15. Vascular pathology I.

DISEASES OF

ARTERIOSCLEROSIS (“hardening of the arteries”): general term reflecting arterial wall thickening and loss of elasticity 3 patterns • : 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 in association with 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 (”” - Greek word for gruel) Structure of atheroma on LM • Intimal lesion • Central lipid core composed of lipids, clefts, necrotic debris + calcium-salts; surrounded by foamy macrophages, T-lymphocytes, fibroblasts, small , 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  • Stable plaques have minimal atheromatous cores and and thick fibrous caps  70% (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 - 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  in the lower extremities • Thinning of aortic wall   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 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 • 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 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

2

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 (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  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

4