Path: Cardiovascular Disease I: Atherosclerosis and Ischemic Heart Disease Set

What is an embolism?

- the lodging of an embolus, which may be a blood clot, fat globule, gas bubble or foreign material in the bloodstream - can cause a blockage in a blood vessel (vascular occlusion)

Atherosclerosis

-intimal lesions called atheromas (or atheromatous or atherosclerotic plaques). -Plaques weaken the underlying media, leading to aneurysm formation

Mönckeberg medial sclerosis

-presence of calcific deposits in muscular arteries usually >50 -lesions do not encroach on the vessel lumen and usually NCS

Arteriolosclerosis

-small arteries and arterioles -may cause downstream ischemic injury -2 forms of small blood vessel diseases (HTN related) 1. hyaline arteriolosclerosis 2. hyperplastic arteriolosclerosis

What are the 3 constituents of atheromas?

1) cellular - smooth muscle cells, macrophages, inflammatory cells 2) intracellular matrix - collagen, elastin, proteoglycan 3) lipid - mainly cholesterol esters

Response to injury in atherogenesis

1. Normal: Chronic Endothelial "injury" 2. Endothelial injury with monocyte and plt adhesion 3. monocyte and SmM cell migration into intima, with macrophage activation 4. Macrophage + smM cell uptake of modified lipids and further activation 5. Intimal SmM cell prolif with ECM, forming well developed plaque

The metabolic syndrome corresponds to the presence of coexisting risk factors for cardiovascular disease in one individual that include:

1. central obesity (abdominal/mesenteric/retroperitoneal adipose tissue) 2. ↓HDL and ↑triglycerides 3. ↑BP 4. insulin resistance or glucose intolerance 5. prothrombotic state (↑fibrinogen or plasminogen activator inhibitor) 6. proinflammatory state (↑ CRP C reactive protein)

What are the causes of fibrosis in atherosclerosis?

1. endothelial injury/dysfunction 2. mononuclear cell recruitment 3. oxidized LDL 4. myocyte recruitment

Are the following major-modifiable, major non-modifiable, or minor risk factors for the development of atherosclerosis? 1. high carb intake 2. diabetes mellitus 3. male gender 4. family history 5. homocysteinemia 6. hypertension 7. hyperlipidemia 8. increasing age

1. high carb intake: minor 2. diabetes mellitus: major modifiable 3. male gender: major non-modifiable 4. family history: major non-modifiable 5. homocysteinemia: minor 6. hypertension: major modifiable 7. hyperlipidemia: major modifiable 8. increasing age: major non-modifiable

What are the causes oxidized LDL in atherosclerosis?

1. hyperlipidemia 2. endothelial injury/dysfunction 3. mononuclear cell recruitment 4. lipid accumulation

What are the 3 major clinical consequences of the metabolic syndrome?

1. progressive arterial stenosis 2. thrombosis/embolism (sudden arterial occlusion) 3. weakening of arterial media → aneurysm formation

Acute plaque change to rupture in unstable/crescendo angina is more likely in atheromas with large cores that constitute __% of the atheroma volume, contain many macrophages, and a thin fibrous cap with little smooth muscle

40%

How many people in the US are diagnosed with the metabolic syndrome in the US?

47 million - epidemic status

Fixed Lesions: *Significant* lesion

>50% ↓ diameter 75% cross-sectional area nutritional demand is met @ rest Sx devel w exertion

Fixed Lesions: *Critical* Lesion

>75% ↓ diameter 90% cross-sectional area Chronic IHD

What is the most common atherosclerotic aortic aneurysm?

Abdominal aorta most common and the majority are infrarenal (below the kidney)

What is Contraction Band Necrosis?

Accelerated necrosis of irreversibly injured myocytes i. More numerous in infarcts after reperfusion and appear after as little as 2 minutes of reperfusion ii. Occurs at margins of infarcts between dead and viable zones iii. Hypercontraction secondary to massive influx of calcium from membrane damage

__ is a symptom complex characterized by recurrent attacks of crushing substernal chest pain, which often radiates to the left arm and jaws.

