Cardio-Information for Experts

Information for healthcare professionals

Micronutrients for the treatment of cardiovascular diseases

Contents 4 Introduction 6 Coronary heart disease and atherosclerosis 8 8 8 9 9 10 10 10 11 11

Cardiovascular risk factors Excess body weight and lack of physical exercise Family history Diabetes mellitus Smoking Dyslipidemias Hyperhomocysteinemia Hypertension Postmenopause Psychosocial factors

12 Healthy diet for the heart and orthomolecular nutritional therapy 14 The orthomolecular principle 15 15 20 23 28 32 37 38

Micronutrients for the dietary management of cardiovascular diseases Phytonutrients (incl. resveratrol, OPC, cocoa polyphenols) Omega-3 fatty acids Vitamin-like substances B vitamins Antioxidants Minerals / trace elements Amino acids

40 Micronutrients – especially effective in combination 44 References

Introduction A healthy diet contributes significantly to a functioning cardiovascular system. This may sound obvious, but it is not always easy to achieve in practice. In modern everyday life we often do not pay sufficient attention to a well-balanced, varied diet that is rich in fruit, vegetables, sea fish and whole-grain products and therefore do not intake adequate amounts of valuable micronutrients that are important for the heart.

In the Western industrialized countries cardiovascular diseases are still the No. 1 cause of death, far ahead of cancer diseases. According to the Statistisches Bundesamt (German Federal Office of Statistics), in 2005 some 152,000 men and 215,000 women died of cardiovascular diseases in Germany. Of these, ischemic heart diseases are responsible for the majority of deaths – together with acute myocardial infarction they also represent the most frequent single cause of death.

Table 1. Most frequent causes of death in Germany in 2005 Deaths

Total

Men

Women

Cancer disease (neoplasms)

216,928

114,542

102,386

Diseases of the cardiovascular system

367,361

152,274

215,087

Ischemic heart diseases

148,641

72,003

76,638

61,056

32,973

28,083

Acute myocardial infarction Source: Statistisches Bundesamt (Sept. 2006)

These figures show that cardiovascular diseases should be paid far more attention than has been the case so far. The following pages will therefore inform the reader in detail about the origins of coronary heart diseases (CHD), cardiovascular risk factors, the orthomolecular principle and in particular about the individual cardioprotective micronutrients and their specific effects.

The brochure thus aims to illustrate the importance and practical benefit of micronutrients in the dietary treatment of atherosclerosis-mediated cardiovascular diseases.

4

5

Coronary heart disease and atherosclerosis The underlying condition of CHD is atherosclerosis. Atherosclerosis is the name for a chronically progressing change of the vessel wall associated with proliferations of the connective tissue and deposits (atherosclerotic plaques).

The most recent findings have shown that atherosclerosis is usually preceded by the development of an inflammatory reaction causing monocytes to first attach to the vessel walls and then penetrate into the inner layer (intima).52 This leads to a dysfunction of the vascular endothelium.13 When the condition progresses, free oxygen radicals oxidize the LDL cholesterol absorbed by the monocytes in the intima that have meanwhile differentiated to macrophages.

The macrophages develop into high-lipid foam cells. Now the first fatty streaks can be seen in the vessels. At the same time, an enzyme, arginine-NOsynthase, is inactivated by the free radicals.

The consequence: Nitrogen monoxide (NO), an endogenous vasodilator that protects the blood vessels against atherosclerosis, is no longer produced to the same extent as before. The resulting narrowing of the vessels favors platelet aggregation and further stimulates plaque formation.

diseases such as a myocardial infarction. In women CHD develops about 10 to 15 years later than in men. Up to the menopause, women benefit from the body’s own cardioprotective steroid hormones.106 However, after the menopause the cardiovascular risk in women rapidly increases. The menopause is actually associated with a number of metabolic changes that are discussed as atherogenic risk factors. Thus, total and LDL cholesterol as well as triglyceride concentrations rise after the menopause, whereas the cardioprotective HDL cholesterol slightly declines, and the glucose metabolism deteriorates.106 Unlike men, women often do not feel the classical chest pain radiating into the left arm when they suffer a myocardial infarction. More frequently, the infarction symptoms are nausea, vomiting, pain in the neck and/or between the scapulae, epigastric pain or shortness of breath.86 These symptoms suggest a gastrointestinal or orthopedic disease rather than a myocardial infarction. This explains why women who suffer a myocardial infarction are transferred to the hospital usually about one hour later than men and appropriate therapies are initiated later and less frequently.86

In this stage of the disease process, activated monocytes, T cells and especially macrophages release numerous cytokines and growth factors.

These in turn activate smooth muscle cells that, as a result, migrate into the intima and release proteins from the connective tissue (in particular collagen and elastin). Clinical complications, such as acute coronary syndromes, may occur if the plaques break due to inflammatory processes and release their atheromatous contents into the vessel. The immediate result is the formation and deposition of clots at the respective sites of the vessel wall which, due to the disturbed blood supply, may lead to 6

7

Cardiovascular risk factors The risk factors leading to the development of cardiovascular diseases essentially include a pathological lipid profile, smoking, hypertension, diabetes mellitus, abdominal obesity, and psychosocial factors. Physical activity, daily intake of fruit and vegetables and moderate alcohol consumption will reduce the myocardial infarction risk.134 On the basis of the INTERHEART Study including some 30,000 individuals from 52 countries, Yusuf et al. (2005) found that the 9 risk factors mentioned above are responsible for 90 % of the male and even 94 % of the female myocardial infarction risk.134 Excess body weight and lack of physical exercise A high cardiovascular risk is associated with excess body weight and lack of physical exercise. This especially applies to people with abdominal obesity, e.g. a waist line of more than 102 cm (men) and more than 88 cm (women).39 Physical activity seems to protect men and women alike.106,134 If excess body weight is combined with elevated lipid levels, hypertension and type-2 diabetes (metabolic syndrome), the cardiovascular risk is particularly high.129 Family history Individuals whose family history includes cases of sudden cardiac death are at a higher risk of dying from the same cause.57 It is not only the cardiovascular family history but also the age reached by the parents that serves as an independent prognostic factor of an individual’s CHD risk.

In individuals whose parents both reached an age of more than 80 years, the CHD risk is significantly lower (OR* 0.49) than it is in individuals whose

parents did not reach that age. In contrast, people with a particularly high number of cardiovascular diseases in the family have a significantly greater CHD risk compared to people without any CHD history in the family (OR 1.93).133 If the number of strokes and/or myocardial infarctions is higher than usual in the history of a patient’s family, this correlates strongly with a hypertensive disease in the descendants (OR 1.8 and 2.1, respectively). Thus, the family’s stroke risk (ischemic insults) correlates with its predisposition for high blood pressure.34 Diabetes mellitus Diabetics, especially when they are resistant to insulin, have an elevated coronary risk associated with an endothelial dysfunction which is to be regarded as the first stage of atherosclerosis progression.9 With every percentage point by which the proportion of glycosylated hemoglobin (HbA1c) decreases, the glycemia-associated risk of myocardial infarction (-14 %), stroke (-12 %) and cardiac insufficiency (-16 %) will also decrease.113 Smoking Smoking is connected with an increased coronary risk. Cigarette smoke, for instance, compromises the endothelial function, promotes the oxidation of LDL and reduces the plasma HDL level. Moreover, smokers have an elevated inflammatory activity and a higher thrombotic risk.43 The combination of cigarette smoking and oral contraception represents a particular risk (up to 20 times the normal risk).106

* OR Odds Ratio

8

9

Dyslipidemias Individuals with an elevated LDL and low HDL cholesterol level76 as well as increased triglycerides are at a higher risk of developing atherosclerotic diseases.38,47 Hyperhomocysteinemia Increased homocysteine levels (> 10 µmol/l) are associated with a higher risk of cardiovascular diseases and higher overall mortality.107 In individuals with a homocysteine level of 11.1 µmol/l (women) and 11.8 µmol/l (men) the risk of heart failure is twice the normal value.118 Hyperhomocysteinemia is considered responsible for roughly 10 % of the total risk of CHD.107 Hypertension People with moderately increased blood pressure (130-139 mmHg and/or 85-89 mmHg) have a greater risk of cardiovascular events than people with normal blood pressure (< 120/80 mmHg).119 The therapeutic aim of most hypertensive individuals is a blood pressure of below 140/90 mmHg. However, patients with diabetes mellitus or a high cardiovascular risk should aim at a markedly lower blood pressure.39

10

Postmenopause The frequency of cardiovascular diseases rises significantly in postmenopausal women. The estrogen deficit associated with various metabolic changes is considered to be the basic factor triggering an elevated atherogenic risk.106 Psychosocial factors Psychosocial stress can also increase the myocardial infarction risk. A recently published analysis by the INTERHEART Study showed that psychosocial factors are the third most important cause of myocardial infarction (after smoking and hyperlipidemia). Individuals with high stress scores were younger, heavier, more frequently smokers; fewer of them had a low income and a low level of education. In such a scenario, permanent stress increases the infarction risk more drastically than transitory stress.92

11

Healthy diet for the heart and orthomolecular nutritional therapy Nutrition has a considerable influence on the development of coronary heart disease. A diet with a lot of fruit and vegetables as well as whole-grain products and fatty sea fish (such as in the Mediterranean diet) is considered cardioprotective. Such foods are rich in micronutrients that influence the heart and vessels. The “Lyon Diet Heart” Study furnished proof that myocardial infarction patients could reduce their risk of another coronary disease by 50-70 % after they had changed to a Mediterranean diet.63 Another study with patients with a high cardiovascular risk showed that, after changing to a Mediterranean diet, the cellular lipid values and LDL oxidation decrease significantly.32 The CORA Study, a large case-control study, also demonstrated impressively that, with regard to the cardiovascular risk, women benefit massively from micronutrient-rich nutrition.136 In addition, a meta-analysis arrived at the conclusion that 3 to 5 daily servings of fruit and vegetables (some 240-400 g) will reduce the risk of strokes by 11 %.

