4a.  Perioperative Antioxidant Treatment With Vitamin C Reduces the Incidence of Atrial Fibrillation After Coronary Artery Bypass Surgery.  Chung, M, et al. JACC Abstract 883-5, page 370A, 2/01

Atrial fibrillation, a rapid, irregular, cardiac rhythm disturbance, occurs in up to 40% or patients undergoing bypass surgery.  Amiodarone, an effective but expensive anti-arrhythmic agent, is often used to prevent post-bypass atrial fibrillation.  Or, when atrial fibrillation occurs, we can treat it with intravenous magnesium or use a short-acting anti-arrhythmic agent, but a non-toxic and inexpensive means of preventing post-bypass atrial fibrillation would certainly be a plus.  

 The re-oxygenation, or "reperfusion" phase of bypass surgery, when the newly placed vein grafts suddenly flood the previously oxygen starved heart muscle cells with highly oxygenated blood, leads to a temporary state of inflammation and free radical stress (termed reperfusion injury-the same thing occurs during recovery from a heart attack).  Chung and colleagues hypothesized that this free-radical-related inflammatory state is one of the causes of post-bypass atrial fibrillation.  Sisto's study, abstracted above, demonstrated that antioxidants were safe and of value when given peri-bypass surgery.  Here Chung and her associates tested the efficacy of Vitamin C as a preventative for post-bypass atrial fibrillation.

50 sequential patients undergoing bypass surgery at the Cleveland Clinic received Vitamin C, 2,000 mg the night before surgery and 500 mg twice a day during their post-operative recovery period.  Six weeks later, a matched group of 50 patients underwent bypass, this time without Vitamin C.  The two groups were otherwise treated in like manner.  The presence or absence of post-operative atrial fibrillation was recorded; here's what Dr. Chung found:

Chung's group found that Vitamin C decreased the rate of post-bypass atrial fibrillation by 57% (similar to the effect of Vitamin C on the need for repeat angioplasty).  A lot of people can be helped for just pennies a day.

5.  Usefulness of Antioxidant Vitamins in Suspected Acute Myocardial Infarction (The Indian Experiment of Infarct Survival-3).  Singh, R, et al.  American Journal of Cardiology 1996;77:232-36

As discussed in article 4, free radical inflammation occurs when heart cells are starved of oxygen and then suddenly resupplied with highly oxygenated blood.  This phenomena occurs following bypass surgery and compromises patient outcome; Dr. Sisto showed us that a Vitamin C containing antioxidant cocktail could blunt this "reperfusion injury" and improve patient outcome following bypass surgery.  Oxygen starvation followed by oxygen resupply occurs during a heart attack, when one of the arteries serving the heart suddenly closes off, and we know that this "reperfusion injury" generates additional heart muscle damage and sets the stage for cardiac rhythm disturbances.  Singh and colleagues proposed that antioxidant supplementation, begun in the emergency room, would blunt reperfusion injury and improve patient outcome following heart attack.

In this study, 125 patients presenting with their first heart attack were randomly divided to receive either a 28 day antioxidant regimen consisting of:  Vitamin C 1,000 mg and Vitamin A 50,000 IU/day, both given IV over 3 days and then taken orally, along with Vitamin E 400 IU and Beta carotene 25 mg/day, both taken orally, or a matching 28 day placebo regimen.  The care the patients received was otherwise the same.  The study was carried out in double-blind format; neither the patients nor the researchers knew who was taking the antioxidant cocktail or the matching placebo preparations.  So what affect, if any, did the antioxidants have on post-heart attack outcome?

Dr. Singh recorded cardiac enzyme values and carried out serial EKGs on all 125 patients.  When we say that a heart attack has been diagnosed because your "enzymes" are elevated, we are referring to proteins which are found exclusively within heart muscle cells.  If the cells die, as occurs with a heart attack, these proteins are released into the circulation.  The higher your enzyme values, the more cells died, the larger the heart attack, and the more likely you are to experience a complication of the heart attack.  The change in your EKG also correlates with the size of the heart attack and the amount of heart muscle lost.  Dr. Singh found that the enzyme levels were lower, and the EKG was less abnormal, in the patients assigned to antioxidant vitamin supplementation.  The antioxidants neutralized the free radicals generated by the heart attack; thus the patients receiving antioxidant vitamins had smaller heart attacks.

Most of the things that can go wrong following a heart attack go wrong within 28 days; Dr. Singh followed his 125 heart attack patients over that time interval, and their 28 day outcome parameters are given below:

We don't like it when our patients experience recurrent angina following a heart attack; this signifies that they are at risk for further damage; the antioxidant patients were 42% less likely to experience post-heart attack angina.  The larger the heart attack, the more likely is the patient to go into heart failure and/or experience hypotension or an arrhythmia; the antioxidants were protective here as well.  Total cardiac events, recurrent heart attack, and cardiac death rates were all blunted by about a third.  A lot of misery was spared for $1 a day's worth of nutritional medicine.  

A Vitamin C containing antioxidant cocktail improves outcome and decreases event rate following heart attack

6a.  The Antioxidant Supplementation Atherosclerosis Prevention Study.  Salonen, J, et all.  European Heart Journal Abstract 1999, cited in Family Practice News.  1999 Oct 15;29(20):8.

Vitamin C, and for that matter all of the nutritional and pharmacologic agents that we use to benefit the heart patient, do not work primarily by opening up the artery, but instead by protecting the narrowed artery from plaque rupture, spasm, and clot formation.  With Vitamin C we aren't attempting to carry out a chemical roto-rooter effect; rather we favorably affect blood flow rate and the functional integrity of the endothelial cells that line the artery.  Vitamin C doesn't change anatomy; it changes physiology, and physiology is more important.  Still, if a treatment delays the rate at which the narrowings progress, then that is a plus.  We know that the statin class cholesterol lowering agents can favorably affect coronary artery anatomy and endothelial tone; can Vitamin C do the same?

