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Acute Coronary Syndromes

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Explain the pathophysiology of the transition between "chronic" and "acute" myocardial ischemia.
1) Unstable atherosclerotic plaque (mild-narrowing, lipid-rich) becomes inflamed because

a- threshold of oxidized lipid is reached
b- infection
c- involvement via systemic inflammatory process

leading to "self digestion" of plaque
What are the 3 worrisome outcomes of an "unstable" plaque?
Calcium and Fibrin-poor, Lipid-rich plaques undergoing waxing and waning self-digestions can

1) Unstable Angina ("platelet plugs"/white clots)
2) Non ST-elevation MI ("red plugs")
3) ST-elevation MI ("red plugs")
Why might you see a NSTEMI vs. an STEMI?
NSTMI occurs if there is total occlusion with thrombus long enough for myocardial necrosis, but for a short period of time (or if SOME flow persists).
What is the difference between Q wave and Non Q wave MI?
Q wave appears if infarction reaches epicardium, and it is called "Transmural."

Otherwise, there is no Q wave, and it is called "sub-endocardium MI"
What are 3 factors that play important roles in the amount of necrosis and the speed of the propagation of the wave front in an MI?
Remember, significant necrosis begins after 20 minutes

1) Presence/magnitude of coronary collaterals to involved vessel
2) Metabolic state of myocardium
3) Anti-thrombotic therapy
What are the essential elements (2) of achieving hemostasis following vascular injury?
1) Formation of platelet plug (adhere..degranulate...thrombin-platelet feedback...plug formation and GP presentation)

a) Platelets become "sticky pseudopods" that adhere to subendothelial matrix and secrete platelet granule products

b) These products generate thrombin, which activates other platelets (feedback loop) involving platelet ADP and 5-HT release and generation of thromboxane A-2

c) Platelets aggregate into plug and expose platelet glycoprotein (GP) IIb/IIIa, an integrin

2) Formation of Fibrin

a) Tissue factor + activated coagulation factor VII (VIIa) cause activation of factor X

b) Factor X catalyzes prothrombin (II) to thrombin (IIa)

c) Thrombin catalyzes formation of fibrin from fibrinogen (insoluble)
**Fibrin cross-linking achieved by Factor XIIIa
How are Thrombi formed and propagated?
1) Platelet plugs are attached by fibrin web, at glycoprotein (IIb/IIIa) complex (stabilization)

2) Web traps red and white cells (converting "white clot" to "red clot"), making it even more stable
How can platelet activation and fibrin formation be inhibited?
1) Endothelial production of Prostacyclin (vasodilator)

2) NO production

3) Heparin potentiation of anti-thrombin mediated inhibition of thrombin and activated factor X (needs to bind thrombin AND AT)
How is thrombolysis achieved and regulated?
1) t-PA activated circulating plasminogen to plasmin, which lysis thrombus

2) Thrombolytic therapy is achieved by
- anti-platelet agents
- anti-thrombin agents (anti-coagulants)
- Thrombolytic agents (plasminogen activators)
How do each of the following anti-platelet agents work?

1) Aspirin
2) Thienopyridines (Clopidogrel)
3) Cyclo-pentyl-triazolo-pyrimidines (CPTPs) (Ticagrelor)
4) GPIIb/IIIa blockers
1) Irreversible COX-1 inhibitor, permanently decreasing thromboxane A2 synthesis, decreasing recruitment of activated platelets in feedback loop of platelet plug

2) Drug metabolites IRREVERSIBLY block platelet protein P2Y12, blocking the binding of ADP to receptor on platelets and decreasing feedback (Clopidogrel commonly used)

3) Bind directly and REVERSIBLY to P2Y12, changing its conformation (Ticagrelor).

4) Abciximab (Ab), Eptifibatide and Tirofiban (smaller molecules)- prevent fibrin binding to platelet plugs.
What are the 3 important GPIIb/IIIa blockers used as anti-platelet therapy
Prevent fibrin web association with platelet plug!

