Dr.Toba kazemiAssociate Professor of CardiologyBUMS-BCRC17 Esfand 1390

: LDL HDL .

Log-linear Relationship Between LDL-C Levels and Relative Risk for CHD This relationship is consistent with a large body of epidemiological data and with data available from clinical trials of LDL-lowering therapy These data suggest that for every 30-mg/dL change in LDL-C, the relative risk for CHD is changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C 40 mg/dL.Grundy S, et al. Circulation. 2004;110:227-239

Risk of CHD by TG LevelThe Framingham Heart Study (30-Year Follow-Up)Reprinted from Castelli WP. Am J Cardiol. 1992;70:3H-9H, with permission from Elsevier.MenWomenUnivariate analysis of data from the Framingham Heart Study, including 5127 patients aged 30to 60 years without CHD, to determine the relationship between TGs and CHD.

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Primary causes : single or multiple gene mutations that result in either overproduction or defective clearance of TG and LDL cholesterol, or in underproduction or excessive clearance of HDLPrimary disorders, the most common cause of dyslipidemia in children, do not cause a large percentage of cases in adults.

Secondary causesSecondary causes contribute to most cases of dyslipidemia in adults.The most important secondary cause in developed countries is a sedentary lifestyle with excessive dietary intake of saturated fat, cholesterol, and trans fats.Other :DM, alcohol overuse, chronic kidney disease, hypothyroidism, primary biliary cirrhosis and liver diseasesDrugs: Thiazides, -blockers, retinoids, highly active antiretroviral agents, estrogen , progestins,

(FH)

FH is an AD disorder characterized :elevated LDL-C + normal TG , tendon xanthomas, premature CADFH is caused by a large number (>1000) mutationsin the LDL receptor gene.The elevated levels of LDL-C in FH are due to an increase in the production of LDL from IDL (since a portion of IDL is normally cleared by LDL receptor-mediated endocytosis) and a delayed removal of LDL from the blood.FH homozygotes: 2 mutated LDL receptorFH heterozygotes: 1 mutant allele Individuals with FH homozygotes have higher LDL-C levels than those FH heterozygotes

LDL receptor

A mutated LDL receptorA normal LDL receptor

Homozygous FH

1 in 1 million persons worldwide.The disease has >90% penetrance so both parents of FH homozygotes usually have hypercholesterolemia.

Clinical manifestation: cutaneous xanthomas on the hands, wrists, elbows, knees, heels, or buttocks present in childhood CHOL are usually >500 mg/dL and can be higher than 1000 mgldL. Important complication of is accelerated atherosclerosis, which can result in disability and death in childhood.Atherosclerosis often develops first in the aortic root, where it can cause aortic valvular or supravalvular stenosis, and typically extends into the coronary ostia, which become stenotic.

Homozygous FH

Exams and Tests:A physical examination may reveal xanthomas and corneal arcus.A strong family history of familial hypercholesterolemia or early heart attacksHigh levels of LDL in either or both parents.Individuals from families with a strong history of early heart attacks should have blood tests done to determine lipid levels.

DysbetalipoproteinemiaDysbetalipoproteinemia,, is a rare lipid disorder characterized by high levels of blood cholesterol & TG.CHOL range from 300-600 mg/dL. TG are usually >400 mg/dL and may exceed 1000 mg/dL. Moderately elevated total cholesterol and triglyceride levels accompanied by the presence of palmar crease xanthomas confirm the diagnosis dysbetalipoproteinemia

Clinical findings

Patients may have no physical findings or may have skin lesions called xanthomas, particularly in more severe presentations. Xanthoma striata palmarisTuberoeruptive and tuberous xanthomasCorneal arcus ,Xanthelasmas Obesity or signs of hypothyroidism may be noted.

High levels of TGs (> 1000 mg/dL) can cause acute pancreatitis. (pancreatitis/premature CAD).

