Atherosclerosis

What are the Constitutional, Non-Modifiable Risk Factors for Atherosclerosis?

1. Genetic abnormalities 2. Family history 3. Increasing age4. Male gender

What are the Modifiable risk factors for atherosclerosis?

1. Hyperlipidemia2. Hypertension 3. Cigarette smoking 4. Diabetes 5. Inflammation

Describe the role of Genetic abnormalities as a risk factor for atherosclerosis

i. Family history is the most significant independent risk factor for atherosclerosis1. Certain mendelian disorders are strongly associated with atherosclerosis (e.g., familial hypercholesterolemiaii. Genetic disorders account for only a small percentage of casesiii. Familial predisposition to atherosclerosis and IHD is usually multifactorial and relates to inheritance of various genetic polymorphisms and familial clustering of other established risk factors, such as hypertension or diabetes1. Most familial risk is related to polygenic traits that go hand- in-hand with atherosclerosis, such as hypertension and diabetes, as well as other genetic polymorphisms.

What is the most significant independent risk factor for atherosclerosis?

Family history

Describe how age is a risk factor for atherosclerosis

i. Atherosclerosis usually remains clinically silent until lesions reach a critical threshold in middle age or later. ii. Thus, there is a 5- fold increase in incidence between ages 40-60iii. Death rates from IHD rise with each decade

Describe how gender is a risk factor for atherosclerosis

i. Premenopausal women are relatively protected against atherosclerosis compared to age-matched men. 1. Thus, myocardial infarction and other complications of atherosclerosis are uncommon in premeno- pausal women in the absence of other predisposing factors such as diabetes, hyperlipidemia, or severe hypertensionii. note that now, premenopausal women may have other risk factors for CVD: diabetes, hyperlipidemia, HTN - particulary in pre-diabetes it is associated with increases # of pts with MI and atherosclerosis i. After menopause the incidence of atherosclerosis-related diseases increases and at older ages exceeds that of menii. The formerly assumed protective effect of estrogen has come under question: in younger postmenopausal women estrogen therapy reduces coronary atherosclerosis, but he effect is unclear in older womeniii. Other gender differences can influence outcomes of IHD: hemostasis, infarct healing, myocardial remodeling

Describe Hypertension as a risk factor for atherosclerosis

a. a major risk factor for development of atherosclerosis. b. On its own, hypertension can increase the risk of IHD by approximately 60% c. Hypertension also is the major cause of left ventricular hypertrophy (LVH), which also can contribute to myocardial ischemia. d. Both systolic and diastolic levels are important.

Describe the effect of cigarette smoking as a risk factor for atherosclerosis

a. Major risk factorb. Probably accounts for the increasing incidence and severity of atherosclerosis in womenc. Prolonged (years) smoking of one pack of cigarettes or more daily doubles the death rate from IHD while Smoking cessation reduces the risk substantially

Describe the effect of hyperlipidemia (hypercholesterolemia) as a risk factor for atherosclerosis

a. Major risk factor; sufficient to stimulate atherosclerosis even in the absence of other factorsa. Low-density lipoprotein (LDL "bad cholesterol") is associated with increased risk; LDL cholesterol is delivered to peripheral tissuesb. High-density lipoprotein (HDL, "good cholesterol") associated with reduced risk. HDL mobilizes cholesterol from tissue and transports it to the liver for excretion in the bile; higher levels of HDL are associated with reduced risk

Describe the effect of Diabetes Mellitus as a risk factor for atherosclerosis

a. Advanced glycation end products (AGEs) damage vascular endothelium inflammationb. AGEs also modify matrix proteins that then trap LDL and retard their removal from the vessel wallc. Increased oxidative stressd. Hypercholesterolemia markedly increases the risk of atherosclerosise. Other factors being equal, the incidence of myocardial infarction is twice as high in diabetics as in nondiabetics.f. Associated with an increased risk of stroke and a 100-fold increase in atherosclerosis-induced gangrene of the lower extremitiesg. 100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities

Describe the effect of Metabolic Syndrome as a risk factor for Atherosclerosis

a. Characterized by glucose intolerance (insulin resistance), hypertension and central obesityb. Abnormal adipose tissue signaling may be the causec. Dyslipidemia causes increased oxidative stress, which leads to endothelial cell dysfunctiond. A systemic proinflammatory state further predisposes to vascular thrombosis

Describe the effect of Hypothyroidism as a risk factor for atherosclerosis

a. Accumulation of LDL cholesterol due to a reduction in the number of cell surface receptors for LDL results in decreased catabolism of LDLb. Increased LDL oxidation - directly related to the serum LDL cholesterol levelc. Diminished secretion of cholesterol into biled. Reduced lipoprotein lipase activity

Describe Kidney Disease as a risk factor for atherosclerosis

Nephrotic syndrome causes increase in VLDL

Describe Liver Disease as a risk factor for athersclerosis

Biliary cirhosis, hepatitis

Describe diet as a risk factor for atherosclerosis

a. High intake of carbohydrates (particularly simple sugars) and low intake of fats causes increase of plasma TG and decrease of HDL b. Trans-unsaturated (hydrogenated) fats raise triglyceridesc. Simple sugars increase blood pressure d. Simple sugars increase inflammation and oxidative stressi. High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol, and/or containing higher ratios of polyunsaturated fats, lower plasma choles- terol levels. ii. Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas (trans)-unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles. iii. Exercise and moderate consumption of ethanol raise HDL levels, whereas obesity and smoking lower them. iv. Statins are a widely used class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis.