Looking at the affect of a given treatment on the caliber of the coronary arteries is rather difficult.  Serial angiograms are necessary, entailing significant cost and some risk to the subjects.  Carrying out carotid ultrasound scans is relatively inexpensive, and involves no risk to the subjects.  In this study, Dr. Salonen and colleagues measure the thickness of the carotid artery wall, the intima-media thickness, in 520 high-risk Finnish patients.  He then assigned them to receive Vitamin C, 500 mg/day, Vitamin E, 272 IU/day, both, or a double placebo.  The ultrasound scans were repeated 3 years later.  Wall thickness increased in the double placebo group, on average by 20 micrometers/year.  All the antioxidant regimens retarded the rate at which atherosclerotic wall thickness progressed, as depicted in the chart below:

Monotherapy with Vitamin E or Vitamin C alone had only a minimal effect.  Our innate antioxidant defense against free radical inflammation is really a team defense, so we are not surprised to see synergy when E and C are taken together; in these patients disease progression was blunted by 45%.  Dr. Salonen points out that one of Vitamin C's functions is to regenerate spent Vitamin E.  In other words, without Vitamin C, Vitamin E supplementation won't be as effective.  Think of what Dr. Salonen might have found if he had given his subjects a cocktail of antioxidant vitamins and minerals (such as we recommend to our patients).  

The treatment effect was greater in smokers than in non-smokers.  This makes sense.  Cigarette smoke destroys Vitamin C, one of the means by which smoking promotes cardiovascular disease.  Smokers thus have a greater relative need for Vitamin C, and consequently a more robust treatment benefit.

6b.  Serial Coronary Angiographic Evidence That Antioxidant Vitamin Intake Reduces Progression of Coronary Artery Atherosclerosis.  Hodis, H, et al.  Journal of the American Medical Association 1995;273:1849-54

In the CLAS, or Cholesterol Lowering Atherosclerosis Study, baseline and 2-year coronary angiograms were carried out in 156 men who had previously undergone bypass surgery (the native arteries were looked at, not the grafts).  The diameter of the coronary arteries was measured at the first angiogram.  The men were then randomized to receive advice on a low cholesterol diet, or to receive dietary advice and cholesterol lowering drug therapy.  The advice and drug therapy group achieved an average LDL cholesterol of 100 mg/dl at the 2-year point; the advice only group maintained an LDL value of 150.  The angiograms were then repeated.  Less disease progression was seen in the LDL 100 group.  This paper was published in '95, and from that point on an LDL of 100 became our treatment goal in individuals with known coronary disease.  

Now, some of the subjects in both groups took antioxidants.  The use of antioxidants was at the discretion of the subjects; here the subjects were not randomized.  The charts below describe disease progression, as the relative change in the percent narrowing of the vessels measured:

The first chart looks at all narrowings; disease progression was obviously blunted by drug treatment, which led to an end-study LDL of 100.   You can also see (charts below) that high Vitamin E intake (>100 IU/day) or high C intake (>250 mg/day) had a favorable effect on disease progression.  Vitamin supplementation synergized with LDL reduction, and this makes sense.  It's not the LDL cholesterol that hurts us, its the oxidized LDL that layers out in our arteries.  The less LDL there is floating around, then the less LDL there is to be oxidized by free radicals.  The more antioxidants floating around, the better can we protect our LDL from free radical mediated oxidation.  The charts below show us that the combination of an LDL of 100 and the intake of antioxidants E and C led to disease regression.  A chemical roto-rooter effect did occur; the diseased arteries opened up a little, certainly a plus.

Vitamin C retards coronary disease progression and with LDL reduction leads to disease regression

6c.  Serial Arteriography in Atherosclerosis.  Willis, G, et al.  Canada Medical  Assoc.  Journal. Dec. 1954. Vol. 71, pages 562-72.

It would be nice if I was on the cutting edge of Vitamin C in cardiovascular medicine, but I can assure you that I am not.  In 1940 Patterson, a pathologist, demonstrated that heart attacks were not due to the build-up of atherosclerotic plaque material within the wall of an artery serving the heart, but rather to destabilization or rupture of the fibrous cap that covers the plaque.  A second report from Patterson, published in 1941, linked this plaque destabilization to Vitamin C deficiency.  Working with conscious objectors in 1944, Sir Hans Krebs found that he could bring out not just scurvy, but chest pain and EKG findings of coronary insufficiency (both Vitamin C responsive), when previously healthy young people were placed on an ultralow Vitamin C ration.  Trimmer and Lundy, in 1947, noted low blood Vitamin C levels in their patients with coronary artery disease.  In the early 50's, Willis demonstrated below normal arterial Vitamin C content in individuals dieing of cardiovascular disease.  Willis placed guinea pigs (like man, guinea pigs cannot manufacture Vitamin C) on a low Vitamin C diet.  The guinea pigs all developed vascular disease, which could be reversed when Vitamin C was resupplied to their diet.  Dr. Willis concluded that Vitamin C deficiency was a critical factor in atherosclerosis, and he put his reasoning to good use in humans in a 1954 report, which is abstracted below.

