Cardiology Exam 1

Atorvastatin

Lipitor, Atorvaliq

Amlodipine/Atorvastatin

Caduet

Fluvastatin

Lescol XL

Lovastatin

Altoprev, Mevacor

Pitavastatin

Livalo, Zypitamag

Pravastatin

Pravachol

Rosuvastatin

Crestor, Ezallor Sprinkle

Simvastatin

Zocor, FloLipid

Ezetimibe/Simvastatin

Vytorin

Ezetimibe

Zetia

Bempedoic Acid/Ezetimibe

Nexlizet

Alirocumab

Praluent

Evolocumab

Repatha, Repatha SureClick, Pushtronex

Colesevelam

Welchol

Cholestyramine

Prevalite

Colestipol

Colestid

Fenofibrate, Fenofibric Acid

Tricor, Trillipix, Fenoglide, Fibricor, Lipofen

Gemfibrozil

Lopid

Niacin

Niacor, Slo-Niacin

Omega-3 Acid Ethyl Esters

Lovaza

Icosapent Ethyl

Vascepa

Bempedoic Acid

Nexletol

Inclisiran

Leqvio

Lomitapide

Juxtapid

Evinacumab

Evkeeza

Familial Hypertriglyceridemia

Increase in total blood triglycerides with a genetic component

Familial Combined Hyperlipidemia

Genetically caused increase in LDL and/or TGs

General structure of a lipoprotein

Internal, hydrophobic core consisting of lipids, mainly triglycerides and cholesteryl esters

Outer, hydrophilic shell consisting of phospholipids, free cholesterol, and apolipoproteins

Functions of apolipoproteins

Structural integrity of lipoproteins

Transport of lipids through the bloodstream

Binding of lipoproteins to various receptors

Cofactors for enzymes

Function of chylomicrons

Deliver dietary triglycerides and cholesterol through the blood to peripheral tissues and the liver

• Mainly triglycerides

How do chylomicrons transport dietary fats?

Dietary triglycerides and cholesterol → digested/packaged into micelles by pancreatic lipase/co-lipase → travel to enterocytes of small intestine (cholesterol can also be absorbed here by NPC1L1) → packaged onto chylomicron containing B48 → lymphatic system → blood → chylomicrons receive Apo-E and Apo-CII from HDL → Apo-CII activates lipoprotein lipase (LPL) → TGs broken down into glycerol and free fatty acids → return Apo-CII to HDL → Apo-E binds to LDL receptors on the liver → chylomicron remnant is internalized and delivers its TGs and cholesterol

Function of VLDL

Deliver TGs to extra-hepatic tissues

How does VLDL transport TGs?

Dietary triglycerides and cholesterol in the liver → packaged into VLDL containing B100 → lymphatic system → blood → chylomicrons receive Apo-E and Apo-CII from HDL → Apo-CII activates lipoprotein lipase (LPL) → TGs broken down into glycerol and free fatty acids → return Apo-CII to HDL, becoming IDL → two possible paths:

• Apo-E binds to LDL receptors on the liver → IDL is internalized along with its remaining TGs and cholesterol

• Apo-E binds to hepatic triglyceride lipase (HTGL) on lliver cells → further removal of TGs from IDL → return Apo-E to HDL, becoming LDL, containing only B100 and low levels of TGs and cholesterol

Function of LDL

Deliver cholesterol to extrahepatic tissues and organs to maintain cholesterol homeostasis

How does LDL transport cholesterol?

LDL (from metabolized VLDL) → can bind to LDL receptors and deliver cholesterol to:

• Liver cells (about 60% of LDL)

• Gonads → release of testosterone, progesterone, estrogen

• Adrenal Cortex → release of aldosterone, cortisol, DHEA

What happens when LDL comes into contact with reactive oxygen species?

Oxidized to Ox-LDL → taken into macrophages in the tunica intima of blood vessels by fatty acid translocase (FAT/CD36) → overaccumulation converts macrophages to foam cells → leads to development of fatty streaks, one of the earliest signs of atherosclerosis → foam cells in athersclerotic plaques can accumulate and attract other inflammatory cells → can lead to plaque instability causing rupture or thrombosis → causes stroke or heart attacks

Function of HDL

Reverse cholesterol transport

• Removes excess cholesterol from peripheral cells and tissues acting as a scavenger, returning it to the liver for removal

How does HDL transport cholesterol?