Explain how Obesity is a risk factor for atherosclerosis

a. Associated with hypertension, diabetes ("diabesity"), hypertriglyceridemia, and decreased HDL

Explain how Stress is a risk factor for athersoclerosis

a. Chronic stress is associated with high plasma cortisol levels, hypertension, obesity and low HDLb. Competitive "type A" personality

True or False: 20% of Cardiovascular Events occur in the absence of hypertension, hyperlipidemia, smoking, or diabetes and >75% of CV events in previously healthy women occur with LDL cholesterol levels below 160 mg/dL (considered low risk)

True

Describe how Inflammation is a risk factor for atherosclerosis

a. Present during all stages of atherogenesisb. Linked with atherosclerotic plaque formation and rupture

Describe how CRP levels are a risk factor for atherosclerosis

a. CRP = acute-phase reactant synthesized primarily by the liverb. Plays a role in the innate immune response by opsonizing bacteria and activating complementc. Activates endothelial cells, induces a pro-thrombotic state and increases the adhesiveness of endothelium for leukocytesd. IMPORTANT: strong independent predictor of the risk of MI, stroke, peripheral arterial disease, and sudden cardiac death even among apparently healthy individualse. Smoking cessation, weight loss and exercise reduce CRP levelsf. Statins reduce CRP levels independent of their effects on LDL cholesterolg. Locally, CRP secreted by cells within atherosclerotic plaques can activate endothelial cells, increasing adhesiveness and inducing a prothrombotic state. Its clinical importance lies in its value as a circulating biomarker: CRP levels strongly and independently predict the risk of myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy persons. While there is no direct evidence that lowering CRP diminishes cardiovascular risk, it is of interest that CRP is reduced by smoking cessation, weight loss, and exercise. Moreover, statins reduce CRP levels independent of their LDL cholesterol-lowering effects, suggesting a possible anti-inflammatory action of these agents.

Describe how Microalbuminuria is a risk factor for atherosclerosis

Marker of kidney damage in diabetes but also predicts severity of atherosclerosis/coronary vascular disease in non-diabetics

Describe how Homocysteinemia is a risk factor for atherosclerosis

a. Clinical and epidemiologic studies show a strong relationship between total serum homocysteine levels and coronary artery disease, peripheral vascular disease, stroke, and venous thrombosisb. Homocystinuria, due to rare inborn errors of metabolism, causes elevated circulating homocysteine (greater than 100 μmol/L) and is associated with early-onset vascular disease. c. Although low folate and vitamin B12 levels can increase homocysteine levels, The effect of folate and vitamin B12 supplementation on the incidence of cardiovascular disease has not been proven

Describe how Lipoprotein (a) levels are a risk factor for atherosclerosis

a. Lipoprotein(a) is an LDL-like particle that contains apolipoprotein B-100 linked to apolipoprotein (i) An altered form of LDL that contains the apolipoprotein B-100 portion of LDL linked to apolipoprotein (a) b. High lipoprotein(a) levels are associated with increased coronary and cerebrovascular disease risk, independent of total cholesterol or LDL levelsc. Low lipoprotein(a) levels are associated with increased risk for DM2

Describe how factors affecting homeostasis are a risk factor for atherosclerosis

a. Elevated levels of procoagulants are potent predictors of risk for major cardiovascular events. Excessive activation of thrombin, which you will recall initiates inflammation through cleavage of protease-activated receptors (PARs) on leukocytes, endothelium, and other cells, may be particularly atherogenic. b. Several markers of hemostatic and/or fibrinolytic function c. e.g., elevated plasminogen activator inhibitor are predictors of risk for atherosclerosis, MI and stroked. Thrombin (procoagulant and proinflammatory effects) and platelet-derived factors are implicated in local vascular pathology

What are factors that appear to REDUCE the risk of IHD?

