Atherogenesis & Coronary Artery Disease (incl O2 demand+supply) Flashcards Preview

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Flashcards in Atherogenesis & Coronary Artery Disease (incl O2 demand+supply) Deck (95):

How do most of Acute Coronary Syndromes (ACSs) occur?

Over 90% of ACLs happen due to disruption of an atherosclerotic plaque -> platelet aggregation + formation of thrombus -> narrowing or complete occlusion of coronary arteries -> impaired blood flow -> lack of O2 to satisfy myocardial demand


What is the name of a partially occluded thrombus in the myocardium?

Unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI).

NSTEMI = non-Q-wave MI.

NSTEMI = unstable angina + myocardial necrosis



What is NSTEMI?

 Non-ST-elevation myocardial infarction (NSTEMI)


NSTEMI = non-Q-wave MI.

NSTEMI = unstable angina + myocardial necrosis


NSTEMI = partial occlusion of coronary vessel


What do you call a partial occlusion of coronary vessel with accompanying myocardial necrosis?

NSTEMI - non-ST-elevated myocardial infarction


What is STEMI?

STEMI = ST-elevation myocardial infarction

STEMI is present when the thrombus completely obstructs the coronary artery - severe ischemia and more necrosis then in NSTEMI = Q wave MI


Name the condition in which a thrombus completely obstructs coronary artery, leading to severe ischemia and  significant amount of myocardial necrosis?

STEMI is present when the thrombus completely obstructs the coronary artery - severe ischemia and more necrosis then in NSTEMI = Q wave MI


Describe renin-angiotensin-aldosterone system?

angiotensinogen (LIVER)


angiotensin I


angiotensin II


angiotensin II in turn:

increases sympathetic activity

increases tubular reabsorption of Na+, Cl-, increases K+ exretion => water retention

encourages adrenal cortex to produce aldosterone (which again leads to increased tubular reabsorption of Na+ and water retention)

increases arteriolar vasoconstriction and so increases blood pressure

influences pituitary to increase ADH secretion -> increases H2O reabsorption in collecting duct

ACE (angiotensin converting enzymes) also convert bradykinin into inactive form. Bradykinin is a vasodilator (but produces cough). Therefore, ACE inhibitors stop vasodilation by preventing bradykinin inactivation. ACE inhibitors also block conversion of angiotensin I into angiotensin II. Angiotensin II is a direct vasoconstrictor, so ACE inhibition drugs block vasoconstriction. 


What are the three layers of arterial wall?

intima - closest to arterial lumen

media - elastic, thick, contains smooth muscle cells that can stretch and recoil

adventitia - external, has nerves, blood vessels and lymphatics


what is vasa vasorum?

vasa vasorum is a network of tiny blood vessels that supply large blood vessels


What is intima?

intima = one of the three layers of the artery, closest to lumen. 

single layer of endothelial cells, metabolically active (produces antithrombotic elements,etc can produce thrombotic elements in stress, produces substances to change contraction of smooth muscle cells in media)

barrier btwn blood and the vessel wall



What is media?

media = one of the layers of arterial wall

media is the thickest layer of the artery

elastin - smooth muscle + extracellular matrix- elastin

elastic component more prominent in big arteries (ex. aorta) to help stretch during high pressure systole and recoil during diastole, moving blood

more smooth muscle in smaller arteries to change vessel resistance (and flow)

extracellular network is produced by smooth muscle cells

collagen = strengths, proteoglycans + elastin = flexibility



what is adventitia?

adventitia = external layer of artery, contains blood vessels (vasa vasorum), nerves, lymphatics



What is the formula for flow?

flow = pressure/resistance


In healthy arteries, which cells regulate nonthrombogenic, vasodilatory and anti-inflammatory properties?

endothelial cells from intima layer can produce

  • antithrombotic molecules  that sit on surface of intima (heparan sulfate, thrombomodulin, plasminogen activators)
  • antithrombotics that enter circulation =prostacyclin and NO 
  • can produce thrombotic molecules during stress
  • substances that can modulate contraction - NO, prostacyclin (in circulation, vasodilatory) and endothelin (vasoconstrictory)
  • vasodilatory substances predominate in healthy endothelium -> net smooth muscle relaxation
  • some of the vasodilators above prevent smooth muscle from traveling and multiplying in intima
  • healthy endothelium resists leukocyte adhesion = opposes local inflammation
  • in inflammation, postcapillary venules release chemokines - WBC attracted to the area -> endothelial cells produce cell surface adhesion molecules that anchor leukocytes to endothelium to migrate to site of injury. endo cells use KLF2 - Kruppel-like factor 2 = gene regulator in endothelial cells to help this adhesion


What properties do smooth muscle cells in arterial wall have?