Angina Pectoris

IHD Syndromes

Angina pectoris MI Sudden cardiac death Chronic IHD

Arteriosclerosis

Arterial or vascular sclerosis; hardening of the arteries

What important role does smooth muscle cell migration from the media to the intima and their proliferation in the intima play in atherogenesis?

Collagen, elastin and proteoglycans are elaborated by smooth muscle cells resulting in the formation of a *fibrous cap* and progression of the lesion. Neovascularization (new blood vessel formation) occurs at the periphery of the plaque. Over time the atheroma may become completely replaced by collagen deposition to form a fibrous plaque.

Athero-

Combining form relating to the deposit of gruel-like, soft, pasty materials

__ is an acute coronary syndrome due to right ventricular failure (with hypertrophy and dilatation) usually secondary to pulmonary hypertension

Cor Pulmonale

Ischemia and IHD

Deficiency of blood flow in a part, due to stenosis/obstruction of a vessel - supply>>demand

Atherosclerosis Definition

Definition: Progressive accumulation of lipids, smooth muscle cells, macrophages and connective tissue, within the intima (atherosclerotic plaque) of large and medium size arteries that results in progressive luminal narrowing with impaired organ perfusion.

In the absence of EKG changes, what clinical observation might be helpful in diagnosing acute coronary syndrome (ACS)?

Elevated C reactive protein (CRP)

T or F: Hypertensive Heart Disease is due to right ventricular failure (with hypertrophy and dilatation) usually secondary to pulmonary hypertension.

FALSE: *Cor Pulmonale* is due to right ventricular failure (with hypertrophy and dilatation) usually secondary to pulmonary hypertension.

T or F: Transmural MI are related to related to global reduction in coronary blood flow and are not limited to just the coronary branch zone. As a result EKGs show no Q wave.

FALSE: *Subendocardial MI* are related to related to global reduction in coronary blood flow and are not limited to just the coronary branch zone. As a result EKGs show no Q wave.

T or F: All fatty streaks become atheromatous plaque.

FALSE: Not all fatty streaks become atheromatous plaque. However, fatty streaks are the probable precursor of atheromatous plaque.

T or F: The fatty streak (accumulation of foam cells in the media) does not disturb blood flow.

FALSE: The fatty streak (accumulation of foam cells in the *intima*) does not disturb blood flow.

*Fibrofatty Atheroma*: SmM prolif Collagen + ECM deposition Accumulation of extracellular lipid

FGF TGF-alpha

T or F: As atheromas enlarge, vascular ingrowth occurs. Lesions are typically concentric and progressively impinge on the vascular lumen.

False: As atheromas enlarge, vascular ingrowth occurs. Lesions are typically eccentric and progressively impinge on the vascular lumen.

__ is a state in which the heart is unable to maintain an output sufficient for metabolic requirements.

Heart Failure (CHF)

B type natiruretic peptide is a useful serum marker for acute coronary syndrome?

Heart failure

__ is the pathological entity of arteriosclerosis characterized by amorphous eosinophilic thickening of the wall of small arteries (arterioles). Found in old age as well as in hypertension and diabetes mellitus. Thought to be due to leakage of plasma proteins into the blood vessel wall. Results in luminal compromise because of the small size of the involved blood vessels.

Hyaline arteriolosclerosis

__ is the pathological entity of arteriosclerosis characterized by hypertrophy/hyperplasia of medial smooth muscle in small arteries producing a characteristic "onion skin" appearance. Typically seen in very severe (malignant) hypertension and may be associated with fibrinoid necrosis in the vessel wall

Hyperplastic arteriolosclerosis

Endothelial dysfunction in atherosclerosis is thought to increase vascular wall permeability and changes in gene expression that increases __ expression which enhance leukocyte adherence

ICAM-1 and VCAM-1 expression

Which cytokine is responsible for smooth muscle migration into intima during the endothelial dysfunction of atherosclerosis?

MCP-1 (Monocyte Chemoattractant Protein-1)

Is the presence of coexisting risk factors for cardiovascular disease in one individual that include a prothrombotic state (increased fibrinogen or plasminogen activator inhibitor) and proinflammatory state (elevated C reactive protein) is sufficient to diagnose a patient with the metabolic syndrome?