 Dr. Willis had observed at autopsy, that all patients with significant coronary disease and prior heart attack also had evidence of atherosclerotic plaque buildup in their femoral and popliteal arteries (the arteries to the legs, between the groin and back of the knee).  He thus felt that vascular changes in the femoral-popliteal region, which he could visualize with angiography, would reflect what was going on in the coronary arteries (in '54 coronary angiography was not being done in Montreal, where Willis practiced).  Based on the work cited above, Dr. Willis felt that Vitamin C deficiency played a role in atherosclerosis, and he reasoned that C supplementation would modify its course.  To test out his hypothesis, Dr. Willis and his associates carried out femoral-popliteal angiographic studies in 22 middle-aged men with symptomatic cardiovascular disease or diabetes.  16 of the men were then placed on Vitamin C at a dose of 500 mg three times a day; the other 6 subjects, matched with the treatment group for baseline disease severity, received no Vitamin C.  Dietary advice was given to the diabetics, but otherwise no other preventive measures were carried out (I wasn't around to tell Willis to co-treat his subjects with Vitamin E as I hadn't been born yet).  The angiograms were repeated 2 to 6 months later and compared against the baseline studies; the cardiologist reading the films did not know which subjects had or had not received Vitamin C.  Two of the original 6 control subjects were placed on Vitamin C after their follow-up angiogram, and a third angiogram was then carried out 3-4 months later.  

In the 6 control patients, plaque size and symptomatic statues was unchanged in 4.  In the other 2, disease progression was noted, accompanied by a worsening of symptoms; these 2 patients were then begun on Vitamin C.

In the Vitamin C group, the narrowings worsened in 3 subjects; 1 died of pneumonia and in 2 symptoms were unchanged.  In 1 subject, no change in angiographic appearance or symptoms was noted.  In the remaining 6 subjects, including the 2 initial control patients who were later switched to Vitamin C after they worsened off C, the vascular plaques decreased in size - angiographic disease regression had occurred.  Symptoms were unchanged in 3 of these 6 angiographic improvers, while in the other 3 symptoms lessened, not something they saw a lot of in '54.  

This brings us back to our lead paper, Dr. Nicolaides' 10 year study showing that Vitamin C supplementation decreases disease progression, event rate, and mortality.  In 1954 Dr. Willis showed that Vitamin C decreased event rate and lessened symptoms in patients with advanced cardiovascular disease.  The principles of medical science don't change much when they are correct.

Vitamin C worked in 1954 and it still works in 2003       

7.  Ascorbic Acid Treatment Lowers Blood Pressure in Patients with Hypertension:  A Randomized, Placebo-Controlled Study.  Duffy, A, et al.  Circulation Abstracts from the 72nd Scientific Sessions, Abstract 4257, page 1-807.

Maintenance of the relaxed, dilated status of our arteries is the job of Nitric oxide, an angiochemical that is manufactured by the endothelial cells that line our arteries; our arteries thus make the substance which keeps them in their relaxed, functional state.  When Nitric Oxide levels are low, our arteries will constrict, and when the arteries constrict, then blood pressure will rise.  All hypertensive individuals can be said to have an arterial Nitric Oxide deficit.  

Our cells manufacture Nitric Oxide from arginine (and arginine supplementation will help with BP control).  The Nitric Oxide so generated can be put to good use, dilating our arteries and keeping our BP low, but not if it is quickly destroyed by Superoxide, a free radical angiochemical.  In health, there is a balance between Nitric Oxide and Superoxide generation.  We need some Superoxide, to prevent Nitric Oxide from lowering our BP too much, but Superoxide excess, as occurs in individuals with vascular disease and in all individuals with hypertension, leads to Nitric Oxide deficiency; our vessels will constrict and our BP will rise.  High BP itself generates more Superoxide, more Nitric oxide will be lost, the BP rises higher...a vicious cycle develops.  This is why, when we treat your hypertension with drugs only, we often have to keep increasing the dose or add in new drugs - drugs themselves are not dealing with the underlying biochemical flaw (Angiotensin Converting Enzyme Inhibitor drugs do address this flaw and are effective as drugs go).  

Now, Vitamin C can neutralize Superoxide.  If enough Vitamin C is available to neutralize Superoxide, Nitric Oxide will be spared and can do what it is supposed to do, dilate our arteries.  An understanding of this biochemistry prompted Dr. Duffy to study the use of Vitamin C as an anti-hypertensive agent.

39 hypertensive subjects were randomly assigned to receive, over 4 weeks, Vitamin C 500 mg/day, or a placebo.  A double-blind protocol was followed; neither the subjects or investigators knew who was taking Vitamin C or who was taking the placebo.  

Diastolic BP fell slightly in the placebo group, but the systolic and mean BP values did not change (not shown).  The graphic to the left shows what happened with Vitamin C supplementation.  The 8 mmHg drop in diastolic BP was not statistically significant, while the 13  and 10 mmHg decreases in systolic and mean BP values were.  This is not a dynamite drop in BP, but the values are certainly going in the right direction.  Vitamin C (preferably taken with other antioxidants and minerals) may be enough to control early or mild hypertension.   Vitamin C alone will not be enough to control severe or long-standing hypertension, but it still makes sense to address the underlying physiologic flaw with Vitamin C, as we prescribe BP lowering pharmaceutical agents.  (Magnesium, Arginine, Co-Enzyme Q, and Calcium also help with BP control, but that is another story).  In the treatment of hypertension, Vitamin C is working primarily as an antioxidant, improving endothelial function, but C also helps by removing lead.  Lead plays a role in hypertension; the effects of Vitamin C on lead levels is examined in another section.

