CV week 3 Flashcards
Smoking and CAD risk
(50% increase in CAD risk) - cessation can normalize risk
- Thrombogenic tendency, platelet activation, increased fibrinogen
- Aryl hydrocarbon compounds promote atherosclerosis
- Endothelial dysfunction, vasospasm
- CO decreases myocardial oxygen delivery
- Adverse effect on lipoproteins (decreased HDL)
HTN and CAD risk
- Increased shear stress on arterial wall → endothelial cell injury and pathologic cell signaling (causes oxidant stress, cell proliferation)
- Circulating hormones increased in HTN (angiotensin, aldosterone, NE) → adverse effects on arterial wall
- LVH due to increased heart work → increased risk
- Treatment reduces CV risk
Diabetes (and insulin resistance) and CAD risk
associated with inflammation, oxidative stress, dyslipidemia which predispose to atherosclerosis
Dyslipidemic triad
high LDL, low HDL, high triglycerides
LDL cholesterol
when oxidized, LDL = proinflammatory/atherogenic →
Injures vascular endothelium, impairs endothelial function
Deposited in arterial wall, taken up by macrophages → progressive increase in plaque volume
Activates inflammatory cells → progression/instability of lesions
Activates platelets, prothrombotic
HDL cholesterol
- beneficial, opposes atherothrombosis
- Inhibits LDL oxidation
- Inhibits endothelial adhesion molecules
- Inhibits tissue factor
- Stimulates NO production
- Enhances reverse cholesterol transport
Inflammation and CAD risk
key in initiation and progression of atherosclerosis
Lipid-laden macrophages (foam cels): in arterial wall plaque, highly pro-inflammatory
Extravascular inflammation (dental, respiratory, immunologic diseases): increase risk of athersclerotic CV events
Circulating markers of inflammation (e.g. CRP, IL-6): provide info about future CV risk
-Originate from inflammatory foam cells in arterial atheroma → IL-6 made by liver → CRP present in high concentrations in blood = amplified signal
Risk factors for CAD
smoking
HTN
diabetes
inflammation
dyslipidemia
Obesity, Psychological Stress, Sedentary Lifestyle
Obesity, Psychological Stress, Sedentary Lifestyle
Progression of atherosclerosis (3 steps)
1) Clinically silent
2) Effort angina claudication
3) Acute vascular events
Features of clinically silent CAD
fatty streak in vessel
Endothelial injury
Lipid deposition
Macrophage and T cell recruitment
Features of Effort Angina claudication
fibrous plaque → occlusive atherosclerotic plaque
Activated macrophages (foam cells)
Smooth muscle proliferation forms fibrous cap
Progressive lipid accumulation in core of plaque
Features of Acute Vascular events
plaque rupture/fissure and thrombosis → unstable angina, MI, stroke, critical leg ischemia
Plaque disruption
Thrombus formation
Vessel occlusion may occur
Distinguishing features of coronary circulation (3)
1) Myocardium depends on AEROBIC metabolism for energy supply
- Skeletal muscle adapted for burst energy production from anaerobic metabolism → lactate, H+ accumulation → fatigue
- Cardiac muscle requires sustained energy production, no fatigue
2) Under resting conditions a near-maximal amount of O2 is extracted from coronary arterial blood
- Must increase BLOOD FLOW RATE in order to increase O2 supply
3) The LV is perfused in diastole only (compression of intramural coronary vessels in systole)
Determinants of myocardial O2 supply
CORONARY BLOOD FLOW RATE
1) Perfusion pressure
2) Perfusion time (1/HR)
3) Vascular resistance
OXYGEN CONTENT
Determinants of myocardial O2 demand
1) Heart Rate
2) Wall Tension: determined by systolic BP, cardiac chamber dimensions (law of LaPlace T = (Ptm)(r)/u)
3) Inotropic State (contractility)
Coronary oxygen delivery = ______ x _______
CBF x O2 content
Perfusion pressure autoregulation
adaptive mechanism to maintain perfusion in face of altered perfusion pressure - at level of small arterioles
Provides protection from moderate changes in perfusion pressure
Dilation of downstream resistance vessels can compensate for pressure drop across stenosis (autoregulation) but only up to a point
Autoregulation of perfusion pressure and CHD
CHD → autoregulation exhausted when pressure drops across an epicardial coronary stenoses (downstream pressure lower than upstream pressure) → Ischemia
Pressure drop related to length and diameter of stenosis
Perfusion time is important why?
