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
Complications associated with MI
1) Arrhythmias
2) LV failure with pulmonary edema
3) Cardiogenic shock (if >40% LV infarction)
4) Pericarditis (CP, friction rub)
5) Infarction/rupture of papillary muscle with mitral valve incompetence
6) Ventricular aneurysm can rupture, or develop mural thrombus
7) Rupture of LV free wall or septum
8) Mural thrombus (+/- embolism) may occur early or late
Rupture of LV free wall or septum
- May occur within first 3 weeks, usually within 2-10 days post infarction
- Due to max softening and macrophage activity at 4-7 days
- 10% of deaths post MI in hospitalized patients
Hypertensive Heart Disease
- Pressure overloaded states → add new sarcomeres → increase diameter of muscle fibers → concentric hypertrophy → increased O2 requirements → vulnerable to ischemic injury since myocardial capillary bed does not expand in step with increased myocardial mass
- Predisposition to atherosclerosis and problems in other organs due to HTN
Aneurysm
localized, congenital, or acquired vessel dilation (saccular, fusiform, berry) secondary to weakening of the wall
Atherosclerotic Aneurysm
Pathogenesis:
- plaque→compress media→degeneration/ thinning wall
- Inflammation → ECM degradation → weaken wall
- Most common type of aneurysm (elderly males)
- Often due to severe atherosclerosis of abdominal aorta below renal arteries
- Often asymptomatic
Aneurysms can form due to…(4)
1) Systemic diseases: atherosclerosis, HTN, vasculitis
2) Developmental defects
3) Infection: mycotic aneurysms secondary to septic emboli from infective endocarditis
4) Congenital diseases: marfan syndrome (defective synthesis of fibrillin)
Berry aneurysms
- congenital defect in media of arteries at bifurcation of cerebral vessels → subarachnoid hemorrhage
- Berry aneurysms associated with polycystic renal disease
- severe rapid onset headache
Vessel Dissection
Most often in aorta
-Blood dissects into media of vessel wall (often due to intimal defect)
Outcomes of dissection
1) Rupture into the mediastinum or retroperitoneum
2) Back into pericardial cavity → tamponade
3) Double barreled aorta
Symptoms of dissection and predisposing factors of dissection
Symptoms:
1) Sudden onset severe CP radiating to back
2) Hypotension, shock
3) CT scan shows double lumen
Men 40-60 with HTN (younger if CT abnormalities - marfan)
Infectious Vasculitis
Direct invasion of arteries by bacteria or fungi (aspergillus/mucor)
Vascular invasion as part of generalized infection (e.g. abscess, pneumonia)
Giant Cell (temporal arteritis)
Most common type of arteritis
- Segmental granulomatous inflammation of branches of carotid arteries (esp. Temporal artery)
- Sometimes involves ophthalmic artery, can cause blindness
- Most commonly elderly females
DX: clinical (headache, localized tenderness, visual symptoms), ESR, biopsy
TX: steroids
Polyarteritis Nodosa
Acute segmental necrotizing vasculitis of small/medium arteries with coexisting different stages of inflammation
- Involves gut, NOT lungs
- most common in middle-aged males
TX: steroids, immunosuppressive drugs
Wegener’s Granulomatosis
- Necrotizing granulomatous inflammation of small to medium vessels
- Cell mediated hypersensitivity response directed against inhaled infectious or environmental antigens
- LUNG AND KIDNEY INVOLVEMENT
- Males more than females
- positive for PR3-ANCA (neutrophil granule)
Churg Strauss Syndrome
- Allergic (assoc. with fever, asthma, increased eosinophils)
- Granulomatous necrotizing vasculitis of small arteries and veins
- more common in young adults
Leukocytoclastic / Hypersensitivity Vasculitis
Involves arterioles, venules, and capillaries of skin mucosa
- Self limited
- Skin (palpable purpura)
- Often hypersensitivity to drugs/infectious organisms
Granuloma Pyogenicum
benign vascular lesion
-polypoid granulation tissue nodule on skin or mucosa
Capillary hemangioma
benign vascular lesion
-Affects skin, mucosal surfaces, occasionally deep organs
In newborns may grow rapidly, but 80% will spontaneously regress
Cavernous hemangioma
benign vascular lesion
