1.  the ABSORPTION & TRANSPORT of triglycerides, cholesterol, and fat-soluble vitamins from the liver to peripheral tissues; and the transport of cholesterol from peripheral tissues to the liver.

Triglycerides - chylomicrons & VLDL

Cholesterol - choletserol esters --> LDL and HDL

1. Activates important enzymes for lipoprotein metabolism

2. Acts as a ligand for cell surface receptors

Apolipoprotien cell surface receptors for:

HDL

LDL
Chylomicrons

VLDL

IDL 

HDL -ApoA-I & ApoA-II

LDL - ApoB-1

Chylomicrons - ApoB-48 (intestine), ApoC & ApoE 

VLDL - ApoB-100, ApoC, ApoE

IDL - ApoB-100, ApoC & ApoE (metabolism & clearance)

Women > Men

Except for: 40-59 yrs old

Autosomal codominant disorder

elevated LDL-C 

normal triglycerides

1. Total cholesterol >500 mg/dL

2. Accerelated atherosclerosis

3. Coronary atherosclerosis before puberty

4. Atypical symptoms and sudden death is common

1. Family history

2. Skin biopsy and measuring LDL receptor activity in skin fibrolasts

3. Flow cytometry analysis of LDL receptors on lymphocytes

4. DNA sequencing to find mutated LDL receptor genes

Hyperlipidemia is diabetes is usually associated with __ type of diabetes mellitus

Type 2 DM

--> high insulin resistance

--> insulin accumulates --> FA synthesis increases

1. Hepatitis - increased VLDL and mild-moderate hypertriglycemia

2. Severe hepatitis & liver failure --> reduced plasma cholesterol and triglycerides

3. Cholestasis --> hypercholestrolemia  --> cholesterol deposited in skin folds as part of particle called Lamellar Particle (LP-X)

1. Increases triglycerides

2. Increases hepatic VLDL

3. Regular consumption --> Increases HDL-C

Lesion progression occurs through the interaction of ___, ____ and ____ with the normal cellular constituents of the arterial wall

modified lipoproteins, 

monocyte-derived macrophages, and

T-cells

What conditions are caused by these events --> Atheresclerosis of:

1. coronary arteries

2. central nervous system

3. Pderipheral circulation

4. Splanchnic circulation

5. Renal artery stenosis

1. coronary arteries --> MI and Angina Pectoris

2. central nervous system --> Stroke

3. Peripheral circulation --> Gangrene and Intermitten Claudication

4. Splanchnic circulation --> Mesenteric ischemia

5. Renal artery stenosis 

___% reduction in total cholesterol equals __% reduction in CHD events

1%,

2%

Primary goal = reduce LDL

Secondary goal = increase HDL levels (independent of LDL) and reduce triglyeride levels

___% reduction in LDL-C equals ___% reduction in CHD events 

and 

___% increase in HDL-C equals ___% reduction in CHD events

1% decrease LDL = 1% CHD decrease

1% HDL increase = 3% CHD decrease

1. Synthesis of steroid hormone ex. glucorticoids, mineralocorticoids and sex hormones.

2. Cell wall membranes

3. Bile acid synthesis

4. Fat and lipid-soluble vitamin absorption in GI

5. Transport of fats from liver to tissues

Explain the steps involved in the synthesis of cholesterol.

What is the rate-limiting step?

Acetyl coA --> HMG-CoA --<HMG-CoA reductase> Mevalonic Acid --> Cholesterol

rate-limiting step = HMG CoA reductase convertion of HMG CoA to Mevolanic acid

1. Improves endothelial function and enhance NO 

2. Down-regulation of AT1 receptor expression

3. Increased plaque stability via:

a. inhibition of vascular smooth muscle proliferation and migration.

b. Inhibition of monocyte infiltration into artery wall

4. Anti-inflammatory due to reduce C-reactive protein (CRP)

5. Antioxidant

6. Antiplatelets

Pitavastatin > Lovastatin > Fluvastatin

Least --> Simvastatin

Atorvastatin

Lovastatin

Simvastatin

Fluvastatin

Rosuvastatin

Pitavastatin

Pravastatin > Atorvastatin > Rosuvastatin

Shortes t.5 = Fluvastatin

1. Hepatoxicity

2. Myopathy --> rhabdomyolysis

3. Cognitive effects

4. Hyperglycemia

5. Thyrotropin (TSH) concentration is falsely decreased

Gemfibrozil --> inhibits uptake of active hydroxy acid forms of statins into hepatocytes and their glucuronidation --> doubles plasma concentrations of statins.

