Causes of Cardiovascular Disease | Literature Review

Causes of Cardiovascular Disease Literature Review2 Abstract3 Introduction 3.1 Cardiovascular DiseaseCardiovascular malady (CVD) is the broad class of ailments that involves the nub or/and stock vessels. CVD holds atherosclerosis, heart valve disease, arrhythmia, heart failure, hypertension, endocarditis, diseases of the aorta, disorders of the peripheral vascular system, and congenital heart disease 1. However, atherosclerosis accounts for the study(ip) naval division of CVD (up to xx%), and some times CVD is mis leash used as a synonym for atherosclerosis REF. Because atherosclerosis is the underlying disease of some(prenominal) CVD, part of patients, where one diagnosis of CVD became manifest, may ease up with further co-morbidities, especi in exclusivelyy a nonher(prenominal) diagnosis of CVD argon parkland. However, the mess of patients with co-morbidities is depending on the baseline disease 2-4. For use 40-60% of patients with encircling(prenominal) arteria l Disease ( vagabond) to a fault train coronary thrombosis arterial slant vessel disease (CAD) and cerebral artery disease, diminutively only 10-30% of patients with CAD give way also PAD (Figure 1) 2, 4. Further, the severity of cardiovascular co-morbidities correlates considerably with each former(a)(a)5-7.CVD is straightaway trus cardinalrthy for ca. 30% of all finishs oecumenical 8, while heart disease and stroke argon the stretching causes of mortality and disability in farm countries 9. Although the mortality rates of CVD has a considerable variation across countries (xx% in xx to xx% in xx) 10, a common trend of change magnitude rates has been discover worldwide. Before 1900, infectious diseases and malnutrition were the more or less common causes of death without the world, and CVD was responsible for The economic burden and the public wellness be atomic number 18 mainly driven by CVD. In terms of feature morbidity and mortality, 148 billion Disabilit y-Adjusted Life-Years (DALYs) were lost worldwide (2002), which represents about 10% of all lost DALYs REF. In 2008, CVD costs about 192 billion Euros a year alone in the European Union, which results in a per capita cost of 391 Euros 13.3.1.1 atherosclerosisAtherosclerosis is the most frequent and important pattern of hardening of the arteries, other forms of Arteriosclerosis be Mnckeberg medial calcific sclerosis and Arteriolosclerosis, which qualify in pathophysiological and clinical presentation 14. As described in a high center (3.1), atherosclerosis is the track cause of death (up to 30%) in real countries and represents the study portion of CVD.Atherosclerosis (literal origin from Greek athero = gruel or paste sclerosis = cruelness) is defined as thickening and loss of elasticity of arterial ramparts and describes a solve, where fertile substances, cholesterol, cellular waste products, calcium and fibrin building up in the inner lining of arteries 14. These inti mal lesions are called atheromas, atheromatous or fibro plenteousty plaques, which lead into an obstruction of vascular lumens and weakness the underlying media. Even within a given arterial bed, lesions or stenoses collect to atherosclerosis tend to slip away focally, typically in certain predisposed regions.3.1.1.1 Pathogenesis of AtherosclerosisDue to whelm importance of atherosclerosis, enormous efforts have been spent to disc everyplace its cause over the last few decades. Today, the currently accepted concept, so called the reception to blemish hypothesis, considers atherosclerosis to be a inveterate rabble-rousing reaction of the arterial paries initiated by injury to the endothelium 15. Furthermore, lesion initiation and progression are sustained by interaction amid lipoproteins, macrophages, T-lymphocytes, and the normal cellular constituents of the arterial wall. This member of under give voiceed atherosclerosis, which typically lasts over a period of some(preno minal) years usually m each decades, can be divided into several(prenominal) consecutive steps, as bedeckd in Figure 2 REF. Parallel, a morphologic change is observed within the artery wall, where fatty streak represents the sign morphological lesion, up to now so the pathogenesis has started quite earlier with a degenerative endothelial injury REF.Figure 2 Illustration of the Pathogenesis and Morphological phylogeny of Atherosclerosis. SMC Smooth muscle Cell 6 m thick histology slices of coronary arteries stained with Movats pentachrome. A pathological intimal thickening with a fatty streak B pathological intimal thickening with a macrophage percolation C beforehand(predicate) fibroatheroma with neoangiogenesis D fibroatheroma with thin fibrous cap and a healed rupture E late fibroatheroma with a sheet calcification. * demarks necrotic s sums. Histology performed by CVPath Laboratory, Maryland, MD.The below described steps of the pathogenesis of atherosclerosis shouldnt bee n hold inn as a separated processes. They are interconnected and occur