—  SHORT COURSE #57  —

Atherosclerosis: Practical Implications for Pathologists

Section 2 - Cardiomegaly

Jagdish Butany
John Veinot


Atherosclerosis - Its Pathogenesis

Case #1:
This 60- year-old (12.12.42) male was admitted for elective repair of a stenosed and incompetent aortic valve. Of note, he had grade 2 LV function and mitral regurgitation. He was not a diabetic, but was moderately obese with mild hypertension. He underwent aortic valve replacement with a porcine aortic valve. Post operatively he came off the cardio-pulmonary bypass easily. However, approximately 24 hours post operative, it became difficult to maintain his blood pressure. He died soon after.

Case 1: Major Autopsy findings: Cardiomegaly
  1. Coronary arteries-mild to moderate disease,

  2. Proximal LAD; Moderate disease with inflamed plaque

  3. acute plaque disruption intraplaque hemorrhage and thrombosis
2.Satatus post aortotomy and aortic valve repair

A: atherosclerosis of aorta, moderate in thoracic aorta and severe in abdominal aorta

The Native Artery:
All arteries are relatively simple structures morphologically. They are comprised of three layers: the tunica intima, which forms the barrier between the artery wall and the circulating blood. The media, which is a multilayered zone comprised of a thick layer of smooth muscle and variable amounts of elastic tissue. The tunica adventitia comprised largely of connective and elastic tissue, which blends into the surrounding connective tissue of adjacent structures and organs and has blood vessels and nerve fibers in and around it.

The Endothelial Cell
The endothelial cell is a spindly, elongated cell, specialized to provide a non-thrombogenic barrier and control blood artery permeability. The borders of these cells, between adjacent endothelial cells, have junctional complexes with specialized structure that increase the mechanical strength and control macromolecule permeability. Endothelial cells lining the arteries, veins, capillaries and the heart, comprise a continuous monolayer of polygonal cells, which fit tightly into each other through these junctions. Functions (See Table 1): The endothelium:
  1. Controls blood - tissue permeability

  2. Controls vascular tone and regulates the vascular surface properties with regard to hemostasis

  3. Regulates vascular surface reaction to inflammation

Endothelial Permeability :
This is delicately controlled and is dependent on the size and the physical chemical properties of molecules. Uncharged, small molecules such as oxygen diffuse without much restriction, across the endothelium, moving along the concentration gradient from blood to the subendothelial space. Other small molecules such as glucose exhibit little restriction against diffusion across the endothelium. This is the process by which the supply of oxygen and nutrients occurs.

Macromolecules:
In contrast, macromolecules can penetrate only to a limited extent, dependent on their size. Small proteins can pass through the interendothelial clefts while large proteins and particles can only reach the subendothelial space through endocytotic vesicles. Lipoproteins are one particle that penetrates the endothelium in this manner. They play a major role in the initiation of atherosclerosis.

Vascular Tone:
On a superficial basis, it is the contraction of the smooth muscle cells in the tunica media that controls the degree of contraction of the vessel and hence maintains its tone. However, it is the endothelial cell, which controls smooth muscle contractility by releasing vasoactive mediators. The most characterized of these mediators is nitrous oxide (NO). This is an inert, inorganic gas that is produced from L-arginine, by an endothelial enzyme - nitric oxide synthase. This mechanism and its modulation are key factors in our understanding of vascular tone, as well as the treatment of clinical problems associated with vascular tone. NO production is increased when the intracellular calcium level is raised in the endothelial cells, possibly as a result of acetylcholine, bradykinin and other circulating mediators. NO activates an enzymatic cascade in smooth muscle cells. This leads to a tendency for relaxation and reduced vascular tone. Other vasoactive factors can counteract or balance this effect, and these include the vasoactive vasoconstrictor peptide Endothelin-1. This is expressed as a large pre proendothelin polypeptide by the endothelial cell and proteolytically processes generate active endothelium-1 during the endothelial activation. Similarly, angiotensin 2 also acts on smooth muscle cells and the intimal contact. Normally present as a circulating angiotensinogen, it is processed into angiotensin 2 by endothelial cells.

Amongst other functions performed by endothelial cells are:

Hemostasis : a role in inflammatory processes and the setting of the vascular tone. For these, the endothelial surface, has a set of factors which allow platelet adhesion or control platelet adhesion, coagulation and fibrinolysis, the Von Willebrand factor, surface active platelet adhesion molecules, coagulation regulating factors such as thrombomodulin and fibrinolysis regulating factors such as plasminogen activators (tissue and urokinase types), as well as plasmogenic activator inhibitor. Several of these are stored in intracellular organelles such as Weibel-Palade bodies, which discharge their contents to the cell surface, when thrombin or other similar mediators activate the cell.

