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Causes of Cardiovascular Disease | Literature Review

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Published: 12th Dec 2019

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2 Abstract

3 Introduction
3.1 Cardiovascular Disease

Cardiovascular disease (CVD) is the broad class of diseases that involves the heart or/and blood vessels. CVD includes 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 major part of CVD (up to xx%), and sometimes CVD is misleading used as a synonym for atherosclerosis [REF]. Because atherosclerosis is the underlying disease of several CVD, part of patients, where one diagnosis of CVD became manifest, may present with further co-morbidities, especially other diagnosis of CVD are common. However, the portion of patients with co-morbidities is depending on the baseline disease [2-4]. For example 40-60% of patients with Peripheral Arterial Disease (PAD) also have coronary artery disease (CAD) and cerebral artery disease, but only 10-30% of patients with CAD have also PAD (Figure 1) [2, 4]. Further, the severity of cardiovascular co-morbidities correlates well with each other[5-7].

CVD is today responsible for ca. 30% of all deaths worldwide [8], while heart disease and stroke are the leading causes of mortality and disability in developed 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 increasing rates has been observed worldwide. Before 1900, infectious diseases and malnutrition were the most common causes of death throughout the world, and CVD was responsible for <10% of all deaths. In 2030, CDV will account for estimated 32.5% off all death worldwide, what will be equal to a number of 24.2 million deaths per year [11]. Therefore, CVD is seen as a true global epidemic [12].

The economic burden and the public health costs are mainly driven by CVD. In terms of combined morbidity and mortality, 148 million Disability-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 Atherosclerosis

Atherosclerosis is the most frequent and important pattern of Arteriosclerosis, other forms of Arteriosclerosis are Mönckeberg medial calcific sclerosis and Arteriolosclerosis, which vary in pathophysiological and clinical presentation [14]. As described above (3.1), atherosclerosis is the leading cause of death (up to 30%) in developed countries and represents the major portion of CVD.

Atherosclerosis (literal origin from Greek: athero = “gruel or paste”; sclerosis = “hardness”) is defined as “thickening and loss of elasticity of arterial walls” and describes a process, where fatty substances, cholesterol, cellular waste products, calcium and fibrin building up in the inner lining of arteries [14]. These intimal lesions are called “atheromas”, “atheromatous” or “fibrofatty plaques”, which lead into an obstruction of vascular lumens and weakness the underlying media. Even within a given arterial bed, lesions or stenoses due to atherosclerosis tend to occur focally, typically in certain predisposed regions. Pathogenesis of Atherosclerosis

Due to overwhelming importance of atherosclerosis, enormous efforts have been spent to discover its cause over the last few decades. Today, the currently accepted concept, so called “the response to injury hypothesis”, considers atherosclerosis to be a chronic inflammatory response of the arterial wall initiated by injury to the endothelium [15]. Furthermore, lesion initiation and progression are sustained by interaction between lipoproteins, macrophages, T-lymphocytes, and the normal cellular constituents of the arterial wall. This process of developing atherosclerosis, which typically lasts over a period of many years – usually many decades, can be divided into several consecutive steps, as illustrated in Figure 2 [REF]. Parallel, a morphological change is observed within the artery wall, where “fatty streak” represents the initial morphological lesion, even so the pathogenesis has started quite earlier with a chronic endothelial injury [REF].

Figure 2: Illustration of the Pathogenesis and Morphological Development of Atherosclerosis. SMC: Smooth muscle Cell; 6 μm thick histology slices of coronary arteries stained with Movat’s pentachrome. A: pathological intimal thickening with a “fatty streak”; B: pathological intimal thickening with a macrophage infiltration; C: early fibroatheroma with neoangiogenesis; D: fibroatheroma with thin fibrous cap and a healed rupture; E; late fibroatheroma with a sheet calcification. * demarks necrotic scores. Histology performed by CVPath Laboratory, Maryland, MD.