Prebeta-1 HDL, which contains Apo-A1, binds to ABCA1 and ABCG1 in peripheral tissues → free cholesterol transported into prebeta-1 HDL, becoming HDL → free cholesterol is esterified into cholesteryl esters by LCAT → multiple possibilities:

• Transferred to VLDL, IDL, LDL, and chylomicrons by CETP (cholesteryl ester transfer protein)

• Bind to scavenger receptor SR-B1 on liver cells, gonads, and adrenal cortex to deliver cholesterol → this does not cause endocytosis of HDL

Where do the main components of HDL come from?

• Apo-A1 is synthesized in the liver and intestine

• Surface phospholipids come from the surface layers of chylomicrons and VLDL during lipolysis

Primary Dyslipidemia

Caused by genetic mutations that affect the metabolism of lipids/lipoproteins

What inheritence patterns are possible for primary dyslipidemia mutations?

Autosomal dominant

Autosomal recessive

X-linked

What are the two main mutations that cause primary hypertriglyceridemia?

Familial Apo-CII Deficiency

Familial Lipoprotein Lipase Deficiency

Familial Apo-CII Deficiency

Apo-CII gene alterations → inefficient activation of LPL → decreased TG hydrolysis → increased chylomicrons and VLDL → increased blood TG

Familial Lipoprotein Lipase Deficiency

LPL gene alterations → Deficiency in LPL hydrolysis of TGs → increased chylomicrons and VLDL → increased blood TG

What are the two main mutations that cause primary hypercholesterolemia?

Familial Hypercholesterolemia

Familial Defective Apo B100

Familial Hypercholesterolemia

LDL receptor gene mutations → reduction in available LDL receptors → increased LDL in blood → increased blood cholesterol

Familial Defective Apo B100

Apo B100 mutations → ineffective binding of Apo B100 containing lipoproteins to LDL receptor → increased LDL in blood → increased blood cholesterol

What is the main mutations that causes mixed hypercholesterolemia and hypertriglyceridemia

Mutational isomers of ApoE → decreased ability of ApoE containing lipoproteins to bind to LDL receptors → increased VLDL, LDL, and chylomicrons → increased blood cholesterol and TGs

Secondary Dyslipidemia

Dyslipidemia caused by lifestyle facators, other medical conditions, or certain prescription drugs

• Often reversible or modifiable by addressing the underlying cause

How can obesity cause secondary dyslipidemia?

Often associated with increased serum levels and production or impaired clearance of VLDL and chylomicrons

Dietary fat → altered adipose tissue function and insulin resistance → increases hepatic release of TG rich lipoproteins (VLDL)

How can diabetes cause secondary dyslipidemia?

Decreased production and effect of insulin or decrease in the body’s response to insulin → decreased efficiency of LPL hydrolysis of TGs → increased TG, VLDL, LDL

How can hypothyroidism cause secondary dyslipidemia?

Decreased production of T3/T4 by the thyroid → decreased expression of LDL receptors and LPL → increased LDL in blood

How can nephrotic syndrome cause secondary dyslipidemia?

Damage to glomeruli → leakage of protein into the urine → hypoalbuminemia (low blood levels of protein) and fluid retention → increased production of protein in the liver → increased VLDL in blood → increased LDL

Also linked to impaired clearance of lipoproteins from the blood, most commonly caused by the intracellular cholesterol levels feedback loop

What drugs can cause secondary dyslipidemia?

Corticosteroids

Beta blockers

Oral contraceptives

Antiretrovirals

Thiazide diuretics

Also excessive alcohol intake and smoking

Complications of Uncontrolled Hyperlipidemia

Atherosclerosis

Pancreatitis

Steatosis

Xanthomas

Xanthelasma

Corneal arcus

Progression of atherosclerosis after fatty streak forms

Development of lipid-laden, cell free necrotic core covered by a fibrous cap

Fibrous cap is formed by a layer of vascular smooth muscle cells that have laid down a fibrous extracellular matrix above the cap but below the endothelial layer of the vessel lumen

When is an atherosclerotic plaque considered vulnerable?