Endothelial cells control or participate in the inflammatory process by expressing leukocyte adhesion molecules such as E-selectin and the intercellular adhesion molecule-1 (otherwise known as ICAM-1), chemokines that promote leukocyte recruitment (MCP-1 and interleukin 8) in cytokines that activate immune cells such as interleukin-1.

The vascular media is comprised largely of smooth muscle cells with an elastic tissue layer between adjacent rows of smooth muscle cells. Smooth muscle cells are arranged circumferentially in the vessel wall. The innermost layer of elastic tissue is more compact - the internal elastic lamina. Similarly, the outermost layer of elastic tissues is also compact - the external elastic lamina. The amount of elastic tissue present between smooth muscle fibers varies according to the size of the vessel. In large elastic arteries such as the aorta, twenty to fifty such lamellae of elastic tissue may be present in the media. In smaller arteries, the organization is not as developed and the amount of elastic tissue is correspondingly less, generally being seen as small strips of elastic tissue rather than circumferential layers of elastic tissue.

The adventitia and its connective tissue are continuous with the external elastic lamina on the inner surface and the surrounding stromal connective tissue on its outer aspect. Its inner part is therefore fibrous and comprised of compact collagen and elastic tissue, which gradually becomes more loosely arranged as the distance from the media increases. The adventitia contains fibroblasts, mast cells, adipocytes and nerve endings (predominantly sympathetic). Blood and lymph vessels are present and these can penetrate the outer third of the media.

Smooth Muscle Cells
These are by far the commonest of cells in the vessel wall, especially the artery, and comprise 95% or more of all cells. Like muscle cells everywhere they contain actin and myosin filaments. However, the contractile apparatus is less developed than that of striated muscle and the vascular smooth muscle cell is especially primitive and has a capacity to change its tone, as well as the ability to transform itself into a fibroblast-like cell, which produces large amounts of extracellular matrix in the vessel wall. Smooth muscle cells are also believed to be the produces of the elastic tissue, seen as elastic lamellae in the arterial wall.

In the adult artery, smooth muscle cells are almost all seen in the medial layer and are packed against each other by junctional complexes which include tight and gap junctions, which allow for rapid transfer of signaling molecules between the cells. A direct result of the ability of vascular smooth muscle cells to contract is the ability to permit and regulate fluctuation of blood pressure and also to regulate perfusion of organs.

Regulation of Smooth Muscle Tone :
There are several mechanisms, which regulate smooth muscle tone.

Local regulation: Endothelium is the local regulator of smooth muscle tone and its function is critical (discussed above under the Endothelial cell and Nitric Oxide).

The surrounding tissues metabolites, autonomic nerves, control by sympathetic nerve endings and the circulating mediators control smooth muscle tone. All of these stimulate and fine tune regulation of vascular tone. Smooth muscle cells can produce a matrix comprised of two types of fibers: elastic fibers and collagen fibers, along with a ground substance containing a loose network of proteoglycans. Elastic fibers are important for the functional, mechanical properties of the vessel wall, while the collagen is secreted by smooth muscle cells in the intima and to a lesser extent in the media.

Smooth muscle as well as endothelial cells are normally quiescent cells that do not divide. Vascular injury however provides the stimulus for proliferation and results in medial smooth muscle cells dividing and migrating into the intima, where they divide again to give rise to a focal intimal thickening. This activation of smooth muscle and endothelial cells are controlled by growth factors initiated by the basic isoform of fibroblast growth factor (B-FGF), released from the extracellular stores in the tissue. Subsequent migration and ongoing proliferation of smooth muscle cells depends on stimulation by platelet derived growth factor (PDGF), released when activated platelets adhere to the vascular surface from infiltrating monocytes and at certain stages from vascular endothelial and smooth muscle cells themselves.

Other cells in the vessel wall:
Macrophages form a small but significant part of the cell population seen in a normal artery. At the same time, mast cells may also be seen in the connective tissue surrounding the vessel wall and in the adventitia. They are derived from blood monocytes and enter by interacting with the leukocyte adhesion molecules on the endothelium. They are localized in the intima and the adventitia.

