SGD Cardiovascular

8/10/2019 SGD Cardiovascular

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CLINICAL CASE DISCUSSIONBiochemistry

ACUTE CORONARY SYNDROMECardiology case

A 45 year old male was admitted at the ICU of Fatima University Medical Centerbecause of severe progressive chest pain with cold sweating./ He is obese withBMI of 32, BP 200/110, RR 30/min, HR 120 bpm. ECG was immediately donewith findings of ST segment elevation in I + AVL V3 V4 V5 V6 with reciprocalchanges in II, III, AVF his TROP T revealed 1, 200 ng/ml. Patient wasimmediately given streptokinase 1,500 units by 1U and Nicardipine drip Isoketwere started.

1. Define obesity. How it is assessed? Why is it linkedto MI?

A.) define obesity

Obesity is an abnormal accumulation of body fat, usually 20% or moreover an individual's ideal body weight. Obesity isassociated with increased risk of illness, disability, anddeath.

The branch of medicine that deals with the study and treatment of obesity is known as bariatrics. As obesity has become amajor health problem in the United States, bariatrics has become a separate medical and surgical specialty.

B.) assessment

Assessment of weight and health risk involves using three keymeasures:

Body mass index (BMI)

Waist circumference

Risk factors for diseases and conditions associated with

obesity

Body Mass Index (BMI)

BMI is a useful measure of overweight andobesity. It is calculated from your height andweight. BMI is an estimate of body fat and agood gauge of your risk for diseases that canoccur with more body fat. The higher your BMI,
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the higher your risk for certain diseases suchas heart disease, high blood pressure, type 2diabetes, gallstones, breathing problems, andcertain cancers.

Although BMI can be used for most men and

women, it does have some limits:It may overestimate body fat in athletesand others who have a muscular build.

It may underestimate body fat in olderpersons and others who have lostmuscle.

Use theBMI CalculatororBMI Tablestoestimate your body fat. The BMI score meansthe following:

BMI

Underweight Below 18.5

Normal 18.524.9

Overweight 25.029.9

Obesity 30.0 and Above

Waist Circumference

Measuring waist circumference helps screenfor possible health risks that come with

overweight and obesity. If most of your fat isaround your waist rather than at your hips,youre at a higher risk for heart disease andtype 2 diabetes. This risk goes up with a waistsize that is greater than 35 inches for womenor greater than 40 inches for men. To correctlymeasure your waist, stand and place a tapemeasure around your middle, just above yourhipbones. Measure your waist just after youbreathe out.The tableRisks of Obesity-Associated

Diseases by BMI and WaistCircumferenceprovides you with an idea ofwhether your BMI combined with your waistcircumference increases your risk fordeveloping obesity-associated diseases orconditions.
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Risk Factors for Health Topics AssociatedWith Obesity

Along with being overweight or obese, thefollowing conditions will put you at greater riskfor heart disease and other conditions:Risk Factors

High blood pressure (hypertension)

High LDL cholesterol ("bad" cholesterol)

Low HDL cholesterol ("good"cholesterol)

High triglycerides

High blood glucose (sugar)

Family history of premature heartdisease

Physical inactivity

Cigarette smoking

For people who are considered obese (BMIgreater than or equal to 30) or those who areoverweight (BMI of 25 to 29.9) and have two ormore risk factors, it is recommended that youlose weight. Even a small weight loss (between5 and 10 percent of your current weight) willhelp lower your risk of developing diseasesassociated with obesity. People who areoverweight, do not have a high waistmeasurement, and have fewer than two riskfactors may need to prevent further weight gainrather than lose weight.Talk to your doctor to see whether you are atan increased risk and whether you should loseweight. Your doctor will evaluate your BMI,waist measurement, and other risk factors forheart disease.The good news is even a small weight loss(between 5 and 10 percent of your currentweight) will help lower your risk of developingthose diseases.

C.) why is it linked to MI


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Until recently the relation between obesity and coronary heartdisease was viewed as indirect, ie, through covariates related toboth obesity and coronary heart disease risk,

12including

hypertension; dyslipidemia, particularly reductions in HDLcholesterol; and impaired glucose tolerance or noninsulin-

dependent diabetes mellitus. Insulin resistance and accompanyinghyperinsulinemia are typically associated with thesecomorbidities.13Although most of the comorbidities relating obesityto coronary artery disease increase as BMI increases, they alsorelate to body fat distribution. Long-term longitudinal studies,however, indicate that obesity as such not only relates to butindependently predicts coronary atherosclerosis.