High levels of LDL :eyelid xanthelasmas; arcus corneae; tendinous xanthomas .familial hypercholesterolemia :the above findings plus planar or cutaneous xanthomassevere elevations of TGs can have eruptive xanthomas Patients with dysbetalipoproteinemia can have palmar and tuberous xanthomasSevere hypertriglyceridemia (> 2000 mg/dL) can give retinal arteries and veins a creamy white appearance (lipemia retinalis).Extremely high lipid levels also give a lactescent (milky) appearance to blood plasma.

Diagnosis

Lipid profile measurementTesting should be postponed until after resolution of acute illness, because TGs increase and cholesterol levels decrease in inflammatory states. Lipid profiles can vary for about 30 days after an acute MI; however, results obtained within 24 h after MI are usually reliable enough to guide initial lipid-lowering therapy.TC, TGs, and HDL cholesterol are measured directly.LDL cholesterol = TC [HDL cholesterol + (TGs 5)] (Friedewald formula).This calculation is valid only when TGs are < 400 mg/dL and patients are fasting

Screening: A fasting TC, TGs, HDL cholesterol, and calculated LDL cholesterol should be obtained in all adults 20 yr and should be repeated every 5 yr.screening patients < 20 yr: atherosclerotic risk factors, such as diabetes, hypertension, cigarette smoking, and obesity; premature CAD in a parent, grandparent, or sibling; or a cholesterol level > 240 mg/dL or known dyslipidemia in a parent.12 hours fasting

Other tests

1- Lp(a) measurement :Patients with premature atherosclerotic cardiovascular disease cardiovascular disease with normal or near-normal lipid levels high LDL levels refractory to drugPatients with an extensive family history of heart disease2-C-reactive protein and homocysteine measurement may be considered in the same populations.3-Tests for secondary causes

3-Tests for secondary causes : FBS, liver enzymes,CreatininTSHurinary proteinFor who? (newly diagnosed dyslipidemia , when a component of the lipid profile has changed for the worse.A definite age after which no require screening ?? into their 80s, especially in the presence of atherosclerotic cardiovascular disease.

US Hypertriglyceridemia (HTG) PrevalenceUS Adult PopulationTotal = 217 millionTG 500 mg/dL ~2.5%5-6 M patientsTG 200-499 mg/dL*~13%~28 M patients

HIGH TGINDEPENDENT RISK FACTOR FOR HEART ATTACKINDEPENDENT RISK FACTOR FOR STROKEASSOCIATED WITH LOW HDLASSOCIATED WITH INCREASED CLOTTING VIA HIGH PLASMINOGEN ACTIVATOR INHIBITOR ACTIVITY, HYPOFIBRINOLYSIS (CANT CHOP UP BLOOD CLOTS EASILY)A FUNDAMENTAL PART OF METABOLIC SYNDROME, HIGH CHD RISK

,OCP

Familial hypertriglyceridemia

Familial hypertriglyceridemia is a common disorder passed down through families in which the level of TG are higher than normal.The condition is not associated with a significant increase in cholesterol levels. An autosomal dominant fashionFamilial hypertriglyceridemia does not usually become noticeable until puberty or early adulthood. Obesity, hyperglycemia (high blood glucose levels), and high levels of insulin are often also present and may cause even higher triglyceride levels.about 1 in 500 individuals in the United States. Risk factors are a family history of hypertriglyceridemia or a family history of heart disease before the age of 50.

Familial hypertriglyceridemia-

Exams and TestsPeople with a family history of this condition should have blood tests to check very low density lipoprotein (VLDL) and triglyceride levels. Blood tests usually show a mild to moderate increase in triglycerides (about 200 to 500 mg/dL)

500 dL/mg 500 -200 ChOLHDL- Non .(Non-HDL chol=Total Chol-HDL) Target Non-HDL =LDL+30))

LOW HDL : ( . 2 ) ( )

LOW HDL

Ddiagnostic approach-summary

1-Measure fasting lipoproteins3- Identify CAD or CAD equivalents & CAD risk factors Slide 32 4- If 2 major risk factors without CAD or CAD equivalent, assess 10-yr risk of MI or CAD death using Framingham risk tables 5-refer to NCEP ATP III Guidelines for Treatment of Hyperlipidemia 2-primary/secondary

(mg/dl)