1. Elimination of modifiable risk factors for atherosclerosis2. Dietary modificationo The Mediterranean diet, etc. o Omega-3 fatty acids (abundant in flax seed and fish oils) are beneficial3. Regular exerciseo Increases myocardial vascularityo Increases HDL4. Moderate consumption of alcohol (what is moderate?) o Increases HDL o Any alcohol appears to be beneficial (lately this has been questioned)o Resveratrol in red wine5. Medications:o Statins lower circulating cholesterol levels by inhibiting hydroxymethylglutarylo coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesiso Fibrates, tocotrienols, phytosterols, ezerimibe, niacin, etc

What is the basis for the development of atherosclerosis

Endothelial Injury - Lesion progression involves interaction of modified lipoproteins, monocyte- derived macrophages, T lymphocytes, and the cellular constituents of the arterial wall

What are activators of Inflammation?

1. Cytokines2. Bacterial products3. Hemodynamic Forces (Hypertension) 4. Lipid products5. Advanced Glycation End-products - in diabetes and metabolic syndrome 6. Viruses7. Complement products8. Hypoxia 9. Induced Genes: Adhesion molecules, cytokines/chemokines, Growth Factors, Vasoactive mediators, Coagulation proteins, MHC molecules

Describe dysfunctional endothelial cells

Early human atherosclerotic lesions begin at sites of intact, but dysfunctional, endothelium. These dysfunctional endothelial cells exhibit increased permeability, enhanced leukocyte adhesion, and altered gene expression, all of which may contribute to the development of atherosclerosis.

Where do plaques tend to occur? What does this mean?

at ostia of exiting vessels, at branch points, and along the posterior wall of the abdominal aorta, where there is turbulent blood flow. This illustrates the importance of hemodynamic factors in atherogenesis

Describe how lipids contribute to atherosclerosis

1. Chronic hyperlipidemia, particularly hypercholesterolemia, can directly impair endothelial cell function by increasing local oxygen free radical production; among other things, oxygen free radicals accelerate NO decay, damping its vasodilator activity.2. With chronic hyperlipidemia, lipoproteins accumulate within the intima, where they are hypothesized to generate two pathogenic derivatives, oxidized LDL and cholesterol crystals. 3. LDL is oxidized through the action of oxygen free radicals generated locally by macrophages or endothelial cells and ingested by macrophages through the scavenger receptor, resulting in foam cell formation. 4. Oxidized LDL stimulates the local release of growth factors, cytokines, and chemokines, increasing monocyte recruitment, and also is cytotoxic to endothelial cells and smooth muscle cells. More recently, it has been shown that minute extracellular cholesterol crystals found in early atherosclerotic lesions serve as "danger" signals that activate innate immune cells such as monocytes and macrophages. *Genetic defects in lipoprotein uptake and metabolism that cause hyperlipoproteinemia are associated with accelerated atherosclerosis. Thus, homozygous familial hypercholesterolemia, caused by defective LDL receptors and inadequate hepatic LDL uptake, can lead to myocardial infarction by age 20. *Other genetic or acquired disorders (e.g., diabetes melli- tus, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis.

Describe how Inflammation contributes to Atherosclerosis

1. Inflammation contributes to the initiation, progression, and complications of atherosclerotic lesions. Normal vessels do not bind inflammatory cells. Early in atherogenesis, however, dysfunctional endothelial cells express adhesion molecules that promote 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. 2. Monocytes differentiate into macrophages and avidly engulf lipoproteins, including oxidized LDL and small cholesterol crystals. Cholesterol crystals appear to be par ticularly important instigators of inflammation through activation of the inflammasome and subsequent release of IL-1. Activated macrophages also produce toxic oxygen species that drive LDL oxidation and elaborate growth factors that stimulate smooth muscle cell proliferation. 3. T lymphocytes recruited to the intima interact with the macrophages and also contribute to a state of chronic inflammation. It is not clear whether the T cells are responding to specific antigens (e.g., bacterial or viral anti- gens, heat-shock proteins [see further on], or modified arterial wall constituents and lipoproteins) or are nonspe- cifically activated by the local inflammatory milieu. Never- theless, activated T cells in the growing intimal lesions elaborate inflammatory cytokines (e.g., IFN-γ), which stimulate macrophages, endothelial cells, and smooth muscle cells. 4. As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth factors that promote smooth muscle cell proliferation and matrix synthesis.

Describe how smooth muscle proliferation contributes to atherosclerosis

• Intimal smooth muscle cell proliferation and ECM deposition lead to conversion of the earliest lesion, a fatty streak, into a mature atheroma, thus contributing to the progressive growth of atherosclerotic lesions. • Intimal smooth muscle cells can originate from the media or from circulating precursors; regardless of their source, they have a proliferative and synthetic phenotype distinct from that of the under- lying medial smooth muscle cells. • Several growth factors are implicated in smooth muscle cell proliferation and matrix synthesis, including platelet-derived growth factor (released by locally adherent platelets, macrophages, endothelial cells, and smooth muscle cells), fibroblast growth factor, and TGF- α. • The recruited smooth muscle cells synthesize ECM (most notably collagen), which stabilizes atherosclerotic plaques. However, activated inflammatory cells in atheromas also can cause intimal smooth muscle cell apoptosis and breakdown of matrix, leading to the development of unstable plaques (see later).