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This relationappears to exist for both men and women with minimal increases inBMI. In a 14-year prospective study, middle-aged women with aBMI >23 but 25 but


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The five conditions described below are metabolic riskfactors. You can have any one of these risk factors by itself,but they tend to occur together. You must have at least threemetabolic risk factors to be diagnosed with metabolicsyndrome.

A large waistline. This also is called abdominal obesity or"having an apple shape." Excess fat in the stomach areais a greater risk factor for heart disease than excess fat inother parts of the body, such as on the hips.

A high triglyceride level (or you're on medicine to treathigh triglycerides). Triglycerides are a type of fat found inthe blood.

A low HDL cholesterol level (or you're on medicine totreat low HDL cholesterol). HDL sometimes is called"good" cholesterol. This is because it helps remove

cholesterol from your arteries. A low HDL cholesterollevel raises your risk for heart disease.

High blood pressure(or you're on medicine to treat highblood pressure). Blood pressure is the force of bloodpushing against the walls of your arteries as your heartpumps blood. If this pressure rises and stays high overtime, it can damage your heart and lead to plaquebuildup.

High fasting blood sugar (or you're on medicine to treathigh blood

sugar). Mildly high blood sugar may be an early sign ofdiabetes.

Large Waist Size For men:40 inches or larger

For women: 35 inches or larger

Cholesterol: High Triglycerides

Either

150 mg/dL or higher

or

Using a cholesterol medicine

Cholesterol: Low Good CholesterolEither
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(HDL) For men:Less than 40 mg/dL

For women:Less than 50 mg/dL

or

Using a cholesterol medicine

High Blood Pressure

Either

Having blood pressure of 135/85mm Hg

or greater

or

Using a high blood pressure medicine

Blood Sugar: High Fasting Glucose

Level 100 mg/dL or higher

3. Discuss the metabolic pathway of LDL and HDLa. LDL

Cholesterol Transport and Utilization

Majority of cholesterol is transported as cholesterol ester.

The ester is synthesized in the plasma from cholesterol and the acylchain of the phosphatidylcholine (Lecithin)

Lecithin + CholesterolLCAT

Lysolecithin + Cholesterolester

LCAT(Lecithin:cholesterol acyltransferase)

The intracellular cholesterol is synthetized by ACAT. (Acyl-CoA:cholesterol acyltransferase)

Acyl-CoA + cholesterolACAT

Cholesterolester + HS-CoA

Low density lipoprotein (LDL) transport cholesterol to peripheral tissues,and high-density lipoprotein (HDL) transport cholesterol from peripheraltissues to the liver.


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Control of Cholesterol Biosynthesis

1)HMG-CoA reductase

The enzyme synthesis inhibited Hydroxy cholesterols Phosphorylation dephosphorylation (active)

2)Hormonal regulation:

insulin cortisol, glucagon

3)Dietary cholesterol intake "feedback inhibitory"

4)LDL (Low-density Lipoprotein) receptor regulation

5)n-3 polyunsaturated fatty acids

6)Drug action on HMG-CoA reductase (statins)

The LDL receptor pathway


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The LDL receptor pathway (cont.)

Plasma LDL is taken up by cells via LDL receptors in clathrin-coaated pits.

LDL are separated from their receptor in endosomes (pH 5 to 6) then undergo digestion in lysosomes (pH ~3). The LDL receptors recycle back to the cell surface making


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Hereditary Hyperlipoproteinamias

Dysbetalipoproteinemia:Accumulation of IDL, VLDL and

chylomicron remnant. Elevated level of total cholesterol andtriglycerides. The disorder caused by Apo-E or Apo-E receptor.Diabetes, hypothyroidism are associated with type III disorders.

Abetalipoproteinemia:Genetic defect in the synthesis of Apo-B.Both chylomicron and VLDL are affected. Fat malabsorbtionoccurs because chylomicron can not be formed by intestine.

Multiple type hyperlipoproteinemiaIncreased level of VLDLand LDL which is resulted from the overproduction of VLDL. Thebiochemical defect is unknown.

Familial hypecholesterolemias:LDL receptor downregulation orreceptor defects. Homozygotes do not have functioning LDLreceptor. The gene defect is caused by mutation, deletions,insertions.