The below described steps of the pathogenesis of atherosclerosis shouldn’t been seen as a separated processes. They are interconnected and occur parallel. Further, several mechanism of vicious circles are described [REF]. However, the stratification into the flowing six steps helps to understand the complex pathogenesis and represents the current understanding:

(1) Chronic Endothelia Injury

As the earliest step in the pathogenesis of atherosclerosis, endothelial activation and chronic injury, also known as endothelial dysfunction, have been described [16]. The following factors contributed in different extent to endothelial dysfunction and are partly known as traditional risk factors for atherosclerosis [17]: advancing age, dyslipidemia, hypertension, increased levels angiotensin, insulin resistance and diabetes, smoking, estrogen deficiency. Several biochemical pathways have been described for those factors increasing the endothelial dysfunction. Other factors like hyperhomocysteinemia, possible infection and especially low or oscillatory 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 decrease of fibrinolytic activity, and an increase in growth-promoting.

(2) Accommodation and Oxidation of Lipoproteins

In addition and due the endothelial dysfunction lipoproteins, especially low density lipoprotein (LDL), sequestered from plasma 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 ferrying through endothelial cells, passive sieving through endothelial-cell pores, passage between cells, it’s not finally understand. However, strong 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 there and are modified subsequently. Especially the modification of the lipoproteins has a trapping function for die selbigen [24]. The most common modification is the oxidation of lipoproteins, giving rise to hydroperoxides, lysophospholipids, oxysterols, and aldehydic breakdown products of fatty acids and phospholipids. But 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 trigger a local 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 various cell types [24, 26, 27].

(3) Migration of Monocytes and Transformation into Macrophages/Foam Cells

More important, the inflammatory response induces migration of leukocytes such 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 necrosis factor alpha (TNF-α) produced by vascular wall cells in response to the inflammatory process [REF]. The activated arterial endothelial cells express 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 mediator stimulated process of maturation, those macrophages become lipid-laden foam cells by uptake of lipoprotein particles through receptor-mediated endocytosis [REF]. The accumulation of lipid in the macrophages results in the apoptosis and necrosis, which lead first to a boosted expression and secretion of inflammatory cytokines and second to a release of their lipid excess into a necrotic lipid-core [REF]. Macrophages further produce enzymes, such as metalloproteinases, that degrade the extracellular matrix and lead to instability of plaques [REF].

(4) Adhesion of platelets and Release of SMC activating factors

The 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 basement 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-α) [28-30]. Thrombin itself generates fibrin that has a pro-fibrotic stimulus [28].

(5) Migration and Proliferation of SMCs

The 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-α and other mediators stimulate the interstitial collagen production by SMC. These mediators may arise not only 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 proteoglycans

The 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 higher 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-α, and can be inhibited by other cytokines (e.g. interferon alpha (IFN-α)) [REF].

As atherosclerotic plaques advance, they show 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 development calcification [32]. SMC can, promoted by several cytokines (e.g. transcription core binding factor α1), 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 particular lesions [REF]. The Role of Inflammation

The role of inflammation is central, while those inflammatory mechanisms mediate initiation, progression, and the complications of atherosclerotic lesions [26, 34]. Through 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 human 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 engulf 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 Factor (TNF)-α. 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 state 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. Vasa Vasorum and Neo-Angiogenesis

The vasa vasorum of the aorta is as a plexus in the wall of artery of microvessels, which are functional endarteries [35, 36]. They either originate 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 demonstrated 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 portal 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 diabetic 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 many aspects of vascular cell function, as described above. Atherosclerotic plaques often contain fibrin and hemosiderin, an indication that episodes of intraplaque hemorrhage contribute to plaque complications.

Multiple and often competing signals regulate these various cellular events. Increasingly, we appreciate links between atherogenic risk factors, inflammation, and the altered 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. Risk Factors for Development of Atherosclerosis

Local shear stress – In the coronary circulation, for example, the proximal left anterior 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, Atherosclerosis of the Aorta

In 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 around the origins (ostia) of major branches. In descending order (after the lower abdominal aorta), the most heavily 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.pdf

3.1.2 Peripheral Arterial Disease

Peripheral 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 shiny skin, reduced skin temperature, cramp, muscle atrophy, or a sense of fatigue 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 people 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].

