ATHEROSCLEROSIS AND HYPERTENSIVE VASCULAR DISEASE

1. ATHEROSCLEROSIS AND HYPERTENSIVE VASCULAR DISEASE Doç.Dr. Işın Doğan Ekici

2. Atherosclerosis • Characterized by intimal lesions called atheromas (also called atheromatous or atherosclerotic plaques), that protrude into vascular lumina. • An atheromatous plaque consists of a raised lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and cholesterol esters) covered by a firm, white fibrous cap. • Besides obstructing blood flow, atherosclerotic plaques weaken the underlying media and can themselves rupture, causing acute catastrophic vessel thrombosis.

3. The major components of a well-developed intimal atheromatous plaque overlying an intact media.

4. ATHEROSCLEROSIS • Causes more morbidity and mortality (roughly half of all deaths) in the Western world than any other disorder. • Because coronary artery disease is an important manifestation of the disease, epidemiologic data related to atherosclerosis mortality typically reflect deaths caused by ischemic heart disease (IHD) ; indeed, myocardial infarction is responsible for almost a quarter of all deaths in the United States. • Not to be minimized, carotid atherosclerotic disease and stroke are also associated with significant morbidity and mortality

5. EPIDEMIOLOGY • Atherosclerosis is much less prevalent in Central and South America, Africa, and Asia. • The mortality rate for IHD in the United States is among the highest in the world and is approximately five times higher than that in Japan. • The prevalence and severity of atherosclerosis and IHD among individuals and groups are related to several risk factors, some constitutional (and therefore less controllable) but others acquired or related to behaviors and potentially amenable to manipulation • Multiple risk factors have a multiplicative effect; two risk factors increase the risk approximately fourfold. When three risk factors are present (e.g., hyperlipidemia, hypertension, and smoking), the rate of myocardial infarction is increased seven times.

7. Estimated 10-year risk of coronary artery disease in hypothetical 55-year-old men and women as a function of traditional risk factors (hyperlipidemia, hypertension, smoking, and diabetes). BP, blood pressure; ECG, electrocardiogram; HDL-C, high-density lipoprotein cholesterol; LVH, left ventricular hypertrophy.

8. Pathogenesis • The overwhelming clinical importance of atherosclerosis has stimulated enormous efforts to understand its cause. • The contemporary view of atherogenesis is expressed by the response-to-injury hypothesis. • This model views atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression occurs through interactions of modified lipoproteins, monocyte-derived macrophages, T lymphocytes, and the normal cellular constituents of the arterial wall.

9. Chronicendothelialinjury,withresultantendothelialdysfunction, causing (amongotherthings) increasedpermeability, leukocyteadhesion, andthrombosis • Accumulation of lipoproteins(mainly LDL anditsoxidizedforms) in thevesselwall • Monocyteadhesiontotheendothelium,followedbymigrationintotheintimaandtransformationintomacrophagesandfoamcells • PlateletadhesionFactorreleasefromactivatedplatelets, macrophages, andvascularwallcells, inducingSMC recruitment,eitherfromthemediaorfromcirculatingprecursors • SMC proliferationand ECM production & Lipidaccumulationbothextracellularlyandwithincells (macrophagesandSMCs)

11. ENDOTHELIAL INJURY • Chronic or repetitive endothelial injury is the cornerstone of the response-to-injury hypothesis. • Endothelial loss due to any kind of injury-whether induced experimentally by mechanical denudation, hemodynamic forces, immune complex deposition, irradiation, or chemicals-results in intimal thickening; in the presence of high-lipid diets, typical atheromas ensue. • However, early human lesions begin at sites of morphologically intact endothelium. • Thus, non-denuding endothelial dysfunction underlies human atherosclerosis; in the setting of intact but dysfunctional ECs there is increased endothelial permeability, enhanced leukocyte adhesion, and altered gene expression.

12. The specific causes of endothelial dysfunction in early atherosclerosis are not completely understood. • Etiologic culprits include toxins from cigarette smoke, homocysteine, and even infectious agents. • Inflammatory cytokines (e.g., tumor necrosis factor, or TNF) can also stimulate the expression of pro-atherogenic genes in EC. • Nevertheless, the two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia. • Inflammation is also an important contributor.