Cholesterol Homeostasis in FH

FH:Familial Hypercholesterolemia

LDL receptor failed to migrate from endoplasmic reticulum to Golgi

Homozygous form (rare)cholesterol level above 650 mg/ 100 mlThey die before age 20.

Heterozygous form (one defective allele)cholesterol level 250 - 500 mg/ 100 mlhigh risk to have heart attack

Involvement of the LDL receptor in cholesterol uptake and metabolism


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Regulatory actions of cholesterol

After the synthesis in the endoplasmic reticulum, the LDL receptormatures in the Golgi complex

then migrates to the cell cell surface, where it clusters in coated pits. After internalization of LDL, multiple vesicles fuse to form endosome. Proton pumping in the endosome membrane causes the pH to drop, which

in turn cause LDL to dissociate from the receptor. The LDL apolipoprotein is degraded in lysosomes. The LDL receptor remains in a vesicle, which returns to the plasma

membrane to start the cycle anew.


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Structure of the LDL receptor

The structure is divided into five domains.

The first domain contains the LDL binding site. This is followed by a large domain that contains homology with the

epidermal growth factor (EGF) precursor. Next, is a small segment that contains a large number of O-linked

carbohydrate residues. The fourth domain spans the plasma membrane. The last domain is a short segment that projects into the


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cytoplasm but does not have any kinase activity.

B. HDL

The hypertriglyceridemia that frequently accompanies diabetes mellitus andpersons with

the metabolic syndrome has important metabolic effects on HDL content, particlesize

and hence affecting its protective function. The increase in visceral fat in case of

abdominal obesity leads to increase free fatty acids in the plasma. In the liver,the

increased fatty acids, is incorporated into triglycerids and secreted as VLDLparticles,

which are further remodeled through hydrolysis in the plasma component to free

fatty

acids that in-turn are incorporated into adipose tissue. Fig.1 demonstrates themetabolic

effect of the VLDL particles with high triglyceride content on HDL and LDLparticles.

As shown in the figure, this triglyceride- loaded VLDL will activate a proteinspecialized

in transfer of cholesterol ester between the different lipoprotein particles. Thischolesterol

ester transfer protein (CETP), will exchange cholesterol esters in HDL and LDLparticles

with the triglyceride content of the VLDL particles, a lipid shuttle activity that willend in

increasing the triglyceride content of both HDL and LDL particles and decreasingtheir

cholesterol ester content, an effect that is enhanced by the activity of the lipaseenzyme.

The resultant HDL particles are dysfunctional and less effective in cholesterolremoval

from the periphery to the liver, with more small LDL particles and progressive

atherosclerosis. This metabolic profile with high triglycerides, low HDL and smallLDL

particles is the atherogenic profile in many cases of diabetes, abdominal obesityand

metabolic syndrome.


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4. Discuss the pathogenesis of atherosclerosis

Pathogenesis of Atherosclerosis

Marchand introduced the term atherosclerosis describing the association offatty degeneration and vessel stiffening.1This process affects medium and large-sized arteries and is characterized by patchy intramural thickening of thesubintima that encroaches on the arterial lumen. Each vascular bed may beaffected by this process; the etiology, treatment and clinical impact ofatherosclerosis varies from one vascular bed to another.2The earliest visiblelesion of atherosclerosis is the fatty streak, which is due to an accumulation oflipid-laden foam cells in the intimal layer of the artery. With time, the fatty streakevolves into a fibrous plaque, the hallmark of established atherosclerosis.Ultimately the lesion may evolve to contain large amounts of lipid; if it becomesunstable, denudation of overlying endothelium, or plaque rupture, may result inthrombotic occlusion of the overlying artery.

Atherosclerotic lesions are composed of three major components. The first is thecellular component comprised predominately of smooth muscle cells andmacrophages. The second component is the connective tissue matrix andextracellular lipid. The third component is intracellular lipid that accumulateswithin macrophages, thereby converting them into foam cells. Atheroscleroticlesions develop as a result of inflammatory stimuli, subsequent release of variouscytokines, proliferation of smooth muscle cells, synthesis of connective tissuematrix, and accumulation of macrophages and lipid.

5. discuss and illustrate the schematic structureof myofilament showing relationship betweentroponin, tropomyosin and myosin

6. Discuss the rise and fall of troponin T together with

other markers for MI. why is it the preferred marker?
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