- Affects skin, mucosa, or organs
- Associated with von Hippel Lindau Disease
- Associated with Sturge Weber Syndrome when in 5th nerve distribution
Kaposi Sarcoma
- Intermediate grade vascular lesion
- Malignant tumor with skin, mucosa, or deep visceral involvement -start with skin/mucosa, progress to internal organs
- Associated with AIDS and HHV-8
Angiosarcoma
- malignant skin lesions
- Rare sarcoma involving skin, soft tissue, breast, liver
- Most common in elderly caucasians
Unfractionated Heparin
Mechanism of action
indirect thrombin-10a inhibitor
-Binds ATIII and accelerates activity –> inactivates 2 and 10
Unfractionated Heparin
Pharmakokinetics
given IV or SC (not absorbed from GI)
- Does NOT cross placenta (safe in pregnancy)
- Requires IV loading dose for immediate anticoag effect
- Continuous infusion preferred (less bleeding complications)
Heparin
Uses (3)
1) prevention and treatment of venous thromboembolism (PE, DVT)
2) prevention of cardioembolic events (stroke) in patients with AFIB
3) Tx of UA, acute MI (NSTEMI, STEMI)
Heparin
Adverse reactions (4) and OD
1) Hemorrhage
2) Hypersensitivity rxns to contaminants
3) Thrombocytopenia (heparin more than LMWH, NOT with fondaparinux)
4) Osteoporosis
Overdose:
- Nosebleeds, hematuria, tarry stools, bruising
- TREATMENT → PROTAMINE (neutralizes heparin within 5 min)
Heparin Drug-Drug interactions (1)
1) drugs that interfere with platelet aggregation
- ASA, indomethacin, ibuprofen, dextran
LMW Heparin
Mechanism of action
- bind ATIII, inactivate Xa but not IIa (thrombin)
- renal elimination
LMW Heparin
benefits over UF Heparin
- Less tendency for bleeding complications
- Less effects on platelets (less thrombocytopenia)
- No effect on aPTT
- less monitoring
Fondaparinux
mechanism of action
activates ATIII, inactivates Xa only
Warfarin (Coumadin)
Mechanism of Action
-acts in liver to block vitamin K-dependent clotting factor synthesis (2, 7, 9, 10, protein S, protein C) by blocking vitamin K reactivation (carboxyglutamic rxn)
Warfarin (Coumadin)
Pharmakokinetics (6)
1) 100% oral absorption
2) Crosses placenta, contraindicated in pregnancy
3) CYP2C9 metabolism → drug interactions
4) VKORC1 enzyme has genetic polymorphisms = different warfarin sensitivity among patients
5) Protein C inhibition can result in early procoagulant effect
6) Onset of anticoag effect delayed to allow turnover of existing clotting factors (dependent on half life - 2=60hrs, 7=6hrs, 9=24hrs, 10=40hrs)
Warfarin (Coumadin)
Uses (2)
1) AFIB: prevention of thromboembolic complications
2) Prophylaxis of thromboembolism (from valve replacement)
Warfarin (Coumadin)
Adverse Reactions (3) and OD
1) Hemorrhage
2) GI
3) Osteoporosis
Overdose:
- Hematuria, excessive menstrual bleeding, gum bleeding, bruising
- Must closely monitor INR
- Use IV infusion of vitamin K
Warfarin (Coumadin)
Drug interactions - increased warfarin effect
Increased effect: Inhibit CYP2C9: 1) amiodarone 2) cimetidine 3) fluconazole 4) fluoxetine 5) metronidazole 6) rosuvastatin
Interfere with platelets: ASA
Interfere with Vitamin K function: oral abx (eliminate intestinal bacteria)
Warfarin (Coumadin)
Drug interactions - decreased warfarin effect
Increased CYP2C9 activity:
1) barbiturates
2) phenytoin
3) rifampin
4) St. John’s Wort
5) Carbamazepine
6) Vitamin K from diet
Dabigatran (Pradaxa)
Mechanism of action
directly inhibit activity of thrombin (2a)
- More rapid onset than warfarin
- Steady state levels in 2-3 days
- Renal excretion
Dabigatran (Pradaxa)
Benefits (4)
1) Does NOT require monitoring and dosage adjustments (but more expensive to assess bleeding risk if you need to)
2) No dietary restrictions
3) Has reversal monoclonal ab (Praxbind)
4) Not a CYP450 substrate → fewer drug/food interactions
Dabigatran (Pradaxa)
Disadvantages (2)
Twice daily dosing
Shorter acting → missed doses = increased risk thrombosis
Dabigatran (Pradaxa)
Uses
Non-valvular AFIB
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
Mechanism of action
directly inhibit factor 10a
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
Benefits/disadvantages