NO: 3 risk factors are required for diagnosis so the patient would need at least one more additional coexisting risk factor such as insulin resistance, increased BP, low serum HDL, central obesity or increased TAGs

Unstable (crescendo) Angina

Pain: -w ↑freq, or progressively less exertion, or @ rest ACUTE PLAQUE CHANGE: erosion rupture -lumenal blood exposed to high thrombogenic core -occulusive thrombosis much more likely than w erosion -more likely in atheromas w large core (>40% vol) w many macrophages and thin fibrous cap (little smM) hemorrhage thrombosis

AII and Mechanical Stress in the Vessel Wall in Pt w HTN --> _____?

Reactive Oxygen Species

What is a downfall to the use of thrombolysis in acute MI?

Reperfusion injury → stunned but viable myocardium is unable to contract (maybe stunned for hours or days)

__ or __ can be used for thrombolysis for acute MI but promotes hemorrhage in the infarct.

Streptokinase or tissue-type plasminogen activator (tPA).

The __ region is most prone to ischemic damage during MI, as it is furthest distant from the coronary arteries (watershed).

Subendocardial region

Which acute coronary syndrome is most associated with cocaine use, cardiomyopathy, and myocarditis?

Sudden cardiac death

T or F: "Backward failure" heart failure is characterized by increased end diastolic pressure and "Forward failure" is characterized by systolic dysfunction.

TRUE

Transmural vs. Subendocardial MI

Transmural - entire wall - plaque rupture and thrombosis - Q waves typical - begin in SE region Subendocardial - inner 1/3 to 1/2 of wall - related to global reduction in coronary blood flow • not limited to a coronary branch zone - non-Q wave

__ from cardiac causes (lethal arrhythmia) within 1 hour of the onset of symptoms and is often the first manifestation of underlying coronary atherosclerosis (often severe lesions with plaque disruption or occlusive thrombus). Less commonly the cause can be non-atherosclerotic (e.g. primary cardiomyopathy).

Unexpected death from cardiac causes

Which variant of angina pectoris is characterized by pain which occurs more frequently, with progressively less exertion or at rest and is associated with acute plaque change (atheroma), and may indicate impending myocardial infarction and is often associated with microscopic foci of infarction?

Unstable (crescendo) angina

Acute Coronary Syndrome (ACS)

Unstable angina, MI, SCD -maybe not readily distinguishable clinically -may benefit from therapeutic intervention -↑ CRP helpful in absence of EKG findings

Which vessel(s) does atherosclerosis preferentially involve?

abdominal aorta coronary artery popliteal artery *generally the walls of large and medium sized arteries

Sclerosis-

an induration or hardening, especially from inflammation and in diseases of the interstitial substance

Sudden Cardiac Death result in death within __ of symptom onset. __ % of cases involve have severe IHD.

i. 1 hour ii. 80-90%

Only __ % of patients with subendocardial infarcts appear to have thrombosis in a major coronary artery. Instead there is usually __ of all coronary arteries without evidence of plaque rupture or thrombosis.

i. 20 - 30% ii. diffuse stenosis

__ is a clinical symptom complex which includes unstable angina and acute MI which can benefit from aggressive clinical management (angioplasty and/or thrombolysis) and Sudden Cardiac Death (SCD).

i. Acute Coronary Syndrome (ACS)

Unstable angina form of __, that leads to the formation of microthrombi and mircoemboli that can be caused by sudden rupture of plaques in a __ or a __ of stable angina. The ruptured plaque can go on to form an occlusive thrombosis leading to __.

i. Acute coronary syndrome ii. complicated atheroma or significant fixed lesion of stable angina iii. acute MI

What is a true aneurysm?

i. True aneurysm is an arterial dilatation with all three normal components in its wall ii. Saccular, cylindric, or fusiform in shape iii. Critical diameter for rupture (c.a. 6 cm.)