Vitamin C helps with BP control  

8.  Lipoprotein(a):  The Ugly Cholesterol

Several of the articles abstracted above refer to Lipoprotein (a), a key cause of atherosclerosis, and a cause of atherosclerosis that most patients and many physicians are not aware of.  I am well aware of Lp(a), because most of the people who see us for EECP have Lp(a) levels off the chart.  Lp(a) promotes restenosis after angioplasty and graft failure after bypass surgery.  Problems recur, further invasive treatments are not felt to be possible, and these patients are then referred to us for EECP.  We treat these patients with EECP, and for sure we address the Lp(a) elevation that made them sick in the first place.  The drug companies have made us aware of the importance of lowering our LDL cholesterol values.  Unfortunately, there are no prescription drugs with significant activity against Lp(a), so we aren't going to see adds during the Super Bowl talking about how bad Lp(a) is and how great Vitamin C is.  The essay below serves as a primer on Lipoprotein(a) and presents the position of two time Nobel Prize winner Dr. Linus Pauling, who considers atherosclerosis to be a disease primarily of Vitamin C deficiency and Lipoprotein(a) excess (we know that other factors play a role, but Dr. Pauling's theory fits well with all the other science that we have).  Lp(a) is covered in great detail in our Lecture:  The Ugly Cholesterol - Lipoprotein (a) and Vitamin C, which will be given in the spring.

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.  It’s 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 vessel wall cellular growth and proliferation, 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 mgs. 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 sugar, and rely on Lp(a) instead to keep their arteries intact.  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 in short supply.  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 than 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, promoting blood clot formation and antagonizing 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.  Individuals who couldn’t make Lp(a) died; those who could make Lp(a) survived the Ice Age and passed on  their Lp(a) producing genes to their descendants.  This is why some Lp(a) is present in all of us.  Lp(a) obviously 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, 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 that patching system ATHEROSCLEROSIS.

        Lp(a) levels are 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 occlude 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 50% narrowing). 

     Lp(a) levels typically range from 1 to 100; the highest level so far in our practice has been 200.  Mg. for mg, Lp(a) has 10 times the plaque producing potential of LDL.  The average American value is 14: 13 in healthy individuals and 19 in coronary patients.  Lp(a) selectively accumulates in your arteries; a level above 30 doubles your risk, and if your LDL is also elevated, your risk rises by a factor of 5.  Lp(a) also concentrates in the walls of your bypass grafts; 90% of individuals whose bypass grafts clog up have Lp(a) levels 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, renarrowing of the blood vessel following 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 40 were 11 times more likely to restenose than those with levels below 4.  Those with levels above 19 were 6 times as likely to renarrow.  

3.  What can I do to lower my Lp(a) related 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 with Niacin and Vitamin C - not the 60 mgs. of Vitamin C present in a one-a-day but by “healthy animal” doses in the 5-10,000 mgs. per day range.  Unfortunately, Lp(a) is not effected by exercise, dietary modification, or our standard cholesterol lowering drugs.

C.  The Lp(a) that cannot be lowered can be neutralized by supplemental Lysine and Proline.  By occupying the binding sites on the circulating Lp(a) particle, Lysine and Proline 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 vascular wall. The now freed-up Lp(a) will take cholesterol out with it, lessening the degree of vessel narrowing.  Many of my patients take Heart Technology™, a preparation designed specifically for Lp(a) control.  Heart Technology™contains measured amounts of Lysine, Proline, Vitamin C, and several other agents with vasoprotective qualities.

D.  To learn more, please attend our next “The Ugly Cholesterol - Lipoprotein (a) and Vitamin C” talk.  Eradicating Heart Disease and Why Animals Don’t Get Heart Attacks, by Mathias Rath MD, are easy to read booklets that also cover this material.

9.  Serum Vitamin C Concentration Is Low in Peripheral Arterial Disease and Is Associated With Inflammation and Severity of Atherosclerosis.  Langlois, M, et al.  Circulation 2001;103:1863-68.

C-Reactive Protein, referred to as CRP, is a bad guy, just as much a problem to you as Lipoprotein(a).  Inflammation, associated with plaque rupture, vasospasm, and clot formation, is the force that destabilizes the arterial narrowing.  Inflammation puts the "vulnerable" in the "vulnerable plaque", and your CRP level reflects the level of inflammation in your circulation.  CRP, irrespective of cholesterol, is a potent, continuous risk factor for cardiovascular disease.  In other words, the higher your CRP, the more likely are you to develop a blocked artery, whether or not your cholesterol or BP are elevated.  In patients with established cardiovascular disease, an elevated CRP is associated with more rapid disease progression, and a worse outcome following heart attack or angioplasty.  Just as with Lp(a), an elevated CRP increases the risk of post-angioplasty restenosis.  CRP is a bad guy, and we spend a lot of time and attention on CRP reduction in our patients.  We know that Vitamin C levels tend to be low, and CRP levels high, in patients with cardiovascular disease.  Dr. Langlois, in the study abstracted below, set out to further understand and explain this relationship:

Langlois and his colleagues measured Vitamin C and CRP levels in 85 patients with symptomatic lower extremity vascular disease (their leg muscles cramped up while walking, due to insufficient blood flow), 106 asymptomatic hypertensive subjects, and in 113 healthy volunteers.  Vitamin C levels were correlated with disease severity in the 85 vascular patients.  The effect of smoking on the Vitamin C and CRP levels was also looked at.  His findings as shown below:

The average Vitamin C level in normal subjects and asymptomatic hypertensives hypertensives is about the same, but its nearly 50% lower in patients with vascular disease.  52% of the vascular patients had Vitamin C levels below normal (<28.4 umol/L), and 14% had severe Vitamin C deficiency (<11.4 umol/L).  The CRP levels are about the same in the normal volunteer and hypertensive subjects, but they are nearly twice as high in the vascular disease patients.  The graph on the left demonstrates an inverse relationship between Vitamin C (Ascorbic Acid) and CRP in the 85 vascular patients.  The charts below demonstrate the inverse relationship that exists between CRP levels and disease severity in this group, and the similar relationship between Vitamin C deficiency and disease activity. 