Increased HR → shorten cardiac cycle mostly by shortening diastole → tachycardia compromises coronary flow (esp. to LV)
Oxygen content of blood can be compromised by ______ and _______
Anemia → less Hgb per ml blood
Hypoxemia → incomplete saturation of Hgb
Pathophysiology of STABLE CAD
Obstructive coronary lesion limits coronary flow and causes myocardial ischemia, particularly when cardiac work and O2 demand increase
Ischemia = imbalance between coronary oxygen delivery and myocardial demand → angina pectoris
Characterized by EFFORT ANGINA
Treatment of stable CAD: improving supply decreasing demand how? 4 strategies for each
Supply:
1) Perfusion Pressure: prevent hypotension
2) Diastolic Time: rate slowing drugs (e.g B-Blockers)
3) Coronary Resistance: vasodilator drugs (nitrates, Ca channel blockers), coronary angioplasty, bypass surgery
4) Oxygen Content: treat anemia and hypoxemia
Demand:
1) Systolic Pressure: antihypertensive drugs
2) Heart rate: rate-slowing drugs (B-B, Ca channel blockers)
3) Wall tension: limit LV cavity size - limit excessive preload (diuretics, nitrates)
4) Inotropic state: negative inotropes to attenuate contractile state (B-B, Ca channel blockers)
Pathophysiology of unstable CAD (5 steps leading to cardiac dysfunction)
1) Inflammation of arterial wall (foam cell, T-lymphocyte)→ weakening of fibromuscular cap
2) → abrupt plaque fissure or rupture → thrombogenic components (lipids, TF) exposed to blood
3) Thrombosis with partial/complete vessel occlusion
4) Myocardial injury and/or necrosis → serum markers
5) Cardiac dysfunction, risk of arrhythmias, death
Markers of inflammation used in CAD
Inflamed arterial atheroma → inflammatory markers (CRP)
Downstream myocardial injury → cardiac markers (troponin, creatine kinase)
Unstable Angina
- “Threatened” heart attack
- Biomarkers usually negative (e.g troponin)
- May not result in permanent myocardial damage if treated successfully
- High risk of recurrent events in first year
Acute MI
- Persistent and severe coronary flow reduction
- Thrombus with complete vessel occlusion
- Necrosis → cardiac dysfunction/failure
- Biomarkers (troponin released from necrotic myocardial cells) elevated
- Cardinal symptoms: severe unremitting chest discomfort at rest (30% of MIs are silent)
- Early reperfusion key to tx but may also provoke additional injury (reperfusion injury)
- High mortality (⅓ don’t get to hospital)
- Late mortality related to extent of LV dysfunction
Within minutes of acute coronary occlusion what happens? (4)
within 1 hour?
1 minute:
1) Impaired Ca2+ re-uptake into SR during diastole → diastolic dysfunction (filling impairment) → increased LV filling pressures → pulmonary congestion and edema
2) Depletion of high energy phosphates, intracellular acidosis → systolic dysfunction (contractile failure)
3) ECG signs of myocardial injury
4) Symptoms (CP, dyspnea, arrhythmias)
1 hour:
myocardial necrosis and infarction
Treatment of unstable coronary heart disease (6)
Hospitalization IV NTG B-Blockers ASA and antiplatelet agents Anticoagulation (heparin) Catheterization and coronary intervention
Treatment of Acute MI with ST elevation
- Tx initiated in the field
- Immediate ASA, NTG, +/- B-blocker
- Reperfusion therapy ASAP (coronary angioplasty)
- thrombolytic therapy
Diagnosis of stable coronary artery disease: history and physical exam
History: CP, dyspnea, risk factors
Exam: may be normal or reveal evidence of cardiac dysfunction from prior myocardial damage (CHF) and evidence of atherosclerosis
Diagnosis of stable coronary artery disease: ECG
Resting ECG: ST segment changes (usually depression), T wave inversion, Q waves (indicate prior infarction)
Exercise ECG: dynamic ST segment changes
Ischemic response: horizontal/down sloping ST DEPRESSION with exercise → subendocardial ischemia
*Sensitivity of stress ECG questionable - use functional information, symptoms, and myocardial perfusion to improve sensitivity and specificity of stress ECG
Diagnosis of stable coronary artery disease: CT
noninvasive diagnosis of coronary atherosclerosis by coronary calcium on CT
Diagnosis of stable coronary artery disease: Coronary angiography
picture of vessel lumen (NOT vessel wall)
Good for diagnosis of coronary obstruction causing anginal symptoms, not good for predicting future events
How to estimate severity of coronary lesion on coronary angiography?
