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LIPOPROTEIN(a) - THE UGLY CHOLESTEROL

 1.  Lipoprotein(a):  What is it and what is its role in health?

          Lipoprotein(a), abbreviated as Lp(a), is composed of one molecule of LDL, the “bad cholesterol”, chemically bound to a carrier protein called apolipoprotein(a).  Lp(a) is an adhesive particle, and in health serves to repair and restore the structural integrity of a damaged blood vessel wall - a sort of biological super glue.  Its apolipoprotein(a) component promotes blood clotting and inhibits your body’s blood clot dissolving system; this is Mother Nature’s mechanism to prevent excessive blood loss from a damaged vessel.  Lp(a) also promotes the migration of smooth muscle cells into the inner lining of the vessel, to thicken the artery wall, and its LDL cholesterol is incorporated into the regenerating cells.  Essentially, Lipoprotein(a) is a repair molecule, an “artery patch”.  

         Vitamin C can also serve to maintain or restore the wall strength of our blood vessels, rendering Lp(a) unnecessary.  A dog the size of an average man will convert dietary sugar (glucose) into 20,000 mg. of Vitamin C each day.  We will see that this is nature’s preferred approach.  Man, the great apes, guinea pigs, and hedgehogs lost the ability to make Vitamin C from glucose, and rely on Lp(a) instead to repair their arteries.  Man and these other species do develop coronary artery disease.  All other animals make Vitamin C.  Lp(a) is not found in their blood, and these animals never develop coronary disease.  These Vitamin C producers do not obstruct their blood vessels with cholesterol and blood clots!    

               During the Ice Age, agriculture ground to a halt and natural fruits and vegetables were not always available.  Animals that could manufacture their own Vitamin C could handle this, but mankind began to die off from blood loss anemia.  Without Vitamin C, we developed chronic scurvy; blood    leaked out from our damaged arteries and we had no way to repair our vessels or to stop the bleeding.  Evolution then provided mankind with a solution.  A genetic mutation of plasminogen, the circulating protein that promotes blood clot dissolution, created apolipoprotein(a), a plasminogen look-alike that does just the opposite; apolipoprotein(a), promotes blood clot formation and antagonizes plasminogen mediated clot dissolving.  Apo(a) plugged the hole in the dike.  Combined with LDL to form Lp(a), it restored the strength of our vessels.  During warmer periods, when Vitamin C was available in the diet, the artery would heal naturally, and the Lp(a)-LDL “patch” would be resorbed from the artery wall.  During colder periods, when dietary C was low, we would again call upon Lp(a).  Mother Nature designed LP(a) to be a temporary plug, to get us through times of dietary Vitamin C deficiency.  Individuals who couldn’t make Lp(a) died; those who could make Lp(a) survived the Ice Age and passed on the Lp(a) producing genes to their descendants.  This is why some Lp(a) is present in all of us.  Lp(a) saved mankind from extinction during the Ice Age, but what is this cholesterol/clot producing patch system doing to us now?

 2.  The role of Lp(a) in vascular disease.         

After the Ice Age, dietary Vitamin C became plentiful again, our vessels were strong, and Lp(a) vascular “repair” was not needed. Our Vitamin C intake was at “animal” levels and mankind did not experience coronary disease.  With the advent of modern day food processing, and our constant exposure to Vitamin C consuming oxidizers (cigarette smoke, lead in the water, mercury in seafood, industrial toxins, etc.) we are again becoming Vitamin C deficient, and in our current “diet induced Ice Age”, we are again calling upon Lp(a) to patch up and repair our arteries, and today we call this patching system ATHEROSCLEROSIS.         

Lp(a) levels are primarily under hereditary control; if your level is high, that is because your ancestors needed more to get them through the Ice Age.  The higher your level, the greater is your risk.  Lp(a) binds to lysine and proline within the wall of a damaged or weakened artery, depositing its LDL and promoting the deposition of circulating, oxidized LDL into the artery’s wall, narrowing the artery.  Lp(a) promotes the formation of blood clots on top of the cholesterol plaque, abruptly narrowing the artery further, bringing on or worsening your symptoms. If the clot is large enough, it will cclude the artery, producing a heart attack.  We now know that most heart attacks are due to a large blood clot developing in vessels with moderate narrowings (therefore you are still at risk with a 40-60% narrowing).           

