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The Vitamin D Newsletter December 2005

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Paradigms and Paradoxes

Last month Dr. Armin Zittermann of Ruhr University, Germany, published the best vitamin D paper of the month. He reviewed the mounting evidence that vitamin D deficiency is a major cause of heart disease. Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005 Oct;94(4):483–92.

Before we start, let's talk about paradigms and paradoxes. A paradigm is a set of assumptions, concepts, and practices that constitutes a way of viewing reality. The current paradigm is that heart disease is caused by a combination of genetics, hypertension, diabetes, cholesterol, smoking, obesity, inactivity, and diet. A paradox is a fact that contradicts the paradigm.

The Framingham Risk Equation is an attempt to use the most reliable risk factors in a paradigm to predict who will get heart disease. When researchers applied it to British men for ten years, they found 84% of the heart disease occurred in the men classified as low risk! Furthermore, 75% of the men classified as high risk were still free of heart disease by the end of the tenth year! It appears the equation may be missing a few variables. Brindle P, Emberson J, Lampe F, Walker M, Whincup P, Fahey T, Ebrahim S. Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study. BMJ. 2003 Nov 29;327(7426):1267.

This month's Vitamin D Quiz reveals several interesting heart disease paradoxes—and some of them just might surprise you. Positive you know what causes heart disease? Let's find out...

The French Paradox is that cardiovascular disease is relatively low in France, despite high intakes of saturated fats.


True. Perhaps the best known of the cardiovascular disease paradoxes, it was first described in 1987, before the dermatologists scared the French out of their bikinis. The most common explanation is that the French love red wine, known for the antioxidants it contains. But the rates of cardiovascular mortality in France are much lower in the South and the West than they are in the North. One of the world's best vitamin D researchers, Dr. Marie Chapuy, found that vitamin D levels of healthy adults in France follow that same pattern, with a mean level of 38 ng/mL in the sunnier and drier South and West, but less than half that (17 ng/mL) in the colder, rainier, more polluted North. Richard JL. Coronary risk factors. The French paradox. Arch Mal Coeur Vaiss. 1987 Apr;80 Spec No:17–21. Thomas F, Bean K, Pannier B, Oppert JM, Guize L, Benetos A. Cardiovascular mortality in overweight subjects: the key role of associated risk factors. Hypertension. 2005 Oct;46(4):654–9. Hu FB. Overweight and increased cardiovascular mortality: no French paradox. Hypertension. 2005 Oct;46(4):645–6. Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S, Meunier PJ. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int. 1997;7(5):439–43.

The Israeli Paradox is that cardiovascular disease is high in Israel, despite a high consumption of polyunsaturated omega-6 fats.


True. Now, according to the current paradigm, polyunsaturated fats contained in vegetable seed oils are supposed to lower the risk of heart disease. Yet, high consumption of these oils doesn't seem to have prevented the Israelis from dying from heart attacks. However, despite its sunny weather, Israel does have a high incidence of vitamin D deficiency. Average vitamin D levels among healthy adults in Lebanon, right next door, are only 9.7 ng/mL—dangerously low. Healthy Jewish mothers, especially orthodox ones, have low vitamin D levels. (If you are wondering how the pro-inflammatory omega-6 oils could ever help heart disease, one possibility is these oils dissociate vitamin D from its binding protein, making more free vitamin D available. Apparently, the Israelis don't have enough vitamin D in their blood to dissociate). Yam D, Eliraz A, Berry EM. Diet and disease—the Israeli paradox: possible dangers of a high omega-6 polyunsaturated fatty acid diet. Isr J Med Sci. 1996 Nov;32(11):1134–43. Hochwald O, Harman-Boehm I, Castel H. Hypovitaminosis D among inpatients in a sunny country. Isr Med Assoc J. 2004 Feb;6(2):82–7. Gannage-Yared MH, Chemali R, Yaacoub N, Halaby G. Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers. J Bone Miner Res. 2000 Sep;15(9):1856–62. Mukamel MN, Weisman Y, Somech R, Eisenberg Z, Landman J, Shapira I, Spirer Z, Jurgenson U. Vitamin D deficiency and insufficiency in Orthodox and non-Orthodox Jewish mothers in Israel. Isr Med Assoc J. 2001 Jun;3(6):419–21. Bouillon R, Xiang DZ, Convents R, Van Baelen H. Polyunsaturated fatty acids decrease the apparent affinity of vitamin D metabolites for human vitamin D-binding protein. J Steroid Biochem Mol Biol. 1992 Sep;42(8):855–61.

The Italian Paradox is that a population of heavy smokers has a low incidence of cardiovascular disease.