Distal pressure (Pd) with solid state catheter, compared to aortic pressure (Pa)
Infuse vasodilatory (adenosine) to have maximal dilation of resistance vessels
Allows you to assess under high flow and thus physiologic significance of stenosis
Ratio of distal coronary/aortic P
Treatment of stable CAD
1) Risk factor modification (for prevention and treatment of overt disease)
- Diet, exercise, smoking cessation
2) Drugs to treat angina, BP, lipids, platelets
- Lipid modifying (Statins)
- HTN treatment
- Antiplatelet (ASA, clopidogrel)
- Anti-anginal (nitrates, B-blockers, Ca channel blockers)
- LV dysfunction: ACEI, ARBs, B-blockers (if prior MI with reduced LV function)
3) Revascularization
- Coronary angioplasty
- Coronary artery bypass surgery
Coronary Angioplasty
- tx of acute occlusion or restenosis
- Balloon dilation of obstructed/narrowed vessel
Acute occlusion → stent and antiplatelet drugs
Restenosis → stents
-Fibrotic inflammatory reaction to stent = restenosis
Coronary Artery Bypass Grafting: (CABG)
Reduces mortality compared to medical therapy, may be better than angioplasty when there are multiple blockages
Used in chronic multi vessel coronary disease - not typically with acute MI (would do angioplasty because it’s faster)
Types of grafts used in CABG
Internal mammary artery (durability of arterial graft better than venous)
Saphenous vein
Prosthetic materials not successful as grafts
Normal properties of endothelium (4)
1) anti-inflammatory
2) anti-thrombotic
3) vasodilatory
4) impermeable to large molecules
Nitric oxide normal expression
- made by nitric oxide synthase + cofactors from L-arginine precursor
- Expressed on luminal side of endothelium
- Responds to multiple stimuli
- Diffuses to vascular smooth muscle → cGMP-mediated vasodilation
Endothelium in inflammatory state (5)
1) Increased Permeability (to LDL)
2) Decreased NO (decreased vasodilation)
3) Decreased antithrombotic molecules
4) Expression of cytokines (IL-I, TNF)
5) Expression of cell adhesion molecules (CAMs, selectins)
Step 1 of atherosclerotic plaque formation:
Fatty Streak
precipitated by endothelial dysfunction (chemical or physical endothelial damage)
→ lipoprotein entry and modification, leukocyte recruitment, foam cell formation (full of LDL and pro-inflammatory molecules)
Step 2 of atherosclerotic plaque formation:
Plaque progression
smooth muscle cell migration into subendothelial space, altered matrix synthesis and degradation
-Foam cells produce MMPs that break down fibrous cap
Step 3 of atherosclerotic plaque formation:
Plaque Rupture
disrupted plaque integrity, thrombus formation
Fibrous rupture → Thrombosis → acute MI or healed rupture with narrowed lumen and fibrous intima
Common mechanisms of ischemic stroke (2)
1) Atheroembolism from carotid bifurcation lesion
- Breaks off and goes to brain
- Debris often goes to ophthalmic artery → loss of vision in one eye
2) Thromboembolization from LA appendage due to AFIB
Common mechanism of myocardial infarction
Thromboembolism
-ruptured plaque, in-situ thrombosis, not necessarily obstructive prior to rupture
Spectrum of severity of MI
1) Plaque rupture → NONOCCLUSIVE thrombosis, some flow, intermittent occlusion or embolization → stabilize with anticoagulation/vasodilators
- Unstable angina or NSTEMI (ST depression and/or T wave inversion)
2) Plaque rupture → OCCLUSIVE thrombus → no flow → clinical emergency → recanalize
- STEMI - emergency (prevention of irreversible myocardial necrosis)
Claudication
Leg pain induced by exertion
Manifestation of peripheral arterial disease (PAD)
-OBSTRUCTIVE (>70% diameter reduction), stable plaque
Acute Limb ischemia
- Manifestation of peripheral arterial disease (PAD)
- Acute event obstructs blood flow without prior development of collaterals
- Atheroembolization or thromboembolization
- Rarely in-situ thrombosis
Stable plaque
rich in fibrous tissue, calcified, less lipid content, less inflammation, less apoptosis → Angina
- Less biologically active
- Cause angina and claudication (exertional ischemia) if obstructive (>70% diameter reduction)
- Less likely to cause thrombotic and embolic events
Unstable/Vulnerable plaque
less fibrous tissue, less calcified, more lipid content, more inflammation/inflammatory cells, more apoptosis → plaque rupture, thrombosis
- More biologically active
- Cause MI and stroke
- More likely via thrombotic and embolic mechanisms
Venous vs. arterial thrombus
Venous = DVT, PE
- Fibrin rich, RBC rich, area of stasis, genetic predisposition, environmental predisposition
- Treat with anticoagulation
Arterial =
- Platelet rich, plaque rupture, areas of high flow, atherosclerosis, trauma, APLA
- Treat with antiplatelet therapy
What information can be obtained from an ECHO