In this context it was particularly interesting to observe that in case of more than 5 daily servings (> 400 g) the risk dropped by as much as 26 %.42 The problem: On average, Germans eat only about half the amounts of fruit and vegetables recommended by the German Nutrition Society (Deutsche Gesellschaft für Ernährung – DGE), i.e. approx. 300 g instead of about 650 g.24 This means that the supply of micronutrients for large parts of the population is far from optimal. The intake of vitamins D3, E, folic acid and pantothenic acid and of the trace element iodine is clearly below the recommended levels.7,24 Thus, according to the current DGE nutrition report, the German population attains about 55 % of the recommended folic acid supply.24

12

Table 2. Heart-healthy Diet95 Phytonutrients Polyphenols Resveratrol

Esp. in red grapes

OPC

Esp. in grape seeds

Cocoa polyphenols

Cocoa

Bioflavonoids

Fruits and vegetables

Carotenoids (lutein, lycopene, beta-carotene etc.)

Fruits and vegetables

Essential fatty acids Omega-3 fatty acids

Fat seafish

Vitamin-like substances Coenzyme Q10

Meat, vegetable oils

L-carnitine

Sheep, lamb, beef and pork

B vitamins Folic acid

Wheat seeds, whole-meal products, green leaf vegetables

B6

Whole-meal products, meat, fish, vegetables (Brussel’s sprouts, avocado etc.)

B12

Meat, milk, dairy products, fish (tuna, salmon etc.)

Antioxidants Vitamin C

Fruits and vegetables (pepper, broccoli etc.)

Vitamin E

Vegetable oils, cereal seeds, nuts

Trace elements and minerals Selenium

Seafish, meat

Zinc

Meat, fish, milk, whole-meal products

Manganese

Cereals, nuts

Copper

Nuts, whole-meal products, legumes

Magnesium

Whole-meal products, legumes, nuts

13

Micronutrients for the dietary management of cardiovascular diseases Conclusion: As CHD patients have an increased micronutrient need, supplementation is to be recommended to ensure an adequate supply of the vitamins and phytonutrients, minerals and omega-3 fatty acids contained in fruit, vegetables and fish. In particular, individuals with CHD and an elevated cardiovascular risk need more of these micronutrients.

For such persons micronutrient combinations are to be recommended that – according to the orthomolecular principle – contain nutrients that keep the heart and blood vessels healthy.

The nutritional physiology of a number of micronutrients supports the function of the heart and vessels. They include in particular omega-3 fatty acids, B vitamins, antioxidants, magnesium and various trace elements.

Phytonutrients, such as mixed carotenoids and oligomeric proanthocyanidins (OPC)*, are potent radical scavengers and protect the vessels against atherosclerosis. The polyphenols of red grapes and cocoa support the vascular function, and coenzyme Q10 as well as L-carnitine are essentially involved in the energy generation of the heart muscle cells.

The orthomolecular principle The term describes a therapeutic and preventive approach whose basis was developed by Linus Pauling, a biochemist who was twice awarded the Nobel Prize, in the 1960s (the Greek “ortho” means right, good).

Basically, orthomolecular medicine means that, to stay or get healthy, the human organism must be supplied with the right amounts of the natural substances that are present in the body itself and contained in the diet. Thus, the underlying idea is that naturally occurring micronutrients must be supplied with the diet in an optimum composition and dosage.

Orthomolecular medicine, which sees itself as the partner of traditional medicine, is particularly useful in the dietary management of chronic diseases of the cardiovascular system.

Phytonutrients Polyphenols The polyphenols resveratrol, oligomeric proanthocyanidins and cocoa flavonoids are contained in large quantities in fruit and drinks of plant origin, such as cocoa and red grapes. These foods that are rich in polyphenols all have the same beneficial effects. All of them can be antithrombotic, antiatherogenic and antihypertensive and have a beneficial influence on the endothelial function.111 A number of studies have demonstrated that polyphenols improve vascular function, support the formation of vasodilating substances, such as NO, and have an antioxidant effect.111 As a result of these wholesome effects, foods that are rich in polyphenols are conducive to cardiac and vascular health.111 Thus, for instance, the INTERHEART Study which involved about 30,000 subjects in several continents was able to show that moderate wine consumption will reduce the myocardial infarction risk.134 Scientists attribute this positive effect of wine, among others, to polyphenols (e.g. proanthocyanidins), a phytonutrient subgroup.25

* OPC are contained in grape seeds, for example

14

15

Resveratrol, an antioxidant, inhibits lipid peroxidation and thus has an antiatherogenic effect.11,80 Besides the antioxidant effects, cardioprotective effects could also be identified in animal models,51 probably due to the inhibition of platelet aggregation.80 This was the result of a study including 19 cardiovascular aspirin-resistant patients who benefited from resveratrol thanks to lower platelet aggregation.109 In addition, resveratrol also supports the endothelial function.

As animal and in-vitro studies have shown, resveratrol increases the production and activity of endothelial NO synthase, stimulates NO release and thus has a vasodilating effect.71,125 In a double-blind trial with non-smokers the consumption of one glass of alcoholic or dealcoholized red wine reduced the detrimental effect of the cigarette smoke inhaled simultaneously on the vascular function (Fig. 1).83 Moreover, Karatzi et al. (2005) demonstrated that the consumption of dealcoholized or normal wine can significantly lower the central systolic blood pressure of CHD patients.58 Oligomeric proanthocyanidins (OPC) are potent radical scavengers and therefore have an antiatherogenic effect. Their antioxidant properties could be confirmed, for example, in animal models.15 It is interesting to note that in the south of France fewer people have CHD than people in other industrialized countries, although their diet contains rather a high level of fat and energy. In this context scientists speak of the “French Paradox”.

They think this phenomenon is due to the antiatherogenic effect of the polyphenols, in particular the proanthocyanidins (OPC), in the Mediterranean diet.20

Cocoa polyphenols. Ever since the 18th century, heart-protective properties have been attributed to cocoa. In the past few years, this could be confirmed by various scientific studies. Unlike white or milk chocolate, cocoa and dark chocolate are rich in flavonoids, a polyphenol subgroup, which are said to have health-promoting effects. Scientists explain such effects, firstly, with the antioxidant characteristics of these polyphenols.44,60,126 which, for instance, protect LDL cholesterol against oxidation and thus minimize one of the most significant risk factors of cardiovascular diseases.4,121,126 Secondly, they say that cocoa supports the endothelial function (Fig. 2).33,114,122 Endothelial cells play a key role in vascular protection.

By releasing nitric oxide, they cause the relaxation of the smooth vascular muscles and thus the widening of the blood vessels. The flavonoids contained in cocoa enhance the formation of nitric oxide114 and in this way

Red wine phenols counteract vascular alterations due to cigarette smoking FMD % 1 cigarette

7 6





5

 





4

1 cigarette + 250 ml dealcoholized wine

*

3 2

*

1

Baseline

15

30

60

90

min

Fig. 1. Effects of cigarette smoking and dealcoholized red wine on vascular function (FMD = flow-mediated vasodilation of the brachial artery, parameter of the endothelial function); FMD (%): percent change of brachial artery diameter; n=16; * p<0.05 (vs. baseline)83

16

17

improve the endothelial function.44,122 Flammer et al. (2007) studied the effect of chocolate that is rich in flavonoids on the coronary blood vessels of patients after heart transplantation. Two hours after they had eaten 40 g of dark chocolate that was rich in flavonoids, a significant increase in the coronary diameter from 2.36 mm to 2.51 mm (p < 0.01) was observed, whereas no such change was found in the control group.