Ankle-Brachial Ratio (ABR) reflects the degree of impairment in lower extremity blood flow, while Maximal Walking Distance reflects the functional impairment experienced by the patient.  To calculate the Ankle-Brachial Ratio, we measure BP in the arm, and again at the level of the ankle.  If all the pipes are open, then the ratio should be 1.0.  Allowing for measurement error, a ratio of 0.9 or above is considered normal, while a ratio of 0.5 or below indicates limb-threatening, severe disease.  As vascular disease worsens, the ABR will fall.  Conversely, we want to see an improvement in ABR as a result of the treatments that we recommend.  You can see from the charts that the ABRs were lower, reflecting more severe disease, in the patients with lower Vitamin C and higher CRP levels.  Maximal Walking Distance reflects how far the patient can walk before having to stop due to claudication (muscle pain brought on by insufficient blood flow to the leg muscles - "angina of the legs").  Here again, low Vitamin C and high CRP patients had much more trouble.

Langlois then asked:  Why are the Vitamin C levels low in the high CRP patients?  There was no difference in dietary Vitamin C intake between the high C and low C blood level groups, and none of the patients were taking vitamin supplements.  Langlois hypothesized that there was something about the high CRP patients that "burned up" Vitamin C.  To test this hypothesis, Langlois took serum samples from non-smoking vascular patients and non-smoking normal volunteers, and added to each sample a defined amount of Vitamin C.  He then let the test tubes sit,  and four hours later measured how much  Vitamin C was left in each sample.  The chart of the left, % Depletion of Vitamin C, reflects how rapidly the added Vitamin C was metabolized, or "burned up".  In the normal volunteers, 40% of the added Vitamin C was used up at 4 hours, while the serum of the vascular patients used up 57%.  Amongst the vascular patients, those with high CRP levels burned up even more.  This makes sense:  CRP reflects inflammation and oxidation; these processes generate free radicals, which in turn "burn up" Vitamin C.  With low Vitamin C levels, the patient cannot cope with or stabilize the inflammatory, atherosclerotic process that is trying to close off their vessels; the vessels continue to narrow with more plaque, the inflammatory process heats up further, more free radicals are generated, and more Vitamin C is consumed - basically there exists in the cardiovascular patient a vicious cycle between Vitamin C depletion and vascular inflammation, leading to the decline and eventual death of the patient, punctuated by recurrent adverse events (unless, of course, we do something to address this process).

As smoking produces free radical stress and inflammation, Langlois reasoned that smokers would have lower Vitamin C and higher CRP levels.  As aspirin has an anti-inflammatory effect, he felt that patients on aspirin might have lower CRP and better preserved Vitamin C levels.  The charts below show that Langlois was right on both counts:

Smoking produces free radicals and wastes Vitamin C.  This is why Vitamin C levels tend to be low in smokers, and is one of the reasons underlying the causative link between smoking, cardiovascular disease, and cancer.  This explains why, in Dr. Salonen's study of the effect of vitamin supplementation on carotid artery disease progression (article 6), Vitamin C had a greater affect in smokers than in non-smokers.  Smoking had no major affect on the CRP level, which is related more to inflammatory processes within the circulation.  Aspirin use spared Vitamin C.  Aspirin blunts inflammation, thus less free radicals are generated, thus Vitamin C is less "burned up".  Aspirin blunts inflammation and inflammation drives up the CRP; thus it makes sense that aspirin users would have lower CRP values, as Langlois found.  Langlois' findings are summarized below:  

Vitamin C deficiency and an elevated CRP are key driving forces underlying atherosclerotic vascular disease.  They typically co-exist in the vascular patient, where the lower the Vitamin C level and the higher the CRP, the worse will be the patient's disease burden and level of symptoms.  Smoking wastes Vitamin C, while aspirin spares Vitamin C and helps keep CRP under control.

Vitamin C deficiency and an elevated CRP drive the atherosclerotic process forward

10a.  Vitamin C and Plasma Cholesterol.  Harri Hemila  Critical Reviews in Food Science & Nutrition 32(1):33-57 '92. 

In cardiology, Vitamin C is used as an anti-inflammatory anti-oxidant that improves endothelial function, not as a lipid lowering agent, but Vitamin C does have a cholesterol lowering effect and it makes sense for us to examine it.

Hundreds of epidemiologic studies have examined the relationship between Vitamin C and cholesterol.  As a rule, high Vitamin C intake, high blood levels, and high cellular levels have been associated with lower total cholesterol, LDL cholesterol, and triglyceride values, and with higher HDL levels.  This rule holds not just for individuals, but for whole societies.  Individuals and societies with low Vitamin C status have, in turn, higher LDL and lower HDL values.

Where things get a little confusing is when Vitamin C supplementation is used as a treatment for high cholesterol.  Some studies show a benefit, while some don't.  When we carry out studies of cholesterol-lowering drugs, the cholesterol falls in every patient treated, even if their cholesterol level was normal to begin with; the only question is how far the level will fall.  So why does Vitamin C lower cholesterol in some but not all people?   