14. HEMODYNAMIC TURBULANCE • The importance of hemodynamic turbulence in atherogenesis is illustrated by the observation that plaques tend to occur at ostia of exiting vessels, branch points, and along the posterior wall of the abdominal aorta, where there are disturbed flow patterns. • In vitro studies further demonstrate that nonturbulent laminar flow in other parts of the normal vasculature leads to the induction of endothelial genes whose products (e.g., the antioxidant superoxide dismutase) actually protect against atherosclerosis. Such "atheroprotective" genes could explain the nonrandom localization of early atherosclerotic lesions.

15. LIPIDS • Lipidsaretypicallytransported in thebloodstreamboundtospecificapoproteins (forminglipoproteincomplexes). • Dyslipoproteinemias can resultfrommutationsthatencodedefectiveapoproteinsoralterthelipoproteinreceptors on cells, orfromsomeotherunderlyingdisorderthataffectsthecirculatinglevels of lipids (e.g., nephroticsyndrome, alcoholism, hypothyroidism, ordiabetesmellitus). • Commonlipoproteinabnormalities in the general population (indeed, present in manysurvivors of myocardialinfarction) include • (1) increased LDL cholesterollevels, • (2) decreased HDL cholesterollevels, and • (3) increasedlevels of theabnormalLp(a)

16. INFLAMMATION • Inflammatory cells and mediators are involved in the initiation, progression, and the complications of atherosclerotic lesions. • Although normal vessels do not bind inflammatory cells, early in atherogenesis dysfunctional arterial ECs express adhesion molecules that encourage leukocyte adhesion; vascular cell adhesion molecule 1 (VCAM-1) in particular binds monocytes and T cells. • After these cells adhere to the endothelium, they migrate into the intima under the influence of locally produced chemokines.

17. INFECTION • Although there is exciting evidence that infections may drive the local inflammatory process that results in atherosclerotic plaque, this hypothesis has yet to be definitively proven. • Herpesvirus, cytomegalovirus, and Chlamydia pneumoniae have all been detected in atherosclerotic plaque but not in normal arteries, and seroepidemiologic studies find increased antibody titers to C. pneumoniae in patients with more severe atherosclerosis. • However, a causal link between any of these infections and the development or progression of atherosclerosis remains to be established.

18. SMOOTH MUSCLE PROLIFERATION • Intimal SMC proliferation and ECM deposition convert a fatty streak into a mature atheroma and contribute to the progressive growth of atherosclerotic lesions. • Recall that the intimal SMCs have a proliferative and synthetic phenotype distinct from the underlying medial SMCs and, in fact, may substantially derive from the recruitment of circulating precursors. • Several growth factors are implicated in SMC proliferation and ECM synthesis, including platelet-derived growth factor (PDGF, released by locally adherent platelets as well as by macrophages, ECs, and SMCs), fibroblast growth factor, and transforming growth factor α. • The recruited SMCs synthesize ECM (notably collagen), which stabilizes atherosclerotic plaques. However, activated inflammatory cells in atheromas can cause intimal SMC apoptosis, and they also increase ECM catabolism, resulting in unstable plaques.

19. Morphology • Fatty Streaks: • Fatty streaks are composed of lipid-filled foam cells but are not significantly raised and thus do not cause any disturbance in blood flow. They begin as multiple minute yellow, flat spots that can coalesce into elongated streaks, 1 cm long or longer • Fatty streaks can appear in the aortas of infants younger than 1 year and are present in virtually all children older than 10 years, regardless of geography, race, sex, or environment. • Coronary fatty streaks begin to form in adolescence, at the same anatomic sites that later tend to develop plaques. The relationship of fatty streaks to atherosclerotic plaques is uncertain; although they may evolve into precursors of plaques, not all fatty streaks are destined to become advanced atherosclerotic lesions.

20. Fatty streak-a collection of foam cells in the intima. A, Aorta with fatty streaks (arrows), associated largely with the ostia of branch vessels. B, Photomicrograph of fatty streak in an experimental hypercholesterolemic rabbit, demonstrating intimal, macrophage-derived foam cells (arrow).

