15. Vascular pathology I.
DISEASES OF ARTERIES
ARTERIOSCLEROSIS (“hardening of the arteries”): general term reflecting arterial wall thickening and loss of elasticity 3 patterns • Atherosclerosis: involves the the aorta and the large arteries • Mönckeberg sclerosis: calcific deposits in the media of middle-sized arteries in persons >age 50 • Arteriolosclerosis: involves the small arteries and arterioles in association with hypertension or diabetes
ATHEROSCLEROSIS Multifactorial, slowly progresive chronic degenerative-inflammatory disease of the aorta and the large arteries, such as • coronary arteries • circle of Willis • popliteal and tibial arteries Significance: > 50% of all death is attributed to atherosclerosis in well-developed countries
Morphology Gross • Atheromatous plaque (pathognomic) - raised white-yellow lesion in the intima, protruding into the lumen • Large plaques in the aorta (> 2 cm) contain a yellow, grumous debris (”atheroma” - Greek word for gruel) Structure of atheroma on LM • Intimal lesion • Central lipid core composed of lipids, cholesterol clefts, necrotic debris + calcium-salts; surrounded by foamy macrophages, T-lymphocytes, fibroblasts, small capillaries, and collagens and proteoglycans • Fibrous ”cap” subendothelially
Types of plaques • Vulnerable plaques have large atheromatous cores, increased inflammatory cell content and thin fibrous caps high risk of rupture thrombosis • Stable plaques have minimal atheromatous cores and inflammation and thick fibrous caps 70% stenosis (critical stenosis) chronic ischemia distally
Pathogenesis Response to chronic endocardial injury hypothesis
Cholesterol can’t dissolve in the blood. It is transported through the bloodstream by lipoproteins. Low density lipoprotein (LDL) carries cholesterol to plaques (“bad cholesterol”). High density lipoprotein (HDL) mobilizes cholesterol from plaques and transports it to the liver for biliary excretion (“good cholesterol”).
Modifiable major risk factors • LDL-hypercholesterolemia (“bad cholesterol”) • Diabetic milieu (hyperglycemia plus dyslipidemia: trigliceridemia and reduced HDL-cholesterol [“good cholesterol”]). • Obesity • Hypertension • Smoking • Reduced physical activity
Nonmodifiable risk factors • Male gender (in women, atherosclerosis is not significant before menopause) • Increasing age • Family history
Chronic endothelial injury due to risk factors, turbulence at branch points and other factors • Endothelial dysfunction: insudation of LDL-cholesterol into the intima + migration of monocytes into the intima + adhesion of platelets to the endothelial layer (PDGF ) • Transformation of monocytes to macrophages (GFs ) • Smooth muscle cell precursors (SMCPs) appear in the intima from the media and the circulation • Macrophages oxidate and engulf LDL-cholesterol foamy macrophages: GF • SMCPs transform into fibroblasts collagens and other ECM material are produced • Vitious circle
Course of atherosclerosis • Starts in teenagers/young adults • Insidious development of plaques within 15-35 years • Clinical disease manifests as consequence of plaque complications in the age between 45-65 ys • Sudden death can be the first manifestation of atherosclerosis
Plaque complications • Rupture, ulceration of the luminal surface thrombus formation: - in arteries: within approx. 4 hours, complete occlusion of the lumen tissue ischemia, then infarction distally - in aorta: mural thrombi • Hemorrhage into a plaque sudden expansion of the plaque or plaque rupture • Cholesterol microembolism. Rupture of large plaques can discharge debris into the blood • Calcification destruction of elastic fibers in tunica media of aorta • Plaques compress the tunica media atrophy of aortic wall thinning aneurysmal dilation 1
15. Vascular pathology I.
CONSEQUENCES OF ATHEROSCLEROSIS
1. Coronaries • Rupture of vulnerable plaques thrombosis: sudden cardiac death or acute myocardial infarction • Slow progression of stable plaques chronic myocardial ischemia congestive heart failure
2. Circle of Willis • Thrombosis in middle cerebral artery - cerebral infarct contralateral hemiplegia, prolonged bed rest • Thrombosis in basilar artery death • Thrombosis of internal carotid artery cerebral infarct; no consequence, if the circle of Willis functions well
3. Aorta Most severe lesions in the abdominal aorta • Mural thrombi embolism in the lower extremities • Thinning of aortic wall aneurysm rupture: may lead to lethal bleeding • Plaque rupture cholesterol microembolism, renal failure
4. Superior mesenteric artery Thrombosis of a vulnerable plaque at the orifice: infarction of small bowels death
5. Unilateral renal artery stenosis at the orifice renovascular hypertension
6. Arteries of lower extremities • Stenosis: intermittent claudation (clinical diagnosis for pain in the calf muscles, which occurs during exercise and is relieved by short period of rest) • Complete occlusion: gangrene of leg
Note: prophylactically administered platelet aggregation inhibitors reduce the incidence of myocardial and cerebal infarction.
