What are the energy sources available to the heart under normal conditions and during starvation?
normal conditions: glucose, fatty acids (favors FA), phosphocreatine: CK uses ATP to phosphorylate creatine to produce phosphocreatine-supplies energy for a number of seconds which can be life saving but supply is not substantial. the heart also does not have large glycogen stores and therefore needs continuous blood supply to function
during starvation: FA and ketone bodies (not favored by the heart) are used for energy production. ketone bodies are short FA produced by the liver during starvation. glucose is preserved for cells that are only able to use glucose as a source of energy
In anaerobic conditions, pyruvate will be converted to lactic acid which will be transported out of the cell. Why is this done?
To avoid acidosis. If intracellular environment becomes to acidic, the lower pH will begin to affect protein function and may cause protein denaturation if it goes low enough. Metabolism will cease and the cell will die. pH also influences pumps and many other cellular functions.
How is lactic acid transported out of cells? What issues may occur with its transportation out of cells and how may this cause pain?
Plasma membranes contain a symport for lactate ion and H+ which relases both into the blood stream. However, if blood flow is inadequate, H+ cannot escape fast enough from the cell and results in pain due to stimulation of pain nerve cells-nociceptors
What is angina pectoris? What is it due to? What are some of its symptoms?
Chest pain associated with reversible myocardial ischemia is angina pectoris (strangling pain in the chest). Pain that results is due to imbalance btwn demand for and supply of blood flow to cardiac muscle and is most commonly caused by narrowing of the coronary arteries. Coronary arteries involved are often obstructed by atherosclerosis or less commonly are narrowed by spasm. Pt experiences squeezing pressure or ache substernally, often radiating to both the shoulder and arm and occasionally to jaw or neck.
What serious cardiac disease may angina pecotris lead to if ischemia persists long enough? What are some symptoms?
Myocardial infarction occurs if the ischemia caused by narrowed coronary arteries perists long enough to cause severe damage (necrosis) to the heart muscle (cells release contents which can be detected in lab work). Commonly, a blood clot forms at the site of narrowing and completely obstructts the vessel. In MI, tissue death occurs and characteristic pain is longer lasting and often more severe.
What are the major risk factors for CAD?
- family hx of premature CAD
- high serum triglyceride levels
- elevated serum cholesterol levels
Discuss the findings of the MRFIT study in relation to serum total cholesterol.
Serum total cholesterol (TC) levels are associated with CAD risk levels. The MRFIT study observed an asymptomatic increasein CAD mortality over 4-fold in 300k+ men followed for 6 years when TC increased from 150 mg/dl to 300 mg/dl. Note in the chart that in cholesterol levels above 200 mg/dl, death rate due to CAD almost exponentially increases.
What are plasma-lipoproteins? What is their function? Where are they synthesized?
Plasma-lipoproteins are synthesized both in the intestine and liver and are heterogeneous group of lipid-protein complexes composed of various types of lipids and proteins (apoproteins). They solubilize fats for transportion in the blood as well as carry fats to and from the tissues. Triglycerides, cholesterol, and fat soluble vitamins (A,D,E,K) are trasnported in lipoproteins. Note that the lipid-protein layer is a single layer.
What are the different types of lipoproteins and how do they differ?
Lipoproteins vary by size, lipid content, and apoprotein type: chylomicron, VLDL, LDL, and HDL
Where are chylomicrons formed? What do they transport and to where? What vascular disease may they play a role in?
Chylomicrons are formed in the intestine and absorb and transport triacylglycerol, cholesterol and fat-soluble vitamins. Fatty acids are taken up by adipose tissue and other tissues forming chylomicron remnants which deliver cholesterol to the liver. In chylomicron remnants, most of the triacylglycerol has been released and the cholesterol content is higher. Chylomicron remnants may play a role in atherogenesis.
Where are VLDLs and LDLs formed? What do they transport and to where? What vascular disease may they play a role in?
VLDLs are synthesized in the liver from newly synthesized triacylglycerol and cholesterol. Fatty acids from triacylglycerols in VLDL are taken up by adipose and other tissues forming VLDL remants with a now higher cholesterol concentration. VLDL remnants then either go to the liver or are converted to LDLs that deliver cholesterol to peripheral tissues and the rest goes back the liver. LDL is thought of as "bad cholesterol" and imposes a direct risk for atherogenesis. LDL becomes an issue when it circulates for a longer than normal amount of time.
Where are HDLs formed? What do they transport and to where? What vascular disease may they play a role in?
HDLs are synthesized by the liver and intestine and play an essential role in picking up cholesterol from the periphery and delivering it back to the liver (egress from arterial wall). HDLs reverse cholesterol trafficking. HDLs play a role in fighting atherogenesis (good cholesterol)
What lipoproteins and apoproteins are associated with an increased risk for CAD? When does risk appearance increase?
Lipoproteins that are associated with increased risk are rich in cholesterol: LDL, VLDL remnants, and chylomicron remnants.
Apo A levels are associated with decreased risk (HDL). Apo E and especially apo B are associated with increased risk (LDL, VLDL remnants and chylomicron remnants
Risk for CAD appears to increase with the presence of breakdown units of lipoproteins in the blood: VLDL- or chylomicron remnants increase risk comapred to complete VLDL or chylomicron particles
When remnants circulate in blood, they release their contents to liver. When the circulation is overloaded with particles, remnants will release contents in blood. If the liver does not get rid of cholesterol fast enough, it goes to arterial walls.
What is the breakdown of total cholesterol btwn HDL, LDL, and VLDLs?
Therefore, total cholesterol levels primarily reflect LDL
What are the normal levels for total cholesterol (TC), HDL cholesterol (HDL-C), triglycerides (TG), and LDL cholesterol (LDL-C)? How is LDL-C determined?