The endothelial response of the coronary arteries after CP-T also improved significantly as a result of chocolate consumption (Fig. 2).33 Besides, cocoa polyphenols reduce platelet aggregation,33,44,60 improve the arterial blood flow and thus counteract vascular diseases.40,44

Dark chocolate improves response of coronary arteries %

7,0 5,0 2,5

40 g of dark chocolate 70 % cocoa content Placebo

0 - 2,5 - 5,0 - 7,5

Moreover, numerous studies have confirmed that cocoa lowers the blood pressure.12,40,41,114,115 Taubert et al. (2007), for instance, found that the daily intake of 30 mg of cocoa polyphenols is able to lower the diastolic and systolic blood pressure of hypertensive patients significantly within 18 weeks and increases the production of vasodilative nitric oxide.114 Cocoa polyphenols also improve the insulin sensitivity of both healthy individuals and hypertensive patients40,41 and have a favorable influence on blood lipids (LDL and HDL cholesterol).4 Thus, cocoa may reduce the cardiovascular risk through a variety of mechanisms. Likewise, in their meta-analysis Ding et al. (2006) were able to prove that consuming cocoa flavonoids (comparison of highest vs lowest tertile) reduced the mortality risk by 19 %.27 Bioflavonoids are yellow-orange colors, amaroids and tannins of plant origin.

They belong to the group of phytonutrients and are antioxidants with multiple effects. Thus, for example, they support the effect of vitamin C.120 Citrus bioflavonoids can especially reduce LDL cholesterol oxidation and in this way minimize one of the greatest risk factors of cardiovascular disease.14 By inhibiting platelet aggregation, bioflavonoids lower the risk of clot formation and the development of atherosclerotic plaques in the vessel walls.14,127 Buschmann et al. (2004) also found an inverse relationship between bioflavonoid consumption and the frequency of CHD and fatal myocardial infarctions.14 In conclusion, it may be stated that a high bioflavonoid uptake will reduce both the risk of cardiovascular disease and mortality.

Fig. 2. Response of coronary arteries two hours after chocolate vs. placebo consumption, measured as percent change of the coronary artery diameter following CP-T (Cold-Pressure Test); n=22; * p=0.0133

18

19

Carotenoids The benefit of the antioxidant carotenoids is demonstrated by the results of the EURAMIC* Study. Individuals with a high beta-carotene concentration in the fatty tissue had up to 40 % fewer myocardial infarctions.59 The Women’s Health Study including 40,000 women also showed that high serum levels of the carotenoid lycopene are associated with a low rate of new CHD cases.98 In contrast, the CHD risk of men with a low lycopene level is more than three times higher.91 Moreover, the concentration of carotenoids (lutein, zeaxanthin, beta-cryptoxanthin and alpha-carotene) in men and women is inversely correlated with the vessel wall thickness (intima media thickness). An elevated carotenoid concentration thus seems to counteract the development of atherosclerosis.28 In addition, a controlled trial involving 68 patients with acute ischemic stroke demonstrated an inverse correlation between the low alpha- and beta-carotene levels and the inflammation marker CRP as well as the occurrence of neurological lesions.19

Omega-3 fatty acids Among the essential fatty acids, omega-3 fatty acids are of special importance for the cardiovascular system. As many trials – such as prospective cohort and clinical interventional trials – have shown, omega-3 fatty acids lower the risk of myocardial infarction and other cardiovascular diseases caused by an atherosclerotic condition. The underlying mechanisms have also been clarified for the most part: omega-3 fatty acids reduce blood viscosity and platelet aggregation, improve the endothelial function,70 lower the blood pressure99,100,116 and reduce inflammatory reactions.99,100

Antiarrhythmic effects are also attributed to them.16 Another study with 160 patients showed that the intake of omega-3 fatty acids reduced the risk of postoperative atrial fibrillation after bypass surgery of the coronary arteries and in addition shortened the patients’ stay at the hospital.16 Epidemiological studies prove the great importance of omega-3 fatty acids for reducing the CHD risk.50,55 In the Nurses‘ Health Study, for instance, which included some 80,000 women, a diet rich in fish with a high omega-3 fatty acid content reduced the CHD risk by 21-34 %50 and the stroke risk by 17-52%.55 In this context, the results of another study with about 41,600 Japanese people are also impressive. Despite the traditionally high fish consumption in Japan, the additional intake of omega-3 fatty acids led to a further reduction in the CHD risk.54

Omega-3 fatty acids reduce mortality risk following myocardial infarction Risk reduction (%)

- 10

Cardiovascular mortality

- 20

Incident sudden cardiac death

Overall mortality 20 %

30 % - 30 45 % - 40

* European community multicenter study on Antioxidants, Myocardial Infarction, and breast Cancer

20

Fig. 3. GISSI-Prevenzione Study; Supplementation of 1 g of omega-3 fatty acids following myocardial infarction; n=11,324; duration: 3.5 years37

21

Fatty acids are of outstanding importance especially in secondary prevention.

An interventional study, for instance, showed that the supplementation of omega-3 fatty acids slows down the progression of coronary sclerosis.123 Four other interventional studies proved that in secondary prevention omega-3 fatty acids significantly reduced the risk of a recurring coronary event.6,37,75,101 Thus, in the GISSI Prevenzione Study which included more than 11,000 patients, the number of sudden cardiac deaths after myocardial infarction dropped by 45â&#x20AC;&#x2030;% (Fig. 3).37 These cardioprotective effects of omega-3 fatty acids caused the American Heart Association (AHA) to recommend in its guidelines that at least two meals a week should consist of fatty fish (e.g. mackerel, salmon, tuna).64 This equals an amount of 300 mg of omega-3 fatty acids. Patients suffering from coronary heart disease should increase the amount of omega-3 fatty acids (eicosapentaenoic and docosahexaenoic acid) to 1 g per day. Fatty coldwater fish is to be given preference, or the respective supplements should be taken.

The European Society of Cardiology (ESC) has adopted the AHA recommendations. In its guidelines it recommends that in addition to the standard therapy after myocardial infarction, fish oil that is rich in omega-3 fatty acids should be taken as secondary prevention.

As it is difficult to intake the required amount with the diet over an extended period, the supplementation of omega-3 fatty acids is recommended.64 Besides, highly fatty fish also contains higher amounts of heavy metals, such as mercury, polychlorinated biphenyl (PCB) and dioxin, which limit the health-promoting effect.64

Vitamin-like substances Vitamin-like substances are vital substances with vitamin-like properties that the body can produce itself in limited quantities. Key substances of the cardiac energy metabolism are, among others, L-carnitine and coenzyme Q10.

Both micronutrients play a crucial role in the cardiac metabolism, are essentially involved in the energy generation of the heart muscle cells, and can improve the performance of the heart muscle â&#x20AC;&#x201C; especially if they are supplemented in combination. Thus, in patients with cardiac diseases due to insufficient heart perfusion this micronutrient duo improves the exercise tolerance. In heart failure patients vitamin-like substances lead to a significant improvement in clinical symptoms (increase in ejection fraction, better NYHA stage*).

L-carnitine L-carnitine is an endogenous substance with a variety of physiological functions. It consists of the amino acids lysine and methionine.26 The vitamin-like substance plays an important role in making energy available to the heart and in the cardiac metabolism. It thus helps to improve the functioning of both the healthy as well as the diseased heart.88 As acylcarnitine, L-carnitine transports fatty acids through the mitochondrial membrane to the cytosol (Fig. 6, p. 26).26,88 As fatty acids are an important source of energy for the human heart, carnitine deficiency may lead to cardiac dysfunction.

Carnitine also supports the extrusion of metabolites and thus lowers the intracellular concentration of cell-damaging substances, such as acyl esters or free radicals.88

* NYHA: Classification of the severity of heart failure by the New York Heart Association

22

23

Low carnitine levels may, for instance, occur in patients with ischemic cardiac disease (e.g. CHD) or diabetes mellitus.73,88 This deficiency may have negative effects on cardiac function. In patients with ischemic cardiac disease, disorders of fatty acid oxidation and the carnitine metabolism damage the cardiac tissue.73

L-carnitine supplementation in heart failure Patients (n) Prior to L-carnitine supplementation 16 After L-carnitine supplementation 2 x 1 g per day

12

The carnitine levels in the heart muscle are, as a rule, considerably reduced in the case of chronic heart failure and heart muscle hypertrophy.88 Clinical studies have shown that, as part of a nutritional therapy, carnitine is highly effective in the treatment of cardiovascular diseases, such as CHD, heart arrhythmia, heart failure and hyperlipoidemia.88 Thus, with heart failure patients, the heart’s exercise tolerance and left-ventricular ejection fraction were improved when carnitine was given.88 Several studies have confirmed that, under nutritive supplementation of L-carnitine, the cardiac output of patients with heart failure can be improved. In a placebo-controlled trial, for instance, the dietary supply of carnitine (2 x 1 g daily) to heart failure patients led to a considerable clinical improvement (measured on the basis of the NYHA stages, Fig. 4).36

8 4

IV

III

II

NYHA stages

Fig. 4. NYHA stages prior to and after supplementation of L-carnitine; n=38; age range: 65–82 years; duration: 45 days36

Coenzyme-Q10 levels during statin therapy Coenzyme-Q10 levels (µg/ml)

1,26

Coenzyme Q10 (Ubiquinone) As an integral component and essential electron carrier in the mitochondrial respiratory chain, coenzyme Q10 is directly involved in the ATP production (Fig. 6, p. 26).21 In heart failure patients and patients with a heart muscle disease the coenzyme Q10 level in the heart muscle is markedly reduced.78 Also patients with hypercholesteremia often have lower coenzyme Q10 levels under statin treatment.68 Statins not only inhibit cholesterol synthesis but also affect the formation of coenzyme Q10, as both products develop from