No monitoring, no dietary restrictions
NO REVERSAL AGENT
Shorter acting → missed doses = increased thrombosis risk
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
Uses
1) Non valvular AFIB
2) Rivaroxaban (Xarelto) the only one approved for VTE and treatment of DVT/PE
Aspirin
inhibit COX-1 synthesis of thromboxane in platelets, effect for 8 days (irreversible)
GI bleeding risk
Clopidogrel (Plavix)
ADP receptor antagonist, interfere with ADP-induced platelet aggregation (irreversible)
Dipyridamole
block PDE break down of cAMP potentiating prostacyclin’s anti-aggregatory action
-Minimal antithrombotic benefit
Abciximab (Reopro), Eptifibatide (Integrilin), Tirofiban (Aggrastat)
block IIb/IIIa receptors on platelet → prevent integrin and fibrinogen binding and platelet aggregation
Continuous IV infusion
Antiplatelet Agent usage:
1) Acute MI (STEMI)
2) Unstable Angina (UA) and NSTEMI
3) Percutaneous coronary interventions
4) Secondary prevention of MI and ischemic stroke
1) Acute MI (STEMI): ASA + ADP antagonist
2) Unstable Angina (UA) and NSTEMI: ASA +/- ADP antagonist
3) Percutaneous coronary interventions: ASA + ADP antagonist +/- GIIb/IIIa inhibitors
4) Secondary prevention of MI and ischemic stroke (ASA)
Tissue Plasminogen Activator (tPA)
Mechanism of action
binds fibrin, activates bound plasminogen
Increases formation of plasmin from plasminogen → lytic state
Tissue Plasminogen Activator (tPA)
Uses
1) Acute MI (STEMI): emergency treatment of coronary artery thrombosis (use within 2 hours)
- PCI may be preferred to thrombolytic therapy in some cases
2) DVT
3) Multiple PE
Venous thrombi vs. arterial thrombi
Venous Thrombi = fibrin and trapped RBCs with relatively FEW PLATELETS
Arterial thrombi = platelet aggregates with SMALL AMOUNT of FIBRIN
Spectrum of acute coronary syndrome due to…
supply/demand mismatch
Complete vessel occlusion
STEMI
Transmural ischemia: spans entire thickness of myocardium
Most often due to complete coronary block
Partial coronary vessel occlusion with myocardial necrosis
NSTEMI
Partial coronary vessel occlusion, escalating symptoms, without myocardial necrosis
Unstable angina
Subendocardial ischemia: involves innermost layers of myocardium
a.Most often due to partial occlusion
Pathophysiology of ACS: ___ + ____ + ____ = ______
dysfunctional endothelium + coagulation + platelet aggregation = coronary thrombosis
Pathophysiology of ACS (4)
i. Inflammation + risk factors promote atherosclerosis
ii. Atherosclerosis promotes dysfunctional endothelium
- Decreased vasodilator effect, decreased antithrombotic effect compared to normal endothelium
iii. Inflammatory mediators weaken atherosclerotic fibrous cap → cap bursts → thrombogenic, TF released → activates coagulation cascade, creates platelet aggregation
iv. All leads to coronary thrombus
Serum markers in NSTEMI and STEMI
Necrosis of myocardial tissue causes intracellular leak of molecules into bloodstream (in STEMI and NSTEMI)
a. Cardiac troponin (Troponin I and T) = sensitive and specific for myocardium, important for diagnosis of MI
b. Creatine Kinase-MB isoenzyme (not as specific for heart)
CK-MB time to initial elevation
4-6 hours
CK-MB time to peak elevation
18 hours
CK-MB time to return to normal
2-4 days
cTnI time to initial elevation
4-6 hours
cTnI time to peak elevation
12 hours
cTnI time to return to normal
3-10 days
cTnT time to initial elevation
4-6 hours
cTnT time to peak elevation
12-48 hours
cTnT time to return to normal
7-10 days
ECG: acute STEMI
ST elevation
ECG: STEMI hours after infarction
ST elevation
Small R wave
Q wave begins
ECG: STEMI, days 1-2
T wave inversion
Q wave deeper
ECG: STEMI, days later
ST normalizes
T wave inverted
ECG: STEMI, weeks later
ST and T normal
Q wave persists
Stable vs. Unstable angina
- Stable angina: present when there is increased demand for myocardial O2 in a reproducible fashion
a. NOT on ACS spectrum - Unstable angina: change in chest symptom - discomfort, new onset or increased duration, frequency or intensity with less exertion or at rest compared to previous episodes of discomfort
Treatment of STEMI
Artery occluded → open it!