          Lp(a) levels typically range from 1 to 100; the highest level so far in our practice has been 170.  Mg. for mg, Lp(a) has 10 times the plaque producing potential of LDL.  The average American value is 14 mg/dl: 13 in healthy individuals and 19 in coronary patients.  The 90th percentile is 30, and the 95th is 45.  Lp(a) selectively accumulates in your arteries; a level above 30 doubles your risk, and if your LDL is also elevated, your risk is increased by a factor of 5.  Lp(a) synergistically increases the risk associated with diabetes, hypertension, an elevated homocysteine level, or a low HDL.  Lp(a) is associated with endothelial dysfunction and an increased risk for heart attack.  Outcome following heart attack or unstable angina is worse in high Lp(a) patients.  Lp(a) concentrates in the walls of your bypass grafts and is felt to “pull LDL in”.  In one study, 90% of individuals whose bypass grafts clogged up had a Lp(a) level above 31.  Balloon angioplasty (PTCA) is basically a controlled trauma to the vascular wall, and Lp(a), always a “repair” molecule, will concentrate at the site of balloon dilation, promoting clot formation and cholesterol deposition.  You certainly won’t be surprised to learn that Lp(a) has been implicated as a cause of restenosis - a renarrowing of the blood vessel following initially successful angioplasty. In one study, the Lp(a) level averaged 7 in patients who did not renarrow, and 19 in those who did.  Those patients with a level above 19 were six times more likely to restenose than those with levels below 4.  Those with levels above 40 were eleven times as likely to renarrow.  Lp(a) is clearly a bad actor. 


3.  What can I do to lower my Lp(a) coronary risk?  Plenty:       

A.  Have your Lp(a) level measured (along with your other risk factors).

B.  If your level is elevated, work with your doctor to lower it.  Niacin, Vitamin C - not the 60 mg. of Vitamin C present in standard vitamins but by “healthy animal” doses in the 5-10,000 mg/day range, fish oil, avoidance of dietary trans-fats, tocotrienols, carnitine, testosterone in men and estradiol/progesterone in women may exert a favorable effect on Lp(a).  Unfortunately, Lp(a) is not affected by exercise, low fat or low carbohydrate dietary modification, while Lp(a) will rise with the use of statin  cholesterol lowering drugs.         

C.  It hasn’t been proven, but we feel that the Lp(a) that cannot be lowered can be in part neutralized by supplemental Lysine, Proline, and Vitamin C.  By occupying the binding sites on the circulating Lp(a) particle, Lysine and Proline in the circulation prevent Lp(a) from attaching to Lysine and Proline within the vascular wall, and if the Lp(a) cannot attach, it cannot promote cholesterol deposition and blood clotting within the coronary artery.  In optimal doses, Lysine and Proline may be able to insinuate themselves between bound Lp(a) and the vascular wall, freeing up Lp(a) and pulling it out of the artery. The now freed-up Lp(a) will take LDL cholesterol out with it, lessening the degree of narrowing, a process known as disease regression.  Vitamin C, independent of its Lp(a) lowering effect, will hydroxylate vascular wall Lysine and Proline, “hiding it” from Lp(a).   

     D.  The risk associated with an elevated Lp(a) synergizes with that associated with the other risk factors.  When thinking about Lp(a) and cardiovascular disease, please remember that “one plus one equals four”.  A modest elevation in LDL in a high Lp(a) patient is not a modest problem – it is a major problem.  The good news is that control of your other risk factors will dramatically decrease the risk associated with an elevated Lp(a); this has been proven with respect to LDL and HDL, and the relationship will likely hold for hypertension, homocysteine, diabetes, etc.  