1,0 49 %* 0,6

0,67

52 %*

0,62

0,2

Baseline values

14

30

Days of statin therpay

Fig. 5. Impact of atorvastatin administration (80 mg per day) on blood coenzyme-Q10 levels (µg/ml); n=34; * p<0.00193

24

25

the same initial stage.78 This may explain the muscular side-effects of a statin therapy which are often described. Various studies have shown that under statin therapy the coenzyme Q10 level dropped besides achieving the desirable decrease of total cholesterol, LDL and triglycerides.78,93 Atorvastatin (80 mg) led to an approx. 50 % decline in the coenzyme Q10 level after 30 days of treatment93, an effect that is observed after only 14 days (Fig. 5).93 78,93

L-carnitine and coenzyme Q10: implications for energy generation

Two other statins, pravastatin and lovastatin, lowered the coenzyme Q10 level by about 20 % and 29 %, respectively, after 18 months of treatment.78 It therefore makes sense to supplement coenzyme Q10 if statins have to be taken for a longer period in order to prevent any weakening of its favorable cholesterol-reducing effect by lowering the level of coenzyme Q10.

A recent study by Caso et al. (2007) confirms that a 30-day coenzyme Q10 supplementation can significantly, i.e. by as much as 40 %, alleviate the severity of the statin-caused muscle pain. Besides, patients experienced fewer restrictions in their everyday activities due to pain.18

Coenzyme Q10 supplementation in cardiovascular diseases Patients (n) Prior to coenzyme Q10 supplementation

200

Q

After coenzyme Q10 supplementation 10

100

I

II

III

IV

Fig. 7. Enhanced cardiac performance with coenzyme Q10; n=424; 8 years; 75–600 mg of coenzyme Q10 per day; ø 242 mg of coenzyme Q1066

Fig. 6. L-carnitine transport of fatty acids through mitochondrial membrane; coenzyme-Q10 involvement in ATP production in the respiratory chain

26

27

The importance of coenzyme Q10 in the prevention of cardiovascular disease has been demonstrated by several studies: under coenzyme Q10 treatment the clinical parameters of ejection fraction, exercise tolerance and the NYHA stage improved.46,130 In a 6-year long-term trial with patients suffering from a heart muscle weakness (dilated cardiomyopathy) the dietary supplementation of coenzyme Q10(100 mg/d) in addition to drug therapy increased the survival rate.67,69 In patients with different cardiovascular diseases coenzyme Q10 supplementation led to a significantly lower severity of heart failure according to NYHA stages (Fig. 7).66 Moreover, coenzyme Q10 markedly improved arrhythmias already manifest in these patients.5,102 B vitamins Vitamins B6, B12 and folic acid which intervene in the homocysteine metabolism are also important for the cardiovascular system. Homocysteine is a metabolite of the amino acid metabolism, and homocysteine levels that are higher than normal are made responsible for about 10 % of the total cardiovascular risk. Many cardiovascular patients have elevated homocysteine levels and thus an increased risk of atherosclerosis. Moreover, two meta-analyses including more than 90 retrospective and prospective studies confirm a causal relationship between pathological homocysteine levels and degenerative vascular diseases.49,124 cited in 45 Accordingly, lowering an elevated homocysteine value by 3-5 µmol/l with a vitamin supplement could reduce the relative cardiovascular risk by about 10% and in highrisk groups by up to 25 %.107 The D.A.CH.-Liga Homocystein (GermanAustrian-Swiss homocysteine society) recommends aiming at a plasma homocysteine level of below 10 µmol/l in the treatment of cardiovascular patients.107 Elevated homocysteine levels can be effectively lowered by supplementation of folic acid103 and vitamins B6 and B12 which was demonstrated, for instance, by a meta-analysis of 12 randomized controlled 28

studies.49 The Nurses‘ Health Study, a prospective cohort trial including some 80,000 nurses, also showed that the regular nutritive supply of vitamin B6 and folic acid clearly reduces the risk of coronary heart disease (CHD).90 Homocysteine is degraded by enzymes that need vitamins B6 and B12 for their catalytic activity. They also depend on folic acid that serves as a methyl group donor.

The nutritional treatment with vitamins B6, B12 and folic acid is also effective in secondary prevention. These vitamins significantly reduce the homocysteine levels and the number of residual stenoses of patients after successful coronary angioplasty.97 The Swiss Heart Study confirmed the beneficial effect of B vitamins on patients after percutaneous transluminal coronary angioplasty (PTCA). In that study, in the vitamin B group compared with the placebo group, 7.4 % fewer deaths, myocardial infarctions and new cases of vascular stenosis were observed which was mainly due to a lower recurrent stenosis rate.96 The “International Task Force for Prevention of Coronary Heart Disease”53 and the D.A.CH.-Liga Homocystein therefore recommend that individuals with an elevated homocysteine level should take folic acid, vitamin B6 and B12 supplements.107 In the last few years, some studies (NORVIT, VISP, HOPE-2) have questioned the effectiveness of vitamin B for reducing the cardiovascular risk. Contrary to the authors’ expectations, no or only a limited benefit of vitamin B supplementation could be identified in the studies mentioned above.

Experts explain this with a faulty study design.84

29

A closer look at the way the studies were performed reveals the following points that attract criticism: • The trials showed weaknesses in the inclusion criteria, patient selection, end point determination, vitamin dosage and statistical evaluation.108 • The inclusion criteria and framework conditions were not appropriate to investigate homocysteine reduction, i.e. the basic primary parameter.

In the course of the VISP and HOPE-2 Study, for instance, the folic acid enrichment of foodstuffs was introduced in the USA and Canada at a national level, and in the NORVIT Study some of the subjects had already been taking vitamin supplements before the trial started. Therefore no increase in homocysteine levels worth mentioning could be detected at the start of the trial.108 • In the VISP Study, patient selection was inadequate with regard to vitamin B12 malabsorption or additional vitamin intake which led to a wrong interpretation of the results.84,108 • The HOPE-2 Study combined several end points and thus masked the fact that some end points, taken by themselves, were improved quite significantly.108

In a cohort study, Yang et al. (2005) also showed that a consistent folic acid enrichment of flour products in the USA and Canada reduced stroke mortality throughout the country132 and, as a result, some 13,000 and 2,800 deaths per year caused by stroke were prevented in the USA and Canada respectively.108 This was not found in countries without folic acid enrichment (England and Wales).132 In this context, the folic acid enrichment of foodstuffs at a national level has been discussed repeatedly in Germany as well, because average folic acid intake is far below the recommended levels.

However, as such a measure is not to be expected in Germany any time soon, folic acid should be supplemented, especially in patients with increased homocysteine levels.

This recommendation also seems to make sense for dialysis patients whose most frequent cause of death is of cardiovascular origin. A placebo-controlled double-blind study showed that the homocysteine levels of dialysis patients could be effectively lowered within just a few months when they took folic acid regularly, which probably may also have contributed to reducing their cardiovascular risk.2

The D.A.CH.-Liga Homocystein has prepared a detailed statement to be found on its homepage (www.dach-liga-homocystein.org).108 The VISP Study and the HOPE-2 Study also included subgroup analyses.

They both showed a significant reduction in the combined end points (stroke, CHD, death; VISP) and isolated stroke risk (HOPE-2) by 21 % and 25 %, respectively, after B vitamin supplementation.45,104,108

30

31

Antioxidants Antioxidants are able to neutralize free radicals and thus protect the organism against oxidative stress. As free radicals play a crucial role in atherosclerosis progression, the capture of these aggressive oxygen compounds has a favorable effect on the disease process.

Vitamin C (ascorbic acid) is the most important antioxidant in the aqueous environment of the organism. The lower the blood vitamin C levels, the higher the risk of cardiovascular disease and stroke.35 Within the framework of a prospective cohort study, researchers followed the eating habits of about 85,000 nurses for 16 years. They found that an ample supply of vitamin C, including vitamin C supplementation, was able to reduce the CHD risk significantly, i.e. by 27 %. When vitamin C was ingested only through the diet, – without any multivitamin supplementation – the CHD risk dropped moderately, but not significantly (Fig. 8).81 Vitamin C also plays a special role in secondary prevention. When patients with arrhythmia take vitamin C supplementation, this appears to significantly reduce the early recurrence of the disease after electric cardioversion.

Moreover, inflammation markers (number of white blood cells and CRP) can be lowered and thus inflammatory processes reduced.62 In addition, a placebo-controlled double-blind study with 30 type-2 diabetics showed that after 1 month of taking ascorbic acid (500 mg/d) the blood pressure declined and arterial stiffness improved (p < 0.01). Vitamin C supplementation thus may also lower the cardiovascular risk of patients with diabetes.79

In patients with recurrent carotid artery stenosis after end-arteriectomy of the carotid artery, Reid et al. (2007) found significantly lower vitamin C and beta-carotene concentrations than in patients without recurrent stenoses.87 Vitamin E is the most important fat-soluble antioxidant in cells and tissues and protects membranes against lipid peroxidation. Especially in the cardiovascular context it prevents the oxidation of LDL cholesterol and thus inhibits an important factor in the development of atherosclerosis.