Lymphocytes are also seen in the artery though much less commonly than macrophages. T-cells may be seen in the intima or the adventitia and B-cells are confined largely to the adventitia. Periarterial lymph nodes are normally present along the aorta and its major branches. Their function is to allow immune activation by circulating antigens that penetrate the vessels wall, which are then transported to the local lymph nodes (lymphatics in the arterial wall). Adipocytes may be found, generally, in the adventitia and in the surrounding loose connective tissue.

Pathogenesis of Atherosclerosis :
Atherosclerotic lesions have been recognized for over 150 years. It was first recognized by the German pathologist, Rudolf Virchow who in 1856 proposed that atherosclerosis was caused by plasma components (lipids), which elicited an inflammatory response in the arterial wall. Soon after, another pathologist, Von Rokitanksy suggested that atherosclerotic lesions were formed by organization of thrombi, on the intimal surface of arteries. Anitschkow in St. Petersburg noted the presence of large lipid deposits in atherosclerotic plaques and speculated that these might be the cause of atherosclerosis. He tested this hypothesis by feeding rabbits cholesterol, which lead to the atherosclerotic lesions, which were similar to those seen in humans. A few years later Starokadomaskij and Sobolev, showed that mechanical injury to the aorta also leads to intimal lesions, which resemble atherosclerotic ones.

Florey and others tied many of these observations together into one theory by showing that a deendothelializing injury increased the accumulation of lipid and macrophages in the artery. [2] More specific hypothesis, which explains the pathogenesis of atherosclerosis, followed from Ross and his group in 1974. He proposed that arterial injury leads to release of EDGF and other factors from platelets and other cells, initiating a proliferative reaction in smooth muscle cells and leading ultimately to atherosclerotic lesions. [3] Brown and Goldstein [4] discovered LDL receptors and mechanisms of cholesterol metabolism. Their findings allowed the "cholesterol hypothesis" to be tested. They showed clearly that in humans, as well as in experimental models a direct correlation existed between serum cholesterol (especially LDL cholesterol) and the extent of atherosclerosis.

The new genetic models of disease based on changes in lipid metabolism in mice with knock out genes have permitted a more detailed dissection of the steps of pathogenesis and allowed a marked increase in our understanding of atherosclerosis, in these past few years [5].

Current hypothesis:
The first detectable changes in the experimental animal, subject to proatherogenic stimuli such as hypercholesterolemia, is the appearance of blood derived lipids in the subendothelial intima and the expression of leukocyte adhesion molecules on the endothelial surface. The over abundant LDL is trapped in the extracellular matrix. Matrix proteoglycans have an infinity for LDL, which leads to their binding of LDL to the matrix and the accumulation of a lipid pool. Here, LDL undergoes a series of modifications, which include aggregation, oxidation, and degradation of LDL components. (Remaining question: Antioxidants, which protect the LDL from oxidation in the blood, are unable to prevent the same process in the intima. Why?) Some of the modified lipids released by the oxidation of the LDL can act as signaling molecules, which activate endothelial and smooth muscle cells. This leads to expression of leukocyte adhesion molecules, vascular cell adhesion molecule-1, a receptor for monocytes and T-cells. Such cells express factors (counter-receptors - VLA4), which can ligate VCAM-1. Amongst other things, surface adhesions molecules, VCAM-1, ligation leads to the aggregation of monocytes and T-cells to the endothelial surface at sites of lipid accumulation.

The Role of Inflammation:
Inflammation is now recognized as being pivotal in the pathogenesis of atherosclerosis. The key concepts in appreciating the role of inflammation in the initiation, progression and complications of atherosclerosis are as follows [44]:

The normal endothelial cell has a broad spectrum of functions and these include anti-inflammatory, anti-thrombotic and vasodilator properties, which maintain blood, flow and at the same time prevent thrombus formation as well as the entry of leukocytes. These properties can be lost, and Pro atherogenic factors occur and these result in endothelial cell dysfunction. Nitric oxide availability can be reduced and this leads to and that the impaired vasodilatation. At the same time it permits the activation of proinflammatory transcription factors which lead to increased expression of cell adhesion molecules, cytokines and chemokines. All of these facilitate attachment of leukocytes to the endothelial cell and their transmigration into the extracellular matrix. Changes in endothelial cell vasodilator properties appear to precede other structural changes of atherosclerosis and may be a useful clinical marker of atherosclerosis [45]. The recruitment of leukocytes is a multi step process [46], and monocytes /macrophages, T cells, and dendritic cells and mast cells are also recruited into the developing atheroma

The integrity of the fibrous plaque of the atherosclerotic lesion is essential for plaque stability. Its formation and maintenance of this endothelial cell covered fibrous plaque, is most likely a smooth muscle cell driven process for enhancing plaque stability. The macrophage tissue factor, the von Willebrand factor and the subendothelial collagen are all highly thrombogenic and their exposure to circulating blood can trigger the coagulation cascade as well as platelet aggregation, leading very rapidly to arterial thrombosis, characteristic of the acute current syndromes.