  • contractile function (regulated by things like angiotensin II, endothelin and NO from endothelial cells, acetylcholine from nerve terminals)
  • produce collagen, elastin and things that form extracellular matrix
  • CAN synthesize IL-6 and tumor necrosis factor alpha, which promote leukocyte formation and expression of leukocyte adhesion molecules


What are the three general stages of atherosclerotic inflammatory process?

fatty streak (normal)

plaque progression

plaque disruption


What is fatty streak?

fatty streak = earlieast visible atherosclerosis

areas of yellow discoloration on arterial inner surface

exist in aorta and coronary arteries of most people by age 20, do not cause symptoms, but in some locations become worse over time

thought to be due to endothelial dysfunction that allows entry and modification of lipids into subendothelial space, where they start inflammation process, inviting leukocytes  to the party and becoming foam cells



Provide a rough outline of how fatty streak forms? Focus on injury to arterial endothelium

1. injury to arterial endothelium

  can be due to chemical irritants (tobacco, abnormal lipid levels, high glucose (risk factors!!!). these irrinats also increase endothelial production of reactive oxygen species - promotes inflammation

physical forces (hemodynamic stress, turbulent flow - high blood pressure (risk factor!!!))

branch points are more predisposed - more turbulent flow, compared to laminar flow in straight sections (laminar flow activates NO and KLF-2, accentuates antioxidant production, etc)

=> common carotid and left coronary artery have lots of branches and are more likely to have atherosclerosis

So what?

endothelial function interrupted - can no longer function as good permeability barrier, releases inflammatory cytokines, increases production of cell survace adhesion molecules for leukocytes to bind, reduced release of vasodilators like NO -> less antithrombotic properties.

2. lipoprotein entry into intima (especially LDL = bad lipid), once in intima LDL accumulates in subendo space by binding to proteoglycans and undergoes modification (oxidation via ROS or glycation in diabetis)

3. inflammation = leukocyte recruitment

4. monocytes -> macrophages -> eat lipids and become foam cells


OPTIONAL: What on earth is KLF-2?

KLF2 expression is induced by fluid laminar flow shear stress, as is caused by blood flow in normal endothelium.

KLF2 then has four key functions in endothelium:
By inhibiting activation of p65 by transcription coactivator p300, VCAM1 and SELE expression is downregulated, genes that encode endothelial cell adhesion molecules, causing decreased lymphocyte and leukocyte activation and hence decreasing inflammation

It upregulates THBD (thrombomodulin) and NOS3 (endothelial nitric oxide synthase) expression, having an anti-thrombotic effect

Through the upregulation of NOS3, as well as NPPC (natriuretic precursor peptide C), KLF2 has a vasodilatory effect

KLF2 also inhibits VEGFR2 (VEGF receptor 2) expression, having an anti-angiogenic effect

Thus KLF2 has an important role in regulating normal endothelium physiology. It is hypothesized that myeloid-specific KLF2 plays a protective role in atherosclerosis.


Provide a rough outline of how fatty streaks form. Focus on lipoprotein entry and modification?

1. injury to arterial endothelium

2. lipoprotein entry into intima (especially LDL = bad lipid), since endothelium injured.  Once in intima LDL accumulates in subendothelial space by binding to proteoglycans (components of extracellular matrix) and undergoes modification (oxidation via ROS or glycation in diabetis). Hypertension promotes retension of LDLs in the intima by increasing production of LDL-binding proteoglycans by SMC (smooth muscle cells)

Modifications of LDL contribute to inflammation -> leukocyte recruitment, especially glycosylated LDL, which now has antigenic properties.

3. inflammation = leukocyte recruitment

4. monocytes -> macrophages -> eat lipids and become foam cells


Describe the steps in fatty streak formation, focus on inflammation and leukocyte recruitment ; foam cell formation

1. injury to arterial endothelium

2. lipoprotein entry into intima (especially LDL = bad lipid), since endothelium injured.  Modification of LDL, such as glycosylation of LDL ->antigenic properties ->

3. inflammation = leukocyte recruitment

process depends on expression of leukocyte adhesion molecules on endothelial surface (normal endo does not express) and proinflammatory cytokines, stimulated by mLDL (modified LDL)

4. monocytes -> macrophages -> eat lipids and become foam cells -> accumulation of plaque,  lipid rich center of plaqye forms necrotic foam cells -> foam cell apoptoss and release of more proinflammatory cytokines.


Describe plaque progression?

not all fatty streaks progress into plaque. early plaque  shows a compensatory outward remodelling of the arterial wall that preserves the diameter of the lumen and permits plaque accumulation without limiting blood flow => no ischemic symptoms (may not be seen on angio). late plaque can no longer compensate and will show on angio. 

fatty streak turns into athero plaque when smooth cells migrate from media to intima, proliferate within it and produce extracellular matrix.

smooth cells migrate b/c foam cells produce cytokines such as TNF alfa, ILs,e tc and platelet-derived growth factor (PDGF). 

smooth muscle cells favour fiber growth and so contribute to formation of fibrous cap around atherosclerosis.  unfortunately, inflammatory cytokines stimulate local foam cells to secrete colagen and elastin-degrading matrix metaloproteinases, which weaken fibrous cap and predispose it to rupture




Describe plaque disruption?

