Lipoprotein disorders and cardiovascular diseases

Date-28-03-2017

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GENERAL STRUCTURE OF LIPO PROTEINSGENERAL STRUCTURE OF LIPO PROTEINS

Lipoproteins consist of a nonpolar core and a single surface layer of amphipathic lipids

The nonpolar lipid core consists of mainly triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules

These are oriented so that their polar groups face outward to the aqueous medium.

The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein.

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GENERAL STRUCTURE OF LIPO PROTEINSGENERAL STRUCTURE OF LIPO PROTEINS

Some apolipoproteins are integral and cannot be removed, whereas others can be freely transferred to other lipoproteins.

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Classification of LipoproteinsClassification of Lipoproteins

Lipoproteins with high lipid content will have low density, larger size and so float on centrifugation. Those with high protein content sediment easily, have compact size and have a high density. 04/02/17 5

APOLIPOPROTEINSAPOLIPOPROTEINS

One or more apolipoproteins (proteins or polypeptides) are present in each lipoprotein.

The major apolipoproteins of HDL (α-lipoprotein) are designated A.

The main apolipoprotein of LDL (β -lipoprotein) is apolipoprotein B (B-100), which is found also in VLDL.

Chylomicons contain a truncated form of apo B (B-48) that is synthesized in the intestine, while B-100 is synthesized in the liver.

Apo E is found in VLDL, HDL, Chylomicons, and chylomicron remnants.

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LIPOPROTEIN METABOLISM AND TRANSPORTLIPOPROTEIN METABOLISM AND TRANSPORT

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LIPOPROTEIN DISORDERSLIPOPROTEIN DISORDERS

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Provided a useful conceptual framework. This classification had many drawbacks: A)did not give much emphasis on HDL-C, B)it does not differentiate severe monogenic lipoprotein

disorders from the more common polygenic disorders. World Health Organization, the European

Atherosclerosis Society, and more recently, the National Cholesterol Education Program (NCEP) classified lipoprotein disorders on the basis of arbitrary cut points.

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GENETIC LIPOPROTEIN DISORDERSGENETIC LIPOPROTEIN DISORDERS

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(TYPE II HYPERLIPIDEMIA)

FAMILIAL HYPERCHOLESTEROLEMIA FAMILIAL HYPERCHOLESTEROLEMIA Affected subjects have an elevated LDL-C level greater

than the 95th percentile for age and sex. In adulthood, clinical manifestations include corneal

arcus, tendinous xanthomas over the extensor tendons (metacarpophalangeal joints, patellar, triceps, and Achilles tendons), and xanthelasmas.

Transmission is autosomal codominant. FH affects approximately 1 in 500.Patients with FH have high risk for the development of

CAD by the third to fourth decade in men and approximately 8 to 10 years later in women.

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PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN TYPE 9 GENE TYPE 9 GENE

An autosomal dominant form of hypercholesterolemia that maps to chromosome 1p34.1 involves a mutation within the PCSK9 gene.

PCSK9 codes for a proprotein convertase belonging to the subtilase family of convertases.

Gain-of-function mutations in the PCSK9 gene decrease surface availability of the LDL-R protein and cause accumulation of LDL-C in plasma.

Subjects with a loss-of-function mutation of PCSK9 have markedly lower LDL-C than do subjects without the mutation.

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Cohen J et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354:1264, 2006.

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AUTOSOMAL RECESSIVE AUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIA HYPERCHOLESTEROLEMIA

HYPOBETALIPOPROTEINEMIAMutations within the APOB gene can lead to

truncations of the mature apo B100 peptide. Many such mutations cause a syndrome characterized by

reduced LDL-C and VLDL-C but little or no clinical manifestations and no known risk for CVD, a condition referred to as hypobetalipoproteinemia .

04/02/17 Curr Opin Lipidol. 2014 June ; 25(3): 161–168. 18

ABETALIPOPROTEINEMIAResults from a mutation in the gene coding for the

microsomal triglyceride transfer protein (MTP), required for assembly of apo B–containing lipoproteins in the liver and the intestine.