True. The overall death rate from cardiovascular disease in Italy, a country of heavy smokers, is relatively low. Before you say it is the olive oil and wine, ask yourself where do those olive trees and grapevines grow?—In the sun, of course! However, at least two good studies show vitamin D levels in Europe are a paradox, the closer a European lives to the equator, the lower their vitamin D level. Nevertheless, an Italian study showed healthy Roman blood donors had robust vitamin D levels of 48 ng/mL in the summer. Even average postmenopausal Italian women reached 36 ng/mL in the summer. Anyone who has traveled in Italy knows that most Italians love the sun. As the old Italian proverb points out: "Where the sun does not go, the doctor does." Grimes DS, Hindle E, Dyer T. Respiratory infection and coronary heart disease: progression of a paradigm. QJM. 2000 Jun;93(6):375–83. Romagnoli E, Caravella P, Scarnecchia L, Martinez P, Minisola S. Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients. Br J Nutr. 1999 Feb;81(2):133–7.

The Northern Ireland Paradox is a very high incidence of coronary heart disease, yet very few of the expected risk factors.


True. In fact, the age adjusted mortality for coronary artery disease was more than four times higher in Belfast than in Toulouse, France, despite almost identical coronary risk factors. There were 761 deaths per 100,000 in Belfast compared to 175 in Toulouse. This is hard to explain, given the current paradigm of heart disease. Of interest, Belfast is at 54 degrees latitude, at sea level, and has 257 rainy days per year. Toulouse is eleven degrees closer to the equator with an altitude that is 500 feet closer to the sun and only 74 rainy days per year. Lots more vitamin D in Toulouse! Evans AE, Ruidavets JB, McCrum EE, Cambou JP, McClean R, Douste-Blazy P, McMaster D, Bingham A, Patterson CC, Richard JL, et al. Autres pays, autres coeurs? Dietary patterns, risk factors and ischaemic heart disease in Belfast and Toulouse. QJM. 1995 Jul;88(7):469–77. Yarnell JW. The PRIME study: classical risk factors do not explain the severalfold differences in risk of coronary heart disease between France and Northern Ireland. Prospective Epidemiological Study of Myocardial Infarction. QJM. 1998 Oct;91(10):667–76.

The Indian Paradox is a high prevalence of coronary artery disease in urban Indians despite their low saturated fat intake.


True. Researchers found that a diet low in saturated fats did not prevent heart disease in the citizens of the brass-works-polluted city of Moradabad in northern India. The authors did not mention that air pollution dramatically lowers vitamin D levels. Singh RB, Niaz MA, Ghosh S, Beegom R, Agarwal P, Nangia S, Moshiri M, Janus ED. Low fat intake and coronary artery disease in a population with higher prevalence of coronary artery disease: the Indian paradox. J Am Coll Nutr. 1998 Aug;17(4):342–50. Agarwal KS, Mughal MZ, Upadhyay P, Berry JL, Mawer EB, Puliyel JM. The impact of atmospheric pollution on vitamin D status of infants and toddlers in Delhi, India. Arch Dis Child. 2002 Aug;87(2):111–3.

The Swedish Paradox is that the association between cold weather and heart disease in Sweden is not explained by the usual risk factors.


True. Researchers tried to explain why higher annual cardiac mortality is associated with residence in colder regions of Sweden. Try as they might, the authors could not support the current paradigm for heart disease. They failed to mention that cold weather is a marker for low vitamin D levels, as outdoor activity in cold weather is both curtailed and requires extensive clothing. Gyllerup S, Lanke J, Lindholm LH, Schersten B. Smoking habits, sales of fat and antihypertensives fail to explain the high coronary mortality in cold regions of Sweden. Scott Med J. 1991 Dec;36(6):165–8.

The point of these six paradoxes is simple. Our current paradigm for understanding heart disease is incomplete. One or more major causes of heart disease remain unknown. The theory that vitamin D deficiency is one of those major causes certainly helps to explain these paradoxes.

A professor named Robert Scragg first proposed that vitamin D deficiency plays a role in cardiovascular disease.


True. For the last 25 years Dr. Scragg, Associate Professor in Epidemiology at the University of Auckland, has been trying to convince anyone who would listen that vitamin D explains many of observations about heart disease, such as: incidence of heart disease is higher at higher latitudes, at lower altitudes, and in the winter. It is also higher in black individuals as well as in older, inactive, and obese patients. Yet, vitamin D blood levels are lower in all these, with altitude being the least known of these associations. The age adjusted mortality for heart disease in the United States showed a striking inverse correlation with altitude in 1979, before the sun scare. American populations at the highest altitude had about half the heart disease of sea level populations. Thirty-five years ago, Leaf observed that most of the long-lived populations in the world reside at high altitude. Scragg R. Seasonality of cardiovascular disease mortality and the possible protective effect of ultra-violet radiation. Int J Epidemiol. 1981 Dec;10(4):337–41. Voors AW, Johnson WD. Altitude and arteriosclerotic heart disease mortality in white residents of 99 of the 100 largest cities in the United States. J Chronic Dis. 1979;32(1–2):157–62. Leaf A. Getting old. Sci Am. 1973 Sep;229(3):44–52.