Disrupted plaque integrity

tug of war between matrix synthesis and degradation (smooth muscle cells produce, MMPs from foam cells degrade)

size of plaque has influences on stability. with increasing size into lumen, stress on plaque border increases. also as size increases, necrosis and degradation of extracellular matrix (via inflammatory proteins) increases, making region more vulnerable to rupture.

thick fibrous caps are thought of more stable plaques, those with thin fibrous caps are called vulnerable plaque.

Thrombus formation

small thrombi may reabsorb into the plaque, encouraging more smooth muscle growth and fibrous content. others can dislodge and clot arteries.


Describe the difference between "stable" plaque and "vulnerable" plaque?

  • Stable plaque - small pool of lipid, thick fibrous cap, good size lumen
  • Vulnerable plaque - large pool of lipid, thin fibrous cap, many inflammatory cells
  • ruptured plaque can heal, causing narrowed lumen and more fibrous intima or can cause acute MI


List complications of atherosclerotic plaques?

  • calcification of atherosclerotic plaque -> pipe-like rigidity to the vessel wall - > increased fragility of vessels
  • rupture or ulceration of atherosclerotic plaque -> thrombus -> can occlude the vessel and result in infarction of the organ or incorporate into plaque and make it bigger
  • hemorrhage into the plaque due to rupture of fibrous cap that had microvessels inside - hematoma can narrow the vessel more
  • embolization of fragment of atheroma to distal site (embolization - lodging of clot (thromb, fat, etc)
  • weakening of vessel wall b/c plaque stresses surrounding tissue


What are the complications of atherosclerosis on body systems?

  • Brain: embolic stroke, thrombotic stroke
  • Coronary artery disease: MI, unstable angina, myocardial ischemia
  • Renal artery disease: atheroembolic renal disease, renal artery stenosis
  • Anneurysms (ex. aortic anneurysm)
  • Peripheral artery disease (limb claudication, limb ischemia)


What are common cardiovascular risk factors? (modifiable and nonmodifiable)

Modifiable risk factors:

dyslipidemia (elevated LDL, decreased HDL (which transports cholesterol away from tissues and back to the liver), could be familial (like familial hypercholesterolemia); optimal LDL

tobacco smoking (accelerates atherogenesis and thrombogenesis)

hypertension (more injury to endothelium)

diabetes mellitus, metabolic syndrome

metabolic syndrome - cluster of hypertension, hypertriglycerimia, reduced HDL, insulin resistance and visceral (tummy) obesity

lack of physical activity


Nonmodifiable risk factors:

advanced age

male gender (before menopause, after menopause rates equal, thought to be related to estrogen which declines post-menopause)



What is angina?

angina refers specifically to uncomfortable sensation in the chest and neighboring structures that arises from an  imbalance between myocardial oxygen supply and demand (myocardial ischemia)



what is ischemic heart disease?

Ischemic heart disease = condition in which imbalance between myocardial oxygen supply and demand results in myocardial hypoxia and accumulation of waste metabolites, most often caused by atherosclerotic disease of the coronary arteries (often termed coronary artery disease)


What is stable angina?

Stable angina = chronic pattern of transient angina pectoris that occurs during exertion or emotional event, relieved by rest within a few minutes. episodes are often associated with temporary ST segment depression, no permanent myocardial damage.


What is variant angina?

Variant angina = angina, often at rest, develops due to coronary artery spasm rather than due to increase in oxygen demand; episodes associated with transient shifts of ST segment, usually ST elevation (= Prinzmetal angina)


What is silent ischemia?

Silent ischemia = asymptomatic myocardial ischemia, can be detected by ECG and other lab techniques


What is unstable angina?

Unstable angina = angina with pattern of increased frequency and duration of angina episodes and with less and less exertion or at rest; high frequency of progression to MI if untreated


What is myocardial infarction?

myocardial infarction = region of myocardial necrosis usually caused by prolonged cessation of blood supply; most often results from acute thrombus at site of coronary atherosclerotic stenosis; may be first clinical manifestation of ischemic heart disease, or there may be a history of angina pectoris


What determines oxygen supply to the myocardium?

oxygen supply depends on oxygen content of the blood and the rate of coronary blood flow


When does heart muscle get perfused with blood?

Coronary perfusion happens during diastole. During systole the flow is blocked by contracting myocardium which occludes blood vessels within. 

coronary perfusion pressure can be approximated by the aortic diastolic pressure. 



What does adenosine do?

