DISEASES OF (“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 progressive 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)

Atheromatous plaque in the middle cerebral : raised white-yellow lesion in the intima, protruding into the lumen (formol-fixed brain) Aorta: the plaques contain a yellow, grumous debris (arrow) Structure of atheroma on LM • Intimal lesion • Central lipid core • Fibrous ”cap” subendothelially

Central lipid core composed of lipids, clefts, necrotic debris + calcium-salts, surrounded by foamy macrophages, T-lymphocytes, fibroblasts, small , and  collagens and  proteoglycans

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 Vulnerable plaque in the coronary artery Inflammatory infiltrates and capillaries around the lipid core. Lumen

Intima

Media 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”).

Pathogenesis Response to chronic endocardial injury hypothesis

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

Pathogenesis 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: GFs  • 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 • 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 Coronary occlusion due ulceration of the plaque leading to thrombosis Plaque complications

• Rupture, ulceration of the luminal surface

• 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 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

Cerebral infarct involving the internal capsule  contralateral hemiparesis 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 Abdominal aorta: mural thrombi

Celiac artery Superior Renal artery mesenteric artery Cholesterol microembolism in the arcuate artery of the kidney 4. Superior mesenteric artery

Thrombosis of a vulnerable plaque at the orifice: infarction of small bowels  death

Thrombosis of sup. mesenteric artery: bowel infarction

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

LDL-hypercholest- Smoking Physical erolemia inactivity

ATHEROSCLEROSIS Myocardial Cerebral Leg infarction infarction gangrene ATHEROSCLEROSIS

Obesity Diabetes Hypertension Note: Prophylacticallly administered platelet aggregation inhibitors reduce the incidence of myocardial and cerebal infarction. 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) - 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

Ruptured aneurysm of abdominal aorta leading to retroperitoneal bleeding and shock (the probe indicates the rupture)

Iliac arteries Therapy

Surgical, either by open placement of tubular prosthetic grafts or with endoluminal insertion of stented grafts

Etiologic factors include • hypertension • + atherosclerosis • + poor intrinsic quality of the vessel matrix associated with elastic tissue loss

Consequences

• Aortic root dilation: aortic valve insufficiency

• Compression of esophagus: dysphagia airways: dyspnea recurrent laryngeal nerves: persistent cough

• Rupture: hemothorax, and death

Saccular aneurysms in the thoracic aorta. Note mural thrombi 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: fragmentation and loss of elastic fibers, formation of cleft-like spaces filled with ECM material

Alcian blue Elastin 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 Dissection of aorta: intimal tear Dissection of aorta, hemopericardium 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

Resistance vessels

Aorta and arteries Capillaries Hyperperfusion injury Ø The actual luminal diameter of resistance vessels depends on the competition between vasoconstrictors and vasodilators

Constrictors Dilators • Angiotensin II • Nitric oxide (ATII) • Prostacyclins • Chatecholamines • Kinins • Endothelin • Atrial natriuretic • Thromboxane peptide • α-adrenergic • β-adrenergic neural factors neural factors

Plasma angiotensinogen

AT I Renin AT II Angiotensin-converting enzyme (ACE)

• 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

Genetic defects in Environmental renal sodium factors-induced excretion vasoconstriction

Salt and water retention  peripheral resistance  cardiac output

Labile hypertension Structural damage to Fixed hypertension resistance Target organ damage vessels 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. Salt, das Salz, sel originates from the latin sal. Salarium: Roman soldiers were paid with salt  salary

• 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 Hypertensive nephrosclerosis: mild, symmetric shrinkage (120- 120 g), the surface is granular Afferent artery: smooth muscle cells are replaced by hyaline material - relaxation is impossible 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

Accelaration of atherosclerosis • Hypertension induces chronic endothelial dysfunction  major risk factor of atherosclerosis Hypertensive retinopathy. Ophtalmoscopic examination reveals the thickeningVérzések of retinal small retinopathiaarteries; microhemorrhages hypertonica can be present- (fundus hypertonicus) ban

Courtesy of Prof. Kolozsvári Lajos Hypertensive emergencies - sudden increase in blood pressure values associated with acute target organ dysfunction

Life-threatening conditions

• Intracerebral hemorrhage due to the ruptures of microaneurysms; survivors become paralysed

• Acute pulmonary edema because the left ventricle is unable to compensate for an abrupt rise in systemic vascular resistance

Hypertensive emergencies

• Dissection of aorta  cardiac tamponade/hemothorax

• Rupture of coincidental berry aneurysm of circle of Willis  subarachnoid hemorrhage Microaneurysms undergo rupture in hypertensive crisis  massive hemorrhage of the basal ganglia 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

Case presentation

• A 64-year-old man was found dead in his garden. Autopsy was ordered to find the cause of death.

• PMH: 1 year earlier the family practitioner evaluated him because of dizziness, headache and epistaxis. His blood pressure value was 180/110 mm Hg, and microalbuminuria was observed in the urine.

• Since the prescribed antihypertensive drugs led to the cessation of his symptoms, the patient stopped the intake of these drugs. Destruction of the left putamen and internal capsule by fresh hematoma Slightly shrunken kidneys; finely granular surface Heart weight 550 g; enlargement of the left ventricle Conclusion of the autopsy

• The death was caused by ganglionic hemorrhage of the brain. • The patient suffered from essential hypertension, which • led to target organ damage involving the brain, the kidneys, and the heart.

Message: Inadequate control of BP in the hypertensive patient carries the risk for the development of fatal cerebral hemorrhage

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 Onionskin lesion in the afferent 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 (the cause is known)

• Chronic renal diseases (renal hypertension)

• Vascular diseases: renal artery stenosis, coarctation of aorta, polyarteritis nodosa

• Endocrine disorders: 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 creatinine, BUN: normal (the contralateral kidney works!!) • Blood pressure normalizes after nephrectomy Unilateral atrophy of the kidney in RAS RAS because of an atheromatous plaque treated with percutaneous transluminal angioplasty

Before dilation After dilation

Nephrectomy:Ø

Courtesy of Endre Nagy, SZTE Radiology