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Lp(a)

Lipoprotein (a)

"The LPA gene that codes for apo(a) evolved from plasminogen in Old World monkeys: high homology between apo(a) and plasminogen"


Working narrative - Lp(a) levels, like other lipoprotiens may or may not have anything to do with heart disease.  It happens as a reaction to the damage of the intima - they have the arrow of causation reversed?

"The LPA gene that codes for apo(a) evolved from plasminogen in Old World monkeys: high homology between apo(a) and plasminogen" 

This is a big hint - Thus, one could interpret the fact that Lp(a) is a clotting factor that CVD is a thrombotic disease rather than a disease of lipids.
 
The clots formed with LP(a) are much harder to be resorbed. 
 
Everyone has some Lp(a)
 
The other important bit is the striations in plaque - which should change the narrative of CVD.
 
https://pubmed.ncbi.nlm.nih.gov/36869878/
 
What is most likely what is going on are repeated clots - which get paved over with new intima (similar to what happens to stents) .   These repeated clot layers eventually narrow the artery.
 
Everyone has some Lp(a) .  80% of the public has some amount of T2D from eating packaged foods.  This translates into chronically elevated insulin levels - insulin further prevents resorption of plaque.  Proper intervention for CVD would Seem to warrant interventions to lower insulin - intermittent fasting ( only eat say 8 hours out of the day).
 
https://www.sciencedirect.com/science/article/pii/S0022227520309792


Contrary evidence

Pro Lp(a) as causative info

So IL-6 => Lp(a) ?

Lp(a) => Il-6 and Il-8


Thumb

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 very much 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.

Thus LDL => oxLDL + APO(a) =>oxLP(a) => oxoxLp(a)=> very bad outcomes.

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

The adhesion effect

Fibrin and Lp(a)

Apo(a) Inhibition of Plasminogen Activation

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.

Reducing Lp(a)


Glutathione promoters:

"Serum Lp(a), a coronary risk factor, was strongly related to measures of selenium status. A significant relationship between measures of selenium status and thyroid function was found. Serum Lp(a) a known risk factor for cardiovascular disease was also related to selenium status in our population."

Possible candidates

Tranexamic (Cyklokapron)


Eprotirome

IGF-I

IGF-I was found to lower Lp(a) by up to 60% (Atherosclerosis: diet and drugs By Arnold von Eckardstein)?

taurine

Low Carb (more fat )

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

Ribose-cysteine

Niceritrol (Pentaerythritol tetranicotinate)

testosterone alone and by 28% when testosterone and testolactone were combined,...
I wonder if people realize that testosterone gets converted to estrogen?

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


Other hormones

Clomid?

Reduce Stearic acid intake?


phosphatidylserine

??

Zetia

This study needs to be re-run using nmol

Estrogen

L-carnitine

2 G?

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

ALA (Alpha Lipoic Acid)

600 - 800mg? http://www.fasebj.org/content/15/13/2423.abstract

Casin

Coconut Oil

Testosterone

Omega-3 fish oil

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

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


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

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.

Montelukast

Almonds

Flaxseed

Gingko biloba

Fibrates

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.. (Creatine? How much? blue berries? http://www.ncbi.nlm.nih.gov/pubmed/15682927 )

Fosinopril

This might be why thyroid optimization is important in CAD

Thyroid

Information is at About_Hypothyroidism

Casein and soy

CQ10

CQ10? 60mg BID

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.

Half-life of Lp(a)

Up regiulation of glutathione

Systemic acetyl-L-carnitine elevates nigral levels of glutathione and GABA

oxLDL oxLp(a) 


www.ncbi.nlm.nih.gov/pubmed/15001526

This could explain why high BG seems causative of CVD - via Lox-1 

 www.springerlink.com/content/3b2ftmx3t5bjbr85/
journals.lww.com/jhypertension/Abstract/2005/01000/Cardioprotective_mechanisms_of_Rho_kinase.17.aspx

www.proteinkinase.biz/modules/GoShopping/article_images/Y27632.pdf atvb.ahajournals.org/cgi/content/abstract/23/12/2203 circ.ahajournals.org/cgi/content/abstract/circulationaha;100/9/899 ACE inhibitors block Angiotensin I => Angiotensin II conversion effect on Lp(a)? www.ncbi.nlm.nih.gov/pubmed/8285181 www.sciencedirect.com/science

ASA? cardiovascres.oxfordjournals.org/content/64/2/243.full circres.ahajournals.org/cgi/content/short/94/3/370 www.enzolifesciences.com/fileadmin/enzo/BML/EI395.pdf

What interleukin(s) increase or decrease Apo(a)?

ASA? http://www.ncbi.nlm.nih.gov/pubmed/10567380

IGF-I was found to lower Lp(a) by up to 60% (Atherosclerosis: diet and drugs 

By Arnold von Eckardstein)?

Fosinopril ACE inhibitor lowers Lp(a)?

Fosinopril seems to be the only ACE inhibitor to reduce Lp(a) concentrations in non-proteinuric patients as well, probably by increasing apo(a) fragmentation and excretion into the urine (Kostner K et al., unpublished data). Other data limits this to kidney diseased?


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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