Describe Sub-Intimal thickening (Fatty Streaks) in early atherosclerosis

• Fatty streaks begin as minute yellow, flat macules that coalesce into elongated lesions, 1 cm or more in length. • They are composed of lipid-filled foamy macrophages but are only minimally raised and do not cause any significant flow disturbance. • Fatty streaks can appear in the aortas of infants younger than 1 year of age and are present in virtually all children older than 10 years, regardless of genetic, clinical, or dietary risk factors. • The relationship of fatty streaks to atherosclerotic plaques is uncertain; although fatty streaks may evolve into plaques, not all are destined to progress. • Nevertheless, it is notable that coronary fatty streaks form during adolescence at the same anatomic sites that are prone to plaques later in life.

Describe the atheromatous plaque

1. Fibrous cap: smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularization2. Necrotic center: cell debris, cholesterol crystals, foam cells, Ca+3. Media • The key features of these lesions are intimal thickening and lipid accumulation• Atheromatous plaques are white to yellow raised lesions; they range from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses. • Thrombus superimposed on ulcerated plaques imparts a red-brown color • Atherosclerotic plaques are patchy, usually involving only a portion of any given arterial wall; on cross-section, therefore, the lesions appear "eccentric

In descending order, the most extensively involved vessels are:

infrarenal, abdominal aorta, coronary arteries, popliteal arteries, internal carotid, Circle of Willis

What are the 3 principle components of atherosclerotic plaques?

(1) cells, including smooth muscle cells, macrophages, and T cells(2) extracellular matrix, including collagen, elastic fibers, and proteoglycans(3) intracellular and extracellular lipid

What is the fibrous cap of atherosclerotic plaques made of?

smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin• Where the cap meets the vessel wall (the "shoulder") is a more cellular area containing macrophages, T cells, and smooth muscle cells.

What is deep to the fibrous cap of an atherosclerotic plaque?

necrotic core, containing lipid (primarily cholesterol and cholesterol esters), necrotic debris, lipid-laden macrophages and smooth muscle cells (foam cells), fibrin, variably organized thrombus, and other plasma proteins

What are cholesterol clefts?

The extracellular cholesterol frequently takes the forms of crystalline aggregates that are washed out during routine tissue processing, leaving behind empty "cholesterol clefts.

Where does neovascularization occur?

Along the periphery of the plaque

Describe acute plaque change

In most patients, unstable angina, infarction, and often sudden cardiac death occur because of abrupt plaque change followed by thrombosis—hence the term acute coronary syndromePlaque erosion or rupture typically triggers thrombosis, leading to partial or complete vascular obstruction and often tissue infarction o Thrombi may partially or completely occlude the lumen, leading to tissue ischemia (e.g., in the heart). If the patient survives, thrombi become organized and incorporated into the growing plaque.

Describe Rupture/Fissuring of a plaque

exposes highly thrombogenic plaque constituents --> can cause atheroembolism: ruptured plaque can discharge debris into the blood microemboli of plaque contentso Plaques that contain large atheromatous cores, or have thin overlying fibrous caps are more likely to rupture, and are therefore termed "vulnerable.

Where do fissures most commonly occur?

Fissures frequently occur at the junction of the fibrous cap and the adjacent normal plaque-free arterial segment, where the mechanical stresses are highest and the fibrous cap is thinnest

Describe Erosion/Ulceration of a plaque

exposes the thrombogenic subendothelial basement membrane to blood

Describe Hemorrhage into an atheroma

expanding the plaque volume, exacerbating the degree of luminal occlusion. *Rupture of the overlying fibrous cap or of the thin-walled vessels in the areas of neovascularization can cause intra-plaque hemorrhage; the resulting hematoma may cause rapid plaque expansion or plaque rupture.

True or false: plaques responsible for MI are asymptomatic before the event

True: It is now recognized that plaques responsible for myocardial infarctions and other acute coronary syndromes often are asymptomatic before the acute event, which superimposes thrombosis on a lesion that previously did not produce significant luminal occlusion

Describe Vulnerable Plaques

Rupture: 2/3 of casesErosion: 1/3 of cases • Vulnerable plaque characterized by high lipid and high inflammatory cell content, low content of vascular smooth muscle cells and collagen=plaques that contain large numbers of foam cells and extracellular lipid, have thin fibrous caps containing few smooth muscle cells, and contain clusters of inflammatory cells• Collagen in atherosclerotic plaques is synthesized primarily by smooth muscle cells, and loss of smooth muscle cells understandably results in cap weakening • In general, plaque inflammation increases collagen degradation and reduces collagen synthesis, thereby destabilizing the mechanical integrity of the cap. Of interest, statins may have a beneficial effect not only by reducing circulating cholesterol levels but also by stabilizing plaques through a reduction in plaque inflammation.