chamber size, function, and structure, wall motion, valves, pressure and hemodynamics, shunts, murmurs, intracardiac masses, bacterial endocarditis, pericardial disease
-Can use micro-bubbles that are too large to pass through pulmonary capillaries - If you see bubbles in L heart → intracardiac shunt, intrapulmonary shunt
Cardiac Catheterization and Coronary Angiography
Catheter inserted into artery or vein, advanced to heart or coronary arteries
Measurements of: pressure, gradients, saturation, intracardiac shunt
Inject contrast for angiography
Contraindications for stress testing
Unstable angina, untreated life-threatening arrhythmias, uncompensated heart failure, advanced AV block, acute myocarditis/pericarditis, critical aortic stenosis, significant HOCM, uncontrolled HTN, acute systemic illness
Pharmacologic agents used in stress testing
Vasodilator (Dipyridamole, Adenosine, Regadenoson)
Dobutamine (B-agonist)
Radionuclide Stress Test General Concepts
Tracer deposited based on blood flow
- Thallium-201 = continuous exchange across cell membrane
- Technetium-99m-Sestamibi (Cardiolite) = one pass
- Imbalance between supply and demand results in relative decreased perfusion
- Compare perfusion during increased demand (stress) and decreased demand (rest)
- Reversible perfusion defects indicate reversible ischemia
- Fixed perfusion defects indicate infarction, scar
Stress ECHO General Concepts
- Imbalance between supply and demand results in wall motion abnormality
- Compare increased demand (stress) wall motion to decreased demand (rest) wall motion
- Normally LV should beat faster and thicken more with exercise or dobutamine
BNP
32-aa peptide found only in ventricles of heart
-Released in response to stretch, and increased ventricular volume
BNP levels correlate with:
- LV EDP
- NYHA classification
- Objective heart failure diagnosis in pts 55 or older
- Levels higher in women, elderly, renal insufficiency
- Negative predictive value
Troponin I and T
- Regulatory proteins involved in actin-myosin interaction
- Specific to heart
- Released into bloodstream with myocyte necrosis
Troponin timeline
Released within 3-12 hrs
Peak 18-24 hrs
Remains elevated for 7-10 days
Exacerbating factors in coronary atherosclerosis
1) Coronary artery vasospasm
2) Platelet aggregation +/- coronary vasospasm
3) Hypotensive episode e.g. shock, massive hemorrhage in presence of critically stenosed coronary artery
Reperfusion Injury
-damage that occurs to myocytes following restoration of blood flow
-Mitochondrial dysfunction
Influx of Ca2+ → myofibril hypercontracture
- Free radical damage to membrane proteins and phospholipids
- Leukocyte aggregation
- Platelet and complement activation
Myocardial Infarction Evolution
-Start in subendocardial region (most poorly perfused and thus vulnerable)
Progress towards epicardial region over several hours (intervention may limit progression)
-Myocardial ischemia due to hypoxia AND low blood flow has more detrimental effect than hypoxia alone due to added detrimental metabolic problems
Myocardial Infarction:
Size/Extent determined by…(4)
1) Site of occlusion
2) Duration of ischemia
3) Extent of collateral circulation
4) Metabolic needs of myocardium
Myocardial infarction typical location
- Majority involve LV and septum (more prone to ischemia due to larger mass, higher workload and oxygen demand)
- Only 1-3% involve RV
Collateral Circulation
preferentially supplies outer myocardium, thus can limit infarcts to subendocardial area
Pathology Evolution of Infarcts:
0-30 min
0-30 min: reversible ultrastructural/biochemical changes
- ATP levels fall, cessation of contractility
- depletion of ATP, cellular edema, decreased membrane potential and susceptibility to arrhythmias
20-24 min: IRREVERSIBLE CELL INJURY
Pathology Evolution of Infarcts:
1-2hrs
4-12hrs
1-2 hr: irreversible ultrastructural changes
-sarcolema disruption, release of intracellular proteins and ion gradient disruption
4-12 hr: wavy myofibers (noncontractile ischemic fibers stretched with each systole)
-No gross changes
Pathology Evolution of Infarcts:
18-24 hrs
24-72 hrs
18-24hr:
- coagulation necrosis (pyknotic nuclei with eosinophilic cytoplasm)
- PMN infiltration
- GROSS CHANGES PRESENT (pallor, contraction bands at edge of infarct
24-72 hours:
- max coagulation necrosis (no nuclei or striations, rimmed by hyperemic tissue)
- neutrophils infiltration peaks
- monocytes appear
Pathology Evolution of Infarcts:
4-7 days
- macrophages with disintegration of myocytes (max softening)
- Gross changes = pallor with hyperemic border
Pathology Evolution of Infarcts:
10 days
4-8 weeks
10 days: granulation tissue
-Gross changes = yellow, soft with dark border
4-8 wks: fibrosis
-Gross changes = firm and gray
