New therapeutic principles focus on HDL raising and Lp (a) lowering drugs

New therapeutic principles
focus on HDL raising and Lp
(a) lowering drugs
Tarek A.Ghaffar MD
Consultant OF CARDIOVASCULAR MEDICINE NHI
introduction
■ lipoprotein levels in general, and HDL, in particular, show strong familial correlations that are compatible with a high level of genetic control. the higher correlations among siblings and parent off spring pairs compared with spouses suggest a genetic basis for this aggregation (1).
Epidemiological studies point to an inverse relationship between high density lipoprotein (HDL-C) (fig 1) levels and the risk of coronary artery disease (CAD).
The past decade has seen great advances in under- standing the underlying mechanisms for HDL metabolism which has been achieved by the application of molecular biology, the use of transgenic and knockout animals, and new findings in human genetics
HDL is the smallest lipoproteins ,it contains the least amount of lipid .(FIG I).
HDL particles are formed in plasma from the coalescence of individual phospholipid- apolipoprotein complex.
HDL and its major apolipoprotein, apo A1, are synthesized by both the liver and intestine.
(FIG II) The other primary apolipoprotein, apo A2. Is
synthesized only by the liver.
Production of HDL. Apolipoprotein (apo) Al accounts for approximately 70% of the protein mass in HDL whereas apo All accounts for another 20%. Apo Al is synthesized in the liver and intestine of mammals and apo All is predominantly synthesized in the liver. HDL particles circulating in plasma consist of a heterogeneous population of discoidal and spherical particles.
The lipid transport system has three principal roles sites:
1) the efficient and rapid transport of triglycerides from dietary origin to storage sites (adipose tissue) or sites of oxidation (muscles), and the continued supply of triglycerides from the liver for constant energy supply;
2) a cholesterol transport system which hallows most tissues to have the cholesterol molecule readily available for various metabolic processes (membrane synthesis, steroid Hormones, bile acids) and
3) the reverse cholesterol transport pathway (HDL pathways)
The increased understanding of the reverse cholesterol transport pathway and identification of ATP-
binding cassette transporter, (ABCAI) as one of the first steps in the HDL biosynthesis represents one of the major break through in mapping out the entire HDL pathway especially when linking clinical phenotypes to genetic mutation or polymorphisms
■ HDL may be secreted by the liver or intestine in the form of nascent particles consisting of phospholipids and apoprotein A1(Nascent HDL).
■ Nascent HDL interacts with peripheral cells, such as macrophages, to facilitate the removal of free cholesterol (FC) generated in part by the
hydrolysis of intracellular cholesteryl ester (CE) stores. A process facilitated by ATP-binding cassette protein 1 (ABC1 gene) (fig l).
■ HDL is then converted into mature CE-rich HDL as a result of the plasma cholesterol-esterifying enzyme lecithin: cholesterol acyltransferase
(LCAT), which is activated by apo A-I.
including selective uptake by the liver, ie, the removal of lipid without the uptake of HDL proteins.
Selective uptake appears to be mediated by the scavenger receptor class-B, type I (SR-Bl), which is expressed in the liver and has been shown to be a receptor for HDL. CE derived from HDL contributes to the hepatic-cholesterol pool used for bile acid synthesis.
Cholesterol is eventually excreted from the body either as bile acid or as free cholesterol in the bile
■ Transport of cholesterol to the liver either directly or by transfer of esterified cholesterol to apo B-containing lipoproteins (this step is mediated by cholesteryl ester transfer protein CETP )
■ The catabolism of HDL particles is enhanced in conditions of HDL-cholesterol deficiency, in part, due to a reduction in particle size
■ HDL or apo Al residence time in normal individuals is approximately 4.1 to 6.6 days and 3.0 to 4.5 days.
■ Hepatic lipase (HL) is a multifunctional protein that plays a major role in lipoprotein metabolism as both, a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins and as a ligand that facilitates the uptake of lipoproteins and/or lipoprotein lipids by cell surface receptors and proteoglycans.