True or false: all plaque ruptures result in occlusive thromboses?

False:In fact, silent plaque disruption and ensuing superficial platelet aggregation and thrombosis probably occur frequently and repeatedly in those with atherosclerosis. Healing of these subclinical plaque disruptions—and their overlying thromboses—is an important mechanism for atheroma enlargement.

Why do many MIs occur between 6am and 12pm?

the surge in adrenergic stimulation associated with awakening and rising may underlie the observation that the incidence of acute MI is highest between 6 AM and 12 noon.

During early stages of atherosclerosis, what allows for preservation of the luminal diameter?

Remodeling of the media --> increases vessel circumference and preserves the luminal diameter

What is critical stenosis

0

Describe an example of sequence of events in atherosclerotic complications that leads to thrombo-embolism

plaque rupture -> thrombus -> emboli from the thrombus and the ruptured plaque

What are the 4 ischemic heart disease syndromes?

o 1) Angina Pectoriso 2) Acute MIo 3) Sudden Cardiac Deatho 4) Chronic Ischemic Heart Disease with CHF

The sydromes of IHD are the ____ (early/late) manifestations of coronary atherosclerosis which began ___

LATEduring childhood or adolescence

What is the main cause of IDH?

thrombus formation • 25% of cases are due to superficial ulceration of endothelium over a plaque.• 75% of cases are due to fissures in the plaque and hemorrhage/bleeding into the body of the plaque with resulting ballooning into the lumen.

Where are the most severe atherosclerotic changes found?

In the first 2 cm after bifurcation of an artery

Stable angina occurs at what level of stenosis?

>75%

Is there thrombosis in stable angina?

No

Is there thrombosis in Unstable angina ?

Yes -- non-occlussive; thromboemboli are common

Is there thrombosis in subendocardial MI?

It is variable -- may be absent, partial, complete, or lysed

Is there thrombosis in Tranmural MI?

Yes -- occlusive thrombosis

Is there thrombosis in sudden death?

Yes -- platelet aggregation, thrombi, &/or thromboemboli are common

Describe typical/stable angina

1. Predictable, episodic chest pain during and after increased demand for myocardial work.2. Caused by low flow in atherosclerotic coronary arteries.3. Usually at least one more than 50% stenotic artery (high grade stenosis) 4. May be modifiable by drugs.5. Relieved by rest (reducing demand) 6. Over long periods of impaired flow diffuse myocardial fibrosis may develop.

Describe Prinzmetal/Variant angina

1. Occurs at rest; may awaken the patient from sleep.2. Associated with coronary artery spasm.3. Spasm may occur in a normal portion of the coronary artery.4. Responds to vasodilators and Ca+ channel blockers

Describe Unstable angina

1. characterized by increasingly frequent pain, precipitated by progressively less exertion or even occurring at rest2. Fissuring of plaques may cause sudden onset angina that increases in frequency and severity.3. Associated with plaque disruption and superimposed thrombosis, distal embolization of the thrombus, and/or vasospasm4. High risk for subsequent total thrombotic occlusion = MISignificant number of patients will progress to myocardial infarction or may die from secondary development of ventricular arrhythmia

Patterns of Acute MI: Regional MI

1. 90% of cases.2. Involves one segment of the ventricular wall.3. Nearly always caused by thrombus formation on an atheromatous plaque.4. Severe ischemia typically caused by coronary artery occlusion and lasting at least 20-40 minutes causes irreversible injury and death of cardiac myocytes. 5. Infarct typically begins in the subendocardial region (least well perfused region of the ventricular wall).6. Zone of necrosis extends outwards and reaches full size in 3-6 hours.7. Complete persistent occlusion results in transmural infarction.8. Lysis of the thrombus or collateral blood flow results in regional subendocardial infarct.

Patterns of Acute MI: Circumferential MI

1. 10% of cases.2. Involves the subendocardial zone of the ventricle.3. Caused by general hypoperfusion of the main coronary arteries.4. Usually due to a hypotensive episode which critically reduces blood flow in arteries already affected by high grade stenosis.The region at the end of the perfusion zone undergoes necrosis

Locations of Infarct:

1. Occlusion of LAD causes antero-septal MI (40-50%) a. anterior LV free wall and anterior septum, apex circumferentially2. Occlusion of RCA causes posterior inferior MI (30-40%) a. (posterior LV free wall and posterior septum)3. Occlusion of LCX causes lateral MI (15-20%) a. Lateral LV free wall but not apex 4. Occlusion of LCA causes massive antero-lateral MI (not common) a. (anterior and lateral LV free wall)

Transmural MI

involve the full thickness of the ventricle and are caused by epicardial vessel occlusion through a combination of chronic atherosclerosis and acute thrombosis; such transmural MIs typically yield ST segment elevations on the electrocardiogram (ECG) and can have a negative Q waves with loss of R wave amplitude. These infarcts are also called ST elevated MIs (STEMIs).