What triggers the inflammatory cascade and the initiation as well as progression of atherosclerosis, is to not really clear. Current evidence does suggest that the established risk factors for atherosclerosis as well as the new risk factors such as infectious agents, likely play a role. The implicated infectious agents include Chlamydia pneumoniae. The obvious question about the role of antibiotics and secondary prevention strategies was reviewed by several studies/authors. While initial study suggested that antibiotics played a beneficial role in acute coronary syndromes, later and larger studies have not borne this out

Clinical implications: The substantial progress and the understanding and appreciation of the inflammatory component of vascular disease, does help to understand some of the clinical benefits of contemporary therapy. The H M G. Co A inhibitors (statins) were believed to play their beneficial role through the lowering of cholesterol. However, there is evidence now to show that this benefit is also likely related to their anti-inflammatory and anti- thrombotic actions. These latter may stabilize plaques. Other significantly beneficial new drugs may also have a similar basis.

The increasing availability of plasma inflammatory cell markers, such as CRP, appear to be able to predict the risk of future cardiovascular events in patients with established coronary artery disease and also in the" apparently healthy "population [48]).

Chemokines/:
a) Chemotactic cytokines are produced by macrophages, endothelial cells, as well as smooth muscle cells and when inducted, appear to lead to the accumulation of lipid and the oxidation of lipid.

(Question: How? The mechanism by which this occurs is not yet understood).

It is likely that there are other substances, which can stimulate endothelial cell activation and allow leukocyte recruitment to the intima. Heat shock protein expressed during cell injury may have the same effect.

(Question: Interesting observation: Immunization with this heat shock protein substantially aggravates atherosclerosis!).

In the intima, monocytes differentiate into macrophages, a process promoted by M-CSF (cytokine monocyte colony stimulating factor).

Histopathology of Atherosclerosis: Pathogenesis
Foam Cells: The macrophage is a key cell in the formation of atherosclerotic plaques. This is based largely on its ability to engulf and store lipoproteins (oxidized lipoproteins), which accumulate and transform the appearance of the cell into that of a foam cell, when stained with hematoxylin and eosin. This cell is accepted as being prototypic of atherosclerosis. It is essential to keep in mind that macrophages cannot take up any significant amount of native LDL, but can take up large amounts of oxidized LDL, by a mechanism of specialized cell surface receptors. The mechanism by which the oxidized LDL is converted to cholesterol esters which form the droplets in the "foam" cells or macrophage, is as follows: cholesterol esters present in the oxidized LDL are hydrolyzed and free cholesterol escapes into the cytoplasm. This, in the cytoplasm, is re-esterified by cytosolic enzymes, creating a pool of cholesterol esters, whichform intracellular droplets. These continue to accumulate in the cytoplasm and give the macrophage the appearance of the "lipid-choked" foam cell. Fatty streaks are essentially an accumulation of foam cells along with some T-cells and extracellular cholesterol (predominantly lipoproteins) with an overlying intact endothelium. In addition to oxidized LDL, which acts as an antigen for immune mediated interactions in the forming atherosclerotic lesion, other antigens have also been proposed. They include heat shock protein 60, chlamydia pneumoniae, cytomegalovirus and herpes simplex type I.

A number of immune cytokines and effector mechanisms have been postulated as playing arole in the activation of macrophages, endothelial cells, smooth muscle cells and also likely that they inhibit inflammation and promote fibrosis.

The Atherosclerotic Plaque
The fatty streak is by itself of no clinical importance. Many of these fatty streaks, which develop around vascular branch or bifurcation points, in fact disappear spontaneously. Others progress to larger and more complex lesions. The fatty streaks that persist, progress to fibrofatty plaque. They typically occur at sites of hemodynamic turbulence and strain.

In these lesions, smooth muscle cells from the media have been activated and multiply and migrate to the subendothelial space, where they divide and synthesize extracellular matrix. The net result of this is a fibrous cap, which separates the lipid filled core from the endothelial surface. The stimuli that promote smooth muscle cell migration and multiplication have been mentioned previously. Some theories postulate that since these lesions occur in localized areas, there must be focal / local factors in the artery wall, which activate smooth muscle cells. Some of these factors have been mentioned already and it is established that basic fibroblast growth factor (BFGF) and PDGF promote proliferation and migration of arterial smooth muscle cells in-vivo. PDGF released by endothelial cells can be increased by turbulence through a sheer stress response element in the PDGF promoter [6] Platelets and macrophages can also release growth factors.

