Primary Prevention of Atherosclerosis - A Clinical Challenge for the Reversal of Epigenetic Mechanisms

And maybe we will finally get to the beginning cause of this and fix that rather than this stupidity of statin lowering.


http://circ.ahajournals.org/content/125/19/2363.full

1. Claudio Napoli, MD, PhD, MBEth;
2. Valeria Crudele, BiolD;
3. Andrea Soricelli, MD;
4. Mohammed Al-Omran, MD;
5. Nicoletta Vitale, PhD;
6. Teresa Infante, BiolD;
7. Francesco P. Mancini, MD, PhD

+ Author Affiliations

1. From the Department of General Pathology, Excellence Research Centre on Cardiovascular Diseases, U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Universitaria Policlinico, 1st School of Medicine, Second University of Naples, Naples, Italy (C.N., V.C.); Fondazione SDN, Istituto di Ricovero e Cura a Carattere Scientifico, Naples, Italy (C.N., A.S., T.I.); Parthenope University, Naples, Italy (A.S.); Peripheral Vascular Disease Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia (M.A.-O.); and Department of Sciences for Biology, Geology, and Environment, University of Sannio, Benevento, Italy (N.V., F.P.M.).

1. Correspondence to Professor Claudio Napoli, MD, PhD, Department of General Pathology, Excellence Research Centre on Cardiovascular Diseases, 1st School of Medicine, Complesso S. Andrea delle Dame, Second University of Naples, Piazza Miraglia 2, 80138 Naples, Italy. E-mail claudio.napoli@unina2.it or claunap@tin.it

Key Words:

• primary prevention
• epigenetics
• statins

Innovative advances in understanding the pathogenesis of atherosclerosis have been achieved over the past 25 years. Although elevated levels of serum low-density lipoprotein cholesterol (LDL-C) are the major cause of onset of the disease, as established by a large number of superb epidemiological, clinical, and experimental studies, important novel factors have entered the arena of the atherogenic process. Besides the historical oxidative hypothesis that states that oxidized LDL, by escaping the homeostatic mechanism, strongly accelerates plaque formation, more recent evidence has given credit to vascular inflammation and apoptosis as crucial players in the progression of atherosclerosis.^1–3 The disease has also been linked to the subintimal infiltration of immune cells and endothelial dysfunction induced by cardiovascular risk factors. Currently, endothelial dysfunction is considered one of the first stages of vascular damage and an early event in atherogenesis.^1–3 Etiologic and pathogenetic factors, of both genetic and environmental origin, act together to promote local and systemic effects that lead to the onset, progression, and final outcome of the atherosclerotic disease. The clinical sequelae of atherosclerosis, myocardial infarction, stroke, and peripheral arterial disease depend on the affected vascular district, which in turn depends on complex gene-environment interplay.
Despite the sudden occurrence of clinical symptoms, however, the evolution of atherosclerosis is very slow, which provides an opportunity for early diagnosis. In fact, a breakthrough in the field has been to recognize that although atherosclerosis generates severe diseases that most frequently affect middle-aged to old people, atherogenesis begins very early in life, even at the fetal stage.^4,5 Primary prevention of any disease is more effective if started sooner. Therefore, it is of paramount importance to identify high-risk individuals and to initiate primary prevention in a timely manner, especially for atherosclerosis, which can begin its slow but relentless damage of the arterial wall even before birth. Epigenetic mechanisms have been recognized recently as possible modifiers of the risk of developing premature atherosclerosis. Therefore, the recognition of epigenetic markers that reveal a tendency to vascular diseases could be an effective aid in the early detection of at-risk individuals. These people can then be targeted for both lifestyle changes and pharmacological treatments to prevent or delay atherosclerotic disease. Although the pharmaceutical industry has provided invaluable preventive and therapeutic tools, general rules of best practice dictate that life habits be modified first, and only if intermediate markers of the disease do not normalize should at-risk individuals be given drug therapy. This approach also allows reducing the health care expenditure on the primary prevention of atherosclerosis-related disease.

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Early Onset of Human Atherogenesis

The prodromal stages of human atherosclerotic lesions are already set during fetal development.^6–8 A seminal observation was that maternal hypercholesterolemia is associated with increased formation of fatty streaks in fetal arteries, which suggests that hypercholesterolemia is atherogenic even before birth.⁹
Fetal lesions occur in the same arterial districts as those of adolescents and adults and are histologically similar to lesions that occur later in life.¹⁰ Moreover, there is evidence that fetal lesions can partially regress during the final stages of pregnancy or early infancy, when cholesterol levels are low.⁸ Atherosclerosis is significantly accelerated in children of mothers with high serum cholesterol compared with children of mothers with normal serum cholesterol. The mechanism by which maternal hypercholesterolemia can promote development of lesions in offspring has been explored in animal models.^11–13 Indeed, lesions doubled in a litter of hypercholesterolemic mother rabbits compared with normocholesterolemic mother rabbits, and there was a linear correlation between maternal cholesterol and vascular injuries at birth.¹¹ Consistently, a similar correlation was observed in LDL receptor–deficient mice.¹³ Maternal cholesterol levels increase physiologically from the first trimester and throughout the pregnancy, even in mothers with normal serum cholesterol levels¹⁴; this increase is much greater in mothers who are already hypercholesterolemic before pregnancy. Microarray analysis of aortas has shown that many genes are elevated or inhibited in the offspring of hypercholesterolemic mothers.¹⁵
Children and young adults are also vulnerable to the effects of cardiovascular risk factors and show early signs of atherosclerosis, which becomes a complex process driven by conventional risk factors.¹⁶ Among cardiovascular risk factors, body mass index, systolic and diastolic blood pressure, serum total cholesterol, triglycerides, LDL-C, and high-density lipoprotein cholesterol are strongly associated with the extension of lesions in the aorta and coronary arteries. In addition, the severity of aortic and coronary artery disease in young people increases in proportion to the number of cardiovascular risk factors they face.⁶

Much more at link.