Subendocardial infarctions

are MIs limited to the inner third of the myocardium; these infarcts typically do not exhibit ST segment elevations or Q waves on the ECG tracing. As already mentioned, the subendocardial region is most vulnerable to hypoperfusion and hypoxia. Thus, in the setting of severe coronary artery disease, transient decreases in oxygen delivery (as from hypotension, anemia, or pneumonia) or increases in oxygen demand (as with tachycardia or hypertension) can cause subendocardial ischemic injury. This pattern also can occur when an occlusive thrombus lyses before a full-thickness infarction can develop.

Coronary artery occlusion

• Initial event is sudden plaque disruption• Exposure to ECM and plaque contents causes immediate platelet adhesion, aggregation, activation, and release of Thromboxane A2, serotonin, and platelet factors 3 and 4• Platelet aggregation and the release of mediators stimulates vasospasm• Extrinsic coagulation pathway is activated• The thrombus occludes the lumen of the coronary artery within minutes

Emboli:

• Left atrial thrombi associated with atrial fibrillation• LV mural thrombi (previous MI; ventricular aneurysm post MI)• Vegetative endocarditis (bacterial endocarditis, non-bacterial thrombotic endocarditis, etc.)• Paradoxical emboli from the right side through patent foramen ovale

Key Events in Ischemic Cardiac Muscle Cells1) Onset of ATP depletion2) Loss of contractility3) ATP reduced to <50% of normal4) ATP reduced to <10% of normal5) Irreversible cell injury6) Microvascular Injury

1) seconds2) <2 minutes3) 10 minutes4) 40 minutes5) 20-40 minutes6) >hour

Macroscopic Findings in MI 1) 0-30 min2) 1-2 hr3) 2-3 hr4) 4-12 hr5) 18-24 hr6) 1-3 days7) 4-7 days8) 10 days9) 4 weeks10) 7-8 weeks

1) none2) can be shown bynitro-blue-tetrazolium (NBT); infarcted area does not stainblue3) at 2-3 hrs immersion into triphenyltetrazolium chloride (TTC) stains intact muscle fibers brick red, where dehydrogenases are preserved; infarcted area stays unstained4) Occasional dark mottling5) Pale with blotchy discoloration/dark mottling 6) Mottling with yellow-tan infarct center7) Hyperemic border; yellow-tan infarct center with softening8) Maximally yellow; soft, shrunken; granulation tissue visible as a purple border at the periphery of the infarct ; depressed red-tan vascular margins9) Visible scarring; Gray-white scarring progresses from margin towards the center of infarct10) Firm, gray with dense collagenous scar

Microscopic Findings in MI 1) 0-30 min2) 1-2 hr3) 2-3 hr4) 4-12 hr5) 18-24 hr6) 1-3 days7) 4-7 days8) 10 days9) 4 weeks10) 7-8 weeks

1) Wavy myocardial fibers with brick-red color in HE stain; REVERSIBLE changes with mitochondrial swelling + relaxation of myofibrils2) LM: few wavy myofibers at margin of infarct (these reflect the stretching and buckling of noncontractile dead fibers) EM: IRREVESIBLE changes with sarcolemmal disruption and electron-dense mitochondrial depositsBiochemical: Loss of ATP, increase in Lactate 3) same 4) Coagulation necrosis with loss of cross striations; contraction band necrosis, edema, hemorrhages; earliest neutrophils appear; increased eosinophilia of myofibers5) - Continuing coagulation necrosis - nuclear pyknosis, karyorrhexis, karyolysis- cytoplasmic eosinophilia- contraction band necrosis (reperfusion injury) at the periphery- neutrophil infiltrate increases6) *- Total loss of nuclei (karyolysis) and striations- heavy neutrophilic infiltrates; - fragmentation of neutrophil nuclei - complete coagulation necrosis*7) o Macrophages appear; o early disintegration and phagocytosis of necrotic myofibers, o loss of integrity of cardiac wall (danger of rupture); o granulation tissue visibleo earliest fibrovascular response begins8) Maximal phagocytosis; prominent granulation tissue in peripheral areas grows in from margins ; collagen deposition, angiogenesis 9) Most of necrotic tissue has been cleared away; maturing granulation tissue with fewer capillaries and more collagen; increased collagen deposition with decreased cellularity = organization10) Fibrosis; dense collagenous scar

Early biochemical changes include

loss of ATP and accumulation of lactate

Classification of MI1) Evolving2) Acute3) Healing4) Healed

1) Evolving: 6 hours2) Acute: 6 hr-7 days3) Healing: 7-28 days4) Healed: 29 days and beyond