In summary it is said that the mechanism of transition from the fatty streak to fibrous plaque may be a hemodynamic stress or inflammatory activation which causes release of PDGF from platelets and / or macrophages, which in turn stimulate smooth muscle cell migration, proliferation and the deposition of the fibrous cap. The net result of this is a progressive increase in plaque size and corresponding decrease in arterial lumen.

Vascular Remodeling:
It is essential to remember that vascular remodeling is an ongoing process. As the plaque grows, the vessel wall undergoes remodeling and the media shows areas of thinning, so that the resultant narrowing of the lumen of the vessel is not in keeping with the increasing plaque size. The lumen is initially preserved by compensatory dilatation of the vessel and outward remodeling. However, at some stage the compensating mechanisms no longer help preserve vessel size and the plaque protrudes into the lumen and alters vascular function.

It is accepted that plaque size per se, is not the critical factor in acute coronary syndromes. On the other hand, acute coronary syndromes are often seen with luminal stenosis of only 30 - 50%. Progressive decrease in vascular lumen size can lead to clinical syndromes such as angina on exercise or stress and intermittent claudication. However, even significantly sized or large plaques can be totally asymptomatic.

The development of acute coronary syndromes (ACS) or complications generally requires an additional pathogenic event to occur such as the formation of a thrombus on the plaque or the disruption of a plaque. Acute coronary syndromes such as myocardial infarction often develop in a plaque, which undergoes additional pathogenic events such as disruption of the plaque or thrombus formation on the plaque.

Question: Why do plaques rupture? Clues supporting the observation that plaque rupture precedes thrombosis and ACS is the morphological observation that plaque rupture occurs in areas that are rich in activated macrophages, T-cells and mast cells are common, in the vicinity of the rupture. [7, 8] Once the components of blood are exposed to the subendothelium, the platelets are activated and the cascade of thrombosis begins.

[Question: Is atherosclerosis a degenerative, metabolic, inflammatory, infectious or hemodynamic disease?]

Many authors have debated the above issue, whether this is a disease of altered cholesterol metabolism, an inflammatory disease process with deposition of fibrous tissue or an abnormality of hemodynamic hemostasis. It is likely that all of these factors played a role, and that the chain of events, which leads to the full-fledged atherosclerotic lesion likely starts with hypercholesterolemia and oxidized LDL. The discussion is more or less unending.

Genetic basis of atherosclerosis:
As the preceding discussion shows, atherosclerosis, the primary cause of vascular disease, involves a number of cell types, organs and several physiological processes. Understandably therefore, its genetic basis is complex. Rodent model studies using transgenic and gene-targeted mice show that the there are at least > 100 genes that can influence the development of atherosclerotic lesions.

First described by Carl Miller, over 70 years ago, the most significant genetic trait that affects atherosclerosis and therefore heart disease is that of Familial Hypercholesterolemia (FH). They showed that FH results from mutations that destroy the ability of the LDH receptor to mediate the binding, internalization and degradation of LDH. Since effective treatments for the heterozygous form of the disease are now available, it would seem to make sense to undertake DNA screening for the disease. Rapid screening methods for FH are available.

The other relatively common hypercholesterolemia gene is Familial defective apolipoprotein (apo B). It is the result of mutations of apo B, the major protein of LDL. This prevents it from binding to the LDL receptor. In contrast to FH, this is a homozygous disorder, and these patients have elevated cholesterol levels though not as high as in FH.

Many other candidate genes have been studied using transgenic mice and these show that genetic factors acting on vascular cells and/or blood cells contribute significantly to the susceptibility to atherosclerosis and CHD. The ongoing genetic studies provide an understanding for new novel diagnostic techniques and the development of new and novel diagnostic tests for the early diagnosis of CHD [40].