Gemfibrozil also inhibit CYP2C9 --> impairs metabolism of fluvastatin

Cholestyramine

Colestipol

Colesevalam

Bile sequestrants

-cholestyramine

- Colestipol

- Colesevelam

Clofibrate

Gemfibrozil

Fenofibrate

1. Oral anticoagulants --> decrease binding to albumin

2. Statins + Femfibrozil --> decreased hepatic uptake

• inhibition of acyl CoA:1,2-diacylglycerol acyltransferase

  ▪ increased mitochondrial & peroxisomal β-oxidation of lipids in liver cells

  ▪ decreased lipogenisis in the liver

  ▪ increased plasma lipoprotein lipase activity

False: fasting lipid panel is not necessary

--> TC and HDL were almost the same in fasting vs. nonfasting

1. Determine lipoprotein level (fasting LP not necessary)

2. Identify if patient has coronary heart disease (CHD --> MI, CAD/PCI, CABG)

3. Determine presence of major (CHD) risk factors (smoking, HTN, low HDL, family history [<55yrs male or  <65yrs female] and age [45yrs or more for males, 55yrs or more for women])

4. If 2+ risk factors (not LDL) are present in absence of CHD orCHD risk equivalent, then do a 10 yr Framingham CHD risk.

5. Determine risk category and determine need to initiate therapeutic lifestyle changes and drug therapy.

6. Initiate therapeutic or lifestyle chabfes if above LDL goal.

7. Consider adding drug therapy if LDL is above goal

8. Identify metabolic syndrome and treat if >3 months of TLC

9. If triglycerides is above 200mg/dL after LDL goal i reach, set secondary goal for non-HDL cholesterol (TC - HDL) to 30 points avove its goal.

Low risk: <10%

Moderate risk: 10-20%

High risk:  >20%

For high risk patient with CHD or CHD risk equivalent (10 yrs risk >20%) what are the:

LDL goal?

When should you initiate TLC?

When should you iniate drugs?

LDL goal: <100 mg/dL (optional goal = <70 mg/dL)

Initiate TLC : if LDL > = 100 mg/dL

Initiate drugs: if LDL > = 100 mg/dL (optional if <100mg/dL)

For moderately high risk patient with 2+  risk factors (10 yrs risk 10-20%) what are the:

LDL goal?

When should you initiate TLC?

When should you iniate drugs?

LDL goal: <130 mg/dL (optional goal: <100 mg/dL)

Initiate TLC: if LDL > = 130 mg/dL

Initiate drugs: if LDL > = 130 mg/dL (optional = 100-129 mg/dL)

LDL goal: <130 mg/dL 

Initiate TLC: > = 130 mg/dL

Initiate drugs  if : > = 160 mg/dL

For lower risk patient with C0-1 risk factors what are the:

LDL goal?

When should you initiate TLC?

When should you iniate drugs?

LDL goal: <160 mg/dL

Initiate TLC: > = 160 mg/dL 

Initiate drug if: > = 190 mg/dL ( optional if 160-189 mg/dL)

If after 3 months of TLC they still have:

a)      Abdominal obesity; waist circumference >  40” men, > 35 ” women)

b)      TG ³    >= 150         mg/dL or receiving drug treatment for elevated TG

c)       Low HDL (< 40   men, <50   women) or receiving drug treatment for low HDL

d)      BP > 130/85    mmHg or receiving treatment for elevated BP

               e) Fasting glucose > 100    or receiving treatment for elevated glucose

1. Set a secondary goal for the non-HDL cholesterol i.e TC - HDL

2. Set the non-HDL secondary goal to 30 points above LDL goal ex. if ptn had CHD and CHD risk equivalent, original goal would be to get their LDL to  a<100 mg/dL, but if triglyceride is still elevated, then shoot for <70 mg/dL.

A 54 year-old male presents to clinic for routine physical.