What is Reperfusion Injury

• REPERFUSION INJURY = Myocardial, vascular, or electrophysiological dysfunction that is induced by the restoration of blood flow to previously ischemic tissue. - For approximately 30 min after the onset of even the most severe ischemia, myocardial injury is potentially reversible. Thereafter, progressive loss of viability occurs that is complete by 6 to 12 hours. The benefits of reperfusion are greatest when it is achieved early, and are progressively lost when reperfusion is delayed. • Such reperfusion is achieved by thrombolysis (dissolution of thrombus by tissue plasminogen activator), angioplasty, or coronary arterial bypass graft. Following coronary occlusion, contractile function is lost within 2 minutes and viability begins to diminish after approximately 20 minutes. If perfusion is not restored, then nearly all myocardium in the affected region will die. If flow is restored, then some necrosis is prevented, myocardium is salvaged, and at least some function will return. The earlier reperfusion occurs, the greater the degree of salvage. However, the process of reperfusion itself may induce some damage (reperfusion injury), and return of function of salvaged myocardium may be delayed for hours to days (post-ischemic ventricular dysfunction).

Pathophysiology of Reperfusion Injury

• Unfortunately, while preservation of viable (but at-risk) heart can improve both short- and long- term outcomes, reperfusion is not an unalloyed blessing. Indeed, restoration of blood flow into ischemic tissues can incite greater local damage than might otherwise have occurred—so-called reperfusion injury. Occlusion of a coronary artery causes disruption of blood flow to cardiac myocytes resulting in cellular injury and death The processes are mostly related to energy production and utilization: - Reduced energy production with a fall in intracellular ATP levels - Transition from aerobic to anaerobic energy metabolism - Accumulation of products of anaerobic metabolism - Reduced intracellular pH

Manifestations of Reperfusion Injury

¥ Reperfusion arrhythmias¥ Endothelial cell damage leading to microvascular dysfunction¥ Myocardial stunning ¥ Myocyte death and infarction

Contributing Factors to Reperfusion Injury

• Damage to cellular and organelle membranes, including mitochondria mitochondrial dysfunction• Hypercontraction of cardiac myocytes (appear as bands across myocytes) with massive influx of calcium• Free radical formation • Aggregation of leukocytes and release of inflammatory mediators• Platelet and complement activation• Activation of the pro-apoptotic signaling cascade• Endothelial damage and vasoconstriction

What is the gold standard for Diagnosis of MI

Troponins• TnI, TnT, TnC; all are components of cardiac muscle• TnI and TnT are cardiospecific• Troponins are not normally detectable• Troponins are more sensitive and can be detected when there is myocardial damage even if CK and CK-MB are not elevated • Troponins are bound to the tropomyosin complex of the sarcomere, partially dissolved in the cytosol of the myocardial cell (ca 2% of total)• Small amounts can leak out even with reversible damage (ischemia) • Levels rise within 6-8 hours (DETECTABLE after 2-3 hours), peak at 12-24 hours, and stay elevated for up to 10-14 days

TnI Decision Levels

• Reference range: <0.01 ng/mL (ARUP) • Abnormal : >0.01 ng/mL• Diagnostic threshold for MI*: >0.3 ng/mL (standard assay from Abbot)• TnI >0.06 ng/mL is Suggestive of myocardial injury with at least one of the following: 1. Ischemic symptoms2. ECG changes indicative of ischemia3. Coronary intervention

If an abnormal (>0.01) TnI level is found, serial tests may be necessary to confirm or exclude ACS. When should they be done?

o Repeat in 4-6 hrs, if clinically indicated.o May be associated with unstable angina, other heart disorders (LVH, CHF, pericarditis), PE, chronic kidney failure and diabetes mellitus

Creatine Kinase as a laboratory diagnostic

• Present in both skeletal and cardiac muscle• Sensitive but not specific • Elevations occur in both myocardial necrosis and skeletal muscle injury (tonic-clonic seizures, rhabdomyolysis)• Isoform CK-MB is the most specific to the myocardium(CK-MM: mostly from skeletal muscle and heart; CK-BB: mostly from brain and lung)• Identified by electrophoresis• CK-MB first elevated 2-4 hrs after onset of symptoms, peaks at 18 hrs, and returns to baseline at 48 hrs• If no rise of CK and CK-MB in the first 48 hrs after the onset of chest pain, MI is excluded

CK-MB Isoforms

• The CK-MB fraction exists in two isoforms, 1 and 2• The ratio of isoform 2:1 of 1.5 or greater is a good indicator of an early acute myocardial infarction• Isoform 2 of CK-MB becomes elevated even before CK-MB

CK-MB index (%)

0

Lactate Dehydrogenase as a lab diagnostic for MI

• Catalyses the conversion of pyruvate to lactate• LDH-1 in heart muscle, LDH-2 in serum; high LDH-1/LDH-2 suggests MI • Peak at 72 hours• Not as specific as troponin