Dr. Hemilia reviewed hundreds of Vitamin C supplementation studies, and came up with a common sense, but still scientifically sound answer:  Your body is smart and uses Vitamin C to lower cholesterol only when it is needed, when the cholesterol levels are significantly elevated to begin with.  Dr. Hemilia looked at 8 studies where subjects with cholesterol levels below 190 mg/dl received 1-2000 mg/day of Vitamin C:  the average cholesterol level rose by 6%.  In 23 studies, Vitamin C was administered to subjects with pre-treatment cholesterol levels above 250; here the average cholesterol level fell by 12%.  In subjects with intermediate cholesterol values, between 190 and 250, guess what:  the cholesterol values fell by 5%.  

21 studies looked at the effect of Vitamin C on HDL levels:  in 6 the HDL level actually decreased, in 3 there was no change, while in 12 the HDL rose, between 2 and 31%.  Triglycerides levels fell in 21 of 27 studies reviewed, between 3 and 51%, where unchanged in 3, and rose in 3, between 7 and 20%.  How does Vitamin C work here?

Most of the cholesterol in our body is manufactured in the liver; the rest is obtained from ingested foodstuffs.  Mother Nature's plan is for the cholesterol entering our circulation to be taken up by our cells and be put to good use (to make hormones and new cell membranes).  Excess cholesterol returns to the liver and is metabolized.  When this process goes out of balance, when cholesterol input into the circulation outpaces cholesterol removal by the liver, then the cholesterol left over can be oxidized and layered out in our vessels as atherosclerotic plaque.  So how does the liver metabolize, or clear, excess cholesterol from the circulation?

Bile acids are manufactured in the liver, stored in the gall bladder, and then injected into the small intestine following a meal.  Bile acids are digestive enzymes; their job is to help you breakdown and then absorb ingested fats.  The bile acids then leave the body in the stool, and the liver then manufactures more.  The liver manufactures bile acids from, you guessed it, cholesterol, and Vitamin C is needed to convert cholesterol into bile acids.  Without Vitamin C, the liver cannot convert cholesterol into bile acids, fat digestion is impaired, but of greater importance, excess cholesterol cannot be removed from the circulation - uh Oh.  So, if your cholesterol is elevated, you need more Vitamin C to metabolize it than would an individual with a lower cholesterol level.  Thus your cholesterol will likely fall with Vitamin C supplementation, while if your cholesterol is normal to begin with, then Vitamin C will have no effect.  Vitamin C, and in general all nutritional treatments, work only when your body needs them; they are simply helping the body do something that it is designed to do, here converting excess cholesterol into bile acids.  So take your Vitamin C and give your liver a fair chance to do what it is supposed to do.

Vitamin C assists in the conversion of cholesterol into bile acids

10b.  Lipoprotein(a) Reduction by Ascorbate.  Mathias Rath MD Journal of Orthomolecular Medicine Vol. 7, No. 2, 1992, pp. 81-82. 

While Vitamin C has modest value as a general cholesterol control agent, Vitamin C is a critical component in our 

approach to Lipoprotein(a) - see Section 8 Lipoprotein(a) - Archrival and nemesis of Vitamin C.  We use Vitamin C primarily to antagonize the plaque and clot forming tendency of Lp(a), but Vitamin C does have some effect on the actual Lp(a) level.  In this paper, Dr. Mathias Rath, who along with two time Nobel Prize winner Dr. Linus Pauling, brought the importance of Lipoprotein(a) to our attention, studied the effects of Vitamin C supplementation on Lp(a) levels in 11 coronary patients.  Lp(a) levels were obtained at baseline and after 14 weeks of Vitamin C taken at 9000 mg/day.  

For the group, Lp(a) fell by 27%, and Vitamin C levels rose from 49 to 94 uM.  Dr. Rath used a sensitive and specific measure of Lp(a) (sandwich ELISA method with monoclonal capture antibodies against apo(a), and pointed out the difficulty that the lab has in accurately measuring Lp(a) levels.  It has been my personal experience that different labs will give us quite different Lp(a) levels, and I keep this in mind when interpreting the values in my own patients.  We also feel that Vitamin C synergizes with Niacin in Lp(a) control; the combination forms NADPH, which is felt by Dr. Rath to inhibit Lp(a) formation in the liver.

Vitamin C lowers Lipoprotein(a)

11.  Vitamin C gets the lead out - Article misplaced and I will track down the citation

Lead overload is an important health problem in the United States.  Lead is not a trace mineral.  Lead serves no role in our physiology and can be considered a "pure toxin".  Unfortunately for us, lead is relatively plentiful in our modern environment.  Even more unfortunate for us, our body doesn't know what to do with it.  We weren't designed by Mother Nature or Evolution to deal with lead; we weren't even exposed to lead until the Industrial Revolution 250 years ago.  To our physiology, lead is "pure trash", but trash that we don't know how to take out, so we store it in our cells.  Intracellular storage space, of course, is in short supply, so the free lead then displaced useful metals, such as selenium, manganese, and zinc, from their binding sites on enzymes and other intracellular proteins, rendering them useless.  

Lead is bad stuff.  Hair lead levels correlate with lower IQs and the presence of learning disabilities in kids.  Bone lead levels correlate with the presence of hypertension in adults.  A "healthy" American adult has over 100 times as much lead in his bones as did a "healthy" man in 1oo years ago.  Lead gums up our physiology and leads to free radical stress.  Lead is an oxidizing agent, generating free radicals that damage cellular structures, such as mitochondrial enzymes (leading to fatigue), the LDL cholesterol particle (leading to heart disease), and our DNA (leading to cancer).  Lead removal, on the other hand, has been shown to decrease cancer risk in animals and in humans.  In a population living adjacent to a highway in Switzerland (when gasoline was still "leaded"), individuals who underwent a lead removal protocol (to address symptoms felt to be lead-related) were 1/10th as likely as their non-treated neighbors to develop a malignancy over the ensuing 12 years.  This was not a randomized, double-blind, placebo controlled study, but the implication here is obvious and the message important:  Get The Lead Out!