Approximately 90% of transmural infarcts are caused by __ usually associated with an ulcerated atheromatous plaque. This results in an area of infarction in the territory supplied by that artery

i. an occlusive intracoronary thrombus

These lesions of coronary atherosclerosis contribute to the four clinical syndromes of IHD. What are these 4 clinical syndromes?

i. angina pectoris ii. Myocardial infarction iii. Chronic ischemic heart disease and congestive heart failure. iv. Sudden cardiac death

What comprises the necrotic core of an atheroma?

intracellular (foam cells) and extracellular lipid deposits

Arteriolosclerosis

is the pathological entity of arteriosclerosis characterized by thickening of the walls of small arteries and arterioles which results in a significant reduction in luminal diameter of the microvasculature. While this process is age dependent, it is markedly accelerated in people with hypertension and/or diabetes mellitus

The decreased velocity of shortening of myocytes in observed in heart failure correlates with decreased activity of __.

myofibrillar and myosin ATPase

Atheromatous plaques

raised lesions composed of soft grumous lipid cores (mainly cholesterol and cholesterol esters, with necrotic debris) covered by fibrous caps

__ is a form of heart failure characterized increased end diastolic pressure (EDP) decreased myocardial compliance (diastolic dysfunction, congestion of veins).

"Backward failure"

__ is a form of heart failure characterized by decreased output due to decreased myocardial contractility and output (systolic dysfunction).

"Forward Failure"

The __ hypothesis is the theory that fits best with our current knowledge of atherosclerosis

"Response to Injury": endothelial injury, lipid insudation, macrophage infiltration; myocyte migration

What are the MAJOR modifiable risk factors for the development of atherosclerosis?

1. hyperlipidemia 2. hypertension 3. cigarette smoking 4. diabetes mellitus

What are the causes endothelial injury and dysfunction in atherosclerosis?

1. hyperlipidemia 2. mononuclear cell recruitment 3. lipid accumulation 4. oxidized LDL 5. myocyte recruitment

What are the MAJOR NON-modifiable risk factors for the development of atherosclerosis?

1. increasing age 2. male gender 3. family history 4. genetic abnormalities in LDL-R, ApoB, ApoE

What are the MINOR risk factors for the development of atherosclerosis?

1. obesity 2. Stress (type A personality) 3. factors affecting thrombosis 4. high carb intake 5. homocyteinemia

Which variant of angina pectoris is precipitated by exertion and relieved by rest or nitroglycerin, and due to a fixed coronary obstruction?

Stable (typical) angina

Arteriosclerosis

"hardening of the arteries" - wall thickening and loss of elasticity 1. Arteriolosclerosis 2. Moncheberg medial sclerosis 3. Atherosclerosis

What characterizes a fibrofatty atheroma?

1. Smooth muscle proliferation 2. collagen and ECM deposition 3. accumulation of extracellular lipid

What are the two forms of arteriolosclerosis and how do they differ?

*Hyaline arteriolosclerosis*: Amorphous eosinophilic thickening of the wall of small arteries (arterioles). Found in old age as well as in hypertension and diabetes mellitus. Thought to be due to leakage of plasma proteins into the blood vessel wall. Results in luminal compromise because of the small size of the involved blood vessels. *Hyperplastic arteriolosclerosis*: Hypertrophy/hyperplasia of medial smooth muscle in small arteries producing a characteristic "onion skin" appearance. Typically seen in very severe (malignant) hypertension and may be associated with fibrinoid necrosis in the vessel wall.

Intimal Thickening in response to Injury

-endothelial loss/dysfunction 1. recruitment of smM cells or precursors to intima 2. smM cell mitosis 3. elaboration of EXM New smM cells lack capacity to contract like medial smM cells, but have capacity to divide and have greater synthetic capacity

Oxidation of LDL by macrophages and endothelial cells or by free radicals generated by the auto-oxidation of __ creates a compound which is preferentially taken up by the scavenger receptor on macrophages resulting the in the formation of __. Oxidized LDL is also toxic to endothelial cells, promotes __ release, and is a __ for macrophages and monocytes

1. homocysteine 2. foam cells 3. pro-inflammatory cytokine 4. chemoattractant

NO acts as a smooth muscle relaxant causing __ especially when produced by endothelial cells. NO is synthesized from __ and oxygen by __ using __ as a cofactor. __ is found in macrophages and endothelial cells, the 'i' indicating that it is inducible by cytokines__ , __, and __ and products of bacterial breakdown.