parallel. Further, several mechanism of wicked circularises are described REF. However, the stratification into the flowing six steps helps to conceive the complex pathogenesis and represents the current understanding(1) Chronic Endothelia InjuryAs the early step in the pathogenesis of atherosclerosis, endothelial activation and chronic injury, also know as endothelial dys blend in, have been described 16. The following cistrons contributed in disparate extent to endothelial dysfunction and are partly known as traditional risk factors for atherosclerosis 17 advancing age, dys lipoidemia, hypertension, change magnitude levels angiotensin, insulin resistance and diabetes, smoking, oestrogen deficiency. Several biochemical pathways have been described for those factors increasing the endothelial dysfunction. some other factors wish well hyperhomocysteinemia, realistic infection and oddly low or periodi cal shear stress are still discussed whether they significantly contribute to endothelial dysfunction 18-22. The phenotypic features of endothelial dysfunction are described as the reduced vasodilator and increased vasoconstrictor capacity, an enhanced leukocyte adhesion, an increase of pro-thrombotic and reducing of fibrinolytic activity, and an increase in maturation-promoting.(2) Accommodation and Oxidation of LipoproteinsIn addition and due the endothelial dysfunction lipoproteins, especially low density lipoprotein (LDL), sequestered from plasm in the extracellular space of the arterial intima. Beside the extent of endothelial dysfunction, this process is depending on the concentration of LDL in the blood circulation 23. Even so several mechanisms have been proposed for transport of LDL into the arterial intima including vesicular ferry through endothelial cells, inactive sieving through endothelial-cell pores, passage between cells, its not finally understand. However, str ong evidence exist, that the accommodation of LDL in the arterial intima is not only a passive effect by a leaking vascular endothelium REF.Part of the lipoproteins that have entered the arterial wall stay on that point and are modified later(prenominal)ly. Especially the modification of the lipoproteins has a trapping function for die sel spoileden 24. The most common modification is the oxidation of lipoproteins, giving educate to hydroperoxides, lysophospholipides, oxysterols, and aldehydic breakdown products of fatty acids and phospholipids. exclusively further modification like fusion of lipoproteins, proteolysis, lipolytic degradation and glycation are well known 25.Such modified lipoproteins or particles of the modification process have inflammatory potential and stumble a topical anaesthetic inflammatory response responsible for signaling subsequent steps in the atherogenesis. It includes a further increased endothelial dysfunction, which may cause a vicious circle of LDL accumulation, and activation of variant cell types 24, 26, 27.(3) Migration of Monocytes and Transformation into Macrophages/Foam CellsMore important, the inflammatory response induces migration of leukocytes much(prenominal) as monocytes or lymphocytes into the lesion. Leukocytes are attracted by chemoattractant factors including modified lipoprotein particles themselves and chemoattractant cytokines depicted by the smaller spheres, such as the chemokine monocyte chemoattractant protein-1, interleukin 1 (IL-1) or tumor humiliation factor alpha (TNF-) get outd by vascular wall cells in response to the inflammatory process REF. The frantic arterial endothelial cells conduct a number of adhesion molecules and receptors on their surface, which participate in the recruitment of leukocytes from the blood to the nascent lesion REF.Macrophages are a key player in atherogenesis 27. They develop from recruited monocytes, which migrated as described above into the lesion. In the med iator stimulated process of maturation, those macrophages become lipid-laden foam cells by uptake of lipoprotein particles through receptor- negociated endocytosis REF. The accumulation of lipid in the macrophages results in the apoptosis and necrosis, which lead first to a boosted facial gesture and secretion of inflammatory cytokines and second to a release of their lipid waste into a necrotic lipid-core REF. Macrophages further produce enzymes, such as metalloproteinases, that drop the extracellular matrix and lead to instability of plaques REF.(4) Adhesion of platelets and Release of SMC energizing factorsThe inflammatory process, especially triggered by the necrosis of the foam cells, microscopic breaches in endothelial integrity may occur. Platelets adhere to such sites of limited endothelial denudation owing to exposure of the thrombogenic extracellular matrix of the underlying wine cellar membrane and form microthrombi. Although most of the arterial mural microthrombi resolve without any clinical manifestation, they lead indirectly to lesion progression by pro-fibrotic stimulation REF. The platelets, activated by adhesion, release numerous factors that promote a fibrotic response, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor 1 (IGF-1), and transforming growth factor alpha (TGF-) 28-30. Thrombin itself generates fibrin that has a pro-fibrotic stimulus 28.