■ The concept of hepatic lipase as mainly a lipolytic enzyme that reduces atherogenic risk has evolved into that of a complex protein with multiple functions which, depending on genetic background and
sites of expression, can have a variable effects on atherosclerosis.
primary (genetic) causes of low HDL-C
■ apoA-1
- cmoplete apoA-l deficiency
- apo A-l mutations (eg, ApoA-l milano)
■ LCAT
- complete LCAT deficincy
partial LCAT deficiency (fish - eye disease)
■ ABC 1
- Tangier disease
■ Homozygous
■ Heterozygous
- familial hypoalphalipoproteinemia (some families)
■ unknown genetic etiology
- familial hypoalphalipoproteinemia (most families)
- familial combined hyperlipidemia with low HDL-C
- metabolic syndrome
complete ApoA-l degicency
■ markedly reduced HDL-C level and absent apoA-l.
■ cutaneous xanthomas (some patients)
■ premature atherosclerotic vascular disease (some patients)
APOA-l mutations
■ modest to marked reducation in HDL-C and apoA-l
■ rapid catabolism of apo -1
■ systemic amyloidosis
■ premature atherosclerotic disease (rare)
LCAT Deficiency and Fish-eye Disease
■ Both due to mutations in LCAT gene:
- LCAT deficiency - complete
- Fish-eye disease - partial
■ Common to both types of LCAT deficiency:
- Markedly reduced HDL-C and apoA-l levels
- Rapid catabolism of apoA-l and apoA-ll
- Corneal arcus
- Premature atherosclerotic vascular disease (rare)
■ Unique to complete LCAT deficiency:
- Proteinuria and progressive renal insufficiency
■ Autosomal co-dominant disorder due to mutations of ABC1 gene
■ Extremely marked reduction in HDL-C and apoA-l
■ Markedly accelerated catabolism of apoA-l and apoA- II
■ Cholesterol accumulation
- Enlarged orange tonsils
- Hepatosplenomegaly
- Peripheral neuropathy
■ Increased risk of premature atherosclerotic vascular disease
■ Pathologic accumulation of cholesterol in macrophages and other cells of reticuloendothelial system
■ Heterozygotes have moderately reduced HDL-C and apoA-l levels and increased risk of premature atherosclerotic vascular disease, but no tonsillar enlargement or hepatosplenomegaly
■ Dominant disorder; due to mutations in one allele of ABC1 gene in some families, and of unknown genetic etiology in other families
■ Moderate reduction in HDL-C and apoA-l
■ Increased risk of premature atherosclerotic vascular disease
Secondary Causes of Low HDL-C
■ Smoking
■ Obesity (visceral fat)
■ Very-low-fat diet
■ Hypertriglyceridemia
■ Drugs
— Beta-blockers
— Androgenic steroids
— Androgenic progestins
genetic causes of high HDL-C
primary (genetic) causes of high HDL-C
■ CETP deficiency
■ Hepatic lipase deficiency
■ unknown genetic etiology
- familia hyper alpha lipoproteinemia
CETP Deficiency
■ Autosomal co-dominant; due to mutations of CETP gene
■ Markedly elevated levels of HDL-C and apoA-l
■ Delayed catabolism of HDL cholesteryl ester and apoA-l
■ HDL particles enlarged and enriched in cholesteryl ester
■ No evidence of protection against atherosclerosis;
■ possible increased risk of premature atherosclerotic vascular disease
■ Autosomal recessive, due to mutations in both alleles of hepatic lipase gene
■ Modestly elevated levels of HDL-C and apoA-l
■ Variable elevations in total cholesterol, triglycerides, and lipoprotein remnant particles
■ No evidence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular disease
■ Autosomal dominant; molecular etiology unknown
■ Modest to marked elevations in HDL-C and apoA-l
■ Selective increased synthesis of apoA-l in some families
■ Associated with longevity and protection against atherosclerotic vascular disease in epidemiologic studies
Secondary Causes of Increased H DL-C
■ Extensive regular aerobic exercise
■ Very-high-fat diet
■ Regular substantial alcohol intake
■ Estrogen replacement therapy
■ Drugs
- Phenytoin