1) Abciximab (non-specific Ab)

2) Eptifibatide
3) Tirofiban
** Small, short-acting molecules that are highly specific
What are the 3 general types of Anti-thrombin agents?
1) Heparin and Heparin-like
a) Unfractioned- binds anti-thrombin, and activates it further, while simultaneously finding to thrombin (less prominatly activates factor Xa)

b) Low-MW- more effect on factor X action and given sub-q with less monitoring

c) Fondaparinux- pentasaccharide analouge (effective but of limited use because of $$)

2) Direct thrombin inhibitors (Bivalarudin and Argatraban)
- Used in place of heparin when heparin-induced thrombocytopenia (HIT) is suspected.
- Given IV

3) Oral vitamin K antagonists (VKAs)
- Warfarin and Coumadin block gamma-carboxylation of clotting factor II (prothrombin), decreasing thrombin production.
- Given orally with a lot of monitoring
What 2 drugs could you try to reduce thrombin if you suspected heparin-induced thrombocytopenia (low platelet count)?
Try the direct thrombin inhibitors, Bivalarudin and Argatraban (from leech saliva!)
What Thrombolytic (Fibrinolytic) Agents (plasminogen activators) are available and how do they work?
Alteplase (recombinant t-PA) and analouges (Tenecteplase and reteplase) activate plasminogen to produce plasmin, which breaks up thrombin.
When should intravenous thrombolytic therapy be considered for a case of MI?
Evolving Q-wave (i.e. transmural) STEMI within first 12 hours after onset, provided there are no contraindications and angioplasty is not possible.

**watch out for bleeding**
When is anti-platelet (aspirin) therapy appropriate for the treatment of acute coronary syndromes?
Use early and indefinitely for all patients with ACS

1) All patients with acute coronary syndromes should receive 162-324 mg upon presentation

2) After, 75-81 mg daily to minimize decreases in vascular prostacyclin production and to decrease GI side effects.
When should Thienopyridines vs. CPTPs be used for acute coronary syndromes?
1) Thienopyridines
- in ALL ACS patients as adjunct to aspirin or as alternative
- use early and for up to 12 months fin case of drug-eluting stents

2) CPTPs like Ticagrelor can replace Theinopyridine, but make sure to limit aspirin to 100 mg
When should GP IIb/IIIa blockers be used for acute coronary syndromes?
Use in selected patients as adjunctive therapy who are

1) Undergoing emergency coronary angioplasty/stenting after STEMI

2) High risk patients with UAP/NSTEMI who are selected for coronary arteriography and possibly stenting.
When should Anti-thrombin therapy be used for acute coronary syndromes?
Use heparin or TDIs initailly in all aptients with ACS

1) Duration depends on clinical setting (if risk of thromboembolism is high with aspirin, use it)

2) Long-term oral vitamin K antagonists limited to higher-risk patients

3) Oral DTI or anti-Xa useful in patients with chronic CAD and A fib instead of warfarin
How should anti-thrombotic therapy for chronic myocardial ischemia be approached?
1. Indefinite lower-dose aspirin unless contraindicated

2. Clopidogrel (Thienopyridine) therapy as alternative to aspiring in patients who cannot take aspirin because of
a) coronary dilatation and stenting
b) high risk (CAD, diabetes, ect)

3. Antithrombin therapy long-term for HIGH-RISK (A-fib, h/x of embolism of LV dysfunction)

** new oral anti-factor Xa and DTIs may replace warfarin for patients with A fib**
How should anti-thrombotic therapy for chronic myocardial ischemia be approached?
1. Indefinite lower-dose aspirin unless contraindicated

2. Clopidogrel (Thienopyridine) therapy as alternative to aspiring in patients who cannot take aspirin because of
a) coronary dilatation and stenting
b) high risk (CAD, diabetes, ect)

3. Antithrombin therapy long-term for HIGH-RISK (A-fib, h/x of embolism of LV dysfunction)

** new oral anti-factor Xa and DTIs may replace warfarin for patients with A fib**
What are 3 h/x that should be concerning for MI?
1) New chest pain at rest or with minimal exercise

2) Change in angina frequency, severity, or difficulty in relief with nitro

3) Chest pain in patient with CAD unrelieved by rest or nito
Why should a patient with pulmonary edema who is at risk for CHF be worried about an MI?
25% of Q-wave infarcts are silent!