When it displays a large necrotic core and a thin fibrous cap

VSMC death and reduced extracellular matrix production can cause the plaque to rupture, releasing inflammatory mediators and pro-coagulatory molecules into the vessel lumen. Wound healing process causes expansion of the intima into the liminal space, obstructing the path through which blood travels

Presentation of pancreatitis

TG > 1000 mg/dL

Epigastric pain

Nausea

Vomiting

Steatosis

“Fatty liver” caused by fatty deposits collecting in the liver

Presents with exceedingly high TG and LDL

Effects of Steatosis

Fatty environment leads to inflammation and recruitment of immune cells to liver (steatohepatitis)

Complications of uncontrolled steatohepatitis

Immune cells produce fibrous tissue resulting in irreversible loss of liver function leading to cirrhosis, also called non-alcoholic steatohepatitis or non-alcoholic fatty liver disease

Functions of cholesterol

Important structural component of cell membranes

Starting material to synthesize steroid hormones which regulate vital functions in the body

Starting material to synthesize bile acids

What are the functions of the steroid hormones synthesized from cholesterol?

• Glucocorticoids (Ex. cortisol)

  • Regulate metabolism, suppress inflammation, help with the stress response

• Mineralocorticoids (Ex. aldosterone)

  • Control blood pressure and electrolyte balance by acting on the kidneys

• Androgens (Ex. testosterone)

  • Develop male traits and reproductive activity

• Estrogens (Ex. estradiol)

  • Regulate the female reproductive system and secondary sex characteristics

• Progestins (Ex. progesterone)

  • Regulates the female menstrual cycle and aids in supporting a pregnancy

Main role of bile acids

Help with digestion and absorption of fats and fat-soluble vitamins (from the diet) in the small intestine

Bile acid cycle/enterohepatic circulation

After aiding in fat digestion, bile acids are reabsorbed in the ileum, return to the liver via the portal vein, and are resecreted into bile

Ileum

The last part of the small intestine

How often does enterohepatic circulation occur?

Several times a day

How do bile acids help to regulate cholesterol blood levels?

By promoting the breakdown of cholesterol which is eliminated from the body as free cholesterol or as a bile acid

Atherosclerosis

Formation of plaque on the inner walls of arteries due to a buildup of fats, cholesterol, and other substances

Asymptomatic, but can lead to ASCVD

Atherosclerotic Cardiovascular Disease (ASCVD) includes:

Myocardial Infarction (MI)

Stroke

Transient Ischemic Attack (TIA)

Stable Angina

Peripheral Arterial Disease (PAD)

Myocardial Infarction (MI)

Blood flow to part of heart muscle (myocardium) is blocked, usuall by a blood clot or plaque rupture in one or more coronary arteries

Without adequate blood flow, the affected heart tissue is deprived of oxygen, leading to tissue damage or death

Stroke

Blood flow to part of the brain is interrupted or reduced, preventing brain tissue from getting the oxygen and nutrients it needs

Brain cells begin dying within minutes, which can lead to permanent brain damage, disability, or death if not treated quickly

Transient Ischemic Attack (TIA)

“Mini stroke”

A temporary blockage of blood flow to the brain, spinal cord, or retina

Unlike a full stroke, does not cause permanent brain damage because the blockage resolves on its own, usually within minutes to a few hours (by definition <24 hours)

Stable angina

A type of chest pain or discomfort that occurs when the heart muscle doesn’t get enough oxygen rich blood, usually during physical exertion or emotional stress

Caused by narrowing of the coronary arteries due to atherosclerosis and is considered a predictable and manageable form of Coronary Artery Disease (CAD)

Peripheral Arterial Disease (PAD)

A condition in which arteries that supply blood to the limbs, especially the legs, become narrowed or blocked, most commonly due to atherosclerosis

This reduces blood flow to the muscles, particulary during physical activity, leading to pain and other symptoms

Two main sources of cholesterol

Diet

De novo (from scratch) biosynthesis by hepatocytes in the liver

Pathway of de novo cholesterol synthesis

Acetyl-CoA

↓ (two steps)

HMG-CoA

↓ HMG-CoA Reductase

Mevalonic Acid

↓ (many steps)

Cholesterol

What is the rate determining step of cholesterol synthesis?