1. vasodilation 2. L-arginine 3. nitric oxidase synthase (NOS) 4. NADPH 5. Inducible (iNOS) 6. IL-1, TNF, IFN-γ

What are the time since onset of MI for the following morphological changes? 1. wavy fiber change 2. coagulation necrosis 3. nuclear pyknosis 4. karyolysis 5. neutrophilic infiltration 6. macrophage infiltration

1. wavy fiber change: 1-3 hrs 2. coagulation necrosis: 4-12 hrs 3. nuclear pyknosis: 5 hrs 4. karyolysis: 24-48 hrs 5. neutrophilic infiltration: 6-8 hrs (48 hrs. peak) 6. macrophage infiltration: 4 days

__ is the pathological entity of arteriosclerosis characterized by progressive accumulation of lipids, smooth muscle cells, macrophages and connective tissue, within the intima of large and medium size arteries that results in progressive luminal narrowing with impaired organ perfusion.

Atherosclerosis

The dominant lipids in atheromatous plaques are?

Cholesterol and cholesterol esters

__ is an acute coronary syndrome usually that occurs in elderly patients with a previous history of myocardial infarction who present with progressive congestive heart failure (ischemic cardiomyopathy). There is typically left ventricular hypertrophy with dilatation and focal white scars corresponding to prior acute infarcts are usually present with severe fixed coronary obstructions. Histologically there is myocardial hypertrophy and focal interstitial fibrosis.

Chronic Ischemic Heart Disease

"Ischemic cardiomyopathy" is another name for which acute coronary syndrome?

Chronic Ischemic Heart Disease (Chronic IHD)

The following characteristics are descriptive of which acute coronary syndrome? i. insidious onset of heart failure over time due to progressive myocardial damage ii. cardiac hypertrophy and marked dilatation usually all 4 chambers iii. myocyte hypertrophy iv. subendocardial vacuolization (myocytolysis) v. replacement fibrosis from previous infarction

Chronic Ischemic Heart Disease (Chronic IHD)

What characterizes a complicated atheroma?

Complicated atheromas have the greatest clinical significance characterized by any: Normal atheroma plus the presence of any of the following i. calcification: coagulative necrosis associated with ischemia ii. evidence of rupture or erosion: exposes high thrombogenic plaque constituents or Subendothelial membrane iii. internal hemorrhage: iv. associated thrombosis v. medial atrophy/replacement

Which acute coronary syndrom is most associated with chronic lung disease (COPD), primary pulmonary hypertension restricted chest wall movement, and tricuspid regurgitation secondary to AV ring dilatation?

Cor pulmonale - right sided failure secondary to pulmonary hypertension

T or F: Fatty streaks are established risk factors for atherosclerosis and always represent a precursor of atheromas

FALSE: Although their extent correlates with established risk factors for atherosclerosis, they also occur in vessels at low risk for atherosclerosis and are not unequivocally proven to be a precursor of atheromas

T or F: Atherosclerosis has a high prevalence in North America, Europe, and Asia but a low prevalence in Africa, Central America and South America.

FALSE: Atherosclerosis has high prevalence in: North America Europe low prevalence in: ASIA, Africa, Central and South America.

T or F: Obesity, stress and cigarette are major modifiable risk factors for the development of atherosclerosis.

FALSE: Cigarette is major modifiable risk factors for the development of atherosclerosis. Obesity and stress are MINOR risk factors for the development of atherosclerosis.

T or F: Fatty streak present in the aorta of an infant younger than 1 years old is very concerning

FALSE: Fatty streaks have been observed in infant aortas and are universally present in those greater than 10 years old

T or F: Lipid accumulation and hyperlipidemia are causes of mononuclear cell recruitment in atherosclerosis.

