update on non-genetic rat models of atherosclerosis and an overview of the main methodologies that are currently available.

Background and Aims: A small crypt in the Santissima Annunziata Church of Santa Maria della Scala Hospital in Siena (Italy) contained three well-preserved mummies, two of which, dated back to the 15th-16th century, were identified as Salimbene Capacci (1433-1497), Rector of the Hospital, and his wife, Margherita Sozzini (?-1511). The third mummy, dressed in clothes of the 17th century, was not initially identified., Methods: Accurate bibliographical, taphonomic and anthropological studies allowed the identification of the mummy of Girolamo Macchi, who lived between 1648 and 1734 and worked as "major writer", an accountant, for the Hospital. He was present when the corpses of the Rector and his wife were discovered in 1678 and, impressed by this finding, wanted to be buried in the same chapel after his death, which occurred at the age of 86. A complete study, including macroscopic, radiological, isotopic and histological analyses, was performed on the natural mummy of Girolamo., Results: Macroscopic investigation showed a large inguinoscrotal hernia and a good preservation of the internal organs. The circulatory system revealed severe atherosclerosis, with multiple calcifications stenosing the lumen of the vessels, in particular of the lumbar aorta and the iliac arteries. The diagnosis was confirmed by imaging techniques (3D Cone Beam Scan) and by histology., Conclusions: This case confirms that atherosclerosis is also a disease of ancient times. The presence of atherosclerosis in pre-contemporary individuals could suggest that the disease may not only be uniquely characteristic of a specific diet or lifestyle, but it could be also an inherent component of human ageing., (Copyright © 2018. Published by Elsevier B.V.)

This review tells the story of atherosclerosis research in the beginning of the 20th century. It presents the significance of cardiovascular diseases and addresses major questions currently being discussed among lipidologists and the current thinking with respect to low LDL-cholesterol levels and HDL. It provides an overview of the period during which lipid-modifying drugs were introduced and their relevance with respect to cardiovascular outcome data and lists possible reasons why some patients develop new cardiovascular events while being treated with statins. Especially impressive is the history of the appearance of the PCSK9 inhibitors on the market - only 12 years after PCSK9 was detected; a study completed in 2017 provides evidence about the cardiovascular effects of these new drugs. Other new drugs are also mentioned: mipomersen, lomitapide, and Alipogen Tiparvovec. Some promising drugs are still in the pipeline which inhibit the synthesis of apolipoprotein CIII, apolipoprotein(a), and the PCSK9 protein. During the 1970s, specific lipoprotein apheresis began to be used in high-risk patients with homozygous familial hypercholesterolemia, severe hypercholesterolemia and elevated Lipoprotein(a) levels and this review provides evidence of the effectiveness of the extracorporeal therapy with respect to the reduction of cardiovascular events. Particularly in patients with high Lipoprotein(a) levels, apheresis has been proven capable of reducing cardiovascular events by more than 80%. The current situation with regard to lipoprotein apheresis centers and patients in Germany is described herein, and, in conclusion, an estimation of the future of the therapeutic options in lipidology is given., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cholesterol is a precursor of steroid hormones and an essential component of the cell membrane, however, altered regulation of the synthesis, absorption and excretion of cholesterol predispose to cardiovascular diseases of atherosclerotic origin. Despite, the recognition of historical events for 200 years, starting with Michel Chevreul naming «cholesterol»; later on, Lobstein coining the term atherosclerosis and Marchand introducing it, Anichkov identifying cholesterol in atheromatous plaque, and Brown and Goldstein discovering LDL receptor; as well as the emerging of different drugs, such as fibrates, statins and cetrapibs this decade, promising to increase HDL and the most recent ezetimibe and anti-PCSK9 to inhibit the degradation of LDL receptor, however morbidity has not been reduced in cardiovascular disease., (Copyright © 2016. Published by Masson Doyma México S.A.)