Also be worried with stroke.
How can the EKG help to distinguish between infarct types?
STEMI vs. Unstable angina pectoris or NSTEMI

(look for transmural injury with ST-elevation or Subendocardial injury/ischemia with SST depression or T-wave inversion or both)

UAP vs. NSTEMI requires cardiac biomarkers for necrosis
What is the location of the infarct if you see Old Q-wave/QS complex in each of the following locations?

1: V1-V5
2. V1-V4
3. V3-V6
4. V3 and/or V4
5. 1, aVL, V6
1-4 are anterior wall infarcts

1. Entire wall
2. Anteroseptum
3. Anterolateral
4. Apex only

5. Lateral Wall
6. Inferior Wall
What are the major cardiac biomarkers used to diagnose type and severity of myocardial infarction?

How are they most effectively used in diagnosis?
CK-MB and Troponins

Use Troponins at admission, 8-12h and 24h as sole marker, UNLESS you suspect recurrence, than use CK-MB

1) CK-MB
- appears within 8 hours, peaks at 24-48 and returns to normal in 3-5 days (so you can see recurrence)

2) Troponins
- appear within 8 hours, peak at 24 and stick around for a week
- sensitive and specific for myocardial damage (but not infarct), and good for both late and early detection
When a patient comes in complaining of new chest pain at rest with a history of CAD, what do you do?

1) Skip full registration, get targeted history and START EKG (serum markers will take longer to detect)

2) Establish IV access and start O2 delivery (not supraphysical)

3) Relieve pain with sub-lingual nitroglycerin (if not, use opiate analgesic)
What are the most important determinants of mortality in acute MI?
1) LV size and function
2) Hemodynamic Status
3) Size of infarct
4) Gender (worse for women)
5) Old age
6) Ventricular rhythm disorder
7) Spontaneous/evoked ischemia
If a patient comes in and their EKG indicates either UAP or NSTEMI, what are the major factors that determine if they are in high/intermediate risk?
Should they get early coronary arteriography and revascularization?

1) H/x of CAD
2) Unstable AP
3) Ongoing chest pain
4) New or dynamic ST changes or T-wave changes
5) Positive biomarkers
6) Hemodynamic instability
7) Ventricular rhythm abnormalities
What do each of the electrical instabilities mean for ACS morbidity/mortality?

1) Early VT,VF,SCD
2) Late VT/VF (after 24-48h)
4) Sinus Bradyrhythms
5) Sinus Tachycardia
1) Warning PVCs, Primary VF, VF following VT, Sustained or non-sustained VT (not torsades)

- will not worsen prognosis if reversed with lidocaine/amiodarone

2) Worsens long-term prognosis

- Polymorphic VT (ongoing ischemia) or Monomorphic VT (reentrant scar)
**Treat with ICD and NOT anti-arrhythmic therapy

3) May be "re-perfusion" arrhythmia and not usually serious

4) Parasympathetic tone dominates because sympathetic inhibited by Neurocardiac reflex
- Lowers O2 demand, but may jeopardize CO and V rythms
** Can treat with Atropine

5) Underlying cause is usually low CO, anemia or hypovolemia
What types of AV nodal blocks are associated with inferior vs. anterior infarcts?
1) Supra-Hisian blocks are usually inferior/posterior

2) Infra-hisian blocks are usually large anterior infarcts
What are 3 major functional consequences of ACS?
1) Systolic LV dysfunction- usually reversible, with severity proportional to number of dying cells

2) Stunned myocardium- tissue at margin between infarct and normal (takes days or even a week to recover

3) Diastolic LV dysfunction-
A patient suffering an MI presents with pulmonary hypertension. How do you manage?