(5) Migration and Proliferation of SMCsThe pro-fibrotic response includes first the migration of SMC from the media of the arterial wall, through the internal elastic membrane, and the accumulation within the expanding intima of the arterial wall. Second, stimulate the proliferation of SMC, which is responsible to form the bulk of the advanced lesion. Another part of the advanced lesions is an increased extracellular matrix. TGF- and other mediators stimulate the interstitial collagen production by SMC. These mediators may arise not o nly from neighboring endothelial cells or leukocytes (a paracrine pathway) but also from the same cell that responds to the factor (an autocrine pathway). Together, these alterations in smooth-muscle cells, signaled by these mediators acting at short distances, can accelerate transformation of the early lesion (fatty streak) into a more fibrous SMC and extracellular matrix-rich plaque.(6) Enhanced accumulation of lipids, collagen and proteoglycansThe formation of a complex atherosclerotic lesion is characteristic by an extent remodeling process. Further foam cells within the expanding intimal lesion perish, while they phagocytose more and more lipids. The fibrotic cap between the so arisen lipid-rich necrotic core and the vascular lumen may vary in thickness and allows the classification of thin cap fibroatheroma, which correlates with a high(prenominal) risk for acute luminal thrombosis REF. The production of extracellular matrix, as well plaque evolution and complication can be stimulated by diverse growth factors or cytokines like IL-1 or TNF-, and can be inhibited by other cytokines (e.g. interferon alpha (IFN-)) REF.As atherosclerotic plaques advance, they introduce intimal arterial calcification REF. The same proteins, which can be found in bone, are also localize in atherosclerotic lesions, e.g., osteocalcin, osteopontin, and bone morphogenetic proteins 31. Both, passive and active models are discussed for the training calcification 32. SMC can, promoted by several cytokines (e.g. transcription core binding factor 1), acquire osteoblast-like characteristics and secrete bone matrix 33.These examples illustrate how the pathogenesis of atherosclerosis involves a complex mix of mediators that in the balance determines the characteristics of fussy lesions REF.3.1.1.2 The Role of InflammationThe role of inflammation is central, while those inflammatory mechanisms mediate initiation, progression, and the complications of atherosclerotic lesions 26, 34. Th rough the inflammatory process, arterial endothelial cells begin to express on their surface selective adhesion molecules that bind various classes of leukocytes, especially monocyte and T lymphocyte which are found in early sympathetic and experimental atheroma REF. After monocytes adhere to the endothelium, they can first migrate in the intima, largely stimulated by chemokines and second transform into macrophages and avidly douse lipoproteins, largely oxidized LDL REF. Although the phagocytosis of potentially harmful lipid particles by macrophages and subsequently the transformation into foam cells has an initially protective, this process involves further expression and secretion of inflammatory chemokines like Interleukin (IL)-1, Monocyte Chemotactic Protein (MCP)-1 or Tumor Necrosis performer (TNF)-. Those enhance the inflammatory reaction and enable the further migration of leukocytes into the lesion REF. Macrophages also produce toxic oxygen species that cause additional oxidation of the LDL in the lesions, and they elaborate growth factors that may contribute to SMC proliferation REF. Similary, T lymphocytes (both CD4+ and CD8+) are also recruited to the intima by chemo-attractants. Cross-talk between macrophages and T cells induces a chronic inflammatory defer regarding cellular and humoral immune activation characteristics.This state of a chronic inflammation leads also to the next observed steps in the development and progression of atherosclerosis. Thus, it stimulates the migration and proliferation of smooth muscle cells (SMC), as well the proliferation of vascular endothelial cells in the lesion. Through fibrogenic mediators, released from activated leukocytes and intrinsic arterial cells, the replication of SMCs is getting enhanced and contributes to elaboration by these cells of a dense extracellular matrix characteristic of the more advanced atherosclerotic lesion.3.1.1.3 Vasa Vasorum and Neo-AngiogenesisThe vasa vasorum of the aorta is as a rete in the wall of artery of microvessels, which are functional endarteries 35, 36. They either get up from major branches, originate from the main lumen of the aorta or drain in concomitant veins 37. These vessels allow the humoral communication between intravascular lumen, vessel wall and adventitial