O2 -> lots of ATP

no O2 -> ADP + AMP accumulate, degraded to adenosine

adenosine is a great vasodilator, binds to receptors on vascular smooth muscle and decreases entry of Ca2+ into the cell -> relaxation, vasodiation

Other local vasodilators are lactate, acetate, H+, carbon dioxide



What are some of the substances released by endothelial cells of the arterial wall? What do they do?

  • endothelium-derived NO = vasorelaxation (vasodilation)
  • prostacyclin = vasodilator
  • EDHF = vasodilatory properties
  • endothelin 1 = vasoconstrictor 


What is NO in the context of vascular endothelial cells?

endothelium-derived NO - diffuses into and relaxes arterial smooth muscle using cyclic GMP (from GTP) mechanism. NO is produced in basal (regular) state

release can be augmented by ACh (parasympa), thrombin, products of aggregating platelets, and shear stress of blood flow. although effect of thrombin and platelets, etc is vasoconstriction, induced release of NO results in net vasodilation instead

memory aid eggNOG = NO works through GMP


What is prostacyclin?

Prostacyclin is released from endothelial cells in response to hypoxia, shear stress, ACh, platelet products. Causes relaxation of smooth muscle cells via cAMP mechanism.

memory aid: prostates tend to be enlarged = dilation

cyclin' = blood is cycling so prostacyclin allows blood to cycle faster as arteries dilate


What is EDHF?

EDHF - relaxes nearby vascular smooth muscle. Release stimulated by ACh, normla blood flow. Seems more important in arteriole relaxation, rather than large arteries.


What is endothelin 1?

endothelin 1 is a vasoconstrictor produced by endothelial cells. Production is stimulated by thrombin, angiotensin II, epinephrine, shear stress of blood flow.

memory aid: endothelium in = vasoconstrictor


What influence does nervous system have on vascular radius/resistance?

Sympathetic receptors seem to play a much bigger role than parasympathetic. Coronary vessels have both alpha and beta-2 adrenergic receptors. Stimulation of alpha adrenergic receptors causes vasoconstriction, stimulation of beta 2 promotes vasodilation


What are three major determinants of myocardial oxygen demand?

  • ventricular wall stress - related to intraventricular pressure (direct +) and radius of ventricle (direct+) and ventricular wall thickness (opposite -)
  • heart rate
  • contractility (inotropic state)


How can one reduce wall stress and why should we?

Reduce wall stress to reduce oxygen demand of the heart to prevent cardiac episode

Things like aortic stenosis and high blood pressure increase interventricular pressure, which in turn increases wall stress and oxygen demand. antihypertensive therapy can decrease wall stress. 

conditions that increase left ventricle size (and thus radius) increase wall stress and consequently oxygen consumption.  try to decrease LV filling and size (ex. NO)

wall stress is inversely proportional to ventricular wall thickness, b/c force spread out over more muscle mass.  hypertrophied heart has less wall stress and oxygen consumption per gram of tissue. 

reminder: wall stress = (interventricular pressure * ventriuclar radius)/ 2* ventricular thickness (since thick on both sides!) = law of Laplace

reminder: thickness is inversely proportional to wall stress - thicker ventricle = less wall stress = decrease in O2 demand

tension developed in the ventricular wall during ejection is also called afterload

reminder: wall stress = tangenital force acting on the myocardial fibers, trying to pull them apart, so need energy to block that force


What is the formula for resistance to blood flow?

where L = length of vessel and r is radius

notice that it is radius^4!

therefore, turbulent flow is most determined by remaining radius of the blood vessel


What is the relationship between stenosis % and blood flow? what is the cut off % under which elevated oxygen demand can not be met?

<60% obstruction - during exertion and increased O2 demand, vessel can still dilate to provide adequate blood flow

>70% obstruction - resting blood flow still adequate, but maximal blood flow is reduced even with full stretched out diameter -> during exercise/exersion oxygen demand exceeds supply -> myocardial ischemia

>90% obstruction - resting blood flow inadequate


Is atherosclerosis the only cause of coronary artery disease?

No, reduced O2 supply to the heart can occur through

1) atherosclerosis

2) bad endothelial cell function

- via inappropriate vasoconstriction (smoking, diabetes, hypercholesterrolemia, hypertension and cigarette smoking) can impair release of vasodilators, so does atherosclerosis

- via loss of antithrombotic properties

3) decreased perfusion pressure due to hypotension (hypovolemia, septic shock)

4) severely decreased blood oxygen content (anemia, lung disease)

ex.  patient with massive bleeding from the GI may develop MI in the absence of atherosclerotic disease because of reduced oxygen supply (loss of hemoglobin and hypotension)

5) rapid myocardial oxygen demand in tachycardia, acute hypertension, etc can cause MI even without atherosclerosis


Does ischemia result in permanent necrosis?

No, ischemia can sometimes result in myocardial dysfunction without necrosis and myocardial recovery may be possible. ex. stunned myocardium, hibernating myocardium


Why does ischemia exhibit with shortness of breath (dyspnea) and chest pain?