In the prevention of cardiovascular diseases, vitamin E supplementation has proved to be of benefit, as major prevention studies including tens of thousands of subjects have shown.72,89,105 Thus, the Nurses‘ Health Study with 87,245 women and the Health Professionals’ Follow-up Study with 39,910 men demonstrated that the daily intake of 100-200 IU of vitamin E will significantly lower the CHD risk.89,105 The results of the studies dealing with the use of antioxidants in secondary prevention are contradictory. In the placebo-controlled CHAOS Study*, the number of non-fatal myocardial infarctions could be reduced by giving 400 IU and 800 IU of vitamin E daily.110 Other trials, such as the HOPE Study**, did not show any protective effect for vitamin E,135 whereas Salonen et al. in the ASAP Study*** were able to demonstrate that the supplementation of 136 IU of vitamin E and 250 mg of vitamin C reduced atherosclerosis progression significantly. The author explicitly emphasizes the importance of giving a combination of vitamin C and vitamin E:

* CHAOS-Studie: Cambridge Heart Anti-Oxidant Study ** HOPE-Studie: The Heart Outcomes Prevention Evaluation Study *** ASAP: Antioxidant Supplementation in Atherosclerosis Prevention

32

33

„When vitamin E works as an antioxidant, it is oxidized to harmful radical, which needs to be reduced back to α-tocopherol, eg, by vitamin C. [...] Thus, it is conceivable that in most completed and ongoing antioxidant supplementation trials, a wrong kind of supplement is given“.94

Vitamin C and CHD risk in women CHD risk (RR) 1,0 1

-27 % 0.86 0.73*

0,5

61 Diet only

209 Diet only

704 Supplement users

Vitamin C (mg/day)

Fig. 8. CHD risk (relative risk; RR) dependent on vitamin-C intake; prospective cohort study (Nurses‘ Health Study); duratin: 16 years; 85,118 women; * p=0.00581

Effect of vitamins C and E on arteriosclerosis progression CCA-IMT (mm/100)

1.6 1.2

Supplement: 2 x 250 mg vitamin C per day + 2 x 136 IU vitamin E per day

1.8

1.7 1.45 1.27

1.13

0.8

0.83

Placebo

0.4

Without plaques

Small plaques

Large plaques

In that study, the combined intake of these antioxidant vitamins for a period of 6 years (2 x 136 IU of vitamin E and 250 mg of vitamin C) significantly reduced the thickening of the intima media of the carotid artery in individuals with elevated cholesterol levels (Fig. 9). The effect of the vitamin intake was most pronounced in those patients who had either low plasma vitamin C levels or had already formed plaques in the carotid artery at the beginning of the trial.94 A number of studies show that this combination has a beneficial influence on atherosclerotic changes and thus on cardiovascular diseases.17 In a dietary therapy of cardiovascular conditions the combined administration of vitamins C and E makes sense because vitamin C supports the regeneration of the antioxidant function of vitamin E (Fig. 10).8 After heart transplantation, vitamins C and E effectively reduce the progression of atherosclerosis (2 x 500 mg of vitamin C and 400 IU of vitamin E daily).29 In stroke patients, the combined intake of vitamins C and E (727 mg of vitamin E, 500 mg of vitamin C) significantly enhances the antioxidant capacity (p < 0.003), lowers antioxidant stress and inhibits inflammatory reactions.117

Fig. 9. Arteriosclerosis progression measured as average annual growth in intima-media thickness of the carotid artery (CCA-IMT). Placebo-controlled double-blind study; duration: 6 years, n=440; p=0.00394

34

35

Bypass surgery is associated with a significant decline in antioxidant capacity and an increase in oxidative stress, giving rise to cell lesions and inflammatory responses that may impair cardiac function.65 In a study Danova et al. have shown impressively that even a week after bypass surgery the antioxidant capacity still decreases. The team of researchers also found that these patients already had a low antioxidant status before the intervention. Thus, the continuously increased oxygen radical production of cardiac patients presumably already leads to the exhaustion of the antioxidant defense before surgery. For these reasons the supplementation of the antioxidant vitamins C and E appears to be advisable for bypass patients.22

Vitamin E regeneration systems: vitamins C and E as a team

ROOË&#x2122; Free radical

Vitamin E Alpha-tocopherol Alpha-tocotrienol

ROOH Reduced radical

Dehydroascorbate

Minerals Besides potassium, magnesium is the most important intracellular mineral.

The heart has the highest magnesium concentration of all organs. Magnesium contributes to regulating the stimulus conduction of the heart and has a special role in blood pressure control. Many hypertensive individuals and CHD patients suffer from a magnesium deficiency.112,128 A meta-analysis has confirmed that magnesium supplementation lowers the blood pressure.56 Epidemiological studies have also identified a correlation between a magnesium deficiency and hypertension and/or an increased cardiovascular risk.3,131 Thus, it was found that low dietary magnesium significantly increased the risk of arrhythmias.61 Magnesium supplementation can be used as an adjunct to drug therapy for patients with arrhythmia and heart failure.112,130 Trace elements The essential trace elements selenium, zinc, manganese and copper are also particularly important for the cardiovascular system. All four trace elements are integral components of the antioxidant enzymes that protect the heart and vessels against oxidative stress. These enzymes include glutathione peroxidases (selenium) and superoxide dismutases (zinc, manganese and copper). A selenium deficiency, for instance, may increase the risk of heart failure, especially when other micronutrients, such as vitamin E, are lacking.130

Ascorbate Vitamin-E radical

Fig. 10. Recycling of vitamin E radicals with vitamin C8

36

37

Amino acids The amino acids arginine and taurine are becoming increasingly important for the dietary management of cardiovascular conditions. Studies suggest that amino acids improve the heart muscle metabolism and counteract endothelial dysfunction.

reperfusion and oxidative stress. This effect is presumably due to the antioxidant activity of taurine. 85 Other in-vitro studies and studies with humans have shown that taurine supplementation has a favorable impact on the endothelial function31 and can protect against microvascular complications in diabetes mellitus patients.74

L-arginine L-arginine is the parent substance in the formation of nitric oxide (NO) which is a vasodilator that causes the blood vessels to widen. Moreover, NO blocks proatherosclerotic processes in the vessel wall and thus has an antiatherogenic effect.10 The formation and biological effectiveness of NO is reduced in atherosclerotically affected arteries.10 The exogenous supply of L-arginine, however, can enhance the endogenous NO production.10 It can therefore be assumed that amino acid is able to protect the endothelium.77 This assumption was confirmed by a study in which the 4-week supplementation of L-arginine improved the endothelial function of hypertensive patients with microvascular angina pectoris.82 The endothelial dysfunction associated with cardiovascular diseases may thus be counteracted by arginine supplementation.77 Taurine Taurine is a metabolite of methionine and cysteine which are sulpherous amino acids. It is mostly present as a free, unbound substance (as a â&#x20AC;&#x153;free amino acidâ&#x20AC;?) and is the amino acid in the heart with the highest concentration.77 Taurine therefore plays an important role for the heart muscle and has a beneficial effect on cardiac output.77 Its significance in the dietary management of cardiovascular diseases has been demonstrated by several studies. Taurine acts as a membrane-stabilizing antioxidant substance that protects the membrane-bound fatty acids against oxidation.74 In animal experiments taurine also protected the heart against damage caused by 38

39

Micronutrients – especially effective in combination In daily clinical work the dietary use of micronutrients in both the prevention and nutritional treatment of cardiovascular diseases has been known to be of benefit for a long time. Well-documented epidemiological data support this positive experience. However, the results of major interventional trials, i.e. those focusing on single antioxidants, often contradict clinical experience.

Such studies are not able to properly cope with the complexity and multifactorial origin of cardiovascular diseases. Therefore we tend to gradually realize that large endpoint trials with single substances are not able to adequately deal with the cardiovascular effectiveness of micronutrients.

This is why in the past few years the scientific community has started to change its approach. In more recent studies many micronutrients are not used as single substances any more but rather as combinations29,94,117 because the combined ranges of action of various micronutrients with an effect on the cardiovascular system can complement one another in a beneficial way. The combination of vitamins C and E is a good example.94 Thus, vitamin E which is oxidized itself with the inactivation of oxygen radicals and therefore loses its effect, can be reduced again by vitamin C and coenzyme Q10 and recycled to its active form.8 Vitamin C in turn is reduced by selenium-containing glutathione peroxidase (GSH).23 The enzyme superoxide dismutase (SOD) that needs zinc as a cofactor, is the last link in this chain.1

In another study the combined supply of important micronutrients was able to significantly lower the blood pressure of type-2 diabetics (without manifest hypertension). It was interesting to note in this context that only the combined supply of vitamin C, vitamin E, magnesium and zinc had a beneficial effect on the blood pressure, whereas the isolated vitamin or mineral supplementation had no effect.30 These results show that the ranges of action of the individual micronutrients effectively complement one another.