Higher vitamin D levels are associated with lower risk for heart attack.


True. Dr. Scragg's research revealed this in 1990. In 1979, the Tromso Heart Study found that by correcting low vitamin D levels the risk for heart attack was lowered. Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol. 1990 Sep;19(3):559–63. Vik B, Try K, Thelle DS, Forde OH. Tromso Heart Study: vitamin D metabolism and myocardial infarction. Br Med J. 1979 Jul 21;2(6183):176.

A scientist would never publish a study that appears to disprove his own theory.


False. Dr. Scragg did publish such a study. He discovered that a single oral dose of 100,000 units of vitamin D had no effect on risk factors (serum cholesterol or blood pressure) five weeks after publishing the study above. This seemed to disprove his theory, but he published the data anyway—always the mark of a good scientist. We now know that 100,000 units are a small dose and that "stoss" therapy is not physiological. Such a small single dose will raise vitamin D levels for a month or two, but then they rapidly fall towards baseline and would have little physiological effect five weeks later. Scragg R, Khaw KT, Murphy S. Effect of winter oral vitamin D3 supplementation on cardiovascular risk factors in elderly adults. Eur J Clin Nutr. 1995 Sep;49(9):640–6.

Vitamin D can be used in the treatment of and prevention of heart disease.


True. It reduces vascular calcification and vascular smooth muscle proliferation. It also decreases parathormone levels and renin, and reduces CRP and other markers of inflammation. In 2005, Zitterman proposed vitamin D deficiency to be connected to heart disease. This explains the excess cardiovascular deaths at high latitude, low altitude, and during the winter. It also explains the higher incidence of heart disease in blacks and individuals who are older, inactive, and obese, as these groups usually have significantly lower vitamin D blood levels. Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005 Oct;94(4):483–92.

Patients with congestive heart failure (CHF) have very low levels of vitamin D.


True. Zittermann discovered this in 2003. He found that protein NT-proANP, which is a predictor of CHF severity, was inversely associated with vitamin D levels. Zittermann A, Schleithoff SS, Tenderich G, Berthold HK, Korfer R, Stehle P. Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol. 2003 Jan 1;41(1):105–12.

Blood cholesterol measurements are worse at higher latitudes, lower altitudes, and in the winter.


True. The effects of latitude on cholesterol seen in the first study are quite remarkable. In the Greek study, total serum cholesterol for both men and women were significantly lower at higher altitude in spite of similar diets. The seasonal variations in cholesterol are well known and not explained by seasonal dietary changes. Grimes DS, Hindle E, Dyer T. Sunlight, cholesterol and coronary heart disease. QJM. 1996 Aug;89(8):579–89. Baibas N, Trichopoulou A, Voridis E, Trichopoulos D. Residence in mountainous compared with lowland areas in relation to total and coronary mortality. A study in rural Greece. J Epidemiol Community Health. 2005 Apr;59(4):274–8. Gordon DJ, Hyde J, Trost DC, Whaley FS, Hannan PJ, Jacobs DR, Ekelund LG. Cyclic seasonal variation in plasma lipid and lipoprotein levels: the Lipid Research Clinics Coronary Primary Prevention Trial Placebo Group. J Clin Epidemiol. 1988;41(7):679–89. Bluher M, Hentschel B, Rassoul F, Richter V. Influence of dietary intake and physical activity on annual rhythm of human blood cholesterol concentrations. Chronobiol Int. 2001 May;18(3):541–57.

Blood pressure is higher at higher latitudes, lower altitudes, in the winter.


True. It is also usually higher in blacks, the aged, and the obese. High blood pressure is one of the strongest predictors of heart disease. Here, six facts about hypertension can be explained by one theory: vitamin D. Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension. 1997 Aug;30(2 Pt 1):150–6. Fiori G, Facchini F, Pettener D, Rimondi A, Battistini N, Bedogni G. Relationships between blood pressure, anthropometric characteristics and blood lipids in high- and low-altitude populations from Central Asia. Ann Hum Biol. 2000 Jan–Feb;27(1):19–28. Komaroff AL. By the way, doctor. My systolic blood pressure is 40 points higher in winter than in the summer (160–180 versus 120–140 mmHg). Do the seasons affect blood pressure. Harv Health Lett. 2005 Sep;30(11):8.