Lack of oxygen -> myocytes switch to anaerobic metabolism -> reduced ATP -> reduction in systolic contraction and diastolic relaxation -> increase in LV diastolic pressure (since heart cannot pump out well) -> felt in left atrium too -> pulmonary capillaries start feeling it (since empty into left atrium) -> congestion of blood in lungs -> shortness of breath (dyspnea)

short ATP supply -> more lactate (due to lack of O2, cells going with anaerobic pathway),more serotonin, more AMP => adenosine, etc -> suspected that one or more of tehse activate pain receptors in C7-T4 ->angina




What is stunned myocardium?

after episode of severe transient ischemia (but not necrosis), stunned myocardium's function is impaired even after blood flow returns to normal. However, "in this setting, the functional, biochemical and ultrastructural abnormalities following ischemia are reversible and contractile function gradually recovers"

clinically important because stunned and hibernating myocardium can improve performance with mechanical revascularization, infarcted could not.


What is hibernating myocardium?

hibernating myocardium shows chronic ventricular contractile dysfunction due to consistently low blood supply (compared to prolonged but not chronic in stunned myocardium). irreversible damage has not occured and ventricular function can improve if blood flow restored.

clinically important because stunned and hibernating myocardium can improve performance with mechanical revascularization, infarcted could not.

stunned myocardium - blood flow restored but function still impaired (can be restored to normal)

hibernating myocardium - low blood flow, chronically bad function, but completely gets restored when blood flow restored

think stunned - no matter what happens still can't move - even if blood flow restored

think hibernating like a bear - resources are low, so performance subpar, but when resources are back to normal, tissue is back to normal


What are 3 types of angina?

  1. stable angina
  2. unstable angina
  3. variant angina


What is stable angina?

Stable angina - predictable, transient chest discomfort during exertion or emotional stress. Generally caused by lumen narrowed by athero plaque. Symptoms would vary with degree of stenosis, especially likely with >70% obstruction when exercise/stress O2 levels could not be met (increased HR -> increased O2 demand)

Symptoms persist until O2 falls - usually at rest

usually impaired vasodilation, tissue may paradoxially vasoconstrict instead because of stimulation of alpha-adrenergic receptors during exercise

fixed-threshold angina - level of physical activity to precipitate angina relatively constant

variable-threshold angina - one day activity produces no symptom, but may produce angina on another day


What is unstable angina?

Unstable angina - sudden increase in tempo and duration of ischemic episodes, happening with lesser degree of exertion and even at rest. 


What is variant angina?

variant angina - focal coronary artery spasm int he absence of overt atherosclerotic lesions. also known as Prinzmetal angina. intense vasospasm reduces O2 supply and results in angina, mechanism not understood, may involve endothelial dysfunction.


What is silent ischemia?

Asymptomatic ischemia - can only be seen in tests, such as continuous ambulatory ECG or exercise stress stesting. More common among diabetic patients, the elderly and in women. 


What is syndrome X?

Syndrome X - patients with typical symptoms of angina pectoris who have no evidence of significant atherosclerotic coronary stenoses on coronary angiograms. Microvascular dysfunction, vasospasms and hypersensitive pain perception may be contributing.


Describe quality of pain felt during angina?

  • usually described as "pressure", "discomfort", "tightness", "burning" or "heaviness" in the chest, rather than pain
  • "elephant sitting on chest"
  • not sharp or stabbing
  • does not vary much with inspiration/movement
  • lasts a few minutes, rarely >5-10 mins
  • always lasts more then few seconds (helps to distinguish it from MSK pain)
  • patient may place a clenched fist over his or her sternum to describe pain = Levine sign


What is Levine sign?

patient may place a clenched fist over his or her sternum to describe angina pain = Levine sign


Describe location of anginal discomfort?

  • diffuse and not localized (usually)
  • if patients can point, usually MSK
  • often in retrosternal area, but may occur anywhere in chest, back, arms, neck, lower face, upper abdomen
  • often radiates to the shoulders and inner aspect of arms, esp. left side


What are some of the usual accompanying symptoms of angina?

  • tachycardia
  • diaphoresis (sweating a lot)
  • nausea
  • dyspnea
  • transient fatuge and weakness, esp. in elderly
  • could be these symptoms but no anginal discomfort


What are some of the questions to ask when dealing with angina-like symptoms?

  • patient history + patient physical (listen for S4 during atrial contraction, look for signs of atherosclerotic disease)
  • Q: quality of pain, location of pain, accompanying symptoms, what precipitated the attack, frequency, risk factors, differential diagnosis


What is on your differential diagnosis when presented with angina-like pain?

see Lilly p.149

  • other cardiac causes (pericarditis)
  • gastrointenstinal disorders (gastroesophageal reflux, esophageal spasm, biliary pain) -> often precipitated by certain foods, unrelated to exertion
  • musculoskeletal conditions (chest wall pain, spinal osteoarthritis, cervical radiculitis) -> tend to be more superficial and localized, often vary with changes in position
  • pericarditis-> presence of pleuritic pain (sharp pain aggravated by respiratory movement -> also acute pulmonary stuff, like pulmonary embolism or acute pneumothorax
  • differentiate through history


What are some diagnostic studies to explore angina?