Lack of apo B–containing lipoproteins in plasma causes a marked deficiency of fat-soluble vitamins (A, D, E, and K) that circulate in lipoproteins.

Results in mental and developmental retardation in affected children.

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Acanthocytosis in PBFOral fat intolerance, steatorrhea, diarrhea, fat

malabsorption, lipid accumulation in enterocytes, failure to thrive and deficiency of fat-soluble vitamins A and E.

Deficiency of vitamin E leads to progressive degeneration of the central nervous system and death.

Unless treated early with vitamin E, subjects develop atypical retinitis pigmentosa, spinocerebellar degeneration with ataxia and a bleeding diathesis secondary to malabsorption of fat-soluble vitamins

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SITOSTEROLEMIAA rare condition of increased intestinal absorption and

decreased excretion of plant sterols (sitosterol and campesterol) can mimic severe FH with extensive xanthoma formation.

Premature atherosclerosis,occurs in patients with sitosterolemia.

Patients with sitosterolemia have homozygous (or compound heterozygous) mutations in the ABCG5 and ABCG8 genes.

A defect in either of the genes inactivates the transport mechanism across the intestinal lumen, and net accumulation of plant sterols (because of impaired elimination) ensues .

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Othman et al. Non-cholesterol sterols andcholesterol metabolism in sitosterolemia. Atherosclerosis.

2013;231(2):291–9.

Quintás-Cardama A et al .Long-term follow-up of a patientwith sitosterolemia and hemolytic anemia with excellent response

to ezetimibe. J Genet Disord Genet Rep. 2013;2:1. 22

LIPOPROTEIN(a)LIPOPROTEIN(a) Lp(a) (pronounced “lipoprotein little a”) consists of an

LDL particle linked covalently with one molecule of apo (a).

The apo (a) moiety consists of a protein with a high degree of homology with plasminogen.

The pathogenesis of Lp(a) may result from an antifibrinolytic potential and/or ability to bind oxidized lipoproteins.

Prospective epidemiologic studies have shown a positive (albeit weak) association between Lp(a) and CAD.

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Di Angelantonio E, Gao P, Pennells L, et al: Lipid-related markers and cardiovascular disease prediction. JAMA 307:2499, 2012.

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TRIGLYCERIDE-RICH LIPOPROTEINS TRIGLYCERIDE-RICH LIPOPROTEINS FAMILIAL HYPERTRIGLYCERIDEMIA (TYPE IV

HYPERLIPOPROTEINEMIA) Clinical signs such as corneal arcus, xanthoma, and

xanthelasmas are absent. Plasma triglycerides, VLDL-C, and VLDL triglycerides

are moderately to markedly elevated; the LDL-C level is usually low, as is HDL-C.

Total cholesterol is normal or elevated, depending on VLDL-C levels.

Fasting plasma concentrations of triglycerides are in the range - 200 to 500 mg/dL.

Weaker relationship with CAD

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(Adult Treatment Panel III): final report. NIH publicationno.: 02-5215. Bethesda, Md.: National Heart, Lung, and

Blood Institute, 2002 25

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(Adult Treatment Panel III): final report. NIH publicationno.: 02-5215. Bethesda, Md.: National Heart, Lung, and

Blood Institute, 200226

FAMILIAL HYPERCHYLOMICRONEMIA (TYPE I HYPERLIPIDEMIA)

Elevations in fasting plasma triglycerides to greater than >1000 mg/dL.

Patients have recurrent bouts of pancreatitis and eruptive xanthomas.

Can also be associated with xerostomia, xerophthalmia, and behavioral abnormalities.

The hypertriglyceridemia results from markedly reduced or absent LPL activity or, more rarely, absence of its activator apo C-II

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DIAGNOSIS/MANAGEMENTDIAGNOSIS/MANAGEMENTBased on the assay of LPL enzyme activity in plasma

following intravenous administration of heparin. Detection of very low or absent LPL enzyme activity in an

assay system that contains either normal plasma or apoprotein C-II and excludes hepatic lipase is diagnostic of familial LPL deficiency.