TC: 120-200 mg/dL
HDL-C: > 40 mg/dL (btwn 40 and 80)
TG: 70-150 mg/dL
LDL-C is calculated to be < 100 mg/dL.
LDL-C levels cannot be measured so they are calculated using the Friedewald formula from the above parameters:
VLDL=Triglycerides/5: cholesterol to TG ratio is 1 to5 so VLDL is calculated this way. A recently modified fomula with 0.16T is also used to calculate VLDL. Total cholesterol=VLDL+HDL+LDL so:
Note serum concentration (particle number) of LDL has a stronger correltion with clincal outcomes than the amount of cholesterol within the LDL particles.
The role of developing atherosclerosis is directly related to plasma (LDL-C/HDL-C) and is inversely related to (LDL-C/HDL-C).
Directly related to LDL-C and inversely related to HDL-C
What 3 things are atherosclerosis characterized by?
Atherosclerosis is a disorder of the arterial wall characterized by:
1. accumulation of cholesteryl esters in cells derived from the monocyte-macrophage line (in tunica intima of typically muscular arteries)
2. smooth muscle cell proliferation
Describe the process of the fomation of an atherosclerotic plaque.
Note that high levels of circulating lipid in blood produces this cascade of events.
1. Endothelial cell receptors in blood vessels bind and take up LDL (VLDL-remnants, chylomicron remnants. Longer than normal circulation of LDLs leads to LDLs oxidizing protein and lipid components which causes endothelial cell injury. If an an LDL is oxidized, it more easily enters and is entrapped in the intima.
2. Monocytes recognize the endothelial cell injury and enter the the intima. They become activated macrophages and take up LDLs and oxLDLs. The scavenger receptor on activated macrophages allows them to become engulfed with particles and causes them to take up more particles than normal, becoming foam cells.
3. Foam cells that are now full with cholesterol and cholesterol esters release growth factors and cytokines. Foam cells release these particles bc they are large and can burst. The release of these particles results in an inflammatory response
4. Growth factors and cytokines stimulate smooth muscle cell migration form the tunica media to the tunica intima and causes their proliferation. Smooth muscle cells also accumulate LDLs and may also become foam cells. Smooth muscle cells deposit an ECM rich in collagen which produces a thickened intima with a roughened surface of the vessel lumen=plaque. Once formed, the plaque is irreversible.
What further events occur in the formation of an atherosclerotic plaque (involving platelets)?
Distortion of the subendothelium leads to platelet aggregation on the endothelial surface and release of platelet derived mitogens such as platelet derived growth factor (PDGF). PDGF may stimulate smooth muscle cell growth. Death of the foam cells results in accumulation of a cellular lipid that can stimulate fibrosis. The resultant plaque narrows the blood vessel, decreasing blood flow and causing ischemia. When the plaque bursts, blood clotting is initiated that completely occludes the artery and lead to cell death-->MI
In what 4 ways does HDL help reduce the risk of forming an atherosclerotic plaque?
1. performs reverse cholesterol transport from peripheral tissues to the liver
2. takes cholesterol from LDL and VLDL and delivers it to the liver
3. inhibits LDL binding to arterial alls
4. inihibits oxidation of LDL
What are the effects of the risk factors listed below?
1. increased LDL, VLDL remnant, chylomicron remnant
2. decresed HDL
4. cigarette smoking
1. increased LDL, VLDL remnant, chylomicron remnant: increased lipoprotein entry into arterial wall
2. decresed HDL: decreased cholesterol egression from arterial wall
3. HTN: arterial endothelial injury, increased lipoprotein entry into arterial wall
4. cigarette smoking: arterial endothelial injury, arterial wall hypoxia and thrombosis
5. DM: multiple effects (LDL modification)
How do diets high in cholesterol, saturated FAs, transunsaturated fats, and obesity affect risk for atherogenesis?
- High cholesterol diets are associated with decreased liver receptor activity for LDL and VLDL, increasing the propensity for peripheral absorption of these particles
- Saturated fatty acids reduce hepatic clearances of VLDL leading to increased remnants and LDL which causes increased peripheral absorption
- Trans fats raise the levels of LDL cholesterol and can lower the levels of HDL cholesterol
- Obesity produces mobilization of free fatty acids from the periphery to the liver, with increased VLDL production and consequently increased LDL levels which leads to more peripheral absorption
How do monounsaturated fatty acids, omega-6 polyunsaturated fatty acids, and omega-3 polyunsaturated fatty acids impact cholesterol?
- Monounsaturated faty acids: decrease triglycerides, decrease LDL-C. Does not change HDL-C. Enhance clearance of VLDL remnant and LDL
- Omega-6 polyunsaturated fatty acids: lower LDL-C, in high concentration may also lower HDL-C. Enhance clearance of VLDL remnant and LDL
- Omega-3 polyunsaturated fatty acids: decrease triglycerides, decrease VLDL triglyceride synthesis
What are some dietary treatment options for treatment of hypercholesterolemia?
- Reduction of dietary cholesterol to less than 300 mg/day
- Reduction of total fat intake to less than 30% of total calories
- About 2/3 of fat should be mono or polyunsaturated fatty acids
What drugs may be used to treat hypercholesterolemia?
• Cholestyramine and colestipol: bile salt-binding drugs that promote excretion of bile salts in the stools. This increases rate of hepatic bile salt synthesis and of LDL uptake by the liver.
• Ezetimibe: lowers absorption of cholesterol
• Fibrate: lowers absorption of cholesterol and triglycerides
• Statins: inhibitors of cholesterol synthesis (inhibition of HMG CoA reductase) and stimulate uptake of LDL by the liver