Ancient mummies have captivated a wide variety of audiences for centuries. In order to better understand the evolution and causative features of atherosclerosis, the Horus group is applying modern scientific methods to study ancient mummies. We have used CT scanning to detect calcification in arteries as an indication of the presence of atherosclerosis, and are correlating these results with cultural and lifestyle features of various populations of ancient people as represented by their ancient mummified remains. We are also pursuing related studies of ancient DNA to define genotypes associated with atherosclerotic phenotypes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Through the study of preserved human remains, it is now known that atherosclerosis, commonly thought to be a modern disease, also existed in historic and prehistoric periods. To date, however, little evidence of atherosclerosis has been reported in samples of tissues from spontaneously mummified bodies that are often found in European crypts and churches., Methods: Within the framework of the Lithuanian Mummy Project, whole-body computed tomographic scans of seven spontaneous mummies from a crypt in Vilnius were obtained and assessed for indications of atherosclerosis., Results: Three of the mummies investigated showed clear evidence of atherosclerosis, which was at times quite severe. Atherosclerosis is believed to have been prevalent among affluent members of Lithuanian society, which is corroborated by historical sources., Conclusions: In accordance with recent, significant data, this study further demonstrates the antiquity of this disease. Documentary and ethnographic data suggest that lifestyle may have played a role in the onset of atherosclerosis in these individuals., (© 2014 Wiley Periodicals, Inc.)

Modern cardiology was born early in the twentieth century. Here I list and review what I believe to be the ten most important advances in the twentieth century in this field. They are as follows: electrocardiography, cholesterol-induced atherosclerosis, cardiac catheterization, cardiovascular surgery, coronary angiography and percutaneous coronary angioplasty, the coronary care unit, the development of new cardiovascular drugs, preventive cardiology, cardiac imaging, and implanted cardiac pacemakers/defibrillators., (Copyright © 2014. Published by Elsevier Inc.)

Computed tomographic findings of atherosclerosis in the ancient cultures of Egypt, Peru, the American Southwest and the Aleutian Islands challenge our understanding of the fundamental causes of atherosclerosis. Could these findings be true? Is so, what traditional risk factors might be present in these cultures that could explain this apparent paradox? The recent computed tomographic findings are consistent with multiple autopsy studies dating as far back as 1852 that demonstrate calcific atherosclerosis in ancient Egyptians and Peruvians. A nontraditional cause of atherosclerosis that could explain this burden of atherosclerosis is the microbial and parasitic inflammatory burden likely to be present in ancient cultures inherently lacking modern hygiene and antimicrobials. Patients with chronic systemic inflammatory diseases of today, including systemic lupus erythematosus, rheumatoid arthritis, and human immunodeficiency virus infection, experience premature atherosclerosis and coronary events. Might the chronic inflammatory load of ancient times secondary to infection have resulted in atherosclerosis? Smoke inhalation from the use of open fires for daily cooking and illumination represents another potential cause. Undiscovered risk factors could also have been present, potential causes that technologically cannot currently be measured in our serum or other tissue. A synthesis of these findings suggests that a gene-environmental interplay is causal for atherosclerosis. That is, humans have an inherent genetic susceptibility to atherosclerosis, whereas the speed and severity of its development are secondary to known and potentially unknown environmental factors., (Copyright © 2014 World Heart Federation (Geneva). Published by Elsevier B.V. All rights reserved.)

One hundred years ago, Nikolai N. Anitschkow published his seminal observations that rabbits fed a diet with only high-cholesterol developed atheromatous lesions in association with greatly elevated blood cholesterol. For many years, Anitschkow's observations received little recognition. However, eventually a combination of experimental work, autopsy studies, epidemiological investigation and clinical trials has led to the firm establishment of the essential role of lipids in the response to injury theory of atherosclerosis. The twists and turns in the acceptance of the lipid hypothesis of atherosclerosis is briefly reviewed. Today, it is well worth celebrating the 100th anniversary of the seminal insight into human vascular disease of the brilliant experimental pathologist, Nikolai N. Anitschkow., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This year marks the 100th anniversary of the publication of Anitschkow's classic paper proposing the central role of hypercholesterolemia in atherogenesis. We at the Journal of Lipid Research take this occasion to acknowledge the debt we all owe to Anitschkow and his colleagues for getting us on the right track. As discussed below in detail, his contributions were insightful and went well beyond simply pinpointing hypercholesterolemia as a major etiologic factor. Anitschkow's work led him to define most of the key elements in the initiation and evolution of lesions in animal models of atherogenesis.

Many have wondered what might have become of the totalitarian state Lenin founded on merciless terror, had he not died so young. He was 52 and at the height of his power when he had his first stroke. Six months later he had another and then a third stroke three months after that. He died 3 months shy of his 54th birthday with cerebral arteries so calcified that when tapped with tweezers at the time of his autopsy, they sounded like stone. The reason for his premature atherosclerosis has yet to be explained. He had a family history of cardiovascular disease and, therefore, is suspected of having had an inherited lipid disorder. Stress too might have had a role in the progression of his atherosclerosis. However, neither would explain the extent of the calcification of his cerebral arteries identified at post mortem examination. A recently described variant of the NT5E mutation might explain such calcification, as well as Lenin's family history of cardiovascular disease, and his premature cerebrovascular attacks., (Published by Elsevier Inc.)