In addition, micronutrient combinations are ideally suited as adjuncts to drug therapy or interventional coronary treatment. A combination including the full range of phytonutrients (resveratrol, OPC and cocoa polyphenols), vitamins, minerals, trace elements, omega-3 fatty acids and vitamin-like substances (L-carnitine, coenzyme Q10) not only covers the increased micronutrient need of cardiovascular patients but also compensates the negative impact of certain medical therapies on the micronutrient balance.

Multi-vitamin supplements and myocardial infarction risk Infarction risk (OR)

80

A number of studies confirm the benefits of a micronutrient combination.29,94 The SHEEP Study, for instance, which included 3,000 patients, found a 21 % (men) and 34 % (women) lower cardiovascular risk compared to the control group when multivitamins were taken regularly (p = 0.03 and p = 0.01, respectively).48

60

100 %

-21 % 79 %

Supplement Controls

100 % -34 % 66 %

40 20

Abb. 11. Myocardial infarction risk (odds ratio; OR) dependent on vitamin intake; n=2,981; Age range: 45-70 years; 1,296 cases; 1.685 controls48

40

41

Table 3. Micronutrients associated with cardiovascular diseases Micronutrients

Dietary features and characteristics

Micronutrients

Dietary features and characteristics

Phytonutrients

Minerals, trace elements

Oligomeric proanthocyanidins (OPC) Have antioxidant effects and thus are able to resveratrol, cocoa polyphenols counteract arteriosclerosis development bioflavonoids and carotenoids

Magnesium

Stabilizes cell membranes and regulize stimulus conduction in the heart

Zinc, selenium, manganese, copper

Co-factors of antioxidant enzymes

Iodine

Important factor of influence on the functions of the thyroid gland

Resveratrol

Supports vascular function

Cocoa polyphenols

Beneficially influence blood pressure and support vascular function

Essential fatty acids Omega-3 fatty acids

Inhibit platelet aggregation, improve blood fluidity, decrease triglycerides, act as antihypertensives, antiarrhythmics and antiinflammatory agents

Vitamin-like substances L-Carnitine and coenzyme Q10

Play an important role for the heart metabolism and are essential contributors for energy generation of cardiac muscle cells; additionally coenzyme Q10 is an antioxidant

Amino acids L-arginine

Vasodilatory effects

Taurine

Has antioxidant effect and thus acts as an antiarteriosclerotic agent; has beneficial impact on cardiac performance

N-acetylcysteine

Is a component of glutathione and thus has antioxidant features

Vitamins

42

Vitamins C and E

Have antioxidant effects and thus are able to counteract arteriosclerosis development; vitamin C is involved in the regeneration of vitamin E

Vitamins B1, B2, nicotinamide (niacin), pantothenic acid and biotin

Optimization of cell function, important for energy metabolism

Folic acid, vitamins B6, B12

Jointly reduce the homocysteine level, play an important role for vascular function and can exert a favorable effect on arteriosclerosis

43

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

44

Adam O. Anti-inflammatory diet in rheumatic disease. Eur J Clin Nutr 1995;49:703-17.

Alvares Delfino VD, de Andrade Vianna AC, Mocelin AJ, et al. Folic acid therapy reduces plasma homocysteine levels and improves plasma antioxidant capacity in hemodialysis patients. Nutrition 2007;23(3):242−7.

Ascherio A, Rimm EB, Giovannucci EL, et al. A prospective study of nutritional factors and hypertension among US men. Circulation 1992;86(5):1475−84.

Baba S, Natsume M, Yasuda A, et al. Plasma LDL and HDL cholesterol and oxidized LDL concentrations are altered in normo- and hypercholesterolemic humans after intake of different levels of cocoa powder. J Nutr 2007;137(6):1436−41.

Baggio E, Gandini R, Plancher AC, et al. ltalian multicenter study on the safety and efficiency of coenzyme Q as adjunctive therapy in heart failure. Clin Invest 1993;71(8 Suppl):145−9.

Bairati I, Roy L, Meyer F. Double-blind, randomized, controlled trial of fish oil supplements in prevention of recurrence of stenosis after coronary angioplasty. Circulation 1992;85(3):950−56.

Beitz R, Mensink GB, Fischer B, et al. Vitamins − dietary intake and intake from dietary supplements in Germany. Eur J Clin Nutr 2002;56(6):539−45.

Biesalski HK. Taschenatlas der Ernährung [Pocket atlas of nutrition]. Stuttgart: Georg Thieme; 2002.

S. 199.

Bigazzi R, Bianchi S. Insulin resistance, metabolic syndrome and endothelial dysfunction. J Nephrol 2007;20(1):10−4.

Bode-Böger S M, Böger R H, Fröhlich J C. Antiarteriosklerotische Wirkungen durch Stimulation der endogenen NO-Synthese [Anti-arteriosclerosis effects due to stimulation of endogenous nitric oxide synthesis]. Internist 1997;38(5):461–5.

Bradamante S, Barenghi L, Villa A. Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev 2004;22(3):169−88.

Buijsse B, Feskens EJ, Kok FJ, et al. Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study. Arch Intern Med 2006;166(4):411−7.

Burkhardt W. Das akute Koronarsyndrom – pathophysiologische Grundlagen [Acute coronary syndrome pathophysiological mechanisms]. Eur J Clin Res 1999;5 (Suppl 05/Newsletter 2). Verfügbar unter: www.klinikundforschung.de/sup/news1/burkhar.htm [11.04.2010] Buschmann P. Der Stand der Flavonoidforschung zu Beginn des 21. Jahrhunderts (unter besonderer Berücksichtigung der Wirkungen und Wirksamkeiten der Flavonoide) [State-of-the-art of flavonoid research at the beginning of the 21st century (with special focus on effects and efficacies)] [Dissertation]. Graz: Naturwissenschaftliche Fakultät der Universität Graz (Austria), 2002.

Busserolles J, Gueux E, Balasinska B, et al. In vivo antioxidant activity of procyanidin-rich extracts from grape seed and pine (Pinus maritima) bark in rats. Int J Vitam Nutr Res 2006;76(1):22−7.

Calo L, Bianconi L, Colivicchi F, et al. N-3 fatty acids for the prevention of atrial fibrillation after coro- nary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol 2005;45(10):1723−8.

Carr AC, Zhu BZ, Frei B. Potential antiatherogenic mechanisms of ascorbate (vitamin C) and alpha-tocopherol (vitamin E). Circ Res 2000;87(5):349−54.

Caso G, Kelly P, McNurlan MA, et al. Effect of coenzyme Q on myopathic symptoms in patients treated with statins. Am J Cardiol 2007;99(10):1409−12.

Chang C-Y, Chen J-Y, Dershin K, et al. Plasma levels of lipophilic antioxidant vitamins in acute ischemic stroke patients: correlation to inflammation markers and neurological deficits. Nutrition 2005;21(10):987−93.

10

10

20.

21.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

Corder R, Mullen W, Khan NQ, et al. Oenology: red wine procyanidins and vascular health. Nature 2006;444(7119):566−7.

Crane FL. Biochemical functions of coenzyme Q . J Am Coll Nutr 2001;20(6):591−98. 22.

Danova K, Dobisova A, Fischer V, et al. Production of reactive oxygen species and antioxidant defense systems in patients after coronary artery bypass grafting: one-week follow-up study.

J Clin Basic Cardiol 2005;8(1-4):33−6.

Darlington LG, Stone TW. Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders. Br J Nutr 2001;85(3):251-69.

Deutsche Gesellschaft für Ernährung [German Nutrition Society]. Ernährungsbericht 2004 [Nutrition Survey 2004]. Bonn: DGE; 2004.

Dell‘Agli M, Buscialà A, Bosisio E. Vascular effects of wine polyphenols. Cardiovasc Res 2004;63(4):593−602.

Dietl H, Ohlenschläger G. Handbuch der orthomolekularen Medizin [Textbook of orthomolecular medicine]. Heidelberg: Karl F. Haug; 1998. S. 68–9.

Ding EL, Hutfless SM, Ding X, et al. Chocolate and prevention of cardiovascular disease: a systematic review. Nutr Metab (Lond). 2006;3:2.

Dwyer JH, Paul-Labrador MJ, Fan J, et al. Progression of carotid intima-media thickness and plasma antioxidants: the Los Angeles Atherosclerosis Study. Arterioscler Thromb Vasc Biol 2004;24(2):313−9.

Fang JC, Kinlay S, Beltrame J, et al. Effect of vitamins C an E on progression of transplant-associated arteriosclerosis: a randomized trial. Lancet 2002;359(9312):1108−13.

Farvid MS, Jalali M, Siassi F, et al. The impact of vitamins and/or mineral supplementation on blood pressure in type 2 diabetes. J Am Coll Nutr 2004;23(3):272−9.

