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Lp(a)

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  • Lp(a) is formed by the "binding" of Apo B100 to apo(a) (Apo B100 is the protein part of LDL).
  • Lp(a) "recruits" inflammatory cells for intrusion into the artery wall.
  • Lp(a) "adheres" and intrudes into the artery wall upon artery wall injury.
  • Lp(a) is extremely heterogeneous. Each Pt can have several subspecies present, each one with a different number of Kringles.
    • Very interesting tidbit.. This means APO(a) must be encoded more than once in our DNA or it gets transformed in some way..
  • It has been shown that Lp(a) is an acute-phase reactant, more than doubling in concentration in response to the proinflammatory cytokine IL-6

Contents

[edit] The oxLDL connection

This is not surprising - for APO(a) to bind to LDL there has to be a source of energy, so there is more to this that what is in these papers. First, oxLDL stimulates the intima wall and starts an immune response - my guess is that there is likely a messenger that tells the liver to make APO(a) which binds to LDL forming Lp(a). Lp(a) can be further oxidized into oxLp(a). (oxLDL can also be double oxidized - and I would guess the same for oxLp(a)).

Another way of thinking about this is Lp(a) is a kind of LDL so the LOX-1 receptor may also bind to oxLp(a).

So until Lp(a) becomes oxLp(a) would not say that Lp(a) is an oxLDL - Lp(a) is made up of apoB-100 linked by a sulfhydryl bond apo(a) of variable size(isoforms). This bond (See www.microbiologytext.com/index.php ) is a covalent bond between cysteine groups. My hunch is this bond's energy comes form the LDL being in the oxidized state - reducing the oxLDL to form Lp(a).


So it could be that APO(a) is protective, but my hunch is if one has the wrong isoforms of Lp(a), then Lp(a) isn't protective - it may actually make things worse. (It appears that APO(a) is heterogeneous - individuals produce more than one isoform) But we don't know for sure - this would make Lp(a) the smoke, not the fire and makes me pause about the goal of reducing the level - different interventions may use different methods to reduce Lp(a). We know Niacin increases HDL - which carries antioxidants that can reduce oxLDL - thus less irritation of the intima wall and less messenger to the liver to produce APO(a) thus less Lp(a). Other methods may interfere with the messanger - and this may be good or bad. It may be that we want a drug that would target only the bad isoforms of APO(a) and leave the good APO(a) alone.

oxLDL (as I keep saying) is central to the disease process - it integrates many things that we know - it has great explainative power. IMHO measuring oxLDL should be central in CVD treatment - particularly for people with elevated Lp(a).

The good news is we know some things that lower oxLDL

[edit] The adhesion effect

[edit] Testing and isoforms

LP(a) appears with different isoforms of apolipoprotein - 40% of the variation in Lp(a) levels when measured in mg/dl can be attributed to different isoforms. Combine that with the lighter Lp(a) being more disease causing and a test in mg/dl is not useful.

  • Lipoprotein (a) Cholesterol, Serum Recently a high correlation was demonstrated between Lp(a) and oxidized LDL, suggesting that the atherogenicity of Lp(a) lipoprotein may be mediated in part by associated proinflammatory oxidized phospholipids.

[edit] Reducing Lp(a)

[edit] Possible candidates - taurine

[edit] Low Carb

[edit] Niacin

a combination with a fibrate (clofibrate) may work better than Niacin alone

Niacin essentially constitutes the nicotinamide ring, the reactive site of the NADP and NADPH molecule. Ascorbate reduces the NADP molecule to NADPH and thereby "recharges" the molecule for metabolic reactions. Niacin and ascorbate have also been shown to be effective in lowering elevated plasma levels of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). Thus NADPH may also be involved in the regulation of other potentially atherogenic lipoproteins. Further confirmation of this therapeutic mechanism will establish the value of dietary niacin and ascorbate supplementation in reducing elevated plasma levels of atherogenic lipoproteins.

Should we be using IR Niacin? Not clear

[edit] Niceritrol (Pentaerythritol tetranicotinate)

testosterone alone and by 28% when testosterone and testolactone were combined,...

  • According to this article one might lower Lp(a) with testosterone (T) ? (Seems to say it won't work and latter it works?)
Additionally, T administered even in combination with an aromatase inhibitor suppresses lipoprotein-a levels. (aromatase inhibitors block the production of estrogen)

Next - is an older study in mass - needs to be redone in nmol


  • via DHEA?

[edit] Other hormones

Clomid?

[edit] Reduce Stearic acid intake?


[edit] phosphatidylserine

??

[edit] Zetia

[edit] Estrogen

  • estrogen is known to lower Lp(a) American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Dyslipidemia from 2000

[edit] L-carnitine

2 G?

These high doses of carnitine may lead to excess energy, restlessness, perhaps insomnia?

[edit] Testosterone

[edit] Omega-3 fish oil

Mostly for people with high trygly? Or does reduction of LDL cause less Lp(a)? Lots of non replicated studies.