21. Atherosclerotic Plaque: • The key processes in atherosclerosis are intimal thickening and lipid accumulation. • Atheromatous plaques (also called fibrous or fibrofatty plaques) impinge on the lumen of the artery and grossly appear white to yellow; thrombosis superimposed over the surface of ulcerated plaques is red-brown in color. Plaques vary from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses • Atherosclerotic lesions are patchy, usually involving only a portion of any given arterial wall. On cross-section, the lesions therefore appear “eccentric”. • The focality of atherosclerotic lesions-despite the uniform exposure of vessel walls to such factors as cigarette smoke toxins, elevated LDL, and hyperglycemia-is almost certainly due to the vagaries of vascular hemodynamics. • Local flow disturbances, such as turbulence at branch points, leads to certain portions of a vessel wall being more susceptible to plaque formation. Although focal and sparsely distributed at first, atherosclerotic lesions become more numerous and more diffuse with time.

22. Gross views of atherosclerosis in the aorta. A, Mild atherosclerosis composed of fibrous plaques (arrow). B, Severe disease with diffuse and complicated lesions, some of which have coalesced.

23. In humans, the abdominal aorta is typically much more frequently involved than the thoracic aorta. • In descending order, the most extensively involved vessels are: • the lower abdominal aorta, • the coronary arteries, • the popliteal arteries, • the internal carotidarteries, 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 its severity in another. Moreover, in any given vessel, lesions at various stages often coexist.

24. Atherosclerotic plaques have three principal components: • (1) cells, including SMCs, macrophages, and T cells; • (2) ECM, including collagen, elastic fibers, and proteoglycans; and • (3) intracellular and extracellular lipid

25. These components occur in varying proportions and configurations in different lesions. • Typically, the superficial fibrous cap is composed of SMCs and relatively dense collagen. Beneath and to the side of the cap (the "shoulder") is a more cellular area containing macrophages, T cells, and SMCs. • Deep to the fibrous cap is anecrotic core, containing lipid (primarily cholesterol and cholesterol esters), debris from dead cells, foam cells (lipid-laden macrophages and SMCs), fibrin, variably organized thrombus, and other plasma proteins; the cholesterol content is frequently present as crystalline aggregates that are washed out during routine tissue processing and leave behind only empty "clefts." • At the periphery of the lesions, there is usually neovascularization (proliferating small blood vessels).

26. Histologic features of atheromatous plaque in the coronary artery. A, fibrous cap (F) and a central necrotic (largely lipid) core (C). The lumen (L) has been moderately narrowed. B, Higher power photograph of a section of the plaque shown in A, stained for elastin (black), demonstrating that the internal and external elastic membranes are destroyed and the media of the artery is thinned under the most advanced plaque (arrow). C, Higher magnification photomicrograph at the junction of the fibrous cap and core, showing scattered inflammatory cells, calcification (arrowhead), and neovascularization (small arrows).

27. Atherosclerotic plaque rupture. A, Plaque rupture (arrow) without superimposed thrombus, in a patient who died suddenly. B, Acute coronary thrombosis superimposed on an atherosclerotic plaque with focal disruption of the fibrous cap (arrow), triggering fatal myocardial infarction.

28. Typical atheromas contain relatively abundant lipid, but some plaques ("fibrous plaques") are composed almost exclusively of SMCs and fibrous tissue. • Plaques generally continue to change and progressively enlarge through cell death and degeneration, synthesis and degradation (remodeling) of ECM, and organization of thrombi. Moreover, atheromas often undergo calcification. • Patients with advanced coronary calcification appear to be at increased risk for coronary events.

29. ATHEROSCLEROTIC PLAQUES ARE SUSCEPTIBLE TO THE FOLLOWING PATHOLOGIC CHANGES WITH CLINICAL SIGNIFICANCE: • Rupture, ulceration, or erosion of the luminal surface of atheromatous plaques exposes the bloodstream to highly thrombogenic substances and induces thrombus formation. Such thrombi can partially or completely occlude the lumen and lead to downstream ischemia • If the patient survives the initial vascular occlusion, thrombi may become organized and incorporated into the growing plaque. • Hemorrhage into a plaque. Rupture of the overlying fibrous cap or of the thin-walled vessels in the areas of neovascularization can cause intra-plaque hemorrhage; a contained hematoma may expand the plaque or induce plaque rupture. • Atheroembolism. Plaque rupture can discharge debris into the bloodstream, producing microemboli composed of plaque contents. • Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes weakness of the vessel wall and development of aneurysms that may rupture.