PMH:   HTN

FH:       Father MI at 53; mother type 2 diabetes

SH:       No smoking or alcohol use

Meds: Chlorthalidone 12.5 mg PO daily

FLP:     TC 220 mg/dL, 152 LDL mg/dL, HDL 34 mg/dL, TG 168 mg/dL

VS:       BP 128/78, HR 72

1.    What is this patient’s goal LDL per ATPIII? 

1st: determine lipoprotein level --> TC is high, LDL is high and HDL is low

2nd: assess CHD risk or CHD risk equivalents--> calculate 10 Framingham if >2 risk factors

3rd: Calculate his risk factors --> 3 Risks: his age: >45; father died of MI before 55yrs old and he is on antihypertensive

10yr framingham = 10% --> moderate risk (note: it's not low risk since he has 2+ risk factors)

Low risk: LDL goal = <130 mg/dL, initiate TLC if LDL >130 mg/dL

Myalgia

Myopathy

Rhabdomyolysis

Fenofibrate (Tricor/Triglide) --> less interactions w/ other drugs and can be used in prevention of CHD in T2DM

Remember: fibric acid derivatives are best for hypertriglycemia

Gemfibrozil (Lopid) should be your last choice

Bile sequestrants

WelChol - Colesevelam

Prevalite^® - Cholestyramine Resin

Questran^® Light - Cholestyramine Resin

Colestid^®  - Micronized Colestipol

Bile sequestrants

WelChol - Colesevelam

Prevalite^® - Cholestyramine Resin

Questran^® Light - Cholestyramine Resin

Colestid^®  - Micronized Colestipol

Myopathy - can still combine but watchout

Statins + Niacin --> to improve LDL and decrease TG

Statin + bile sequestrants

Statin + Ezetimibe -->Vytorin -->  most potent agent

Niacin + Bile acid sequestrants

Statin + Fibrates (esp fenofibrates)

Statin + Niacin

Ischemic heart disease (IHD)

--> It typically occurs when there is an imbalance between myocardial oxygen supply and demand

phasic fashion;

diastole

1. Large epicardial arteries (resistance 1) - not important to coronary resistance

2. Prearteriolar vessels (resistance 2) - important to coronary resistance

3. Arteriolar and Intramyocardial capillary vessels (resistance 3) - important to coronary resistance

resistance 2 (R2) - prearteriolar vessels

resistance 3 (R3) - arteriolar and intramyocardial capillary

1. Sites of increased turbulence in coronary flow

2. Branch points in epicardial arteries

3. Risk factors such as high LDL, low HDL, smoking, HTN and DM

STEMI (ST-elevation Myocardial infarction) --> worst of the two; it is when the entire myocardial tissue is necrotic --> treated with PCI (preferred) within 90 mins or fibrinolysis (within 30 mins).

NSTEMI (nonST-elevatiom MI) --> you will see an ST-segment elevation lasting for just <20 mins, and then a ST-segment depression in high risk ptns, and T-wave depression (in normal ptns) only when he endocardium layer is necrotic --> treat with medications

--> do a PCI if classified as high risk within 90 mins and antiplatelets/anticoagulants.

1. Ventricular premature beats

2. Ventricular tachycardia (most cause of death in IHD ptns)

3. Ventricular fibrillation

False --> Q-waves not seen at all in right-sided leads, only left-sided leads (I,aVL, V5 and V6)

left-sided leads = left-to-right depolarization of the interventricular septum

1. Angina pectoris

2. Dyspnea

3. Fatigue

4. Faintness

Stable angina --> symptom occur with exertion or emotion

Unstable angina --> symptoms occur even at rest or at wakening up from sleep

Anterior --> tachycardia and/or hypertension 

Posterior --> bradycardia and/or hypotension

1. Revascularization

2. Coronary artery bypass grafting (CABG)

3. Percutaneous coronary intervention (PCI)

low dose nitrates: vasodilates veins > arterioles 

high dose nitrates (has opposite effect) : increase venous pooling and decrease arterioles pressure --> reflex tachycardia (compensatory sympathetic reflex) and eventually results in decreased blood flow if cardiac output & BP decrease

All nitrates except ___ have short T1/2 & high clearance rates

Aggrenox = Aspirin + Dipyridamole

Dipyridamole --> 1. ANTI-platelets: inhibits adenosine uptake in platelets and increase cAMP in platelets causing decrease platelet activation

2. PDE inhibitor --> increase cGMP --> increase K+ --> decreased intracellular Ca2+ --> muscle relaxant

1. While thienopyridines (Plavix, Effient, Ticlid) irreversibly inhibits platelet aggregation, Ticagrelor is reversible.

2. Thienopyridines are prodrugs that need CYP2C19 for metabolism, Ticagrelor is not a prodrug and it is metabolized by CYP3A4.