  • ECG - look got ST and T changes, horizontal or downwards STs tend to be acute (subendocardial), elevated for severe (transmural). in 50% of patients, ECG normal during non-ischemia time in stable angina
  • stress testing - to "fake" angina by reducing O2
  • standard exercise testing - treadmill or stationary bike to higher workloads until either angina develops or target HR (85% of maximal HR = 220 beats/min - age) achieved
  • nuclear imaging stuies
  • exercise echo
  • pharmacologic stress tests
  • coronary angio


How is maximal predicted heart rate calculated?

standard exercise testing - treadmill or stationary bike to higher workloads until either angina develops or target HR (85% of maximal HR = 220 beats/min - age) achieved


When is exercise test considered positive ?

Positive if:

1) patient's typical chest discomfort is reproduced

2) OR ECG abnormlaities are consident with ischemia (>1mm horizontal or donsloping ST segment depression)

sensitivity of about 65-70%

markedly positive if:

1) ischemic ECG changes develop in the first 3 minutes or persist 5 minutes after exercise was stopped

2) the magnitude of the ST segment depression is >2mm

3) systolic blood pressure abnormlaly falls during exercise (resulting from ischemia-induced impairment of contractile function)

4) high-grade ventricular arrhythmias develop

5) patient cannot exercise for at least 2 minutes because of cardiopulmonary limitations


make sure medications are withheld for 24-48 hrs


Till what time is exercise test continued? When might it be not the best measure?

  • Do until maximal heart rate 0.85*(220-age) is reached
  • OR angina is developed
  • OR patient too fatigued to continue

certain medications would not allow stress test to be effective. for instance, beta blockers and some calcium channel blockers may not allow one to achieve their target heart rate. may not be best


Acute myocardial infarction within 48 hours
Unstable angina not yet stabilized with medical therapy
Uncontrolled cardiac arrhythmia
Severe symptomatic aortic stenosis, aortic dissection, pulmonary embolism, and pericarditis


What do nuclear imaging studies do?

nuclear imaging studies

radionuclear substance is injected IV at peak exercise, then imaging is performed. Radionucleotide will accumulate in proportion to the degree of perfusion of viable myocardial cells. Areas of poor perfusion (ischemic areas) do not accumulate = cold spots. both transient ischemic and infarcted tissues will not perfuse well, so imaging repeated at rest to compare. If cold spots are filled in, these muscles were in transient ischemia, if cold spot unchaged - infarcted region. 

80-90% sensitive, 80% specific for CAD

expensive, use for patients with baseline ECG abnormalities (can't interpret ECGs as already changed) or when standard stress tests are not conclusive with previous suspicions of CAD


What is exercise echo?

exercise echo

LV contractile function assessed by echo at baseline and immediately after treadmill or bike. test can indicate inducible myocardial ischemia if regions of ventricular disfunction are noticed on exertion. 


What are pharmacologic stress tests?

pharma stress tests are great for patients not able to exercise (ex. hip or knee arthritis). give vasodilators such as dipyridamole or adenosine -> oronary vasodilatation -> ischemic regions already maximally dilated, so drug induced vasodilation steals flow from these regions to now more dilated healthy myocardium -> coupled with nuclear imaging or echo, could see regions of impaired perfusion



What is coronary angiography?

coronary angiography - most direct means of idnetifying coronary stenoses -> injection of radiopaque contrast material into the artery and visualization of coronary lumens and narrowing 

as invasive, risk of coplications, usually reserved for patients who dont' respond to drugs or unstable patients, where revascularization is likely, so want to understand where.

"gold standard" for diagnosis of CAD, but only anatomic info  - not seen viobility of myocardium segments affected, degree of ventircular contractile dysfunciton, etc



What is echocardiogram (echo)?

Echocardiogram, often referred to as a cardiac echo or simply an echo, is a sonogram (ultrasound) of the heart. Can be done with contrast (colours!)


_______ = arteriosclerosis (hardening, thickening and loss of elasticity of artery wall) with fatty component



What is arteriosclerosis? How does it relate to atherosclerosis?

skleros means hardness

arteriosclerosis is hardening, thickening and loss of elasticity of the artery walls

athere means porridge (think fatty porridge)

atherosclerosis is arteriosclerosis (narrowing, hardening) with fatty component. atherosclerosis is a type of arteriosclerosis



What is arterothrombosis?

atherothrombosis = arteriosclerosis with prominent fatty and thrombotic components


______ = hardening, thickening and loss of elasticity of the artery wall



______ = arteriosclerosis with prominent fatty and thrombotic combonents



Which cells in arterial layers can produce antioxidants and which cells produce oxidized free radicals?