30. The natural history, morphologic features, main pathogenic events, and clinical complications of atherosclerosis.

31. Common Sites • Large Arteries : Aorta, Carotid & Iliac (large vessels) • Medium Arteries : Coronary, Cerebral, Limbs. • Small Arteries & Veins: Never affected.

32. PREVENTION OF ATHEROSCLEROTIC VASCULAR DISEASE • Efforts to reduce the consequences and impact of atherosclerosis include • Primary prevention programs aimed at either delaying atheroma formation or encouraging regression of established lesions in persons who have not yet suffered a serious complication of atherosclerosis • Secondary prevention programs intended to prevent recurrence of events such as myocardial infarction or stroke in symptomatic patients

33. SUMMARY • Atherosclerosis • Atherosclerosis is an intima-based lesion organized into a fibrous cap and an atheromatous (gruel-like) core and composed of SMCs, ECM, inflammatory cells, lipids, and necrotic debris. • Atherogenesis is driven by an interplay of inflammation and injury to vessel wall cells. • Many known risk factors influence EC dysfunction, as well as SMC recruitment and stimulation. • Atherosclerotic plaques accrue slowly over decades but may acutely cause symptoms due to rupture, thrombosis, hemorrhage, or embolization. • Risk factor recognition and reduction can reduce the incidence and severity of atherosclerosis-related disease.

34. HYPERTENSIVE VASCULAR DISEASE

35. HYPERTENSION • Elevated blood pressure is called hypertension; it is one of the major risk factors for atherosclerosis. • Here we will first discuss the mechanisms of normal blood pressure control, followed by pathways that may underlie hypertension, and finally the pathologic changes in vessels associated with hypertension. • Low pressures result in inadequate organ perfusion, leading to dysfunction and/or tissue death. Conversely, high pressures that drive blood flow in excess of metabolic demands provide no additional benefit but result in blood vessel and end-organ damage.

36. Hypertension is a common health problem with occasionally devastating outcomes, • It typically remains asymptomatic until late in its course. • Besides contributing to the pathogenesis of coronary heart disease and cerebrovascular accidents, hypertension can also cause cardiac hypertrophy and heart failure (hypertensive heart disease), aortic dissection, and renal failure. • Although we have an improving understanding of the molecular pathways that regulate normal blood pressure, the mechanisms of hypertension in the vast majority of people remain unknown; consequently, we refer to most of these as "essential hypertension"

37. REGULATION OF BLOOD PRESSURE • Blood pressure is a complex trait involving the interaction of multiple genetic and environmental factors that influence two hemodynamic variables: cardiac output and peripheral vascular resistance. • Cardiac output is affected by blood volume, itself strongly dependent on sodium concentrations. • Peripheral resistance is regulated predominantly at the level of the arterioles and is influenced by neural and hormonal inputs. • Normal vascular tone reflects an interplay between circulating factors that induce vasoconstriction (e.g., angiotensin II and catecholamines) and vasodilation (e.g., kinins, prostaglandins, and nitric oxide).

38. Resistance vessels also exhibit autoregulation, whereby increased blood flow induces vasoconstriction to protect tissues against hyperperfusion. • Other local factors such as pH and hypoxia, as well as neural interactions (α- and β-adrenergic systems), are also involved. • The integrated function of these systems ensures adequate systemic perfusion, despite regional demand differences.

39. The kidney influences peripheral resistance and sodium homeostasis primarily through the renin-angiotensin system. • Renin is a proteolytic enzyme produced in the kidney by the juxtaglomerular cells-modified myoepithelial cells that surround the glomerular afferent arterioles. • When blood volume or pressure is reduced, the kidney senses this as a decreased pressure in the afferent arterioles. • Moreover, lower volumes or pressures result in a reduced glomerular filtration rate in the kidney with increased resorption of sodium by proximal tubules; these latter two effects putatively conserve sodium and expand the blood volume. • The juxtaglomerular cells respond to reduced intraluminal pressures in the afferent arterioles by releasing renin; they also produce renin when the cells of the macula densa sense decreased sodium concentration in the distal convoluted tubule.