What if they were hypotensive?
1) Diuretics and IV morphine

2) IV inotropic and/or pressure agents (maybe an indwelling pulmonary artery catheter if severe)
What are the 4 typical mechanical complications of an MI?
1) Cardiogenic Shock (hypotension, reduced CO, elevated LV filling pressure, mental obtundation/sweating/tachycardia/cold clammy extremities)

2) RV involvement with inferoposterior MI (proximal right coronary artery)
- can lead to LV filling issue

3) Myocardial rupture (dramatic worsened symptoms and shock)
- Can be of papillary muscle (regurgitation) or IV septum (left to right shunt)

4) Ventricular aneurysm and thrombus
- always STEMI from anterior or apical infarct (NEVER RUPTURE)
- problem is CHF and thromboembolism
How can you distinguish between Atypical Cardiogenic Shock due to Neurocardiac reflex, Atypical shock due to Hypovolemia, and Typical shock from RV infarct?

How does this distinction alter treatment?
1) Typical RV presents with lowered filling pressures and low CO
- Fluid administration, inotropic agents (NOT vasodilator/beta-blocker until RV contraction improves)

2) Atypical due to neurocardiac will have normal filling pressures and normal CO w/o pulmonary edema
- Treat with dopamine, phenylephrine or NE to restore vascular resistance

3) Atypical due to Hypovolemia with have normal filling pressure, but LOW CO and elevated systemic resistance.
- Give volemic support until wedge pressure reaches normal limiits
How can you use LV filling pressure, CO and pulmonary edema to tell between "typical cardiogenic shock," "shock due to RV infarct," "atypical shock due to neurocardiac reflex" and "atypical shock due to hypovolemia?"
1) Typical (Elevated LV filling pressure, low CO)

2) RV infarct (Low LV filling pressure, low CO)

3) Atypical due to neurocardiac (Normal LV filling pressure, normal CO, no pulmonary edema)

4) Atypical due to hypovolemia (Normal LV filling pressure, low CO and increased systemic resistance)
What is the appropriate Emergency Re-perfusion Therapy for STEMI and UAP/NSTEMI?
1) STEMI- Angioplasty/stenting in 90 minutes > IV thrombolytic

2) NSTEMI/UAP- Neither Angioplasticy nor Thrombolytics are effective for low-risk, because artery is not completely walled off

- For high-risk patients, use vigorous anti-thrombotic regimen (GP IIb/IIIa or Bivalarudin) with angioplasty
How can you "change the myocardial oxygen demand flow to demand ratio" in ACS ischemia pharmacologically?
1) Beta blockers
- Use those without ISA
- Carvedilol (alpha activity) > Metoprolol for post-MI LV dysfunction

2) Nitrates (decrease preload and reduced O2 demand)
- NOT recommended for aggressive or prolonged treatment
- Discharged patients should have nitroglycerin prescription, but use should be stopped whenever possible

3) Calcium channel blockers
- ONLY slow-actvity dihydropyridines should be used during ACS and NOT without beta blockers

- Verapamil and Diltiazem can be used for patients with intact LV function, but NOT for recurrent cardiac death
Why disrupt the Angtiotensin system to treat ACS?
Reduce blood pressures contributing to heart failure

1) ACE-i given to all patients after ACS (receptor blockers are equally as effective)

2) If patients are not in renal failure, adding Eplerenone (Aldosterone blocker) is further protective.
Why might you give a patient with ACS a statin drug?
reduce cholesterol to stabilize lipid-rich (unstable) atheromatous plaques to prevent thromboembolism.
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