Diabetes mellitus: Patients with diabetes mellitus have a higher incidence and severity of ischemic heart disease. This leads to increase use all medical resources, chorion tree interventions including surgery as well as a higher incidence of acute Kari syndromes. The incidence of diabetes mellitus has reached epidemic proportions, with a prevalence of over 5%, in developed countries and considerably higher (likely close to 40%) in developing countries such as the South Aisan countries. The incidence in those over 60 even in developed countries is greater than 20%. The risk of developing coronary artery disease, in these individuals, is 2 to 6x that in non-diabetics and over 75% of individuals with diabetes mellitus, die of vascular causes (in comparison to one third of the general population). [41, 42, 43] These increased risks are related to specific risk factors resulting from insulin resistance and hyperinsulinemia that increase the risk of coronary heart disease:
  1. Dyslipidemia: Increased LDL and triglyceride rich VLDL and reduced HDL

  2. Endothelial dysfunction: Increased plasminogen activator (PAI-1) and cellular adhesion molecules

  3. Inflammation: Increased oxidized LDL

  4. Impaired vasomotor activity

  5. Abnormalities of coagulation and fibrinolysis

  6. Glycation of proteins: Formation of pro-atherogenic advanced end products

Practical Considerations:
  1. Perform a complete autopsy

  2. Concentrate on the area of interest; the heart , the aortic valve surgery site and
    1. the coronary arteries, proximal to and immediately past the anastomosis.
Examination of the coronary arteries is discussed with case 2.

References

Atherosclerosis
  1. Murray CJ, Lopez AG. Global Mortality, Disability and Contribution of Risk Factors: Global Burden of Disease Study. Lancet 1997;349:1426-42

  2. Poole J, Florey HW. Changes in the endothelium of the aorta and the behaviour of macrophages in experimental atheroma-of rabbits. J Pathol Bacteriol 1958; 75:245-52).

  3. Ross R, Glomcet JA, Kariya B, Harker LA. A platelet dependency serum factor that stimulates the proliferation of smooth of arterial cell muscle cells in-virto. Proc Natl Acad Sci USA. 1974; 71: 1207 - 11.)

  4. Brown MS, Goldstein JL. A receptor medicated pathway for cholesterol hemostasis. Science 1986; 272: 265 - 8)

  5. Breslow JL. Mouse models of atherosclerosis. Science 1996; 272: 685-8.

  6. Gimbrone MA, Mago T, Topper JM. Biomechanical activation: An emerging paradigm in endothelial adhesion biology. J Clin Invest 1997; 100: S61-5).

  7. Kovenen PT, Kaartinen M, Paavoen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995; 92: 1084 - 8.)

Coronary artery interventions
  1. Van der wal AC, Becker AE, Van der loos CN, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994; 89: 36 - 44.)

  2. Senning A. Strip grafting and coronary arteries. J Thorac Cardiovasc Surg 1961; 41: 542 - 9.)

  3. Semp K, Udwai TE, Kinare SG, Parulkar GB. Transmyocardial acupuncture: A new approach to myocardial revascularization. J Thorac Cardiovasc Surg 1965; 50: 181 - 9).

  4. Weinberg A, Bullard W. Technical factors which favor mammary - coronary anastomosis: Report of 45 cases of human coronary artery disease, thus treated. J Thorac Surg 1955; 30: 411-31).

  5. Kolessov VI. Mammary artery - coronary artery anastomosis as methods of treatment for angina pectoris. J Thorac Cardiovasc Surg 1967; 54: 535-44.)

  6. Rahimtoola SH, Fessler CL, Grunkemeier GL et al. Survival 15 to 20 years after coronary bypass surgery for angina. J Am Coll Cardiol. 1993; 21: 151-7

  7. Segreant P, Blackstone E, Meyns B, Stockman B, Jashari R. First cardiological or cardiosurgical re-intervention for ischemic heart disease after primary CABG. Eur J Cardiothorac Surg 1998; 14: 480 - 7

PCI-Angioplasty and stents
  1. Gruentizg AR, King SC, Schlumpf M, et al. Long-term follow up after percutaneous transluminal coronary angioplasty. The early Zurich experience. N Eng J of Med 316: 1127 - 1132, 1987.

  2. Fishman DL, Leone MB, Bain DS et al. A randomized comparison of coronary - stent placement and balloon angioplasty and the treatment of coronary artery disease. Stent restenosis study investigators. N Engl J of Med; 331: 496 - 501,1994.

  3. Cutlip DE, Chauhan MS, Bain DS, et al. Clinical restenosis after coronary stenting: Respective from multicenter clinical trials. J Am Col Cardiol 40: 2082 - 2089, 2002

  4. Isles CG, Robertson S, Phil D: Management of renal vascular disease: A review of renal artery stenting in ten studies. QJN 92: 159 - 167, 1999.