i. Within 90 minutes go to cath lab to open vessel mechanically with cardiac catheterization
ii. Outside of 90 min:
1. Consider fibrinolytics
2. Hemodynamically stable → oral B-Blockers, nitrates → decrease myocardial oxygen demand
Treatment of NSTEMI and unstable angina (3)
artery partially occluded → halt thrombotic process from completely occluding the artery (halt propagation of clot)
i. Anticoagulants (1): unfractionated heparin, LMW heparin, fondaparinux
ii. Antiplatelets (2):P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor), GIIb/IIIa inhibitors PLUS ASPIRIN
iii. If hemodynamically stable consider oral B-Blockers, nitrates → decrease myocardial oxygen demand
Development of Atherosclerosis and progression to ASCVD: (7 Steps)
1) LDL infiltrates subendothelial space
2) LDL modified (oxidized, glycosylated)
3) Release of proinflammatory cytokines (TNFa, IL-1, IL-6, IFN), increased expression of cell adhesion molecules (CAMs), monocyte chemotactic protein-1 (MCP-1) and IL-8
4) Monocytes recruited to clean up oxidized LDL
5) Phagocytosis of LDL → foam cell formation
6) Foam cells and T-lymphocytes within the plaque cause MMP secretion and activation of tissue factors
7) Plaque rupture occurs in “unstable” lesions → vessel thrombosis and acute coronary events
Lipoproteins
5 different classes
ferry water-insolible fats through the blood stream
-hydrophilic phospholipid + free cholesterol + apolipoproteins
5 different classes:
1) Chylomicrons
2) Very Low Density Lipoproteins (VLDL)
3) Intermediate-density Lipoproteins (IDL)
4) LDL
5) HDL
Exogenous Lipid Metabolism Pathway:
1) Fats absorbed in _________ –> repackaged as ________ with apo _____
* (HDL adds _____ and ____)
2) Chylomicrons enter circulation via the ____________
3) _________ cleaves fatty acids from chylomicrons and stores FFA in ______, used as energy in ______ or _______ muscle
4) _________ removed from circulation by ______ via remnant receptor and apo-____
5) Cholesterol in liver can be incorporated into ______ –> exported to _______
1) Fats absorbed in small intestine –> repackaged as chylomicrons with apo B-48
* (HDL adds ApoE and ApoC)
2) Chylomicrons enter circulation via the lymphatic system
3) Lipoprotein lipase (LPL) cleaves fatty acids from chylomicrons and stores FFA in adipose tissue, used as energy in cardiac or skeletal muscle
4) Chylomicron Remnants removed from circulation by liver via remnant receptor and apo-E
5) Cholesterol in liver can be incorporated into bile acids –> exported to intestine
* Normal is no chilomicrons in blood if you haven’t eaten in 8-10 hours
Endogenous Lipid Metabolism Pathway:
1) Liver packages cholesterol and triglycerides into _____ particles with apo-_____
* (HDL adds ____ and ____)
2) VLDL broken down by _____ –> release fatty acids to muscle and adipose tissue –> _____
* some _____ cleared in liver via hepatic receptors that recognize _____
3) LPL and hepatic lipase (HL) hydrolyze _____ –> ______
4) _____ cleared from plasma via _____ receptor-mediated endocytosis in the liver and peripheral cells, directed by LDL’s apo-____ and apo____
1) Liver packages cholesterol and triglycerides into VLDL particles with apo-B100
* (HDL adds apoC and apoE)
2) VLDL broken down by LPL –> release fatty acids to muscle and adipose tissue –> IDL
* some IDL cleared in liver via hepatic receptors that recognize apoE
3) LPL and hepatic lipase (HL) hydrolyze IDL –> LDL
4) LDL cleared from plasma via LDL receptor-mediated endocytosis in the liver and peripheral cells, directed by LDL’s apo-B100 and apoE
HDL transfers lipids to VLDL and Chylomicrons via ________
Cholesteryl Ester Transferase Protein (CETP)
HDL beneficial effects
2 possible mechanisms
HDL “removes” cholesterol from periphery
HDL has antioxidant and anti-inflammatory effects
Cholesterol and progression of atherosclerosis
Atherogenic lipoproteins (LDL, VLDL, IDL) are central to initiation and progression of atherosclerosis
Cholesterol lowering stabilizes plaque and reduces ASCVD-related events
Hypertriglyceridemia puts patients at risk for…(3)
Acute pancreatitis
ASCVD
Metabolic syndrome
Calculating LDL
LDL = total cholesterol - HDL - (TG/5)