FALSE: Lipid accumulation and hyperlipidemia are *NOT* causes of mononuclear cell recruitment in atherosclerosis. Endothelial injury/dysfunction, oxidized LDL, and myocyte recruitment are THE causes of mononuclear cell recruitment in atherosclerosis.

T or F: Myocardial necrosis after coronary occlusion during transmural MI begins with epicardium and progresses to the endocardium. The epicardium is the most at risk for necrosis.

FALSE: Myocardial necrosis after coronary occlusion during transmural MI begins with *endocardium and progresses to the epicardium*. The *endocardium* is the most at risk for necrosis during and MI.

What sort of necrosis is most associated with hyperplastic arteriolosclerosis?

Fibrinoid necrosis

Pathogenesis of IHD

Fixed coronary obstruction Acute plaque changes Coronary thrombus Vasoconstriction

According reaction to injury model what are the two most important causes of endothelial dysfunction?

Hemodynamic disturbances Hypercholesterolemia

__ is an acute coronary syndrome defined as left ventricular hypertrophy in the absence of cardiovascular causes other than hypertension (although this process almost always coexists with chronic IHD). The left ventricle is thickened and the overall weight of the heart is increased, exceeding 375 gr. in men and 350 gr. in women. Microscopically the myocardial cells appear hypertrophic with enlarged nuclei (polyploid)

Hypertensive Heart Disease

Endothelial Dysfunction in Atherosclerosis: Increased luminal ICAM & VCAM expression --> ____?

Increased leukocyte adhesion and migration

According reaction to injury model, what is thought to initially propagate the endothelial cell injury/dysfunction?

Injury is thought to occur from: i. mechanical shear stress (turbulent flow at arterial bifurcations) and AII (usually Pts with hypertension) ii. hyperlipidemia iii. free radicals (via oxidation of LDL) iv. hyperhomocysteinemia

Which variant of angina pectoris is uncommon, but occurs at rest and is due to coronary vasospasm either in a normal coronary artery or close to an atherosclerotic plaque, and responds to vasodilator therapy?

Prinzmetal (variant) angina

Evolution of an infarct: Necrosis → ? → ? → loss of tissue organization → ?

Necrosis → acute inflammation → chronic inflammation → loss of tissue organization → fibrosis

Pathogenesis of *Coronary Thrombosis*

PLAQUE RUPTURE -microthrombi w microemboli (unstable angina) -occlusive thrombosis (MI) VASOCONSTRICTION -may exacerbate ischemia resulting from thrombosis (release of pro-vasoconstrict factors from damaged endothelium)

Prinzmetal/Variant Angina

Pain @ rest, usually unpredictable Caused by Coronary A spasm -on or near plaques -can also occur in normal vessels -responds well to vasodilators (nitroglycerin + Ca channel blockers)

In addition to occlusive coronary thrombi, what additional mechanism resulting from coronary plaque rupture exacerbates myocardial infarction?

Plaque rupture > release pro-vasoconstrictive factors from damaged endothelium > vasoconstriction exacerbate ischemia

What is an atheroma?

Raised lesion composed of a fibrous cap overlying an accumulation of lipids, smooth muscle cells, macrophages and connective tissue, within the intima (atherosclerotic plaque); it is the key pathophysiologic process of atherosclerosis

At which % reduction of the luminal cross-sectional area and % decreased in luminal diameter does Coronary atherosclerosis typically becomes? What % reductions qualify for critical lesion and chronic ischemic heart disease is diagnosed?

Symptomatic: 75% reduction in luminal cross-sectional area; 50% decreased diameter Chronic ischemic heart disease: 90% reduction in luminal cross-sectional area; 75% reduction in diameter

Which of the following cell types are NOT recruited into the developing atheromatous plaque during cellular infiltration phase of atherosclerosis pathogenesis? i. monocyte/ macrophages ii. B-lymphocytes iii. T-lymphocytes iv. Smooth muscle cells

TRICK QUESTION: all of these cell types are recruited

T or F: Atherosclerosis accounts for more deaths and serious morbidity in the Western world than any other disease. The major complications of atherosclerosis, including ischemic heart disease, myocardial infarction, stroke, and gangrene of the extremities, account for more than half of the annual mortality in the US.