Rule out secondary causes(FBS,U/A,CR,TSH,LFT)Sedentary lifestyle, obesity, and smoking are all associated with low HDL-C levels, and patients should be counseled about these issues.Patients with hyperlipidemia, especially hypertriglyceridemia, who drink alcohol should be encouraged to decrease their intake.DrugsAttempts should be made to diagnose the primary lipid disorder

CAD equivalents:Peripheral arterial diseaseAbdominal aortic aneurysmSymptomatic carotid artery diseaseDiabetes mellitusMajor CAD risk factors in dyslipidemia:Cigarette smokingHypertension (BP 140/90 or on antihypertensive drug)Low HDL ( 40 mg/dL [1.03 mmol/L])Family history of premature CAD (CAD in a male 1st-degree relative < 55 or in a female 1st-degree relative < 65)Age (men 45, women 55)

Framingham Ten Year RiskMenWomen

Framingham Ten Year Risk0

Framingham Ten Year Risk03Non-Smoker0

Framingham Ten Year Risk030HDL = 431

Framingham Ten Year Risk0301SBP = 119, untreated04

Framingham Ten Year Risk030104

LDLNon HDL

TREATMENT

Ddiagnostic approach-summary

1-Measure fasting lipoproteins3- Identify CAD or CAD equivalents & CAD risk factors4- If 2 major risk factors without CAD or CAD equivalent, assess 10-yr risk of MI or CAD death using Framingham risk 5-refer to NCEP ATP III Guidelines for Treatment of Hyperlipidemia 2-primary/secondary

1:

54 . . . . 12 :FBS=85 Chol = 220 TG= 332 HDL=42 LDL=111

54 . . LDL HDL

Non HDL- ChOL = 220-42=178

www.bums.ac.ir/heart

*Log-linear Relationship Between LDL-C Levels and Relative Risk for CHD.This slide identifies that the relationship between relative risk for coronary heart disease is consistent with a large body of epidemiological data and with data available from clinical trials of LDL-lowering therapy. Also, it suggests that for every 30-mg/dL change in LDL-C, the relative risk for CHD is changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C 40 mg/dL.

ReferencesGrundy SM, Cleeman JI, Merz NB, et al; for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227-239.

*ACCESS Medical Group

*Risk of CHD by TG Level. The Framingham Heart StudyAn analysis of the Framingham Heart Study was composed of 5127 men and women, 30 to 60 years of age, who were free of clinically overt heart disease.1 A simple linear relationship was observed between serum TG levels and the subsequent development of coronary artery disease (CAD). In women, this relationship was significant, even after adjusting for blood pressure, smoking, and left ventricular hypertrophy.Original Study:The Framingham Heart Study is a longitudinal, population-based family study.2,3 Original cohort of 5209 men and women between the ages of 30 and 62 who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke received examinations every 2 years beginning in 1948 Two subsequent generations were recruited in 1971 and 2002 to receive similar examinations Objective is to identify the common factors or characteristics that contribute to CVD

ReferenceCastelli WP. Epidemiology of Triglycerides: A View from Framingham. Am J Cardiol. 1992;70:3H-9H.2. Castelli WP. Cholesterol and lipids in the risk of coronary artery diseasethe Framingham Heart Study. Can J Cardiol. 1988;4(suppl A):5A-10A.3. Framingham Heart Study. History of the Framingham Heart Study: a project of the National Heart, Lung, and Blood Institute and Boston University. http://www.framinghamheartstudy.org/about/history.html. Accessed September 21, 2008.

*Hypertriglyceridemia PrevalenceIt is estimated that 5-6 million people in the United States have TG levels that exceed 500 mg/dL, comprising roughly 2.5% of the population, and 28 million people (13%) have TG levels in the range of 200-499 mg/dL.

References:U.S. Census Bureau. Population. In: Statistical Abstract of the United States 2004-2005. Available at http://www.census.gov/prod/www/statistical-abstract-04.html. Accessed August 2, 2005.National Institutes of Health. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). NIH Publication No. 02-5215. Bethesda, Md: National Institutes of Health; 2002:VII-3-VII-5, Appendix III-A.

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