Treatment – 1. Medical nutrition therapy to maintain plasma

triglyceride concentration at less than 1000 mg/dL. 2. Restriction of dietary fat to no more than 20 g/day or

15% of a total energy intake is usually sufficient.3. The acute pancreatitis episode is treated with standard

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TYPE III HYPERLIPOPROTEINEMIA (Dysbetalipoproteinemia or Broad Beta Disease)

Increased cardiovascular risk.Pathognomonic tuberous xanthomas and palmar

striated xanthomas are present. Increased cholesterol and triglyceride levels and reduced

HDL-C. Remnant lipoproteins (partly catabolized chylomicrons

and VLDL) accumulate in plasma resulting from abnormal apo E, which does not bind to hepatic receptors that recognize apo E as a ligand.

Ratio of VLDL cholesterol to triglycerides, normally less than 0.7 is elevated in patients with type III hyperlipoproteinemia because of cholesteryl ester enrichment of remnant particles. 04/02/17 29

Treatment of dysbetalipoproteinemia is the same as for hypertriglyceridemia.

Weight loss, diet fat restriction and treatment of secondary factors, such as diabetes and hypothyroidism are important for all dysbetalipoproteinemia patients.

Administration of fibrates, statins, omega-3 fatty acids and niacin or their combinations is very effective.

However, it has to be underlined that fibrates, with or without statin, seem to comprise the cornerstone of dysbetalipoproteinemia treatment.

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FAMILIAL COMBINED HYPERLIPIDEMIACharacterized by the presence of elevated total

cholesterol and/or triglyceride levels .Prevalence of approximately 1 in 50 .Accounts for 10% to 20% of patients with premature

CAD. Corneal arcus, xanthomas, and xanthelasmas occur

infrequently. Diagnosis of familial combined hyperlipoproteinemia

requires identification of the disorder in at least one first-degree relative.

Underlying metabolic disorders appear to include hepatic overproduction of apo B–containing lipoproteins, delayed postprandial clearance of TRLs, and increased flux of FFAs to the liver.04/02/17 31

HIGH-DENSITY LIPOPROTEINSHIGH-DENSITY LIPOPROTEINS

Disorders of High-Density Lipoprotein BiogenesisApolipoprotein A-I Gene DefectsPrimary defects affecting the production of HDL particles

may be caused by mutations in the apo A-I–C-III–A-IV gene complex.

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TANGIER DISEASE AND FAMILIAL HIGH-DENSITY LIPOPROTEIN DEFICIENCY.

The cellular defect - consists of reduced cellular cholesterol efflux in skin fibroblasts and macrophages from affected subjects.

A more common entity, familial HDL deficiency, was also found to result from decreased cellular cholesterol.

Tangier disease and familial HDL deficiency result from mutations in the ABCA1 gene, which encodes the ABCA1 transporter .

Increased risk for CAD

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DIAGNOSISDIAGNOSISOther tests:1. 2D electrophoresis with

subsequent anti-apoA-I immunoblotting.

2. Cholesterol efflux assay on cultivated skin fibroblasts.

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von Eckardstein A, et al.. Atherosclerosis 1998; 138: 25-34

Joyce C, et al.. Arterioscler Thromb Vasc Biol 2003; 23: 965-7134

MANAGEMENTMANAGEMENTTo date, the only definite therapeutic intervention for

Tangier patients is a very low fat diet, thus reducing the potential to develop fatty liver.

CETP Inhibitors-Torcetrapib(ILLUMINATE), Dalcetrapib(dal-VESSEL).

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Niemann-Pick type C disease is a disorder of lysosomal cholesterol transport.

In patients with Niemann-Pick type C disease, mental retardation and neurologic manifestations occur frequently.

The cellular phenotype involves markedly decreased cholesterol esterification and a defect in the cellular transport of cholesterol to the Golgi apparatus.

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DISORDERS OF HIGH-DENSITY LIPOPROTEIN– DISORDERS OF HIGH-DENSITY LIPOPROTEIN– PROCESSING ENZYMES PROCESSING ENZYMES

LECITHIN-CHOLESTEROL ACYLTRANSFERASE DEFICIENCY

Deficiencies of LCAT, the enzyme that catalyzes the formation of cholesteryl esters in plasma, cause corneal infiltration of neutral lipids and hematologic abnormalities as a result of the abnormal constitution of red blood cell membranes .