Diabetes is more common at higher latitudes, lower altitudes, in black, aged, and obese individuals.


True. Both blood sugar and hemoglobin A1c are higher in the winter. Garancini P, Gallus G, Calori G, Formigaro F, Micossi P. Incidence and prevalence rates of diabetes mellitus in Italy from routine data: a methodological assessment. Eur J Epidemiol. 1991 Jan;7(1):55–63. Santos JL, Perez-Bravo F, Carrasco E, Calvillan M, Albala C. Low prevalence of type 2 diabetes despite a high average body mass index in the Aymara natives from Chile. Nutrition. 2001 Apr;17(4):305–9. Lora-Gomez RE, Morales-Perez FM, Arroyo-Diez FJ, Barquero-Romero J. Incidence of Type 1 diabetes in children in Caceres, Spain, during 1988–1999. Diabetes Res Clin Pract. 2005 Aug;69(2):169–74. Suarez L, Barrett-Connor E. Seasonal variation in fasting plasma glucose levels in man. Diabetologia. 1982 Apr;22(4):250–3. Tseng CL, Brimacombe M, Xie M, Rajan M, Wang H, Kolassa J, Crystal S, Chen TC, Pogach L, Safford M. Seasonal patterns in monthly hemoglobin A1c values. Am J Epidemiol. 2005 Mar 15;161(6):565–74.

Vitamin D has been shown to significantly reduce C-reactive protein (CRP), which may be a better predictor of heart disease than LDL cholesterol.


True. A Belgian study found a significant reduction in CRP, even though their high-dose vitamin D group received only 500 units a day. Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002 Dec;95(12):787–96. Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R. Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab. 2003 Oct;88(10):4623–32.

The risk for total mortality is significantly lower in subjects with high vitamin D levels.


True. However, the study that determined this is in Finnish and has not been translated into English (author communication). Seppanen R, Marniemi J, Alanen E, Impivaara O, Jarvislo J, Ronnemaa T, et al. Ravinnon ja seerumin vitamiinit ja kivennaisaineet vanhusten kuolleisuuden ennustajina. Suom Laakaril 2000;42:4255–60 [Finnish]. Reported in Nutr Metab Cardiovasc Dis. 2005 Jun;15(3):188–97.

It is now a proven scientific fact that vitamin D both prevents and treats heart disease.


False. Like so may other fields of vitamin D research, we lack the definitive interventional trials that would settle the point. It would be simple for the National Institutes of Health to fund a study giving physiological doses of real vitamin D (5,000 units of cholecalciferol) to heart disease patients for a year and see if CRP, proinsulin, blood pressure, cholesterol, body weight, heart attacks, and/or death rates decrease.

We will have to wait years for science to find out if vitamin D prevents and/or treats heart disease. Although, while you are waiting, you do have a choice. You can wait vitamin D deficient (levels less than 40 ng/mL) or you can wait vitamin D sufficient (levels around 40–60 ng/mL). The choice is yours—another Pascal's Wager—this time you are betting your heart.

Also, while we wait for more studies, remember that vitamin D should be obtained daily—not monthly or weekly. It should be obtained physiologically and not in an all-then-none manner, as would happen if you took 100,000 units one day a month and nothing the other 29 days. It appears likely that high blood levels followed by low blood levels may do harm. The reason is that falling blood levels reset the enzymes maintaining intracellular levels of activated vitamin D, resulting in low intracellular levels. Vieth R. Enzyme kinetics hypothesis to explain the U-shaped risk curve for prostate cancer vs. 25-hydroxyvitamin D in nordic countries. Int J Cancer. 2004 Sep 1;111(3):468; author reply 469.

Vitamin D should be consumed the way the human genome consumed it during its evolution in subequatorial Africa, a steady amount every day. If you live down south, you can go in the sun for a few minutes every day. Up north, you can sun in the warmer months and in the winter either use a sunlamp or take vitamin D cholecalciferol. Adults in the north could take one 5,000 unit capsule a day in late fall, winter, and early spring; less in the late spring and early fall; and none in the summer months—depending on your sunning habits. Children over 50 pounds need two of the 1,000 unit capsules every day in the colder months while children under 50 pounds need about 1,000 units in the colder months. Few people need to take oral vitamin D in the summer (unless you are a sunphobe). Get enough vitamin D every day to maintain stable vitamin D blood levels, around 50 ng/mL, year-round.

One last question: should patients dying from heart disease be allowed to die vitamin D deficient? According to the current paradigm, the answer appears to be yes, for none of the cardiologists I know even bother to check a vitamin D level. Given the scientific literature, that's a bit paradoxical.

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John Jacob Cannell MD Executive Director

*These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.