layer of large arteries including oxygen and nutrients supply REF.Several studies present that hypoxia 38, cytokines (e.g. vascular endothelial growth factor) 39, 40, pro-angiogenic factors (e.g. hypertension or hypercholesterolemia) stimulate the growth of the vasa vasorum 41. Those increased microvascular network may contribute to inflammation and lesion complications in several ways. First, the vasa vasorum provides an abundant surface area for leukocytes trafficking and may serve as the inlet of entry and exit of white blood cells from the established atheroma.Microvessels in the plaques may also furnish foci for intraplaque hemorrhage. Like the neovessels in the diabeti c retina, microvessels in the atheroma may be friable and prone to rupture and can produce focal hemorrhage. Such a vascular leak leads to thrombosis in situ and thrombin generation from prothrombin. In addition to its role in blood coagulation, thrombin can modulate more aspects of vascular cell function, as described above. Atherosclerotic plaques ofttimes occupy fibrin and hemosiderin, an indication that episodes of intraplaque hemorrhage contribute to plaque complications.Multiple and often competing signals settle these various cellular events. Increasingly, we appreciate links between atherogenic risk factors, inflammation, and the neutered behavior of intrinsic vascular wall cells and infiltrating leukocytes that underlie the complex pathogenesis of these lesions.The present data indicate that vasa vasorum neoangiogenesis and atherosclerosis are seemingly inseparably linked, triggered and perpetuated by inflammatory reactions within the vascular wall.3.1.1.4 Risk Factors for Development of Atherosclerosis topical anesthetic shear stress In the coronary circulation, for example, the proximal left preliminary descending coronary artery exhibits a particular predilection for developing atherosclerotic disease. Likewise, atherosclerosis preferentially affects the proximal portions of the renal arteries and, in the extracranial circulation to the brain, the carotid bifurcation. Indeed, atherosclerotic lesions often form at branching points of arteries, regions of disturbed blood flow.Age, Gender, HTN, HLP, DM, Smoking, Race/Ethnicity,3.1.1.5 Atherosclerosis of the AortaIn the characteristic distribution of atherosclerotic plaques in humans the abdominal aorta (Fig. 11-8) is usually much more involved than the thoracic aorta, and lesions tend to be much more prominent or so the origins (ostia) of major branches. In descending order (after the lower abdominal aorta), the most severely involved vessels are the coronary arteries, the popliteal arteries, the internal carotid arteries, and the vessels of the circle of Willis. Vessels of the upper extremities are usually spared, as are the mesenteric and renal arteries, except at their ostia. Nevertheless, in an individual case, the severity of atherosclerosis in one artery does not predict the severity in another. In an individual, and indeed within a particular artery, lesions at various stages often coexist.2009_Dijk_The natural history of aortic atherosclerosis_A systematic histopathological evaluation of the peri-renal region.pdf3.1.2 peripheral arterial Disease circumferential Arterial Disease (PAD) is caused by atherosclerosis and represents the most common cause of lower extremity ischemic syndromes in developed countries 42. Symptoms of PAD are variable including pain, ache, hair loss, thickened nails, smooth and undimmed skin, reduced skin temperature, cramp, muscle atrophy, or a mother wit of tire out in the muscles. Because of the variability of symptoms, the diagnosis of PDA is frequently missed 43. In addition, the major part of patients with PAD is asymptomatic REF.Beside these diagnostic challenges, PAD affects a large and increasing numbers of patients worldwide. Round 30 million plurality are diseased in worldwide, but of those only 10 million patients are presenting with symptoms 44. Further, the prevalence is increasing with age 6, 45, while the prevalence is 10% at the age of 60 years 46. link to mortality3.1.2.1 Pathogenesis of Peripheral Artery DiseaseThe leading cause of PAD is atherosclerosis, especially in older patients (40 years) and at the lower extremities 42. Other, but rare causes of PAD include embolism, vasculitis, fibromuscular dysplasia, entrapment, and trauma.Atherosclerotic lesions, which are segmental and cause stenosis, are usually place to large and medium-sized vessels. The pathology of these lesions is based on atherosclerotic plaques development, as described above (xxx). The primary sites of involvement are the a bdominal aorta and iliac arteries (30% of symptomatic patients), the femoral and popliteal arteries (80-90%), and the more distal arteries (40-50%) REF. Atherosclerotic lesions have been predominantly observed at arterial branch points. These may be explained by change shear stress REF. However, the involvement of the distal and smaller arteries is more common in elderly individuals