40. Renin catabolizes plasma angiotensinogen to angiotensin I, which in turn is converted to angiotensin II by angiotensin-converting enzyme in the periphery. • Angiotensin II raises blood pressure by: increasing peripheral resistance by inducing vascular SMC contraction; increasing blood volume by stimulating aldosterone secretion in the adrenals; increasing distal tubular reabsorption of sodium. • The kidneys filter 170 liters of plasma containing 23 moles of salt daily! Moreover, 99.5% of the filtered salt must be reabsorbed to maintain homeostasis (assuming daily ingestion of only 100 mEq).

41. As it turns out, the absorption of the last 2% of sodium is the key to normal sodium homeostasis; this is regulated by the renin-angiotensin system acting on the epithelial Na+ channel (ENaC). • The kidney also produces a variety of vasorelaxant or antihypertensive substances (including prostaglandins and nitric oxide) that presumably counterbalance the vasopressor effects of angiotensin. • When renal excretory function is impaired, increased arterial pressure is a compensatory mechanism that can help restore fluid and electrolyte balance. • Other tissues can also influence influence blood pressure and volume. • Thus, atrial natriuretic peptide, secreted by heart atria in response to volume expansion(e.g., in heart failure) inhibits sodium reabsorption in distal tubules and causes global vasodilation.

44. ESSENTIAL HYPERTENSION • Evenwithoutknowingthespecificlesion(s), it is reasonabletoconcludethatalterations in renalsodiumhomeostasisand/orvesselwalltoneorstructureunderlieessentialhypertension. • Inestablishedhypertension, bothincreasedbloodvolumeandincreasedperipheralresistancecontributetotheincreasedpressure. • Reducedrenalsodiumexcretionin the presence of normal arterialpressure is probably a keyinitiatingevent; indeed, it is a final commonpathwayforthepathogenesis of mostforms of hypertension.

45. Decreasedsodiumexcretionwillcause an obligatoryincrease in fluidvolumeandincreasedcardiacoutput, therebyelevatingbloodpressure. • At thehighersetting of bloodpressure, enoughadditionalsodiumwill be excretedbythekidneystoequalintakeandpreventfluidretention. • Thus, a newsteadystate of sodiumexcretionwould be achieved, but at theexpense of an elevatedbloodpressure. • Vascularchangesmayinvolvefunctionalvasoconstrictionorchanges in vascularwallstructurethatresult in increasedresistance. • Chronicfunctionalvasoconstrictioncouldalsoconceivablyresult in permanentstructuralthickening of theresistantvessels.

46. GENETIC FACTORS IN HYPERTENSION. • Studies comparing blood pressure in monozygotic and dizygotic twins, and studies of familial clustering of hypertension, clearly establish a strong genetic component. • Moreover, several single-gene disorders cause relatively rare forms of hypertension (and hypotension) by altering net renal sodium resorption. • Allelic variations in the genes encoding components of the renin-angiotensin system. • Hypertension is associated with polymorphisms in both the angiotensinogen locus and the angiotensin II type I receptor locus. • Genetic variants in the renin-angiotensin system may contribute to the known racial differences in blood pressure regulation.

47. Susceptibilitygenesforessentialhypertension in thelargerpopulationarecurrentlyunknown but maywellincludegenesthatgovernresponsesto an increasedrenalsodiumload, levels of pressorsubstances, reactivity of vascularsmoothmusclecells (SMC) topressoragents, or SMC growth. • Environmentalfactorsmodifytheexpression of anyunderlyinggeneticdeterminants of hypertension; stress, obesity, smoking, physicalinactivity, andheavyconsumption of saltareallimplicated. • Indeed, evidencelinkingdietarysodiumintakewiththeprevalence of hypertension in differentpopulationgroups is particularlyimpressive.

49. VASCULAR PATHOLOGY IN HYPERTENSION • In addition to accelerating atherogenesis, hypertension-associated degenerative changes in the walls of large and medium arteries can potentiate both aortic dissection and cerebrovascular hemorrhage. • Hypertension is also associated with two forms of small blood vessel disease: • hyaline arteriolosclerosis • hyperplastic arteriolosclerosis.

50. A, Hyaline arteriolosclerosis. The arteriolar wall is hyalinized and the lumen is markedly narrowed. • B, Hyperplastic arteriolosclerosis (onion-skinning) causing luminal obliteration (arrow), with secondary ischemic changes, manifest by wrinkling of the glomerular capillary vessels at the upper left