There are several means available to remove lead from the body and I have been trained in these techniques.  I tested myself and was quite distressed to find that my lead (and mercury) levels were on the high side.  Where did the lead come from?  I have lived in several old houses, with lead pipes, and I run a lot, inhaling the wonderful exhaust vapors from cars and industry - these are the likely sources.  I got "deleaded"; my thinking now seems to be more creative and running is certainly easier.  So, how can we minimize our lead burdens?  How can we prevent lead overload in the first place?  We can take prudent measures, but we city dwellers can't totally avoid lead exposure, but we can take Vitamin C.  Individuals with high lead levels tend to have low Vitamin C levels, and visa versa.  Does this mean that Vitamin C detoxifies lead, or that lead wastes Vitamin C?  Actually its both.  Old studies, carried out in the 30s, described the use of Vitamin C as a lead detoxifier.  This notion was resurrected in the following study.  Here 75 male smokers were randomized to receive placebo, Vitamin C at 200 mg/day, or C at 1000 mg/day.  Blood lead levels were obtained at baseline and after 4 weeks of treatment.  Low dose C didn't have much effect, but look what happened to the 1000 mg group - their lead levels plummeted.  Now, blood lead levels don't necessarily reflect your long-term, intracellular burden, but before lead can get into your cells, it has to go through the blood, but its not going to get into the blood if you take Vitamin C 1000 mg/day.  

So, take Vitamin C and Get The Lead Out!  

12.  Vitamin C:  How much should you take and how should you take it?     

Given the profound cardiovascular health benefits (and I didn't event touch on Vitamin C's extra-cardiovascular effects) associated with Vitamin C supplementation, and the essential lack of toxicity of Vitamin C at reasonable doses, I can't think of a good reason why every adult in America should not take 1000 mg of Vitamin C (as part of a multinutritional - see the next section) every day.  In my own patients, larger doses are often prescribed, depending on the patient's Lp(a) and C-Reactive Protein levels, and my estimate as to the degree of inflammation present within their circulation.  Dosing studies (charts below) show us that the more Vitamin C you take, the more will get into your blood.  The chart on the right gives us Vitamin C blood levels, at specific time points following a single 2000 mg dose.  You can see that the blood level begins to fall off at 5 hours.  Therefore, it is best if you split your daily Vitamin C dose into 2 or 3 servings, taken throughout the day.  However, I'd rather have you take 1000 mg in the morning than 500 mg in the morning and forget to take the evening 500 mg dose.   

Now, when you take Vitamin C orally, your body will absorb only as much Vitamin C as it needs at that particular time.  Unabsorbed Vitamin C will remain in the intestines, where it will draw in water, and the result will be loose stools and/or diarrhea.  There are specific circumstances and specific disease states where a patient might benefit from an intentional "GI overdose" of Vitamin C as a detoxifying procedure (this is termed the "C Flush"), but from the cardiac perspective, we don't want you to experience any Vitamin C related GI tract symptoms.  If a given dose of Vitamin C is giving you trouble, then the dose is too high for you.  Split the dose into more frequent, smaller servings, or cut back the total mgs.  Dosing "to GI tolerance" involves taking 1000 mg of Vitamin C every hour, up to the point where loose stools develop, and then taking the total dose minus 1000 mg as your maintenance daily dose, split into 2 to 3 servings.  Of interest, healthy people "can tolerate" less Vitamin C than can unhealthy patients.  The sicker people are experiencing greater free radical stress, have lower Vitamin C levels, and their body's are delighted to "soak up" all the Vitamin C that they can take.  If you are healthy and can take, say 3000 mgs of Vitamin C each day without difficulty, when you have the flu you will be able to tolerate 2 to 3 times that amount, as your body is then under stress and will need more Vitamin C and will absorb more Vitamin C.

You will hear that Vitamin C "goes right through you" to create "expensive urine".  It is true that much of the Vitamin C that we take orally is excreted in the urine soon after we take it in, but much of the Vitamin C does enter our cells, and the Vitamin C that is excreted probably carried out an antioxidant or detoxifying chemical process while it was in transit within your circulation.