Fennessy FM, Moneley DS, Wang JH, et al. Taurine and vitamin C modify monocyte and endothelial dysfunction in young smokers. Circulation 2003;107(3):410-5.

Fitó M, Guxens M, Corella D, et al. Effect of a traditional Mediterranean diet on lipoprotein oxidation: a randomized controlled trial. Arch Intern Med 2007;167(11):1195−203.

Flammer AJ, Hermann F, Sudano I, et al. Dark chocolate improves coronary vasomotion and reduces platelet reactivity. Circulation. 2007;116(21):2376−82.

Flossmann E, Rothwell PM. Family history of stroke in patients with transient ischemic attack in relation to hypertension and other intermediate phenotypes. Stroke 2005;36:830−5.

Gey KF, Stahelin HB, Eichholzer M. Poor plasma status of carotene and vitamin C is associated with higher mortality from ischemic heart disease and stroke: Basel prospective study. Clin Invest 1993;71(1):3−6.

Ghidini O, Azzurro M, Vita G, et al. Evaluation of the therapeutic efficacy of L-carnitine in congestive heart failure. Int J Clin Pharmacol Ther Toxicol 1988;26(4):217−20.

GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione Trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardio. Lancet 1999;354(9177):447−55.

Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation 1989; 79(1):8−15.

Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives 10

45

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

46

of nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil 2007;14(Suppl 2):S1-113.

Grassi D, Lippi C, Necozione S, et al. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr 2005;81(3):611−4.

Grassi D, Necozione S, Lippi C, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension 2005;46(2):398−405.

He FJ, Nowson CA, MacGregor GA. Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet 2006;367(9507):320−6.

Heitzer T, Meinertz T. Rauchen und koronare Herzkrankheit [Prevention of coronary heart disease: smoking]. Z Kardiol 2005;94(Suppl 3):iii30−42..

Hermann F, Spieker LE, Ruschitzka F, et al. Dark chocolate improves endothelial and platelet function. Heart 2006;92(1):119−20.

Herrmann W, Herrmann M, Obeid R. Hyperhomocysteinaemia: a critical review of old and new aspects. Curr Drug Metab 2007;8(1):17–31.

Hofman-Bang C, Rehnqvist N, Swedberg K, et al. Coenzyme Q as an adjunctive treatment of chronic congestive heart failure: the Q study group. J Card Fail 1995;1(2):101−7.

Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996;3(2):213−9.

Holmquist C, Larsson S, Wolk A, et al. Multivitamin supplements are inversely associated with risk of myocardial infarction in men and women – Stockholm Heart Epidemiology Program (SHEEP). J Nutr 2003;133(8):2650−4.

Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 1998;316(7135):894−8.

Hu FB, Bronner L,Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 2002;287(14):1815−21.

Hung LM, Chen JK, Huang SS, et al. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res 2000;47(3):549−55.

Ihling C. Pathomorphologie der koronaren Atherosklerose [Pathomorphologic classification of coronary atherosclerosis]. Herz 1998;23(2):69−77.

International Task Force for Prevention of Coronary Heart Disease. Prävention der koronaren Herzkrank- heit [Prevention of coronary heart disease]. Grünwald: Börm Bruckmeier; 2003. S. 105.

Iso H, Kobayashi M, Ishihara J, et al. Intake of fish and n3 fatty acids and risk of coronary ceart disease among Japanese. The Japan Public Health Center-Based (JPHC) Study Cohort I. Circulation 2006 ;113(2):195–202.

Iso H, Rexrode KM, Stampfer MJ, et al. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA 2001;285(3):304−12.

Jee SH,Miller ER 3rd, Guallar E, et al. The effect of magnesium supplementation on blood pressure: a meta-analysis of randomized clinical trials. Am J Hypertens 2002;15(8):691−6.

Kaikkonen KS, Kortelainen M-L, Linna E, et al. Family history and the risk of sudden cardiac death as a manifestation of an acute coronary event. Circulation 2006;114(14):1462−7.

10

10

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

Karatzi KN, Papamichael CM, Karatzis EN, et al. Red wine acutely induces favorable effects on wave reflections and central pressures in coronary artery disease patients. Am J Hypertens 2005;18(9 Pt 1):1161−7.

Kardinaal AF, Kok FJ, Ringstad J, et al. Antioxidants in adipose tissue and risk of myocardial infarction: The EURAMIC-Study. Lancet 1993;342(8884):1379−84.

Keen CL. Chocolate: food as medicine/medicine as food. J Am Coll Nutr 2001;20(5 Suppl):436−9.

Klevay LM, Milne DB. Low dietary magnesium increases supraventricular ectopy. Am J Clin Nutr 2002;75(3):550−4.

Korantzopoulos P, Kolettis TM, Kountouris E, et al. Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation. Int J Cardiol 2005;102(2): 321–6.

Kris-Etherton P, Eckel RH, Howard BV, et al. AHA Science Advisory: Lyon Diet Heart Study. Benefits of a Mediterranean-style, National Cholesterol Education Program/American Heart Association step I dietary pattern on cardiovascular disease. Circulation 2001;103(13):1823–5.

Kris-Etherton PM, Harris WS, Appel LJ, et al. Fish consumption, fish oil, omega-3-fatty acids, and cardiovascular disease. Circulation 2002;106(21):2747–52.

Kunt AS, Selek S, Celik H, et al. Decrease of total antioxidant capacity during coronary artery bypass surgery. Mt Sinai J Med 2006;73(5):777–83.

Langsjoen H, Langsjoen P, Langsjoen P, et al. Usefulness of a coenzyme Q in clinical cardiology: A long term study. Mol Aspects Med 1994;15(Suppl):S165–75.

Langsjoen PH, Folkers K, Lyson K, et al. Pronounced increased of survival of patients with cardiomyopathy when treated with coenzyme Q and conventional therapy. Int J Tissue React 1990;12(3):163–8.

Langsjoen PH, Langsjoen AM. Overview of the use of CoQ in cardiovascular disease. Bio Factors 1999;9(2–4):273–84.

Langsjoen PH, Langsjoen PH, Folkers K. A six-year clinical study of therapy of cardiomyopathy with coenzyme Q . Int J Tissue React 1990;12(3):169–71.

Leeson CP, Mann A, Kattenhorn M, et al. Relationship between circulating n-3 fatty acid concentrations and endothelial function in early adulthood. Eur Heart J 2002;23(3):216–22.

Leikert JF, Räthel TR, Wohlfart P, et al. Red wine polyphenols enhance endothelial nitric oxide synthase expression and subsequent nitric oxide release from endothelial cells. Circulation 2002;106(13):1614–7.

Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr 1996;64(2):190–6.

Löster H. Carnitin und seine Bedeutung bei kardiovaskulären Erkrankungen [Carnitine and its role in cardiovascular diseases]. Bottrop: Ponte Press Verlag; 2007.

McCarty MF. Complementary vascular-protective actions of magnesium and taurine: a rationale for magnesium taurate. Med Hypotheses 1996 ;46(2):89–100.

Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell‘Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105(16): 1897–903.

10

10

10

10

47

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

48

Maron DJ. The epidemiology of low levels of high-density lipoprotein cholesterol in patients with and without coronary artery disease. Am J Cardiol 2000;86(12A):11L–4L. Metzner C, Ulrich-Merzenich G, Lüder W: Arginin und Taurin – präventive Nahrungsfaktoren bei kardiovaskulären Erkrankungen [Arginine and taurine – dietary factors preventing cardiovascular diseases]? Ernähr Umsch 2001;48(5):188–92.

Mortensen SA, Leth A, Agner EA, et al. Dose-related decrease of serum coenzyme Q during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med 1997;18(Suppl):137–44.

Mullan BA, Young IS, Fee H, et al. Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes. Hypertension 2002;40(6):804–9.

Olas B, Wachowicz B. Resveratrol, a phenolic antioxidant with effects on blood platelet functions.

Platelets 2005;16(5):251–60.

Osganian SK, Stampfer MJ, Rimm E, et al. Vitamin C and risk of coronary heart disease in women.

J Am Coll Cardiol 2003;42(2):246–52.

Palloshi A, Fragasso G, Piatti P, et al. Effect of oral L-arginine on blood pressure and symptoms and endothelial function in patients with systemic hypertension, positive exercise tests, and normal coronary arteries. Am J Cardiol 2004;93(7):933–5.

Papamichael C, Karatzis E, Karatzi K, et al. Red wine‘s antioxidants counteract acute endothelial dysfunction caused by cigarette smoking in healthy nonsmokers. Am Heart J 2004;147(2):G1–5.

Pietrzik K, Golly I, Loew D. Handbuch Vitamine [Handbook of vitamins]. München: Urban & Fischer; 2008.

S. 394–400.

Raschke P, Massoudy P, Becker BF. Taurine protects the heart from neutrophil-induced reperfusion injury. Free Radic Biol Med 1995;19(4):461–71.

Regitz-Zagrosek V, Lehmkuhl E. Kardiovaskuläre Erkrankungen bei Frauen [Cardiovascular diseases in women]. medical spezial 2003;4:8–10.