4.  To learn more, please review our DVD presentation “Vitamin C, LDL, and Lipoprotein(a):  The Good, the Bad, and the Ugly” (available at the office or at heartfixer.com).  Eradicating  Heart Disease and Why Animals Don’t Get Heart Attacks, by Mathias Rath MD, are easy to read booklets that cover much of this material.  Lysine and Proline can be obtained on-line from Emerson Ecologics (the codes are LLLY11 and PROL2); a link to Emerson is available on heartfixer.com.

                                                                                                                                       James C. Roberts MD FACC FAARFM



LIPOPROTEIN(a), THE “UGLY” CHOLESTEROL: ITS ATHEROGENIC AND THROMBOGENIC ROLE IN HUMAN CORONARY DISEASE, AND THE ROLES OF VITAMIN C, LYSINE, AND PROLINE IN THE PREVENTION, STABILIZATION, AND REGRESSION OF ATHEROSCLEROSIS.

The following comments consist of facts, backed up by research, medical hypothesis not yet proven by ten year, randomized, controlled trials, and recommendations, which draw on both of the above. 

FACTS: 

A.  Man, non-human primates, guinea pigs, and hedgehogs do not make Vitamin C; all other Members of the animal kingdom synthesize Vitamin C from glucose. A 70 kg dog would produce 20 gm of Vitamin C each day.  The RDA for Vitamin C in humans is only 60 mg. 

B.  Man, non-human primates, guinea pigs, and hedgehogs all produce lipoprotein(a); this lipoprotein particle has not been detected in other members of the animal kingdom. 

C.  Man, non-human primates, guinea pigs (and probably hedgehogs as well, although no one has looked) all can develop atherosclerosis in their native environment; non-experimental atherosclerosis simply does not occur in animals that can make Vitamin C. 

D.  Vitamin C, functioning as an antioxidant, reducing and hydroxylating agent, participates in multiple physiologic reactions.  Vitamin C, by serving to hydroxylate Lysine and Proline, articipates in collagen synthesis, and is therefore critical in maintaining the integrity of the vascular wall.

E.  Lipoprotein(a) is mankind’s most potent risk factor for coronary atherosclerosis; on a milligram for milligram basis, it is ten time as potent a plaque producer as is LDL.  An elevated lipoprotein(a) value correlates with an increased risk of native coronary disease, graft closure, stroke, and restenosis following angioplasty. 

F.  Cholesterol and other lipid particles, lacking an electrostatic charge, cannot be transported alone within the vasculature.  Our body coats them with charged protein particles, termed apolipoproteins, thus solubilizing the lipid and providing for its transport from the GI tract and liver to the tissues where it is needed for membrane synthesis and repair.  LDL, a prototypical lipoprotein often referred to as the “bad” cholesterol, consists of 2,000 molecules of cholesterol, 1,000 molecules of phospholipid, and one molecule of apolipoprotein B-100, often referred to as apo(B). 

G.  Lipoprotein(a) consists of one LDL particle, covalently bound to an apolipoprotein(a) (also nown as an apo(a) particle).  One’s lipoprotein(a) level is not affected by gender or age and is related instead to the rate of apolipoprotein(a) production.  Neither exercise, weight loss, or conventional LDL lowering medications have any effect on lipoprotein(a) levels, which to this point have been shown to fall only with Vitamin C, estradiol in women, testosterone in men, tocotrienols, and Niacin.  Niacin and Vitamin C combine to form NADPH (nicotinamide dinucleotide phosphate), which may somehow decrease apo(a) synthesis.     .

H.  Apolipoprotein(a) can bind to fibrin, Lysine and Proline residues in exposed collagen, as well as to other components of the extra-cellular matrix within a vascular wall that has been damaged and thus exposed to the circulation.  Lipoprotein(a) can also bind to additional LDL cholesterol particles.  Lipoprotein(a) can thus carry its cholesterol and additional LDL particles to the site of vascular wall injury where it is needed for tissue repair. 

I.   Plasminogen circulates as an inactive molecule, but will bind to fibrin at the site of clot formation upon a damaged vascular surface, where it is acted upon by tissue plasminogen activators to form plasmin, which will then digest the blood clot, preventing intravascular hrombus formation (and a heart attack if the vessel happens to be a coronary artery).  We ive recombinant tissue plasminogen activator therapeutically, to hasten conversion of plasminogen into plasmin, hopefully to digest the blood clot that is occluding a coronary artery involved in an acute myocardial infarction. 