Association to mortality!!! Pathogenesis of Peripheral Artery Disease

The 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 localized 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 abdominal 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 altered shear stress [REF]. However, the involvement of the distal and smaller arteries is more common in elderly individuals and patients with diabetes mellitus [REF]. Risk Factors for Peripheral Arterial Disease

While 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 Table 1 [47-50]. However, the risk factors smoking and diabetes may have even greater effect for PAD as compared for CAD [51].

Risk Factors

Increased risk for PAD


1- to 2-fold (low)


1- to 3-fold (moderate)


1- to 3-fold (moderate)

Smoking (current and past)

2- to 4-fold (high)

Diabetes mellitus

2- to 4-fold (high)

Table 1: Risk Factors for Peripheral Arterial Disease Clinical Presentation of Peripheral Artery Disease

PAD affects more often the lower extremities (xx times more often than upper extremities) [REF]. The most common symptom of PAD is intermittent claudication, 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 ischemia 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 gangrene. Two major classifications based on the clinical presentations are established, the Fontaine and the Rutherford classification.

While the more simple Fontaine classification consists of four stages (Table 2) [52], the Rutherford classification has four grades (0-III) and seven categories (0-6). Asymptomatic patients are classified into Rutherford category 0. Any 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 tissue 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 Classification

Rutherford Classification












Mild claudication



Mild claudication


Moderate to severe claudication



Moderate claudication



Severe claudication


Ischemic rest pain



Ischemic rest pain


Ulceration or gangrene



Minor tissue loss



Major tissue loss

Table 2: Classification of Peripheral Arterial Disease based on the Fontaine Classification in Comparison the Rutherford Classification

In 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 <0.90, was present in 3.9 percent of males and 3.3 percent of females. Yet, the prevalence of intermittent claudication was only 1.9 percent in males and 0.8 percent in females suggesting that only half of men and only a quarter of women have subjective symptoms. Lower extremity bruits were present in 2.4 percent of males, 2.3 percent of females; prior surgical intervention was 1.4 percent in males and 0.5 percent in females. The PARTNERS (PAD Awareness, Risk, and Treatment: New Resources for Survival) program assessed the prevalence of PAD in patients older than age 70 years and those ages 50 to 69 years with a smoking history or diabetes at 250 primary clinics across the United States.56 As defined by a charted or screening ABI of <0.90, 29 percent of the population was found to have PAD. There was a high incidence (nearly half) of concurrent coronary or cerebral vascular disease.

ABI – Severity of PAD

The physician also queried the participant about symptoms of intermittent claudication using a standardized questionnaire [53].

3.2 Local Adipose Tissue Depots
3.2.1 Variability of Adipose Tissue Anatomy and Morphology

SACK: Epicardial, mesenteric, and omental fat all share the same origin from the splanchnopleuric mesoderm associated with the gut.11

Pericardial fat (pericardial adipose 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.15

Paracardial fat originates from the primitive thoracic mesenchyme, which splits to form the parietal (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 sources including the pericardiacophrenic artery, a branch of the internal mammary.17 Lipolysis and lipogenesis have not been measured 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 capture and store intravascular free fatty acid (FFA) to protect cardiomyocytes from exposure to excessive coronary arterial FFA concentrations during increased energy 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 Secretion of Biomarkers by Adipose Tissue

Adipose 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 demonstrated higher expression of inflammatory biomarkers compared to other adipose tissue depots in the body [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 Atherosclerosis Peripheral Arterial Disease
3.2.3 In-Vivo Assessmentof Adipose Tissue Traditional Measures

* BMI and WC [54] Imaging-based Assessment

* dual energy X-ray absorptiometry (DXA) [55]

* magnetic resonance imaging (MRI) [56, 57]

* ultrasound [58]

* multi-detector computed tomography (MDCT) [59, 60]

3.3 Framingham Heart Study
3.3.1 Historical Origin of the Framingham Heart Study

Infectious diseases were prior to World War II the major burden for public health. 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 reduction 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 reaching 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 worldwide atherosclerotic CVD problem.

Furthermore there was no known treatment to prolong 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 search 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 characteristics 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 designed given the charge to identify these modifiable characteristics of host and environment for CVD.

3.3.2 Initiation of the Framingham Heart Study

By the mid 1940s several striking 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 association between the circumstances 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

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