Monday, May 05, 2008

Revisiting Lipoprotein(a): good, bad or ugly?

Take a step back in time to 1990 when Matthias Rath and Linus Pauling published two landmark studies showing species of animals that internally produce a natural form of vitamin C (ascorbate) do not exhibit a blood fat-protein called lipoprotein(a), but humans, monkeys, guinea pigs and other species that have incurred a genetic mutation that has resulted in an inability to synthesize vitamin C, do have variable levels of lipoprotein(a) in their blood serum.

In a legendary experiment, Rath and Pauling removed vitamin C from the diet of a guinea pig and noted the development of arterial plaque that contained lipoprotein(a). The provision of supplemental vitamin C, at an oral dosage of 40 milligrams per kilogram of body weight, which is equivalent to 2800 mg in a 160-pound adult human, completely abolished arterial plaque formation.

Their published paper said “We suggest an analogous mechanism in humans because of the similarity between guinea pigs and humans with respect to both the lack of endogenous ascorbate production and the role of Lp(a) in humans.” [Proceedings National Academy Science U S A. 1990 Dec; 87(23):9388-90] Pauling and Rath’s earlier paper that year hypothesized lipoprotein(a) as “a surrogate for ascorbate in humans and other species.” [Proceedings National Academy Science U S A. 1990 Aug; 87(16):6204-7]

Pay careful attention to that description. It suggests lipoprotein(a) as a substitute for vitamin C of some kind. It was guilt by association --- lipoprotein(a) was declared a risk factor for heart disease because it was found within arterial plaque. Is lipoprotein(a) a villain to the coronary arteries, as often portrayed? Or does lipoprotein(a) accumulate within artery walls in defense of otherwise weakened tissues, as a substitute for ascorbate?

Is lipoprotein(a) a risk factor?

Lipoprotein(a) is not a highly regarded risk factor for coronary artery disease. Authorities say Lp(a) cannot yet be regarded as a conventional, well established risk factor for cardiovascular disease, although studies show an ASSOCIATION of Lp(a) and cardiovascular disease, which does not automatically mean it is a causal factor. [Circulation 102 (10): 1082–5, 2000]

Lp(a) concentrations vary over one thousand-fold between individuals, from <> 200 milligrams per deciliter of blood serum. Lipoprotein(a) - Lp(a) is sometimes considered a risk factor for heart disease, as describe in one book. [Ryan, George M; Julius Torelli (2005). Beyond cholesterol: 7 life-saving heart disease tests that your doctor may not give you. New York: St. Martin's Griffin, page 91]

Desirable: <>

Borderline risk: 14 - 30 mg/dL

High risk: 31 - 50 mg/dL

Very high risk: > 50 mg/dL

Researchers in Denmark measure the increased relative risk for a heart attack based upon the Lp(a) level. [Circulation 2008 Jan 15; 117(2):176-84]

Lp(a) level Relative risk for heart attack

5-29 mg/dL 1.1

30-84 mg/dL 1.7

85-119 mg/dL 2.6

120+ mg/dL 3.6 times greater risk

Usually when increasing amounts of something produce undesirable effects, it is said to be causal.

Among smoking women over age 60, their risk for a heart attack is 10% when their Lp(a) levels is less than 5.0. Their risk for a heart attack rises to 20% (doubles) when their Lp(a) is greater than 120.0. [Circulation 2008 Jan 15; 117(2):176-84]

So Lp(a) shows up at the scene of the crime, but does it directly cause heart attacks, strokes, etc?

Lp(a) concentrations may be affected by disease states, but are only slightly affected by diet, exercise, and other environmental factors. Commonly prescribed cholesterol-reducing drugs have little or no effect on Lp(a) concentration. In one study, a statin drug (atorvastatin) modestly lowered Lp(a) levels (~10%). [Annals Pharmacotherapy 2008 Jan; 42(1):9-15]

Niacin (nicotinic acid) and aspirin are two relatively safe, easily available and inexpensive drugs known to significantly reduce the levels of Lp(a) in some individuals with high Lp(a).