  5. Lee ES, Steenson CE, Trimble KE, et al. Comparing patency rates between external iliac and common iliac artery stents. J Vasc Surg 31: 889 - 894, 2000

  6. Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans. Circulation 99: 44 - 52, 1999.

  7. Reference: Barth KH, Virmani R, Frolich J, et al. A comparison of vascular wall reactions to Palmaz stents, Strecker Tamplin stents and Wall stents in canine iliac and femoral arteries. Circulation 93: 2161 - 2169, 1996.

  8. Ajani AE, Kim HS, Waksman R. Clinical trials of vascular brachytherapy for in-stent restenosis update. Cardiovascular Radiation Medicine 2001; 2: 107 - 103.

  9. Hansrani N, Overbeck K, Smout J et al. Intravascular brachytherapy: A systematic review of its role in reducing restenosis after endovascular treatmenin peripheral arterial disease. European Journal of Vascular and Endovascular Surgery 24: 377-382, 2002.

Stents and Drugs
  1. De Scheerder I, Wang K, Wilczec K et al. Local methylprednisolone inhibition offoreign body response to coated intracoronary stents. Coronary Artery Disease. 1996; 7: 161 - 166.

  2. Jordan MA, Toss RJ, Wilson L. The mechanism of mitotic block and inhibition ofcell proliferation by paclitaxel at low concentration. Proc Nat Acad Sci. USA, 1993, 90: 9552-6.

  3. Farb A, Haller PS, Carter JA. Paclitaxel polymer-coated stents reduce neointima. Abstract. Circulation 1997: 96 suppl 1: 609.

  4. Drachman DE, Edelman ER, Seifret P, et al. Neointimal thickening after stent delivery of: paclitaxel change in composition and arrest of growth over six months. J Am Coll Cardiol 2001; 36: 2325 - 32

  5. Heldman AW, Cheng L, Jenkins GM, et al. Paclitaxel stent coating inhibits neointimal hyperplasia at four weeks in a post angioplasty model of coronary restenosis. Circulation 2001; 103: 2289 - 95
  1. Fajadet A. Morice MC. Bode C etal. Maintainance of long-term clinical benefit with Sirolimus eluting coronary stents: 3 year results of RAVEL trial. Circulation.111:1040-44.2005.
  1. Svensson LG: Natural history of aneurysms of the descending and thoracoabdominal aorta. J Card Surg 12(suppl); 279-284, 1997

  2. Crawford ES, De Natale RW. Thoracoabdominal aortic aneurysms: Observations regarding the natural course of the disease. J Vasc Surg 3: 578-582, 1986

  3. Cooley DA. The history of surgery of the thoracic aorta. Cardiol Clinic 70: 609 - 613. 1999.

  4. Cosellie JS, Lemiere SA, Miller CC, et al. Mortality and paraplegia after thoracoabdominal aortic aneurysm repair: A risk factor analysis. Ann Thorac Surg 69: 409-414, 2000

  5. Parodi JC, Palmaz JC, Barone HD. Transfemoral interluminal graft implantation for abdominal aortic aneurysm. Am Vasc Surg 5: 49 - 59. 1991

  6. Dack MD, Miller DC, Semba CP, et al. Transluminal placement of endovascularstent grafts for the treatment of ascending thoracic aortic aneurysms. New England Journal of Medicine 33: 1729 - 1734, 1994

  7. Parodi JC. Endovascular stent graft repair of aortic aneurysms. Curr Opinion in Cardiology 12: 396 - 405. 1997).

  8. Zucker D, Paduzzi P, et al: Effect of coronary artery bypass graft surgery onsurvival: Overview of ten year results from randomized trials by the coronary artery bypass graft surgery trialists collaboration. Lancet 344: 563, 1994).

Aortic Stent Grafts
  1. Parodi JC. Endovascular repair of abdominal aortic aneurysms and other arterial lesions. J Vasc Surg 21; 549 - 556, 1995).

  2. Dorros G, Parodi J, Schonholz C, et al. Evaluation of endovascular abdominalaortic aneurysm repair: Anatomical classification, procedural success, clinicalassessment and data collection. J Endo Vasc Surg 4: 203 - 211, 1997).

  3. Ernst CB. Present therapy for infrarenal aortic aneurysms. N Engl J Med 336: 591997.

General
  1. Lusis AJ, Fogelman AM, Fonorov GC. Genetic Basis of Atherosclerosis (Part 1)New genes and Pathways.Circulation ; 110:1868-1873. 2004.