and patients with diabetes mellitus REF.3.1.2.2 Risk Factors for Peripheral Arterial Disease firearm atherosclerosis is the major underlying condition of PAD, the risk factors for PAD are essentially the same as those for other form of atherosclerosis (like e.g. CAD), see remit 1 47-50. However, the risk factors smoking and diabetes may have even greater effect for PAD as compared for CAD 51.Risk Factors change magnitude risk for PADHypercholesterolemia1- to 2-fold (low)Homocysteinemia1- to 3-fold (moderate)Hypertension1- to 3-fold (moderate)Smoking (current and past)2- to 4-fold (high)Diabetes mellitu s2- to 4-fold (high)Table 1 Risk Factors for Peripheral Arterial Disease3.1.2.3 clinical Presentation of Peripheral Artery DiseasePAD affects more often the lower extremities (xx times more often than upper extremities) REF. The most common symptom of PAD is intermittent gameness, which is defined as presence of pain, ache, cramp, numbness, or a sense of fatigue in the muscles. Those symptoms occur during exercise and are relieved by rest, as result of the increased muscle ischaemia during exercise caused by obstruction to arterial flow.Patients with PAD in the lower extremities resulting in ischemia may range in presentation from no symptoms to limb-threatening subdue. Two major classifications based on the clinical presentations are established, the Fontaine and the Rutherford classification.While the more unproblematic Fontaine classification consists of four stages (Table 2) 52, the Rutherford classification has four sexual conquests (0- leash) and seven categories (0-6). Asymptomatic patients are classified into Rutherford category 0. whatever patient with claudicants are stratified into Rutherford grade I and divided into three categories based on the severity of the symptoms. If patients have pain at rest, they belong to Rutherford grade II and category 4. Any patient with create from raw stuff loss are classified into Rutherford grade III and categories 5 and 6, based on the significance of the tissue loss 4. These two clinical classifications can be translated into each other according to Table 2.Fontaine ClassificationRutherford ClassificationStageClinicalGradeCategoryClinicalIAsymptomatic00AsymptomaticIIaMild claudicationI1Mild claudicationIIbModerate to severe claudicationI2Moderate claudicationI3 distasteful claudicationIIIIschemic rest painII4Ischemic rest painIVUlceration or gangreneIII5Minor tissue lossIII6Major tissue lossTable 2 Classification of Peripheral Arterial Disease based on the Fontaine Classification in affinity the Ruther ford ClassificationIn the Framingham Offspring Study, the prevalence of PAD was determined in 1554 males and 1759 females from 1995 to 1998.55 The mean age was 59 years. PAD, defined as an ankle-brachial (blood pressure) index (ABI) of ABI causticity of PADThe physician also queried the participant about symptoms of intermittent claudication using a standardized questionnaire 53.3.2 Local fatty Tissue Depots 3.2.1 variance of Adipose Tissue 3.2.1.1 Anatomy and MorphologySACK Epicardial, mesenteric, and omental fat all share the same origin from the splanchnopleuric mesoderm associated with the gut.11Pericardial fat (pericardial fatty tissue PAT) is defined as epicardial fat in all these possible locations plus paracardial fat.14 Paracardial fat is situated on the external surface of the parietal pericardium within the mediastinum and has alternatively been termed mediastinal fat.15Paracardial fat originates from the primitive thoracic mesenchyme, which splits to form the pariet al (fibrous) pericardium and the outer thoracic wall.16 Epicardial adipose tissue is supplied by branches of the coronary arteries, whereas paracardial fat is supplied from different etymons including the pericardiacophrenic artery, a branch of the internal mammary.17 Lipolysis and lipogenesis have not been calculated directly in human epicardial fat. Based on approximately 2-fold higher rates of lipolysis and lipogenesis in guineapig epicardial fat than other fat depots, Marchington et al18,19 proposed that EAT serves to buzz off and store intravascular free fatty acid (FFA) to protect cardiomyocytes from exposure to riotous coronary arterial FFA concentrations during increased naught intake and, at other times, to release FFA as an immediate ATP source for the myocardium during periods of need. Epicardial fat and the myocardium are contiguous. Islands of mature adipocytes are more frequent within the subepicardial myocardium of the RV than the LV13 and may act as more readily available, direct sources of FFA for cardiomyocytes.The thickness of the wall of the right atrium is about 2 mm the left atrium, 3 to 5 mm the RV, 3 to 5 mm and the LV, 13 to 15 mm.20 Possibly, FFAs could diffusebidirectionally in interstitial fluid across concentration gradients from epicardial fat into the atrial and RV walls where EAT predominates and vice versa, but this process in the LV wall can be questioned because the diffusion distance is much longer.Peri-vascular