J.   Apolipoprotein(a) is homologous to plasminogen, sharing many amino acid sequences.  Apolipoprotein(a) probably arose from mutations involving internal duplication of the plasminogen gene.  As such, they look alike chemically, and apolipoprotein(a) can compete with plasminogen for binding sites on fibrin and on other components of the exposed vascular extra-cellular matrix.  If plasminogen is inhibited from binding to fibrin, it cannot be converted into plasmin by tissue plasminogen activator, and hence the blood clot is less likely to be dissolved.  Another physiologic role for apolipoprotein(a), besides its ability to bring LDL cholesterol to the site of vascular wall injury where it is needed for membrane synthesis and vascular repair, may be to prevent excessive, plasmin mediated, intravascular thrombolysis. 

By virtue of its abilities to inhibit plasmin mediated fibrinolysis, and to bring cholesterol into the site of vascular wall injury, apolipoprotein(a) promotes both clot formation and intravascular cholesterol deposition, the two major forces producing human coronary artery disease.  To explain the presence of lipoprotein(a), its close homology to plasminogen, and the fact that evolution has allowed as deadly a disease as atherosclerosis to occur, the late Dr. Linus Paulding has proposed the following schema.  His explanation, beginning with events that occurred 40 million years ago, can of course never be proven, but Dr. Paulding won two Nobel prizes and his thoughts certainly make sense. They are:

 A.   The predecessors of mankind lost the ability to manufacture Vitamin C from glucose approximately 40 million years ago.  This was not a problem, as our ancestors lived off the land and could obtain adequate Vitamins C from dietary plant sources.  Collagen synthesis could go on, and the integrity of our vasculature was maintained. 

B.   Soon after that, the Ice Age hit; man-managed agriculture and all plant life decreased.  Sources of dietary Vitamin C became few and far between, and with this chronic Vitamin C deficiency our ancestors began to develop scurvy, with marked vascular fragility and consequent life-threatening blood loss.  Other animals, which retained the ability to manufacture Vitamin C from glucose, were not compromised. 

C.  Obviously, any factor that could “plug the leak” in our damaged arteries, preventing further blood loss, would be physiologically advantageous.  A mutation, producing apolipoprotein(a) from plasminogen, created a particle that prevented plasmin from digesting clots that would form at the site of vascular injury (thus minimizing scurvy-related bleeding), and which would bring cholesterol to the site of vascular injury to promote repair, allowing apolipoprotein(a) bearing individuals to survive into adulthood and reproduce, and thus was favored by evolution.  This apolipoprotein(a) gene became selected into the population, because it allowed mankind to survive Vitamin C deficiency during the Ice Age. 

D.  Normal agriculture returned after the Ice Age was over; mankind then obtained adequate amounts of Vitamin C from plant sources, the integrity of our vascular was thus not compromised, and lipoprotein(a) was not called upon to plug the leak.  Thus, mankind did not have atherosclerosis. 

E.  With the coming of the industrial age in this century, food processing and changes in our eating habits have again put mankind into a Vitamin C deficiency state.  As collagen synthesis is suboptimal, our vessel walls are weak and breaks develop.  These breaks are patched by the apolipoprotein(a) containing lipoprotein(a).  As we remain Vitamin C deficient throughout our lives, vascular wall damage continues, additional lipoprotein(a) is laid out within the arteries, and eventually a high grade narrowing develops.  Lipoprotein(a), by virtue of its ability to inhibit plasmin formation, can also promote intravascular clot formation, converting the narrowing into an occluded vessel and a full myocardial infarction.   

F.   Lipoprotein(a) is deposited within the vascular wall extra-cellular space as an intact particle.  As its physiologic function is really to “plug the leak”, patching up an artery damaged by (hopefully temporary) Vitamin C deficiency, it can also be removed from the arterial wall as an intact particle.  