“FISH EYE DISEASE” No increased risk of cad.

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CHOLESTERYL ESTER TRANSFER PROTEIN DEFICIENCY

Patients without CETP have very elevated levels of HDL-C, which is enriched in cholesteryl esters as it facilitates the transfer of HDL cholesteryl esters into TRLs.

CETP deficiency is not associated with premature CAD.

Niemann-Pick type I disease (subtypes A and B), which is caused by mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene, is associated with a low HDL-C level .

Decrease in LCAT reaction because of abnormal HDL constituents. 04/02/17 38

SECONDARY CAUSES OF DYSLIPOPROTEINEMIAS SECONDARY CAUSES OF DYSLIPOPROTEINEMIAS

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DYSLIPIDEMIA MANAGEMENTDYSLIPIDEMIA MANAGEMENT

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2013 ACC/AHA Guidelines: 2013 ACC/AHA Guidelines: Statins without any lipid “goals” Statins without any lipid “goals”

Circulation 2014; 129: S1-S45

• Clinical ASCVD* • LDL-C ≥190 mg/dL, Age ≥21 years• Primary prevention – Diabetes: Age 40-75 years, LDL-C

70-189 mg/dL

• Primary prevention - No Diabetes†: ≥7.5%‡ 10-year ASCVD risk, Age 40-75 years, LDL-C 70-189 mg/dL

*Atherosclerotic cardiovascular disease†Requires risk discussion between clinician and patient before statin initiation‡Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator

Circulation. 2014;129[suppl 2]:S1-S45

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INDIAN GUIDELINESINDIAN GUIDELINES

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  INDIAN DYSLIPIDEMIAINDIAN DYSLIPIDEMIA    

RISK FACTORSRISK FACTORS

NON TRADITIONAL CV RISKS IN INDIANON TRADITIONAL CV RISKS IN INDIA

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CORONARY CALCIUM

Both LDL-C and HDL-C were found to be independent predictors of CAC

CAC score >400 had 100% specificity

CIMT

For 0.1 mm increase in CIMT the future risk of MI increased by 10-15% A 10% reduction in LDL-C per year accounted for a reduction of CIMT by 0.73 presence of carotid plaques is a marker of already existing ASCVD

Lp(a) more common among CAD patients with existing family history

Lp(a) levels in Asian Indian newborns were significantly higher than in Chinese in Singapore

Level > 20 mg/dL indicates increased ASCVD risk in Indians

Presence of obesity and/or metabolic syndrome in an individual who is otherwise at low 10-year risk of ASCVD should indicate high lifetime ASCVD risk.

OBESITY/ MET Syn.OBESITY/ MET Syn.

A 5-μmol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL)

Very high prevalence of hyperhomocystinemia (>15 µmol/L) in 75% of subjects in India, which was strongly correlated with cobalamin deficiency

Impaired cobalamin status appears more important than folate deficiency among Asian Indians

HOMOCYSTEINEHOMOCYSTEINE

CRP

significant ASCVD risk reduction with statin in individuals with elevated CRP despite relatively normal LDL-C

A value of > 2 mg/l of hs-CRP indicates increased ASCVD risk.

When the value is >10 mg/L, it usually indicates a non-atherosclerotic cause of Inflammation

But Quality control and proper standardization of hs-CRP is challenging in India

JBS3: LIFETIME ASCVD RISK CALCULATOR

Estimate lifetime riskValidated in indians

Non-conventional risk factors

<30% = LOW RISK30-44% = MODERATE RISK

>45% = HIGH RISK

The Indian ApproachThe Indian Approach

1. History of MI or documented CAD2. History of ischemic stroke or TIA3. Hemodynamically significant carotid plaque4. Atherosclerotic peripheral arterial

disease(ABPI<0.9)5. Atherosclerotic aortic aneurysms6. Atherosclerotic renal artery stenosis

Pre-existing ASCVDPre-existing ASCVD

30-44% risk

>45% risk

Moderate risk

Highrisk

INDIAN INDIAN RISK RISK

STRATIFICATIONSTRATIFICATION

SETTING INDIAN TARGETSSETTING INDIAN TARGETS

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Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279