Healthy endothelial cells can produce antioxidants, such as superoxide dismutase, which can scavenge free radicals and prevent LDL oxidation.

Smooth muscle cells can produce oxidized free radicals (with onset of endothelial dysfunction!), which can in turn modify LDLs by oxidation and make them permanent residents in endothelium.

memory aid: superoxide  b/c prevents oxidation dismutase b/c prevents mutations by blocking super-reactive free radicals (cells that have valence electrons that are super reactive!)


what is diapedesis?

diapedesis = migration of WBCs into the subendothelial space of arteries, marks beginning of atherosclerosis, inflammatory response. done via adhesion molecules

how is it related to extravasation?

extravasation is the leakage of a fluid out of its container. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to the tissues surrounding them (diapedesis). Seems extravasation is more into any tissues, where as diapedesis is into nearby surrounding tissues.


What is the function of WBCs in atherogenesis?

  • dendritic cells or antigen presenting cells (APC) - a specialized form of macrophage that presents antigens to T-cells and B-cells - bridges innate and adaptive immunity (reminder that antigens can form from modified LDL's, such as glycosylated LDLs) -> further inflammation
    • generates inflammatory cytokines like TNF, IL 12, inflammatory chemokines
    • antigen presentation - activation of T helper immune cells
    • but can also produce anti-inflammatory cytokines IL 10 and IL 27
  • The majority of pathogenic T cells in atherosclerosis are of the Th1 profile producing high levels of IFN-γ. Th1-driven responses are detrimental to the atherosclerotic process (1). IFN-γ is known to activate monocytes/macrophages and DCs, leading to perpetuation of the pathogenic Th1 response. In addition, IFN-γ may inhibit vascular smooth muscle cell proliferation and reduces their collagen production while upregulating the expression of matrix metalloproteinases, thereby contributing to the thinning of the fibrous cap
  • dysfunctional endothelial cells can also produce IL 6 and TNF alpha especially because LDL gets oxidized -> "oxidative stress can induce local cytokines" -> cytokines promote expression of leukocyte adhesion molecules + chemoattractants for monocytes and other WBCs
  • monocytes -> macrophages -> engulf a lot of LDLs via scavenger receptors and become foam cells


What are some of the events in endothelium and with smooth muscle cells that happen with endothelial dysfunction?

endothelial cells:
  • endothelial cells can produce contractile signals, such as endothelin and angiotensin II - smooth muscles constrict
  • vasodilatory signals, such as prostacyclin and NO are inactivated by free radicals produced bo smooth muscle cells etc
  • endothelial cells produce inflammatory mediators, like IL-6, TNF alpha, etc

smooth muscle cells:

  • synthesize too much ECM (extracellular matrix) -> this traps even more LDLs
  • replicate and migrate to subendothelial space ->remodel artery
  • produce free radicals


So what is with thrombotic processes, why does atherosclerotic rupture end with the trombus?

Easy. endothelial cells damaged -> platelet/thrombin complexes can attach to endothelium and get "sucked in" into plaque -> as plaque ruptures, these platelet/thrombin complexes are exposed promoting formation of thrombus


What is Glagov effect?

Compensatory remodelling to maintain constant lumen (atherosclerosis goes around the vessel rather then into middle of it)


Knowing how atherosclerosis is formed, what can you do to manage its formation (pharma therapy and lifestyle modifications?)

  • ASA to reduce platelet reactivity (Aspirin)
  • statins to reduce # LDL particles -> less foam cells, improved endothelial function
  • smoking cessation -> less oxidized LDLs, decreased platelet reactivity, reduced sympathetic constriction of vessels, improved endo function
  • antihypertensives: decreased endothelial cell and smooth muscle cell barotrauma, reduction of SMC production of free radicals, improved endothelial function
  • diabetes therapy: reduction of glycated LDL ->reduction in inflammation
  • exercise: increased blood flow = increased shear stimulation of endothelial cells


So to recap, what is the role of T-cells in atherogenesis again?