ANEURYSMS OF AORTA • Aneurysm: circumscribed dilation of aorta, arteries • True aneurysm: bounded by all three vessel wall layers (intima, media, and adventitia); the layers can be individually attenuated • False aneurysm: extravascular hematoma that communicates with the intravascular space, part of the vessel wall is destructed
Abdominal aortic aneurysm • Usually in smoking men older than age 50 • Wall thinning through medial destruction secondary to atheromatous intimal plaques • Between the renal arteries and the aortic bifurcation • Can be saccular (saclike bulging on one side of the artery) or fusiform (symmetrical spindle shaped), up to 15 cm in diameter and 25 cm in length Complications • Mural thrombi impair blood flow to the renal, mesenteric, vertebral, or iliac arteries ischemia of the kidneys, bowels, spinal cord, or legs • Embolism acute obstruction, usually in the leg(s) culminating in gangrene • Expansion compression of an ureter or erosion of vertebrae • Rupture (above 5 cm) often fatal retroperitoneal or peritoneal bleeding Therapy Surgical, either by open placement of tubular prosthetic grafts or with endoluminal insertion of stented grafts
Thoracic aortic aneurysm Etiologic factors include • hypertension • + atherosclerosis • + poor intrinsic quality of the vessel matrix associated with elastic tissue loss Consequences • Aortic root dilation: aortic valve insufficiency • Rupture: hemothorax, and death • Compression of - esophagus: dysphagia - airways: dyspnea - recurrent laryngeal nerves: persistent cough
DISSECTION OF AORTA A dissection occurs when blood enters the aortic wall and separates the various layers The most common catastrophe of the aorta Pathogenesis • Insidious degeneration of the tunica media • Mainly in men aged 40 to 60 who are often hypertensive • Younger individuals with connective tissue disorder that give rise to abnormal aortic extracellular matrix (e.g., Marfan’s sy: mutation in the fibrillin-1 gene progressive loss of elastic tissue matrix) LM of media degeneration
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15. Vascular pathology I.
Fragmentation and loss of elastic fibers, formation of cleft-like spaces filled with ECM material Consequences • Spontaneously developing long tears in the intima forceful separation of the intima from the media by the blood, extending toward the heart or the descending aorta • Most frequent site of tears: the first 10 cm of the aortic arch, measured from the aortic valve • Rupture of the adventitia: hemopericardium and cardiac tamponade or hemothorax Clinical features • Sudden onset of excruciating pain, usually beginning in the anterior chest, radiating to the back, and moving downward as the dissection progresses • Lethal if surgical treatment is not available
REGULATION OF BLOOD PRESSURE (BP; for details see pathophysiology) • BP is determined by the cardiac output and the vascular resistance • Cardiac output is determined by heart rate and stroke volume. The determinant of stroke volume is the filling pressure which is regulated through renal sodium excretion or resorption. • Vascular resistance is determined by the luminal diameter of small arteries and arterioles (resistance vessels). Resistance vessels induce sharp reduction in pressure and velocity and a change from pulsatile flow to low pressure steady flow: the capillaries are defended from hyperperfusion injury • The actual luminal diameter of resistance vessels depends on the competition between vasoconstrictors (angiotensin II [ATII], chatecholamines, endothelin, thromboxane, α-adrenergic neural factors) and vasodilators (nitric oxide, prostacyclins, kinins, atrial natriuretic peptide, β-adrenergic neural factors) • A decrease in blood pressure or plasma volume stimulates JGAs to release renin • Angiotensin II causes vasoconstriction of resistance vessels (blood pressure ), and stimulates the secretion of aldosterone • Aldosterone in the presence of ADH the sodium reabsorption (+ water) in the distal tubules: the volume of plasma expands
BENIGN ESSENTIAL HYPERTENSION Optimum BP value in adults: 120/80 mm Hg; elevated BP (above 140/90 mm Hg) lasting for years: hypertension 90-95% of hypertension is idiopathic: essential hypertension Features • Very common • Starts insidiously (in the third decade?) and leads to death 20-25 years later (the silent killer) • Diastolic blood pressure remains below 115 mm Hg, and is stable for decades (benign hypertension) • The prevalence increases with age • Blacks are affected twice as often as whites Pathogenesis 3 key issues: 1. Genetic defects in renal sodium excretion salt and water retention, increased cadiac output 2. Environmental factors-induced vasoconstriction increase in peripheral resistance 3. Structural damage to resistance vessels labile hypertension becomes fixed Excitatory environmental effects • ”Stress situations” in daily life (job, marriage, traffic, etc.), competitive personality continuous release of vasoconstrictor agents • Salt-rich diet! Salt is extensively used for preservation of food and to make the food tasty. • Lack of physical exercise • Disordered sleep as in sleep apnea