What about safety concerns?  Well, the risk to you from oral Vitamin C is negligible.  The old adage that Vitamin C causes kidney stones is probably not accurate (Vitamin C added to urine samples outside of the body causes oxalate crystals to form but Vitamin C taken orally or IV does not aggravate oxalate stone formation in the kidneys).  If you have a rare disorder of hemoglobin function (G-6 PD deficiency, something that I have never encountered in an adult), then you should not take Vitamin C IV, but oral Vitamin C is not likely to be a problem.  I gave myself 40,000 mgs of Vitamin C IV and then went out and ran 10 miles; here we're talking about 1-2,000 mgs taken orally - this stuff is safe.  Vitamin C enhances iron absorption, and thus may be of additional value to menstruating women, but in men and post-menopausal women this is an area of potential concern.  We need enough iron in our diet to make a normal compliment of red blood cells, but beyond that iron has negative health effects.  Free iron, not participating in hemoglobin formation or another iron-requiring biochemical process, actually acts as a free radical, promoting the oxidation of LDL cholesterol and other intracellular and extracellular structures.  Iron excess is associated with endothelial dysfunction, insulin insensitivity, and an increased risk for cardiovascular disease and adverse cardiovascular events.  Iron binding therapy improves endothelial dysfunction, decreases the medication needs of previously iron overloaded diabetics, and in animal studies, decreases heart attack size.  A genetic abnormality associated with excessive iron absorption from the GI tract, Hemochromatosis, is rare, and occurs only if you inherit the Hemochromatosis gene from both your mother and your father.  However, the presence of one faulty gene, causing a moderate iron over absorption problem, is quite common.  We can look for evidence of iron overload with a routine lab test (serum ferritin); if the value is above 100, I simply recommend that you donate blood on a periodic basis to the Red Cross.  Then you can take all the Vitamin C that you want.  This protocol gives you Vitamin C cardiac protection, keeps your ferritin level within the desirable range, and does good for others.  It also does good for you; individuals who donate blood live 10 years longer than people who don't.  If you are to undergo dental work, don't take Vitamin C that morning; the detoxifying effect of Vitamin C will metabolize the local anesthesia the dentist uses to numb your teeth, rendering your trip to the dentist a little uncomfortable.  The recommendations on this webpage are general in nature, and assume the absence of important extra-cardiovascular problems.  There are certain situations where your physician may not want you to take Vitamin C (i.e. dialysis patients, cancer patients undergoing therapy), so if any question exists, ask your doctor

What type of Vitamin C should you take?  Vitamin C's chemical name is ascorbic acid, and yes, if you have a sensitive stomach, it can cause some irritation.  If plain Vitamin C bothers you, then a  "buffered" or "mineral ascorbate" might work better for you.  Bioflavonoids are "Vitamin C helpers"; they shepherd Vitamin C into the body, have beneficial effects of their own, and synergize with Vitamin C (Vitamin C and Bioflavonoids taken together decrease abnormal bleeding related to coumadin anticoagulation better than do Vitamin C or Bioflavonoids taken alone).  It is worth it to pay a little more for Vitamin C complexed with Bioflavonoids.  "Esterified" Vitamin C is better absorbed than regular C; Esterified C is typically well tolerated but does cost more.  My own patients take a buffered Vitamin C complexed with GMS-Ribose and biopterin to enhance absorption.  The key here is not which Vitamin C preparation you take, but simply to take Vitamin C.  Find a preparation that you tolerate well and that you can easily afford, and then take it.  Remember:

 Vitamin C that sits on the shelf will not lower your 10-year mortality rate by 43%

13.  Vitamin C as a member of your Antioxidant Defense Team - Understanding Nutritional Medicine 

My goal with the Tip of the Month webpage series is not to get you interested in taking Vitamin C, but rather to convince you of the importance of incorporating the principles of nutritional medicine into your (what can be a long and healthy) life.  For purposes of clarity and to make a point, on this page we focused only on Vitamin C.  

In this section I want to point out that Vitamin C is not a magic bullet, but merely one component of your body's anti-oxidant, anti-inflammatory, anti-cancer, and anti-infective defense systems.  Vitamin C works best as a player on your antioxidant defense team, a player with healthy teammates, and reserves at each position.  Please realize that a multitude of free-radical inflammatory stressors are working on us, trying to harm us, at multiple levels in different organ systems.  Vitamin C is a great general anti-oxidant, but Vitamin C alone has no effect on many of these toxic free radicals.  Vitamin C can also be used up; spent Vitamin C, however, can be "recharged" by Bioflavonoid vitamins, that is if Bioflavonoids are present within your circulation.  Vitamin C is also tasked with the responsibility to "recharge" spent Vitamin E, and Vitamin E in turn works within the cell with Lycopene, Beta-carotene, and Co-Enzyme Q₁₀.  To play great defense, a football team needs 11 players.  High doses of Vitamin C alone may constitute a great front line, but without the other anti-oxidants and nutritionals to serve as line backers, cornerbacks, and free safeties, the Vitamin C only team is not going to stop the run and its not going to stop the pass.  Vitamin C alone, no matter how much you take, is not going to sack coronary disease at an early stage.  Mother Nature expects us to take in 96 nutrients every day.  The key here is to take Vitamin C, along with the other nutritional substances that you need.  You are going to hear about the specific health-promoting effects of individual nutritionals in specific disease states (Co-Enzyme Q₁₀ and Glutathione in Parkinson's disease, Lutein and Zeaxanthine in macular degeneration, Lycopene in prostate cancer, etc.), and indeed these benefits are real and important, but please remember that these individual nutritionals, like Vitamin C, work best when combined with the other vitamins and minerals that you need.  So take Vitamin C, but take Vitamin C as a component of a broad-spectrum vitamin and mineral supplement.  A one-a-day multi, such as the commercial preparations advertised on TV, is better than nothing, but a one-a-day is not going to provide you with the protection you need.  To get enough Vitamin C and Vitamin E to prevent heart disease, enough Calcium to prevent osteoporosis, enough B Vitamins to keep your Homocysteine level down, etc., you need to take a 4 to 6 tablet-a-day multinutritional.  The table below lists the contents of a representative preparation.  Most of my patients take Amni Preventive V, compounded by Douglas Labs; other good preparations are Twin Labs Mega Six and Carlson's Cardirite.  Every major nutritional company has such a multinutritional, and the people at area health food stores can help you here.  Expect to pay $20-30 per month for a good preparation.  Cost is always an issue, but also keep in mind the cost to you, your family, and to our society if you sustain an adverse health event that could have been prevented (As Vitamin C decreases 10-year event rate by up to 50%, consider what would happen to health care costs if every American adult with mild to moderate atherosclerosis took 1000 mg/day.).