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RESIDUAL CVD RISK WITH INTENSIVE STATIN THERAPY LESS, BUT STILL UNACCEPTABLY HIGH

Pat

ient

s E

xper

ienc

ing

Ma

jor

CV

D E

ven

ts, %

PROVE IT-TIMI 222 IDEAL3 TNT4

n

LDL-C* mg/dL

1Superko HR. Br J Cardiol. 2006;13:131-136. 2Cannon CP et al. N Engl J Med. 2004;350:1495-1504.3Pedersen TR et al. JAMA. 2005;294:2437-2445. 4LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

4162 8888 10,00195

*Mean or median LDL-C after treatment

62 104 81 101 77

Statistically significant, but clinically inadequate CVD reduction1

Standard statin therapy

Intensive high-dose statin therapy

BEYOND TARGETING LDLThere are several atherogenic

lipoproteins and LDL accounts for only about 75% of them

Residual risk of ASCVD in statin-treated patients remains as high as 55%-70%.

It is thus evident that in order to reduce ASCVD effectively, we need to concentrate on all atherogenic lipoproteins, and not just LDL alone

increased non-HDL-C is associated with increased risk of future CV events

even if LDL-C is under control with statin

Better correlate of ASCVD than LDLIncludes TG and Lp(a)Does not need fastingCan be easily calculated by total cholesterol and HDLSurrogate for small dense LDL

NON HDL CHOLESTEROL NON HDL CHOLESTEROL BETTER THAN LDL?BETTER THAN LDL?

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Prevalence of low HDL-C levels was much higher low HDL-C levels was much higher in the South Asian populations than in the other populations (82% vs 60% of acute MI cases)

Increaseing HDL-C was associated with a mere 13% reduction in MI risk in South Asians as compared to 23% risk reduction in the other Asians

The patients with low HDL-C are three times more likely to die after an acute coronary event

INTERHEART: HDL IN INDIANSINTERHEART: HDL IN INDIANS

THERAPY FOR INDIAN DYSLIPIDEMIATHERAPY FOR INDIAN DYSLIPIDEMIA

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Smoking

It is never too late to quit smoking. After quitting smoking,

the ASCVD risk decreases by 50% within 2 years.

Alcohol consumption was not found to be protective among South Asians

INTERHEARTINTERHEARTAlcohol

DIET AND NUTRITION DIET AND NUTRITION

Statin doses

STATINS STATINS

Statin adr

FIBRATESFIBRATES

A meta-analysis of 18 trials providing data for 45058 participants, including 2870 major CV events, 4552 coronary events, and 3880 deaths.

It was found that fibrates could reduce the risk of major CV events predominantly by prevention of coronary events.

Patients with higher baseline TG and lower HDL-C levels benefited from fenofibrate therapy in addition to pre-existing simvastatin (ACCORD).

Look for reversible causesEg.DM, hypothyroidsm, CKD,

immuocomprised

LSM

TG<500 TG>500

Statin

Achieve LDL target

Achieve non HDL cholesterol

Non-statin drugs

Fibrate

Achieve TG target

Statin

Achieve LDL and non HDL cholesterol target

Hyper

TG

CURRENT LAI GUIDELINES – KEY POINTSCURRENT LAI GUIDELINES – KEY POINTS

Enas EA, Dharmarajan T S. The Lipid Association of India Expert Consensus Statement 2016: A sea change for management of dyslipidemia in Indians. J Clin Prev Cardiol 2016;5:62-6

TAKE HOME MESSAGETAKE HOME MESSAGELIFE SIMPLE SEVENLIFE SIMPLE SEVEN

1. No tobacco2. Physical activity: ≥150 min moderate intensity or

equivalent exercise per week 3. Body-mass index <23 kg/m24. Healthy diet: achieving at least four of the five important

dietary components, focusing on fruits and vegetables, fish, fibre, and sodium intake and sweetened beverage intake

5. LDL-C level should be below 100mg/dl6. Blood pressure: <120/80 mmHg 7. Fasting plasma glucose level: <100 mg/d

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THANKSTHANKS

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