Atherosclerosis has been thought to be a disease of modern society, and its occurrence was closely related to contemporary diet and lifestyle. However, a series of investigations on ancient mummies by autopsy and CT scan concluded that atherosclerosis was commonly seen in ancient times. The presence of atherosclerosis in ancient human beings suggested that aging and genetic predisposition might be essential risk factors for atherosclerosis.

Background: Atherosclerotic cardiovascular disease is often thought of as a disease of modernity, a disease affecting primarily men and a disease primarily affecting members of affluent Western societies., Methods: We reviewed CT scans for evidence of vascular calcification as a manifestation of atherosclerosis in ancient Egyptian female mummies and compared the results to clinical features of contemporary Egyptian women, who are suffering from an epidemic of atherosclerotic cardiovascular disease., Results: The common assumption that atherosclerosis is strictly a modern disease which spares women, mainly affecting men, is not true. We report the CT examination of an ancient Egyptian woman who lived more than 3000 years ago, finding calcified atherosclerotic plaque in her systemic arteries and other abnormalities probably due to prior myocardial infarction. We also confirmed recent reports of a virtual epidemic of atherosclerotic cardiovascular disease in contemporary Egyptian women., Conclusions: Atherosclerosis, both ancient and contemporary, is common in women as well as in men, and is related to both a genetic predisposition and to environmental factors including diet, exercise, obesity and exposure to smoke and other toxins., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Many studies have proven atherosclerosis is an inflammatory immune disease. The spleen plays an important immune role in the human body. Splenectomy is often used in several clinical disorders; but recent studies have shown that splenectomy may be effective in the development of atheroma lesions. Ibn Sina or Avicenna was known as one of the greatest philosopher and physician in Islam and in Medicine. He is remembered for his masterpiece, The "Al-Qanun fi al-Tibb" or "Qanun of medicine". According to the "Al-Qanun fi al-Tibb", spleen as storage organ plays an important role in absorption and secretion of the black bile in the human body. Therefore any disruption in the function of the spleen can lead to various diseases such as atherosclerosis. Based on his description, it is clear that Ibn Sina first described the role of spleen in prevention of atherosclerosis. In this review, we discuss the Avicenna (Ibn Sina) aspect of atheroprotector role of the spleen., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Atherosclerosis is thought to be a disease of modern human beings and related to contemporary lifestyles. However, its prevalence before the modern era is unknown. We aimed to evaluate preindustrial populations for atherosclerosis., Methods: We obtained whole body CT scans of 137 mummies from four different geographical regions or populations spanning more than 4000 years. Individuals from ancient Egypt, ancient Peru, the Ancestral Puebloans of southwest America, and the Unangan of the Aleutian Islands were imaged. Atherosclerosis was regarded as definite if a calcified plaque was seen in the wall of an artery and probable if calcifications were seen along the expected course of an artery., Findings: Probable or definite atherosclerosis was noted in 47 (34%) of 137 mummies and in all four geographical populations: 29 (38%) of 76 ancient Egyptians, 13 (25%) of 51 ancient Peruvians, two (40%) of five Ancestral Puebloans, and three (60%) of five Unangan hunter gatherers (p=NS). Atherosclerosis was present in the aorta in 28 (20%) mummies, iliac or femoral arteries in 25 (18%), popliteal or tibial arteries in 25 (18%), carotid arteries in 17 (12%), and coronary arteries in six (4%). Of the five vascular beds examined, atherosclerosis was present in one to two beds in 34 (25%) mummies, in three to four beds in 11 (8%), and in all five vascular beds in two (1%). Age at time of death was positively correlated with atherosclerosis (mean age at death was 43 [SD 10] years for mummies with atherosclerosis vs 32 [15] years for those without; p<0·0001) and with the number of arterial beds involved (mean age was 32 [SD 15] years for mummies with no atherosclerosis, 42 [10] years for those with atherosclerosis in one or two beds, and 44 [8] years for those with atherosclerosis in three to five beds; p<0·0001)., Interpretation: Atherosclerosis was common in four preindustrial populations including preagricultural hunter-gatherers. Although commonly assumed to be a modern disease, the presence of atherosclerosis in premodern human beings raises the possibility of a more basic predisposition to the disease., Funding: National Endowment for the Humanities, Paleocardiology Foundation, The National Bank of Egypt, Siemens, and St Luke's Hospital Foundation of Kansas City., (Copyright © 2013 Elsevier Ltd. All rights reserved.)