G.  It is a fact that apolipoprotein(a) and lipoprotein(a) will bind to exposed Lysine and Proline.  Oral administration of Lysine and Proline should bind to circulating lipoprotein(a), neutralizing it, and preventing it from binding to Lysine and Proline in collagen that has been exposed to the circulation due to the presence of a disruption in the vascular wall.  Thus, lipoprotein(a) will not deposit within the vessel wall, and atherosclerosis will not develop.  Given in higher doses, Lysine and Proline entering the circulation will be able to pull intact lipoprotein(a) out of the plaque, thus producing disease regression.  Dr. Paulding has published case reports that suggest that high grade atherosclerosis can be regressed by adequate supplemental doses of Lysine and Proline.

H.  LDL cholesterol is still important, but by this theory is no longer felt to be the “lead particle” in atherosclerosis.  We know that LDL by itself cannot overfill a vascular cell; the LDL receptor senses that the cell has taken in enough cholesterol and will not let in additional LDL.  The LDL can, however, become oxidized when free radical forces overwhelm our antioxidant defenses (which are in general rather weak due to our exposure to cigarette smoke and toxins, and our limited intake of antioxidant vitamins and minerals).  Oxidized LDL is recognized by the scavenger receptor of macrophages, which internalizes the LDL, and then traverses the endothelial surface, entering the extra-cellular space within the vascular wall and carrying with it the internalized, oxidized LDL.  The oxidized LDL then releases toxic substances, immobilizing the macrophage within the vascular wall, damaging the endothelial cell, allowing additional LDL to bypass the LDL receptor and enter the artery.  Oxidized LDL causes endothelial dysfunction, blocking the ability of our artery lining endothelial cells to manufacture Nitric Oxide, the angiochemical that maintains our vessels in their physiologic, dilated state.  The oxidized LDL also produces factors that promote smooth muscle growth, narrowing the artery, and which attract platelets, tending to promote thrombus formation.  Deposition of oxidized LDL within the vascular wall is still felt to be important, but as a secondary factor promoting atherosclerosis, which was actually initiated when lipoprotein(a) bound to components of the vascular wall which were weakened and exposed to the circulation due to Vitamin C deficiency. 

 

RECOMMENDATIONS BASED ON THE ABOVE: 

A.  Humans should take in at least 1,000 mg of Vitamin C, not the 60 mg recommended by the RDA.  Individuals with known coronary disease, might certainly benefit from higher doses, in the 2-5 gm per day range. (Increasing your Vitamin C intake can initially produce abdominal cramping and diarrhea; the dosage needs to be advanced slowly). 

B.  Lipoprotein(a) levels should be measured as a part of risk factor assessment, especially in individuals who manifest coronary disease in the absence of other, traditionally accepted risk factors.  25% of myocardial infarctions in individuals under 60 years of age are felt to be related solely to an elevated lipoprotein(a) level.  The 90th percentile of lipoprotein(a) is 35 mg/ml; 30 is the cut off between normal and abnormal values, but it is likely that values lower than this are ideal. 

C.  Elevated lipoprotein(a) values will respond to Vitamin C, tocotrienols, Niacin, testosterone in men, estradiol in women; lipoprotein(a) does not respond to resins, exercise, HMG Co-A reductase inhibitors (statins), or dietary cholesterol reduction.  In some individuals’ statins may actually increase Lp(a) levels.

D.  Lysine 1000 mg and Proline 500 mg, taken twice a day, can be considered in the treatment of atherosclerosis, especially in the presence of an elevated lipoprotein(a) level.  To date, there have been no published, randomized, controlled trials of this form of therapy and it will obviously take years for Dr. Paulding’s recommendations to be proven.  These amino acid supplements are inexpensive and not associated with toxicity.  Thus, I do not hesitate to recommended this form of anti-atherosclerosis nutritional therapy to my patients (especially those with advanced, otherwise non-treatable atherosclerosis who are not in a position to await the results of long term studies). 

 

                                                                                                                                                                                                                               James C. Roberts MD FACC FAARFM 3/28/17