adipose tissue is defined as any adipocytes, which are located close to the vascular wall and has the possibility to secret their biomarkers into the vasa vasora of the wall (see 3.2.1.2).3.2.1.2 Secretion of Biomarkers by Adipose TissueAdipose tissue is known to have more functions than lipid storing. Adipose tissue secrets biomarkers and serves as an endocrine organ. Beside hormones, it secrets also different inflammatory cytokines and chemokines. The amount of adipose tissue were associated to xxx, xxx, xxx ( FRAMINGHAM?). Especially peri-vascular adipose tissue like epicardial or visceral adipose tissue exhibit higher expression of inflammatory biomarkers compared to other adipose tissue depots in the trunk REF.Beside the systemic effect of the secreted cytokines and chemokines, also a local effect/paracrine is hypothesied. Biomarkers secreted of peri-vascular adipose tissue reach over the vasa vasora of the major arteries their adventitia, media, and intima. Therefore it might be involved in the inflammatory process of atherosclerotic plaque. Further, a local effect can be thought by direct diffusion.3.2.2 Association of Adipose Tissue to Cardiovascular Disease 3.2.2.1 Atherosclerosis 3.2.2.2 Peripheral Arterial Disease 3.2.3 In-Vivo Assessmentof Adipose Tissue 3.2.3.1 Traditional Measures* BMI and WC 543.2.3.2 Imaging-based Assessment* dual energy X-ray absorptiometry (DXA) 55* magnetic resonance imaging (MRI) 56, 57* ultrasound 58* multi-detector computed tomography (MDCT) 59, 603. 3 Framingham punk Study 3.3.1 Historical Origin of the Framingham Heart StudyInfectious diseases were forward to orbit War II the major burden for public wellness. But through a greater microbiological knowledge and improved sanitation, the morbidity and mortality of infectious disease decreased continuously. When penicillin was introduced in 1942, a dramatic decrement was made in the prevalence and incidence of infectious diseases, especially by controlling tuberculosis and pneumococcal pneumonia REF.Replacing infectious diseases, public health was challenged by a mounting epidemic of CVD starting in the 1940s. With World War II over the alarming rise of CVD became increasingly evident. In the United States, 30% of all men developed CVD before reach the age sixty. The prevalence of CVD was twice of cancer by 1950 and had become the leading cause of death REF. Even so the available statistic data from around the world was often crude and inaccurate, it clearly demonstrated a wo rldwide atherosclerotic CVD problem.Furthermore there was no known treatment to go life and to reduce mortality. Added to these distresses was the fact that little was known about etiology, pathogenesis and epidemiology of CVD.The big gap between the enormous public health burden of CVD on the one site and the little understanding of this disease on the other site increased drastically the need for action. At this time, some believed a primary preventative approach was more promising than a appear for cures Dawber, Thomas R. (1980), The Framingham Study The Epidemiology of Atherosclerotic Disease, Cambridge, Mass. Harvard University Press., while the secrets of the etiology of CVD and subsequently for treatment were not being uncovered by basic laboratory and clinical research. Some of these prevention-minded individuals occupied positions of influence and were able to translate their beliefs into actions.The key was to develop a preventive approach, where first of all the char acteristics of the host and environment, which lead to the early appearance of the disease, had to be determined. In particular, preventable or modifiable predisposing factors had to be identified. If a practical preventive approach was developed, the hope was that doctors and public health officials would adopt it and so have a widespread impact on the reduction of CVD-based morbidity and mortality.Accordingly to the preventive approach, the Framingham Heart Study was knowing given the charge to identify these modifiable characteristics of host and environment for CVD.3.3.2 excogitation of the Framingham Heart StudyBy the mid 1940s several contact lens studies were conducted with an examples epidemiological approach in the fields of nutritional imbalance, metabolic disorders, occupational hazards, accidents, cancer and rheumatic fever under principle investigators (PI) Drs. Dawber, Meadors and Moore REF, Dawber, Meadors and Moore 1951. In common, an familiarity between the circ umstances and the disease could be identified with-out knowledge of the precise etiology.One of those studies was performed by Dr. John Snow in 1936. He demonstrated that cut-ting off the water supply from contaminated wells, despite incomplete knowledge of the pathogenesis of the disease, stopped cholera. He observed on the one hand the source of the water supply and on the other hand the time and place where the disease occurred. He sufficiently pinpointed based on his observations the major environmental factor for cholera. Further investi