Structural damage to resistance vessels Vasospasm + endothelial injury lasting for several years induce structural damage (remodeling) to small arteries and arterioles relaxation during sleep does not occur hypertension becomes fixed
Consequences of hypertension, called target organ damage In kidneys, heart, brain, arteries, and retina
Hypertensive kidney disease Gross • Mild, symmetric shrinkage of kidneys (nephrosclerosis), weight: 120-120 g • The surface is granular LM • Changes in afferent arterioles termed hyaline arteriolosclerosis: thickening of the walls and narrowing of the lumina due to the deposition of hyaline (proteinaceous, eosinophilic material) • Glomerulosclerosis focally Clinical features • In majority of patients: microalbuminuria (daily albumin excretion: 30-300 mg) + mild increase in serum creatinine and BUN levels • In minority of patients: significant glomerular damage marked proteinuria and progressive renal insufficiency • Microalbuminuria: strong predictor of cardiovascular and/or cerebrovascular events!!
Hypertensive heart disease • Pressure overload-induced left ventricular hypertrophy chronic left-sided heart failure
Damage to arterioles in the CNS • Microaneurysms develop; predominantly in the basal ganglia 3
15. Vascular pathology I.
Accelaration of atherosclerosis • Hypertension induces chronic endothelial dysfunction major risk factor of atherosclerosis
Hypertensive retinopathy • Ophtalmoscopic examination reveals the thickening of retinal small arteries; microhemorrhages can be present (fundus hypertonicus)
Hypertensive emergencies (sudden increase in blood pressure values associated with acute target organ dysfunction) Life-threatining conditions • Intracerebral hemorrhage because of the ruptures of arteriolar microaneurysms; survivors become paralysed • Acute pulmonary edema because the left ventricle is unable to compensate for an abrupt rise in systemic vascular resistance • Dissection of aorta cardiac tamponade or hemothorax • Rupture of coincidental congenital berry aneurysm of circle of Willis subarachnoid hemorrhage
Most frequent causes of death Direct effect of hypertension • Left-sided heart failure • Intracerebral hemorrhage Indirect effect of hypertension via aggravation of atherosclerosis coronary occlusion: sudden cardiac death; myocardial infarction
MALIGNANT ESSENTIAL HYPERTENSION Pathogenesis: ? • Hyperreninaemia, and extreme BP values • In normotensive patients between 30 and 40 y; mainly males • May superimpose on pre-existing benign hypertension (accelerated hypertension) Gross changes • Early changes: enlarged kidneys, pinpoint petechial cortical hemorrhages + tiny infarcts • Later, infarcts are replaced by vascular scars LM • Hyperplastic arteriolosclerosis: hyperplastic SMCs + deposition of collagen concentric thickening of afferent arterioles severe narrowing of the lumina (onionskin lesion) • + Necrosis of afferent arterioles • + Necrosis of glomerular tufts crescents Clinical features • Infrequent; rapidly increasing blood pressure (systolic BP over 220 mm Hg, diastolic BP over 120-130 mm Hg) • Renal failure • Left-sided HF • Hypertensive encephalopathy high risk of cerebral hemorrhage • Retinal hemorrhages If untreated, death within 1 year due to uremia or hypertensive hemorrhage in the brain or left-sided heart failure
SECONDARY HYPERTENSION (the cause is known) • Chronic renal diseases (renal hypertension) • Vascular diseases: renal artery stenosis, coarctation of aorta, polyarteritis nodosa • Endocrine disorders: pheochromocytoma, Cushing’s disease, hyperthyroidism, etc. • Neurogenic cause: increased intracranial pressure
RENAL ARTERY STENOSIS (RAS) • Unilateral • Narrowing of the renal artery by atheroma at the origin (70%) or fibromuscular thickening of the media (30%) • Ischemic atrophy of the kidney; however, JGA-s secrete renin leading to renovascular hypertension • Serum creatinin, BUN: normal (the contralateral kidney works!!) • Blood pressure is normalized after nephrectomy
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