TRUE

T or F: Inflammatory mediators including prostaglandins (cyclooxygenase pathway) and leukotrienes (lipoxygenase pathway) are also implicated in the pathophysiology of atherosclerosis

TRUE

T or F: The metabolic syndrome is a significant risk factor for developing atherosclerosis and diabetes mellitus.

TRUE

Which form or MI are the usually the result of plaque rupture and thrombosis, typically exhibit Q waves on EKG, and begin in the subendocardial region?

Transmural MI

T or F: Lowering serum cholesterol by diet or drug slows the rate of progression of atherosclerosis, causes regression of some plaques, ad reduces the risk of cardiovascular events.

True

Hyaline Arteriolosclerosis

associated w benign HTN -homogenous, pink hyaline thickening arteriolar walls, loss of underlying structural detail, luminal narrowing -lesions stem from plasma leakage across endothelial cells into vessel walls + incr ECM production (by smM cells) in response to chronic hemodynamic stress -elderly pt show same changes but hyaline arteriole more generalized + severe w HTN -same lesions also common in diabetic microangiopathy (etiology: hyperglycemia-assoc endothelial cell dysfunction

Ischemic heart disease (IHD)

broad term encompassing several closely related syndromes caused by myocardial ischemia—an imbalance between cardiac blood supply (perfusion) and myocardial oxygen and nutritional requirements

The reaction to injury model proposes that atherosclerosis is a __response to subtle vascular wall injuries occurring over time.

chronic inflammatory

Embolus vs. thrombus (blood clot)

embolism: vascular occlusion may affect a part of the body distanced from the actual site of the embolism. This is in contrast to a thrombus, which causes a blockage at the site of origin.

Fatty streaks are the non-raised accumulation of __ in the intima and are present universally in individuals __ years olds and do not disturb blood flow

foam cells and extracellular lipid > 10 years old

The following characteristics are descriptive of which acute coronary syndrome? i. β-adrenergic receptor density decreased ii. Second messenger c-AMP decreased iii. Plasma endothelin-1 increased (vasoconstrictor) iv. Apoptosis v. increased B type natiruretic peptide (BNP) synthesis

heart failure

On gross examination, an acute myocardial infarct __ after onset is often visible as dark mottling. At __ it can be recognized by its increasingly pale center. At __ , the infarct is more sharply outlined with a central pale, yellow region bordered by a hyperemic zone. By __ the infarct is maximally yellow and necrotic with a depressed red margin. At __ the margin becomes red-gray and between __ the infarcted region progresses to a gray-white scar with scarring complete after 8 weeks

i. 4 hours ii. 1-3 days iii. 3-7 days iv. 7-10 days v. 10-14 days vi. 2 and 8 weeks.

Within the first 10 minutes of MI onset a __% reduction of ATP occur. Cellular edema and arrhythmias develop secondary to __ due to insufficient energy/ATP production to power __. The ensuing energy failure leads to __ which activates degradative enzymes.

i. 50% ii. rise in intracellular Na+ and K+ iii. Na+/K+ ATPase and ion pumps iv. high intracellular [Ca2+]

What is responsible for the drastic pH decrease within 1-2 minutes of MI onset? What effect does this pH drop have on the function of the myocytes?

i. Anaerobic glycolysis → lactic acid production → pH falls in 1-2 minutes ii. pH drop → decreased compliance and contractility

The acute coronary syndrome Hypertensive Heart Disease is characterized by...?

i. Concentric left ventricular hypertrophy (LVH) ii. resulting from hypertension only iii. myocyte hypertrophy with nuclear enlargement (polyploidy)

Which aspects of the pathogenesis of atherosclerosis favor the the accumulation of lipoproteins LDL and VLDL the arterial intima?