    • ...12 g/day of fish oil (approximately 8.5 g of n-3 fatty acids) ... Plasma Lp(a) levels were reduced by 14% in the fish oil group, but unaffected in the rapeseed oil group...Patients treated with fish oil could be categorized into 2 subgroups: "responders," with a reduction in Lp(a) by 24% and "nonresponders," with a small nonsignificant increase in serum Lp(a)....

Sadly, the control for the above was rapeseed oil - which is 21% 18:2 ω-6 linoleic acid thought to increase LDL oxidation.


[edit] DHEA

18.1% (95% CI -32.2, -3.9) decline in Lp(a) from baseline, but these declines did not significantly differ from women who received placebo.

DHEAS was negatively related to apolipoprotein A

[edit] N-acetylcysteine

Lp(a) reductions over 70% -- one small study. May be slight risk here - A human would have to take in 448,000 mg of NAC per day to = this level of mouse intake. - From:

NAC-treated mice developed pulmonary arterial hypertension (PAH) that mimicked the effects of chronic hypoxia.

  • Gavish D, Breslow JL. Lipoprotein(a) reduction by N-acetylcysteine. Lancet 1991;337:203–204.
  • Kroon AA, Demacker PN, Stalenhoef AF. N-acetylcysteine and serum concentrations of lipoprotein(a). J Intern Med 1991 Dec; 239(6):519–526.

[edit] Almonds

[edit] Flaxseed

[edit] Gingko biloba

[edit] Fibrates

[edit] IGF-1

Perhaps IGF-1( insulin-like growth factor–I) may reduce lipoprotein(a) levels.

Contrasting Effects of Growth Hormone and Insulin-Like Growth Factor–I}

According to Wikipiedia

IGF-1 in the circulation include an individual's genetic make-up, the time of day, his or her age, gender, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake

More at:

There do appear to be some drugs that increase IGF-1 according to the Wiki article..

This might be why thyroid optimization is important in CAD

[edit] thyroid

as you move from hypothyroid towards hyperthyroid, HDL-C, ApoA-I, and HDL2b/large HDL-P are lowered, and Hepatic Lipase and Cholesterol Esther Transfer Protein are increased. Normally, we think that high HDL-C, ApoA-I, and HDL2b are good -- Perhaps this is where oxLDL comes in - should it be part of the yardstick to set thyroid replacement dosage? And do the declines in HDL cause an increase in oxLDL and Lp(a)?

(These people had no thyroid - not mild hypothyroid).

[edit] Casein and soy

[edit] CQ10

CQ10? 60mg BID

[edit] Apheresis

Apheresis is the most effective way of reducing lipoprotein a levels. Apheresis involves separating the blood externally to the body, so that the lipoprotein(a) may be effectively 'filtered out', and the blood is then returned back to the patient. This treatment is very expensive and generally only available to very high risk patients.

[edit] Half-life of Lp(a)

  • After creation, Lp(a) particles last for about 6 days in the blood before being eliminated by the kidneys.

[edit] oxLDL oxLp(a)


I also found more than one article that shows that Human grow hormone may INCREASE Lp(a) while improving the overall lipid profile. Makes me question DHEA?





  1. Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. J Clin Invest 2009;119:136-45
  2. ^ Curtiss LK, Clinical Implications of Basic Research: Reversing Atherosclerosis? N Engl J Med 2009;360:1114-1116

From Wiki

NADPH oxidase is a major cause of atherosclerosis, and NADPH oxidase inhibitors may reverse atherosclerosis. Atherosclerosis is caused by the accumulation of macrophages containing cholesterol (foam cells) in artery walls (in the intima). NADPH oxidase produces ROSs. These ROSs activate an enzyme that makes the macrophages adhere to the artery wall (by polymerizing actin fibers). This process is counterbalanced by NADPH oxidase inhibitors, and by antioxidants. An inbalance in favor of ROS produces atherosclerosis. In vitro studies have found that the NADPH oxidase inhibitors apocynin and diphenyleneiodonium, along with the antioxidants N-acetyl-cystine and resveratrol, depolymerized the actin, broke the adhesions and allowed foam cells to migrate out of the intima


This suggests that vit C will reduce Lp(a) and L-lysine and L-proline may protect the arteries.:

It may be that Vit C helps because it converta proline to hydroxyproline.. The latest reference in this paper was 1992..

www.pubmedcentral.nih.gov/picrender.fcgi Evidence that the Fibrinogen Binding Domain of Apo(a) Is Outside the Lysine Binding Site of Kringle IV-10 A Study Involving Naturally Occurring Lysine Binding Defective Lipoprotein(a) Phenotypes

EACA decreased the binding of Lp(a) to PM-fibrinogen

Core of the Proteoglycan Decorin ]

So:

What dosage of L-lysine and L-proline would make sense?

What about apocynin ?


It appears that actone and Homocysteine thiolactone are related in some way.. and Homocysteine is related to Osteoporosis. Vitamin D, estrogen, actone, HGH, and testosterone all increase bone density and might reduce Lp(a). This seems somehow linked to reducing Lp(a).

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