Stable Angina
lumen narrowed by plaque, inappropriate vasoconstriction
Exertional angina - myocardial oxygen demand increases → supply unable to increase in response (autoregulation coronary artery dilation ineffective)
Fixed, stenotic, endothelialized atheromatous plaque
Treatment of stable angina (3)
Goal: reduce O2 demand
Nitrates, Ca2+ channel blockers, B-blockers
Unstable Angina
- plaque rupture, platelet aggregation, thrombus formation, unopposed vasoconstriction
- MI from occlusive thrombus generally imminent
- Angina at rest, change in frequency, character, duration, and precipitating factors
Treatment of Unstable Angina (acute)
Clot: ASA, heparin, GPIIb/IIIa inhibitors, PTCA/CABG, fibrinolytics
Arrhythmias: B-blockers
Pain: NTG, morphine
Treatment of UA post MI (5)
ACEI, Statin, B-blocker, ASA, clopidogrel (if post stent)
Variant Angina
coronary vasospasm with or without atheromatous plaque
Oxygen supply decreases due to reversible coronary vasospasm
-occurs at rest, NOT associated with exercise
Treatment of variant angina (2)
Goal: reverse/prevent vasospasm
Vasodilators (Ca2+ channel blockers, nitrates)
Nitrates
Mechanism of action
nitrates → NO → activate GC → cGMP increased in VSM → relaxation of VSM
- Primary target is venous capacitance vessels → reduce preload (LVEDP) → reduce myocardial O2 demand
- Dilate coronary artery vessels → increase myocardial O2 supply
Nitrates
Pharmacokinetics
Sublingually, transdermally, parenterally
Isosorbide Mononitrate (PO, chronic treatment)
Nitroglycerin (rapid onset, sublingual or translingual spray)
Nitrates
uses
Treatment of acute angina
Prophylaxis for stable angina (long acting nitrates)
Nitrates
side effects (4)
Due to VASODILATION →
1) Throbbing headache
2) **orthostatic hypotension
3) **reflex tachycardia
4) facial flushing
Can get tachyphylaxis (tolerance) with continuous exposure - recommended to have nitrate free interval (6-14 hrs daily)
Nitrates
drug interactions
sildenafil, vardenafil or tadalafil (viagra) → unsafe drop in BP
Propanolol vs. metoprolol/atenolol
Propranolol = non selective B1 and B2
Metoprolol, Atenolol = B1 selective (cardioselective)
-Selectivity at low doses only
B-blockers mechanism of action
target B-adrenergic receptors to decrease HR, BP, contractility → reduce O2 requirements
VSM:
A1 adrenergic receptor activation –> ?
B2 adrenergic receptors –> ?
A1 adrenergic receptors → increased Ca2+ intracellularly → VSM contraction
B2 adrenergic receptors → increased cAMP → VSM relaxation
B-blocker uses (2)
NOT vasodilatory → No role in variant (vasospastic) angina
- First-line therapy for stable angina
- Used in acute and post-MI therapy for unstable angina
B-blocker contraindications
- asthma
- severe bradycardia
- peripheral vascular disorder
- abrupt withdrawal precipitates sympathetic overreactivity
Nifedipine and Amlodipine are ______ LTCC blockers
DHP class
DHP class (Nifedipine, Amlodipine)
more vascular relaxation than cardiac actions (contractility, SA node impulse generation, AV nodal conduction)
**DO NOT use short acting DHPs (Immediate-Release Nifedipine) - too rapid of BP lowering → **Reflex activation of SNS (tachycardia, worsening of angina)
Diltiazem and Verapamil
more effect on cardiac nodal tissue, SA and AV, (phase 0) and cardiac muscle (phase 2)
Verapamil has the highest risk of negative inotropic effect
Adverse reactions associated with DHPs (4)
1) Edema
2) Hypotension
3) Flushing
4) Reflex tachycardia with short acting Nifedipine
Adverse reactions associated with non-DHPs
1) Cardiac depression (bradycardia, AV block, arrest) - more likely with verapamil and diltiazem
2) Dizziness
3) Constipation (more with verapamil)
4) Gingival hyperplasia
LTCC blocker uses (DHP and non DHP)
- Vasospastic angina
- Stable angina
- Arrhythmias
- HTN
- Inhibition of premature labor
- Subarachnoid hemorrhage
Ranolazine mechanism of action
-block Na+ channel that mediate late current in cardiac AP
Late Na+ current can cause intracellular Na+ overload → NCX Ca2+in/Na+ out → intracellular Ca2+ overload → more myocardial O2 demand
Ranolazine adverse reaction
prolong QT interval (do not use with other QT prolonging drugs)