Reid JA, Lau LL, Hannon RJ. Decreased antioxidant vitamin concentration may be a risk factor for recurrent carotid stenosis. Vasc Endovascular Surg 2007;41(4):330–4.

Retter AS. Carnitine and its role in cardiovascular disease. Heart Dis 1999;1(2):108–13.

Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328(20):1450–6.

Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279(5):359–64.

Rissanen TH, Voutilainen S, Nyyssönen K, et al. Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr 2001;85(6):749–54.

Rosengren A, Hawken S, Ôunpuu S, et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 2004;364(9438):953–62.

Rundek T, Naini A, Sacco R, et al. Atorvastatin decreases the coenzyme Q level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol 2004;61(6):889–92.

Salonen RM, Nyyssonen K, Kaikkonen J, et al. Six-year effect of combined vitamin C and E supple- mentation on atherosclerotic progression: The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. Circulation 2003;107(7):947–53.

10

6

10

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

Scherz H, Herausgeber. Souci-Fachmann-Kraut. Die Zusammensetzung der Lebensmittel, Nährwert- Tabellen [Food composition and nutrition tables]. 6. Aufl., Stuttgart: Medpharm Scientific Publishers; 2000.

Schnyder G, Roffi M, Flammer Y, et al. Effect of homocysteine-lowering therapy with folic acid, vitamin B , and vitamin B on clinical outcome after percutaneous coronary intervention: The Swiss Heart study: a randomized controlled trial. JAMA 2002;288(8):973–9.

Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345(22):1593–600.

Sesso HD, Buring JE, Norkus EP, et al. Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in women. Am J Clin Nutr 2004;79(1):47–53.

Singer P, Wirth M. Fischöl vermindert Herzrhythmusstörungen – Bedeutung für die Reduktion von Reinfarkten und plötzlichem Herztod [Fish oil reduces cardiac arrhythmias - impact on the reduction of reinfarctions and sudden cardiac death]. Med Welt 2003;54(4):68–74.

Singer P, Wirth M. Günstiger Einfluss von n-3 Fettsäuren auf Herzrhythmusstörungen [Beneficial influence of n-3 fatty acids on cardiac arrhythmias]. Ernähr Umsch 2002;49(5):178–81.

Singh RB, Niaz MA, Sharma JP, et al. Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival. Cardiovasc Drugs Ther 1997;11(3):485–91.

Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coen- zyme Q in patients with acute myocardial infarction. Cardiovasc Drugs Ther 1998;12(4):347–53.

Solini A, Santini E, Ferrannini E. Effect of short-term folic acid supplementation on insulin sensitivity and inflammatory markers in overweight subjects. Int J Obes 2006;30:1197–202.

Spence JD, Bang H, Chambless LE, et al. Vitamin intervention for stroke prevention trial. An efficacy analysis. Stroke 2005;36(22):2404–9.

Stampfer MJ, Hennekens CH,Manson JE, et al. Vitamin E consumption and risk of coronary heart disease in women. N Engl J Med 1993;328(20):1444–9.

Stangl V, Baumann G, Stangl K, et al. Kardiovaskuläre Risikofaktoren bei Frauen [Cardiovascular risk factors in women]. Dtsch Med Wochenschr 2003;128(31/32):1659–64.

Stanger O, Hermann W, Pietrzik K, et al. Konsensuspapier der D.A.CH.-Liga Homocystein über den rationellen klinischen Umgang mit Homocystein, Folsäure und B-Vitaminen bei kardiovaskulären und thrombotischen Erkrankungen – Richtlinien und Empfehlungen [Consensus paper on the rational clinical use of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations]. J Kardiol 2003;10(5):190–9.

Stanger O. Homocystein, Folsäure und B-Vitamine als Sekundärprophylaxe. Kommentar zu aktuellen Therapiestudien. 2006. Verfügbar unter: www.dach-liga-homocystein.org [27.02. 2008] Stef G, Csiszar A, Lerea K, et al. Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance. J Cardiovasc Pharmacol 2006;48(2):1–5.

Stephens NG, Parsons A, Schofield PM, et al. Randomized controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347(9004):781–6.

Stoclet JC, Chataigneau T, Ndiaye M, et al. Vascular protection by dietary polyphenols.

Eur J Pharmacol 2004;500(1–3):299–313.

Stühlinger HG. Die Bedeutung von Magnesium bei kardiovaskulären Erkrankungen [Role of magnesium in cardiovascular diseases]. J Kardiol 2002;9(9):389–95.

12

6

10

49

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

50

Stratton IM, Adler AI, Neil HA, Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.

BMJ 2000;321(7258):405–12.

Taubert D, Roesen R, Lehmann C, et al. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial. JAMA 2007;298(1):49–60.

Taubert D, Roesen R, Schömig E. Effect of cocoa and tea intake on blood pressure: a meta-analysis.

Arch Intern Med 2007;167(7):626–34.

Theobald HE, Goodall AH, Sattar N, et al. Low-dose docosahexaenoic acid lowers diastolic blood pressure in middle-aged men and women. J Nutr 2007;137(4):973–8.

Ullegaddi R, Powers HJ, Gariballa SE. Antioxidant supplementation enhances antioxidant capacity and mitigates oxidative damage following acute ischaemic stroke.

Eur J Clin Nutr 2005;59 (12):1367–73.

Vasan RS, Beiser A, D‘Agostino RB, et al. Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. JAMA 2003;289(10):1251–7.

Vasan RS, Larson MG, Leip EP, et al. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet 2001;358(9294):1682–6.

Vinson J A, Bose P. Relative bioavailability of synthetic ascorbic acid alone or in a citrus extract.

Am J Clin Nutr 1988;48(3):601–4.

Vinson JA, Proch J, Bose P, et al. Chocolate is a powerful ex vivo and in vivo antioxidant, an antiatherosclerotic agent in an animal model, and a significant contributor to antioxidants in the European and American Diets. J Agric Food Chem 2006;54(21):8071–6.

Vlachopoulos C, Alexopoulos N, Stefanadis C. Effect of dark chocolate on arterial function in healthy individuals: cocoa instead of ambrosia? Curr Hypertens Rep 2006;8(3):205–11.

Von Schacky C, Angerer P, Kothny W, et al. The effect of dietary omega-3-fatty acids on coronary atherosclerosis. A randomized, double-blind placebo controlled trial.

Ann Intern Med 1999;130(7):554–62.

Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325(7374):1202–6.

Wallerath T, Deckert G, Ternes T, et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 2002;106(13):1652–8.

Wan Y, Vinson JA, Etherton TD, et al. Effects of cocoa powder and dark chocolate on LDL oxidative susceptibility and prostaglandin concentrations in humans. Am J Clin Nutr 2001;74(5):596–602.

Watzl B, Leitzmann C. Bioaktive Substanzen in Lebensmitteln [Bioactive substances in foods]. 2. Aufl., Stuttgart: Hippokrates; 1999. S. 124.

Westermann GW, Tokmak F, Rahn KH, et al. Erniedrigte Membran-Mg++-Konzentrationen in einer Untergruppe von Hochdruckkranken – Ein Membranmodell für die Pathogenese der primären Hypertonie [Decreased Mg++ levels of membranes in a group of hypertensives - a membrane model of the pathogenesis of primary hypertension]. J Hypertonie 1999;3(3):34–8.

Wirth A. Mit den Kilos schwinden auch Blutzucker und Fette [Also blood glucose and fats vanish with the kilos]. Cardiovasc 2003;3(1):22–30.

Witte KK, Clark AL, Cleland JG. Chronic heart failure and micronutrients. J Am Coll Cardiol 2001;37(7):1765–74.

1 31.

132.

133.

134.

135.

136.

Witteman JC, Willett WC, Stampfer MJ, et al. A prospective study of nutritional factors and hypertension among US women. Circulation 1989;80(5):1320–7.

Yang Q, Botto LD, Erickson JD, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 2006;14;113(10):1335–43.

Yarnell J, Yu S, Patterson C, et al. Family history, longevity, and risk of coronary heart disease: the PRIME Study. Int J Epidemiol 2003;32(1):71–7.

Yusuf S, Howken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.

Lancet 2004;364(9438):937–52.

Yusuf S, Sleight P, Pogue J, et al. The heart outcomes prevention evaluation study – Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000;342(3):154–60.

Zyriax BC. Die CORA-Studie: Ernährungs- und Lebensstilbedingte Risikofaktoren für koronare Herzkrank- heit bei Frauen [The CORA study: nutrition- and lifestyle-dependent risk factors predisposing women for coronary heart disease] [Dissertation]. Gießen: Justus-Liebig-Universität; 2002.

© 2010 Orthomol. All rights, particularly those relating to translation into foreign languages, are reserved. No part of this brochure may be reproduced in any form – by photocopying, microfilm or any other process – or transmitted/translated into a language used by machines, in particular data processing machines, without the written permission of the author.

XXXXXXXXX 06/10

We Value Your Health.

Orthomol pharmazeutische Vertriebs GmbH Herzogstr. 30 40764 Langenfeld Germany export@orthomol.de www.orthomol.com