Back in 1995 researchers in Germany found that blood serum concentrations of Lp(a) greater than 25 milligrams per decliter were indicative of rapid progressing coronary artery disease – 67% of men with rapid progressive disease, but only 33% of men without progression. [Circulation. 1995 Feb 15; 91(4):948-50]

Among patients admitted to a hospital due to a heart attack, a baseline lipoprotein(a) concentration of > or =30 mg/dL was associated with a 62% increase in subsequent cardiac death compared to a lower concentration group (actual 29.8% vs 18.6% increased risk). [European Heart Journal 1998 Sep; 19(9):1355-64]

A telling experiment was conducted at the University of Virginia School of Medicine in 1995. Angina (chest pain) patients undergoing balloon angioplasty (a catheter is inserted into the coronary artery and a balloon is inflated at the site of narrowing or blockage), were tested for Lp(a), total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein A-I, and apolipoprotein B-100 and the recurrence of angina was also monitored. Only elevated Lp(a) predicted the recurrence of angina (27% recurrence of angina in the group with the lowest Lp(a) and 60% recurrence in the group with the highest Lp(a). Other cholesterol factors were not predictive. [Circulation. 1995 Mar 1; 91(5):1403-9]

Some time ago researchers in London attempted to rank the predictors of a future heart attack among middle-aged men. High total cholesterol increased the risk by 1.5 times. Diabetes by 4.1 times. Smoking by 2.5 times. Lipoprotein(a) by 1.9 times – which was more predictive than cholesterol! [American Journal Medicine 2001 Jan; 110(1):22-7]

It is very interesting to evaluate factors which raise the risk for coronary artery disease. Metabolic disease (diabetes, insulin resistance) produces significantly higher Lp(a) levels (29.2) versus healthy controls (16.2). Homocysteine and C-reactive protein levels are about the same among patients with metabolic disease versus healthy controls. However, the assumption here is that the Lp(a) “contributed to the premature atherosclerosis observed in these patients.” [Anadolu Kardiyol Derg. 2008 Apr; 8(2):111-5]

There is no sound reason why lipoprotein(a) is being overlooked as a risk factor for coronary heart disease.

Plaque rupture and sudden death

A mortal and often unforeseeable event is sudden death heart attack. Whereas the lack of vitamin C within artery walls would make them prone to collapse and the sudden development of a blood clot that impairs the heart of oxygenated blood, sudden coronary death is often attributed to the sudden rupture of small plaque and subsequent development of an arterial blockage in a coronary artery. [Journal American College Cardiology 2006 Apr 18; 47(8 Suppl):C13-8]

Plaque rupture is more common among men who suddenly die after physical exertion. [Current Opinion Cardiology 2001 Sep; 16(5):285-92] Shear forces within the artery likely tear open the already existing scar tissue to produce a blockage.

Upon autopsy, it is found that the sudden rupture of a fibrotic (scarred) cap, only about 2 to 17 millimeters long, is what many authorities believe causes sudden cardiac death. White blood cells called macrophages arrive in droves within the ruptured plaque in a typical wound healing response to prevent infection. However, this results in massive inflammation. [Circulation. 1996 Apr 1; 93(7):1354-63]

Lp(a) has been found to be a risk factor for plaque destabilization and thrombosis (blood clotting) in patients with high risk unstable angina. [Anadolu Kardiyol Derg. 2006 Mar; 6(1):13-7]

An interesting finding is that cigarette smoking, which depletes vitamin C, is more likely to result in an acute thrombosis (blood clot) within coronary arteries whereas in non-smokers, sudden death is more often caused by vulnerable plaque rupture. [New England Journal Medicine 1997 May 1; 336(18):1276-82]

It is the scarred tissue in response to wound healing that produces the volume of plaque in the artery. Prior healed ruptures were found in 61% of men who died of a sudden heart attack. [Circulation. 2001 Feb 20; 103(7):934-40; Journal American Medical Assn 1999 Mar 10; 281(10):921-6] These would represent prior silent heart attacks these men would not have been aware of.

Contrary data

What is difficult to fathom is that centenarians (those who live to 100 years and beyond) lipoprotein(a) is surprisingly high. [Haematologica. 2007 Apr; 92(4):e48] Strikingly, lipoprotein(a) is a longevity factor!

Surprisingly, Lp(a) levels are generally consistent from decade to decade and are not related to other traditional risk factors such as total cholesterol, sex, age or blood pressure. [Archives Internal Medicine 2008 Mar 24; 168(6):598-608] There is not an age-related increase in Lp(a).

While elevated levels of Lp(a) are positively associated with coronary artery disease among younger men (2.45 times increased risk for men under 65 years of age) but not for men over the age of 65 (44% reduced risk). [Annals New York Academy Science 2007 Apr; 1100:179-84]

How can this be?

So is Lp(a) only a risk factor for younger aged males? We need to dig deeper for answers to this question.