Conversion of HMG CoA to Mevalonic Acid catalyzed by HMG-CoA Reductase

Main strategies to lower blood levels of cholesterol

1. Block the absorption of cholesterol from the diet into the blood

2. Inhibit de novo synthesis of cholesterol

3. Block the enterohepatic circulation of bile acids → increased removal of cholesterol via feces

What drug class is first line treatment for high LDL blood levels?

Statins

Mechanism of statins

Bind tightly to HMG-CoA Reductase, strongly inhibiting the rate-determining step in cholesterol synthesis

HMG-CoA has a C-S bond that is broken by HMG-CoA Reductase, while statins have a C-C bond that cannot be broken by HMG-CoA Reductase

What statins are prodrugs?

Lovastatin and Simvastatin

How do Lovastatin and Simvastatin function as prodrugs?

They contain a lactone that is hydrolyzed in vivo to form an ionized carboxylic acid. This carboxylic acid allows statins to form a key ionic anchoring interaction with a Lysine residue on HMG-CoA Reductase.

What effects occur in hepatocytes when a statin binds to HMG-CoA Reductase?

Decreased cholesterol synthesis (Direct effect of statin)

Upregulation of the number of LDL receptors in response to low intracellular cholesterol levels

• Leads to increased uptake/clearance of LDL-C from the blood into the liver

• Also seen with ezetimibe, PCSK9 inhibitors, bile acid sequestrans, inclisiran, and bempedoic acid

What are the statin equivalent doses for each statin compared to atorvastatin 10 mg?

Pitavastatin 2 mg

Rosuvastatin 5 mg

Atorvastatin 10 mg

Simvastatin 20 mg

Lovastatin 40 mg

Pravastatin 40 mg

Fluvastatin 80 mg

What is the most potent statin?

Pitavastatin

What is the least potent statin?

Fluvastatin

What time of day should statins be taken?

Simvastatin and Lovastatin are short half-life statins (half life of 5 hours or less) and should be taken at bedtime because maximum de novo cholesterol synthesis occurs between 12:00 am and 2:00 am

Other longer half-life statins can be taken at any time of day

What is the most common adverse effect associated with statins?

Muscle Damage/Statin Associated Muscle Symptoms (SAMS)

How do Statin Associated Muscle Symptoms usually present?

Symmetrical (both sides of the body) soreness, tiredness, or weakness in large muscle groups in the legs, back, and arms

When do muscle symptoms from statins develop?

Usually within 6 weeks of starting treatment, but can develop at any time

Potential muscle effects of statins

Myalgia

Myopathy

Myositis

Rhabdomyolysis

Myalgia

Muscle soreness and tenderness

Myopathy

Muscle Disease

Muscle Weakness +/- Increased Creatinine Phosphokinase (CPK)

What does elevated creatinine phosphokinase (CPK) indicate?

Damage of creatinine kinase-rich tissue, such as heart muscle tissue in myocardial infarction

Myositis

Muscle inflammation

Rhabdomyolysis

Muscle breakdown

• Leads to muscle symptoms, very high CPK (>10000 IU/L), and myoglobulinuria, which can lead to acute kidney/renal failure

Myoglobulinuria

Muscle protein in the urine

• Urine appears tea-colored

• Can lead to acute kidney failure

Why do statins cause muscle damage?

Inhibition of HMG-CoA Reductase in myocytes causes two undesired effects:

• Decreased synthesis of Coenzyme Q10 (Ubiquinone) synthesis

• Disruption of muscle cell membrane integrity

How do statins decrease synthesis of Coenzyme Q10 (Ubiquinone) and how does this impact the muscle?

Inhibition of HMG-CoA Reductase decreases the amount of mevalonic acid, which is needed to synthesize CoQ10 in muscles

CoQ10 is crucial for mitochondrial ATP production in muscle cells

• Low levels can impair muscle energy metabolism leading to muscle pain, weakness, and fatigue

• CoQ10 supplementation can help with SAMS