The majority of pathogenic T cells in atherosclerosis are of the Th1 profile producing high levels of IFN-γ. Th1-driven responses are detrimental to the atherosclerotic process (1). IFN-γ is known to activate monocytes/macrophages and DCs, leading to perpetuation of the pathogenic Th1 response. In addition, IFN-γ may inhibit vascular smooth muscle cell proliferation and reduces their collagen production while upregulating the expression of matrix metalloproteinases, thereby contributing to the thinning of the fibrous cap


Describe the mechanisms by which cholesterol, hypertension and smoking promote atherogenesis?

cholesterol -> higher level of LDLs -> more gets deposited in subendothelium; cholesterol is also general irritant - promotes inflammation and production of reactive oxygen species - more inflammation

smoking -> chemical irritant -> damages endothelium (and promotes production of more reactive oxygen species - more endothelial damage) -> deposit of LDL -> many steps later atherosclerosis

hypertension -> hemodynamic stress, turbulent flow -> physical force on endothelium increases -> damaged endothelium -> more likely to get LDL deposited -> many steps later ... atherosclerosis

endothelial function interrupted - can no longer function as good permeability barrier, releases inflammatory cytokines, increases production of cell survace adhesion molecules for leukocytes to bind, reduced release of vasodilators like NO -> less antithrombotic properties.


 lipoprotein entry into intima (LDL ), once in intima LDL accumulates in subendo space by binding to proteoglycans and undergoes modification (oxidation via ROS or glycation in diabetis)

inflammation = leukocyte recruitment


monocytes -> macrophages -> eat lipids and become foam cells


How many ml does heart pump per heart beat?

70 ml/beat, 5L/min, 7200 L/day (lecture notes)


What do myocytes use for fuel during fasting? after a meal?

From lecture notes:

In fasting state, free fatty acids (FFA) are preferred (60-70% of cardiac needs), glucose/glycogen <30%, lactate 10%

After a high-carb meal, glucose 70%

After a fatty meal, FFA up to 80%

(FFA enters Krebs as AcetylCoA)


Provide a brief overview of coronary vessel anatomy?

The left main coronary artery (LMCA) originates from the left sinus of Valsalva (referred to as left coronary sinus by cardiologists) located just distal to the left cusp (valvule) of the aortic valve. The right coronary artery (RCA) originates from the right sinus of Valsalva (referred toas the right coronary sinus by cardiologists) located just distal to the right cusp of the aotic valve.

Clinically there are considered to be three coronary arteries, because the LMCA soon divides into the left anterior descending coronary artery (LCA) to supply the anterior wall of the left ventricle (diagonal branches) and most of the interventricular septum (septal branches), and the circumflex coronary artery (Cx) to supply the lateral wall of the left ventricle.

The RCA supplies the right ventricle and usually the posterior part of the interventricular septum. It also usually supplies the SA and AV nodes. Coronary veins accompany the coronary arteries distally and eventually converge on the coronary sinus which runs along the posterior surface of the heart in the AV groove and empties into the right atrium.

Notice that diagonal branch comes of LAD

Marginal branch comes off Cx


What is coronary perfusion gradient? 

coronary perfusion gradient = aortic root pressure (at aorta, when blood just leaves to go into coronary vessels) - LV pressure (at the very end of blood vessels at endocardial surface). basically it is a difference in pressure between where coronary blood enters and where at the tips of arterioles where it ends. the more pressure difference, the better the flow -> better perfused heart

at systole: Aortic pressure = 120; left ventricular pressure = 120, pressure gradient = 0  - no coronary blood flow

at diastole: aortic pressure = 90, LV pressure = 10, coronary perfusion gradient = 80 - coronary blood flow

coronary blood flow happens during diastole. during systole left ventricular chamber pressure is so high that it literally squeezes coronary arteries to a point no blood flow can get through

because flow occurs only in diastole, duration of diastole is very important. normally 2:1 so heart can perfuse well, but this ratio decreases as HR rises


What determines coronary blood flow?

coronary perfusion gradient = difference in pressure between aortic root (entry of blood) and left ventricular chamber (end of blood flow) is what forces blood through coronary circulation.

coronary circulation is opposed by coronary resistance, which is a combination of arteriolar tone (ex.vasoconstriction) and LV pressure in diastole when blood flow happens (if LV pressure high even in diastole, not a lot of blood can make it through coronary vessels if LV squeezes coronary vessels in)

duration of diastole is important. at resting 2:1 so heart has enough time to perfuse, as HR increases, diastole becomes shorter

from lecture


What are some of the factors that influence coronary artery resistance?

from lecture, in the order of importance

  • metabolic - ischemia produces increase in adenosine, H+, K+, CO2 an fall in O2 - causes vasodilation of arterioles and relaxation of precapillary sphincters
  • endothelial - secretes EDRF/NO - vasodilatory, can also produce prostacyclin (vasodilator), endothelin (vasoconstrictor)
  • neurogenic - alpha stimulated - vasoconstriction, beta 2 - vasodilation; parasympathetic - vasodilation
  • myogenic - smooth muscle contracts/relaxes depending on perfusion pressure 
  • stenoses - atherosclerotic plaques and spasms


What is coronary reserve?

Difference between resting coronary blood flow and maximum coronary blood flow is called coronary reserve.

Coronary flow may increase up to 5x during heavy exercise and coronary reserve must be adequate to meet this increase. if it is not adequate, ischemia results. if ischemia is prolonged for more then 15-20 minutes, myocardium begins to infarct/necrose.