Only recently has the relationship between coronary artery calcification and lipoprotein(a) been investigated. Researchers at the University of Michigan found that Lp(a) was a significant predictor of presence and quantity of coronary artery calcification in women (mean age 57 years). In men, Lp(a) was a risk factor for coronary artery calcification if they smoked tobacco. [Medical Science Monitoring 2004 Sep; 10(9):CR493-503]

An interesting study was conducted by cardiologists in Turkey. They screened 285 patients over 60 years of age for calcification of their aortic valve (stiffening of the valve). This is the valve that controls the flow of blood from the heart into the aorta, the first blood vessel outside the heart. These researchers found 112 of the 285 subjects had aortic valve calcification. Compared to healthy subjects, patients with aortic valve calcification were significantly older (73.0 versus 68.5 years) and had significantly higher serum levels of Lp(a) (27.4 versus 19.9). [Journal Heart Valve Disease 2007 Jul; 16(4):387-93]

Researchers at Yonsei University College of Medicine took the investigation of lipoprotein(a) and its role in coronary artery disease one step further. They found coronary artery calcification was more prevalent among individuals with a Lp(a) level of 35 mg/deciliter or greater (24%) than those with a lower Lp(a) score (15.7%). In younger patients (less than 60 years of age), Lp(a) was an independent risk factor for coronary artery calcification, but in older patients, coronary artery calcification but not Lp(a) was a risk factor. [Yonsei Medical Journal 2003 Jun 30; 44(3):445-53]

The riddle of lipoprotein(a) is solved. Calcification is the culprit.

An animal experiment sheds more light on the subject. Rabbits were bred so they produced more lipoprotein(a). These rabbits exhibited more advanced arterial plaque than normal rabbits. Most of these arterial plaques were calcifications which were barely evident in the normal rabbits. [Journal Biological Chemistry 2002 Dec 6; 277(49):47486-92]

The cholesterol theory of heart disease dominates. Yet the prevalence of coronary artery calcification is about 17.6% among males and only 4.3% among females age 39-45 years. [Am Heart J. 2001 Mar; 141(3):463-8] Younger premenopausal women would not have begun to lose calcium from their bones, to be deposited in their arteries, at this young age. Men accumulate calcium in their arteries once childhood growth ceases.

A few hundred thousand adult Americans succumb to sudden-death heart attack with low-to-normal cholesterol levels and clear coronary arteries. Yet a coronary artery calcium score of zero means a person’s risk for a sudden heart attack is near zero. Researchers have found, among adults who experienced their first heart attack, 86% had calcium artery scores of ~400. [International Journal Cardiology 2006 Jun 16; 110(2):231-6]

A study was conducted among 102 “fresh” heart attack patients who had survived their first heart attack (19-59 years of age, 88% male) and found coronary artery calcification in 95% of these patients compared to just 59% of healthy adults. The calcium arterial score was 529 (mean) among the heart attack patients and only 119 in healthy adults. In young patients with their first, unheralded acute heart attack, the presence and extent of coronary calcium are significantly greater than in matched controls. [Heart 2003 Jun; 89(6):625-8]

It was Dr. Stephan Seely who noted in 1991 that countries of the world that consume the most calcium (Ireland, Scandinavia, New Zealand and North America) have the highest rates of heart disease. At the time, Dr. Seely proposed rice bran IP6 as a natural antidote to arterial calcifications. [International Journal Cardiology 1991 Nov; 33(2):191-8]

It should also be noted that in the 1970s cardiologist Lester Morrison proposed and demonstrated that oral chondroitin sulfate blocks the calcification of arteries. [Atherosclerosis 1972 Jul-Aug; 16(1):105-18]

The subject of vitamin C as an inhibitor of calcification is limited by sparse data. A retrospective study showed that among 865 consecutive patients age 39-45 years without known coronary artery disease who consumed, on average, 371 milligrams of vitamin C daily, the prevalence of coronary artery calcification was 20% and vitamin C intake had no effect upon calcification. [Preventive Cardiology 9: 75-81, 2006] This is about 3 times the dietary intake level of vitamin C.

In another study, researchers at the St. Francis Hospital in New York conducted a double-blind, placebo-controlled randomized clinical trial of a statin cholesterol-lowering drug (atorvastatin 20 mg daily), vitamin C (1000 mg daily), and vitamin E (alpha-tocopherol 1,000 IU daily), versus matching inactive placebos in 1,005 non-symptomatic patients, apparently healthy men and women age 50 to 70 years with coronary calcium scores at or above the 80th percentile for age and gender. All study participants also received aspirin 81 mg daily. Mean duration of treatment was 4.3 years. Treatment with alpha-tocopherol, vitamin C, and low doses of atorvastatin (20 mg once daily) did not affect the progression of coronary calcification. [Journal American College Cardiology 2005 Jul 5; 46(1):166-72] The amount of vitamin C extrapolated from Pauling and Rath’s studies, 2800 mg for a 160-pound adult, was not employed. - Copyright 2008 Bill Sardi, Knowledge of Health, Inc.

Labels: coronary artery calcification, lipoprotein(a), Vitamin C