Abciximab (Reopro)

Eptifibatide (Integrilin)

Tirofiban (Aggrastat)

Alteplase (Activase)

Reteplase (Retavase)

Tenecteplase (TKNase)

Hemorrhagic stroke - damage of blood vessel --> bleeding  (higher mortality)

Ischemic stroke - blockage of blood vessel  (more common)

1. carotid endarterectomy

2. carotid stenting

1. Antifibrinolytic/Thrombolytic agents --> Alteplase (Activase), Reteplase (Retavase) and Tenecteplase (TNKase) --why? since there is already a clot there that needs to be lysed

2. Antiplatelets --> aspirin

Secondary prevention of ischemic stroke :

Antiplatelets (cornerstone)--> Aspirin, Aggrenox, or ADP receptor blockers/P2Y12 inhibitors

Anticoagulants (most effective for prevention of stroke in patients w/ atrial fibrillation) --> warfarin (combo w/ aspirin) 

Candersartan (Atacand)

Telmisartan (Micardis)

age 35 in men and 40 in women, repeated every 5 years

Cardioembolic stroke/ TIA --> Atrial fibrillation --> CHADS2 score:

Age >75 - 1 point

Diabetes - 1 point

Previous stroke - 2 points

Hypertension - 1 point

Congestive heart failure - 1 point

0 - no antithrombotic/anticoagulant needed

1- antithrombotic/anticoagulant probably recommended

2 - Strongly recommend antithrombotic/anticoagulant

When administering the "triple antithrombotic therapy", which is dual antiplatelet therapy combined with warfarin:

Warfarin + Aspirin + Clopidogrel

Target INR is 2-2.5 to further decrease the risk of bleeding

In chronic stable angina, substernal chest discomfort is cause by ____ and is typically relieved by ___and/or ____(usually 5-10 min, no more than 20 min)

Substernal chest pain caused by = exertion, emotional stress, cold, meals

Relieved by nitroglycerin and/or rest

High risk symptoms: Angina + these factors

1. Pulmonary edema

2. Rales

3. Hypotension

4. Nocturnal angina

1. Rest angina: occurs at rest for >20 mins

2. New Onset angina: class III angina for >2 months --> limits activity 

3. Increasing angina: increase frequency of angina

4. High risk symptoms angina: PE, rales, hypotension and nocturnal angina

heart rate: 50-60 bpm or sx of dizziness of fatigue

blood pressure: 110/65 or sx of dizziness & fatigue

Beta blockers -

beta-1 and mixed alpha/beta

Percutaneous coronary intervention (PCI) - balloon angioplasty or stents

Coronary Artery Bypass Graft Z(CABG) 

NonDHP CCB - Verapamil (Covera, Calan, Verelan, Isoptin) and

Diltiziam (Cardizem, Tiazec, Dilacor)

1. if taking beta blockers - increase cardiodepression

2. heart failure - systolic hf, left ventricular disorder and reduce ejection fraction

·        Those undergoing PCI (UA/NSTEMI or STEMI) are at high risk of thrombosis, particularly during the catheterization and stent placement, so a  ___ is usually added for PCI

2b3a inhibitor

Reopro (Abciximab)

Integrillin (Eptifibatide)

Aggrastat (Tirofiban)

Those undergoing fibrinolysis (STEMI) are at a high risk of bleeding and we use _____

For Plavix, what is the:

1. normal loading 

2. Loading dose for PCI

3. Maintenance dose

4. When is loading dose not given?

5. How long to hold for if CABG is necessary?

1. normal loading = 300 mg PO x 1

2. Loading dose for PCI = 600 mg PO x 1

3. Maintenance dose = 75 mg PO daily

4. When is loading dose not given? do not give if >75yrs old

5. How long to hold for if CABG is necessary? 5 days

Aggrastat (Tirofiban) - reduce infusion by 50% if CrCl <30%

Eptifibatide (Integrillin) - reduce infusion by 50% if CrCl is <50%

Enoxaparin (Lovenox) - Avoid if CrCl < 15, give q24h if <30

Fondaparinux (Arixtra) - Avoid if CrCl <30, caution if <50

Bivalirudin (Angiomax) - decrease dose if CrCl <30