Myoglobin as a lab diagnostic for MI

• Storage molecule of oxygen in muscle• The earliest marker of AMI and the first marker to clear• Rises within 2-4 hours of infarction and peaks at 6-12 hours• Returns to normal in 24-36 hours• Not specific

What is the earliest marker of AMI and the first marker to clear

myoglobin

B-type Natriuretic Peptide as a lab diagnostic for MI

• Secreted primarily by the ventricular myocardium in response to wall stress, including volume expansion and pressure overload. • Not specific

Ischemia modified albumin

• Produced when circulating serum albumin contacts ischemic heart tissues. • can be measured by the albumin cobalt binding assay that is based on the ischemia-modified-albumin inability to bind to cobalt

Lab Diagnosis of MI and Infarct Size

1) Q-waves do not usually appear below an infarct size of 10 grams, or about 3%-4% of total myocardial mass. 2) Echocardiographic changes also appear at this level of injury. 3) Significant total CPK elevation occurs at around 0.3 grams. 4) CK-MB becomes abnormal when about 0.03 grams of heart muscle is dead. 5) Troponin becomes positive at about 0.003 grams, which is less than 1/100,000 of the mass of the heart.

Clinical Decision Making in MI

• Up to 80% of patients with acute MI will have an elevated troponin level within 2-3 hours of arrival in the ER, versus 6-9 hours or more with CK-MB and other cardiac markers•Patients with elevated troponin levels but negative creatine kinase-MB (CK-MB) values who were formerly diagnosed with unstable angina or minor myocardial injury are now classified as NSTEMI, even in the absence of diagnostic ECG changes. • Only 1 elevated troponin level above the established cutoff (troponin is above the 10% CV or 99th percentile upper reference limit) in the appropriate clinical setting is required to make the diagnosis of acute MI, according to the American College of Cardiology (ACC) guidelines for NSTEMI.• Cardiac markers are not necessary for the diagnosis of patients who present with ischemic chest pain and diagnostic ECGs with ST-segment elevation • ACC/American Heart Association (AHA) guidelines recommend immediate reperfusion therapy for qualifying patients with ST-segment elevation MI (STEMI), without waiting for cardiac marker results, because the sensitivity of cardiac markers is low in the first 6 hours after the onset of symptoms

Conditions where TnI can be elevated

1. Heart failure - chronic 2. Heart failure - acute elevated in up to 90% of cases3. LVH4. Myocardial Infarction 5. Pulmonary embolism

Complications of MI

1. Arrhythmias and conduction defects with possible sudden death2. Extension of infarction or re-infarction3. Congestive heart failure with pulmonary edema4. Cardiogenic shock5. Pericarditis6. Mural thrombosis, with possible systemic embolization7. Myocardial wall rupture, with possible tamponade (3-5 days after MI, when there is maximal PMN infiltration)8. Papillary muscle rupture leading to valvular insufficiency9. Ventricular aneurysm (late complication)

When is myocardial wall rupture with possible tamponade most likely to occur?

This is most likely to occur in the first week between 3 to 5 days following the initial event, when the myocardium is the softest and there is max neutrophil infiltration

Describe Ventricular Aneurysm as a complication of MI

a. Late omplication of a large transmural infarctb. The thin scar tissue wall of an aneurysm paradoxically bulgesc. during systole.d. Complications of ventricular aneurysms include mural thrombus with a risk of systemic thromboembolism, arrhythmias and heart failure.e. Tough fibrotic wall does not usually rupture.f. The aneurysm bulges out. The stasis in this aneurysm allows mural thrombus, which is present here, to form within the aneurysm. The wall of the aneurysm is thin, as seen here in cross section, but it is formed of dense collagenous tissue and does not rupture. However, the aneurysm is formed of non-functional tissue that does not contract, causing the ejection fraction and stroke volume of the heart to diminish. In addition, mural thrombus can form in the aneurysm. Portions of the mural thrombus can break off and embolize into the systemic circulation.

Describe Chronic Ischemic Heart Disease with CHF

Definition: Progressive heart failure due to ischemic myocardial damage (ischemic cardiomyopathy)Mechanisms:• Post MI cardiac decompensation due to exhaustion of compensatory hypertrophy of remaining viable heart muscle• Severe CAD may lead to diffuse fibrosis and CIHD without clinically manifest acute MI - About 50% of cardiac transplant patients belong to this group • Alveoli contain macrophages which contain hemosiderin and stain positive for iron (Prussian blue stain)

Sudden Cardiac Death

• In 50% of cases sudden death is the first symptom of IHD• Death occurs within an hour of onset of symptoms• Severe coronary atherosclerosis:o Critical stenosis (>75% luminal narrowing) is found in 80-90% patients and >90% stenosis is common• Coronary thrombosis, plaque rupture, or hemorrhage into a plaque (frequent)• Mechanism of death is usually an arrhythmia