  2. Houner H.Occurrence of diabetes mellitus in Germany(in German). Dsth Med Wochenschr 123: 777-82.1998.

  3. Stamler J et al.Diabetes,other risk factors and 12 year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.Diabetes Care; 16:434-44.

  4. Marso P et al.Optimising the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT. Circulation 100:2477-84:2000.

  5. Tiong A. Y,Brieger D. Inflammation and coronary artery disease.Am H J:150:11-182005

  6. Willerson J, Kereiakes D. Endothelial dysfunction. Circulation 108:2060-1.2003.

  7. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multi step paradigm. Cell76:301-14.1994.

  8. Cleland J, Loh P, Freemantle N et al. Clinical trials update from the European Society for Cardiology:SENIORS.ACES.PRIOVE_IT.ACTION.and the HF-ACTION trial Eur J Heart Fail 6:787-91.2004.

  9. Ridker P,Brown P,Vaughn D et al.Established and emerging plasma biomarkers inthe prediction of first atherothrombotic events. Circulation109(Suppl):6-19.2004.

  10. Rankin JM,Spinelli JJ,Carrere RG et al. improved clinical outcome after widespread use of coronary artery stenting in Canada. N Engl J Med .341:1957-65.1999.

  11. Kuntz RE, Rogers C, Baim DS .Percutaneous coronary intervention-induced emboli during primary PC I for STEMI: Too little, too much, or too late? Am Heart J.150: 4-6.2005.

  12. Al Suwaidi J,Berger PB. Do stents reduce mortality compared to balloonangioplasty? A critical review of all the evidence. Am Heart J.150:7-10.2005

New References

Atherosclerosis:
  1. Napoli C et al.. Rethinking primary prevention of atherosclerosis- related diseases. Circulation.2006. 28;114:2390-27

  2. Tofler GH & Muller JE.Triggering of acute CV disease and potential preventive strategies.Circ.2006.24: 114(17):1863-72.

  3. Semenkovitch CE. Insulin resistance and atherosclerosis. J Clin Invest, 2006;116:1813-22.

  4. Lucas AR et al. Inflammation in atherosclerosis: some thoughts about acute coronary syndromes. Circ '06;113(17):e728-32.

  5. Goldschmidt-Clermont PJ et al. Atherosclerosis 2005: recent discoveries and novel hypotheses. Circulatiion 05;112(21):3348:-53.

  6. Libby P,Theroux P.Pathophysiology of coronary artery disease.Circulation '05 111(25):3481-8.

  7. Davignon J, Ganz P. Role of Endothelial dysfunction in atherosccclerosis.Circ '04;(23Suppl)L 111) 27-32.

Bypass Grafts:
  1. Hochman JS,Steg PG, Does preventive PCI work? (Editorial),NEJM 10;1056.

  2. Martens TP et al. New technology for surgical coronary revascularization.Circ '06; 114(6):606-14.

  3. Verma S et al.Shold radial arteries be used routinely for CABG ? Circulation '04;110(5):240-6.

Stents (coronary):
  1. Hochman JS,Steg PG, Does preventive PCI work? (Editorial),NEJM 10;1056

  2. Boder WE et al;Optimal medical therapy with or without PCI for Stable Coronary Disease. NEJM 10.1056. ( COURAGE Trial)

  3. Khot UN et al. Radial artery bypass grafts have an increased occurrence of angiographically severe stenosis and occlusion compared with the left internal mammary arteries and saphenous vein grafts. Circulation'04;109(17):2086-91.

  4. Ligthart S et al.The cost-effectiveness of Drug eluting stents: a systematic review.CMAJ '07;176(2):199-205.

  5. Keriakis DJ et al.Lt main coronary revascularization at the crossroads.Circ '06;113(21):2480-4.

  6. Anis KK et al.The future of Drug eluting stents.Heart '06;9295):650-7.

  7. Butany J et al.Coronary artery stents: identification and evaluation. J Clin Pathol 05; 58:795-804.

Aortic stent Grafts:
  1. Endovascular Stent Grafting of descending aortic aneurysms. Chest'03;124(2):714-9.

Ventricular Assist Devices:
  1. Stevenson LW et al. Left ventricular assist devices:bridges to transplantation, recovery, and destination for whom? Circulation '03; 108(25):3059-63.

  2. Mancini D et al'Mechanical device -based methods of managing and treating heart failure.Circulation '05;112(3);438-48.

  3. Copeland JG et al. Caarduac replacement with a total artificial heart as a bridge to transplantation. NEJM '04:351 (9):859-67.