i. Hyperlipidemia ii. increased endothelial permeability

__ is a constellation of disorders in which myocardial ischemia is the common pathophysiologic mechanism. In the vast majority of cases, this ischemia results from __ by atherosclerosis but its severity and consequences are affected by numerous factors which affect myocardial oxygen demand (e.g. concurrent valvular disease, chronic hypertension), blood pressure, blood oxygenation, microvascular disease (arteriolosclerosis), etc.

i. Ischemic Heart Disease ii. obstruction of coronary artery blood flow

What 5 factors are important in determining the extent of MI?

i. Location, severity, and rate of occlusion ii. Size of vascular bed - e.g. left main CA vs smaller branches iii. Duration of ischemic episode - (vasospasm) iv. Metabolic demands - Heart rate, rhythm, BP v. Collateral vessels

According to the response to injury hypothesis, what are the 4 major events, which involve multiple positive feedback loops, the result in the formation of an atherosclerotic plaque?

i. endothelial cell injury/dysfunction > leukocyte activation ii. lipid insudation/hyperlipidemia > accumulation of oxidized LDL > foam cells iii. cellular infiltration > as monocyte/macrophages, T and B-lymphocytes, smooth muscle iv. smooth muscle proliferation and collagen deposition > fibrous cap > fibrous lesion > fibrous plaque

What are the causes mononuclear cell recruitment in atherosclerosis?

i. endothelial injury/dysfunction ii. oxidized LDL iii. myocyte recruitment

What are the causes lipid accumulation in atherosclerosis?

i. hyperlipidemia ii. endothelial injury/dysfunction iii. mononuclear cell recruitment

*Myocardial Infarction* is a discrete focus of __ in the heart that occurs when myocardial ischemia is prolonged for more than __ minutes.

i. ischemic necrosis (coagulation necrosis) ii. 20 or 30 minutes

What are the causes of myocyte recruitment in atherosclerosis?

i. mononuclear cell recruitment ii. oxidized LDL

Coronary atherosclerosis typically becomes symptomatic when the luminal cross-sectional area is reduced by __% (i.e. a __ % decreased in luminal diameter). Lesions typically occur in the __ portions of the LAD and LC arteries and the entire length of the __. The plaques can progressively occlude (severe fixed coronary obstruction) or an acute plaque change (hemorrhage, rupture, and erosion) can occur with resulting thrombosis and/or embolization.

i. more than 75% ii. 50% decreased in luminal diameter iii. proximal portion of the LAD and LC iv. RCA

What are the major complications associated with atherosclerotic aortic aneurysm?

i. rupture (risk proportional to diameter) ii. blockage of tributary blood vessels

What is the key pathophysiologic process of Atherosclerosis?

intimal thickening and lipid accumulation resulting in an atherosclerotic plaque, aka "atheroma"

What is the microscopic appearance of contraction band necrosis?

irreversibly injured myocyte sarcomeres hypercontract with overlapping of Z lines producing eosinophilic bands visible by light microscopy

Blockage of venous drainage rarely results infarction due to collateral vessels. However which organs are exceptions where blockage of venous drainage can result in infarction?

ovary and testis

Which molecules are involved in Macrophage accumulation & activation with foam cell formation SmM migration into intima?

oxidized LDL IL-1 TNF MCP-1

Mönckeberg Medial Sclerosis

pathological entity of arteriosclerosis characterized by medial calcification of in muscular arteries (intermediate size) in older individuals which is usually not clinically significant (i.e. no luminal compromise)

Complicated Atheroma: plaque rupture and hemorrhage

plaque rupture and hemorrhage

Complicated Atheroma: plaque rupture and thrombosis

plaque rupture and thrombosis

Hyperplastic Arteriolosclerosis

usually more severe HTN -vessels have "onion skin": concentric, laminated, thickening + luminal narrowing -laminations are smM, thickened, reduplicated BM - in malignant HTN - changes accompanied by fibrinoid deposits & vessel wall necrosis (necrotizing arteriolitis)

MI

~1.5mil people/yr in US suffer MI ~1/3 die (half before they can get to a hospital) -major underlying cause: atherosclerosis -can occur @ any age, freq rises progressively w increasing age and risk factors ~10% of MIs occur <40yo 45% <65yo -men incr risk (but gap narrows w age)