Nutrients versus whole foods

[Guest guest]

Hi All,

The above subject of this post may be a somewhat

generalized explanation of what the below editorial

review presents I thought well regarding the various

studies done recently in which nutrients thought to

be among our health benefits have on their own

been found in randomized control trials to be ineffective

in their purported health benefits.

It appears that the whole foods and the not understood

completely mixture of nutrients that maybe synergize

to provide us with their overall benefit regarding the

particular health outcome.

Lichtenstein AH.

Nutrients and cardiovascular disease: no easy answers - editorial

review.

Curr Opin Lipidol. 2005 Feb;16(1):1-3. No abstract available.

PMID: 15650556 [PubMed - in process]

The past few years have brought some disappointing outcomes

regarding the potential benefit of single nutrients or nutrient

cocktails and cardiovascular disease risk. The supplements involved

include [beta]-carotene, vitamin E and folate. The question is, what

can we learn from these experiences?

beta-Carotene and cardiovascular disease illustrate a number of

points. Good observational data suggested that diets high in fruit

and vegetables were associated with lower risk of cardiovascular

disease [1–3]. Limited animal work suggested that [beta]-carotene, a

nutrient found in abundance in fruits and vegetables, prevented

lesion development [4]. The supposition was that [beta]-carotene

functioned as an antioxidant; hence, either alone or in combination

with other antioxidants it would decrease the risk of developing

cardiovascular disease. However, the outcome of intervention trials

suggested that [beta]-carotene had a null effect on the risk of

developing cardiovascular disease and in susceptible individuals

increased the risk of developing lung cancer, convincingly enough to

halt concurrent interventions [5–7]. Using the smoke-exposed ferret

as an animal model of lung cancer it was subsequently found that the

oxidative breakdown products of [beta]-carotene interfered with

retinoid signaling, resulting in the formation of pre-cancerous

(squamous metaplasia) lesions [8].

Another example is vitamin E and cardiovascular disease.

Epidemiological data suggested that the use of vitamin E supplements

was associated with decreased risk of developing cardiovascular

disease [9,10]. Small-scale intervention studies in humans [11–13]

and animal work [14] supported these observations. Tissue-culture

studies demonstrated that oxidized low-density lipoprotein was

proatherogenic [15,16] and in-vitro assays using isolated low-density

lipoprotein showed that vitamin E in low-density lipoprotein

particles decreased susceptibility to oxidation [17,18]. There was

also some evidence that vitamin E inhibited smooth muscle cell

proliferation, decreased platelet aggregation, decreased inflammatory

cytokines and chemokines, and increased nitrous oxide production in

endothelial tissue (resulting in vasodilatation) [19]. However,

regardless of these meticulously collected data, a series of

intervention studies using vitamin E supplements to prevent

cardiovascular disease events have been negative [20].

Additional wrinkles have been introduced in the tortuous vitamin E

and cardiovascular disease story. If confirmed, these findings might

suggest negative, rather than null, effects. Data from the HDL

Atherosclerosis Treatment Study (HATS) indicated that subjects

randomized to simvastatin and niacin therapy plus an antioxidant

cocktail (vitamin E, vitamin C and selenium) had a less favorable

outcome with respect to lesion progression than subjects randomized

to simvastatin and niacin therapy alone [21,22]. The unexpected

outcome with antioxidant therapy has been attributed to the

attenuation of the increase in high-density lipoprotein-cholesterol

resulting from simvastatin and niacin therapy. More recently, from a

very different perspective, it has been suggested that vitamin E may

interfere with the ability of [omega]-3 fatty acids to decrease

triglyceride levels [23]. Kinetic studies demonstrated that [omega]-3

fatty acids decrease triglyceride levels, at least in part, through

decreased hepatic production of very-low-density lipoprotein [24].

Studies in tissue culture have demonstrated that this effect is

attributable to the ability of very-long-chain [omega]-3 fatty acids,

eicosapentaenoic acid and docosahexaenoic acid, to stimulate a post-

endoplasmic reticulum, presecretory proteolysis pathway. This results

in the premature degradation of apolipoprotein B-100 which diminishes

the capacity of the liver to secrete triglyceride-rich particles

[23]. Addition of vitamin E to primary hepatocytes blocked this

effect.

More recent is the case of folate and cardiovascular disease.

Animal and human evidence demonstrated a link between elevated

homocysteine levels and increased cardiovascular disease. This

relationship is thought to be mediated through damage to the vascular

matrix which results in proliferation of endothelial cells and leads

to oxidative injury of the vascular wall, disturbing endothelium-

dependent vasomotor regulation and promoting arterial thrombosis [25–

27]. Data in animals indicated that folate deficiency increased

homocysteine levels and atherosclerotic lesion formation [28,29].

Clinical data in humans suggested that an elevated plasma

homocysteine level was positively associated with carotid artery

medial-intima thickness and epidemiological data suggested it was a

risk factor for cardiovascular disease [30]. However, the

relationship between diet and plasma homocysteine appears to be more

complex than anticipated. Plasma levels of homocysteine tend to be

inversely associated with plasma folate, vitamin B12 and vitamin B6,

presumably through their role as catalysts for the enzymes involved

in homocysteine metabolism: methylene tetrahydrofolate reductase,

methionine synthase and cystathionine [beta]-synthase, respectively

[30]. Supplementation with folate decreases homocysteine levels [31].

Initial results from ongoing intervention studies have been

unexpected. In the Vitamin Intervention for Stroke Prevention (VISP)

study, a cocktail of folic acid, vitamin B6 and vitamin B12 given to

subjects who had a non-disabling cerebral infarction was successful

in moderately lowering homocysteine levels but over a 2-year period

had no significant effect on vascular outcomes [32]. Even more

unexpectedly, Lange et al. [33] reported that those patients

recovering from successful coronary stenting procedures who received

an intravenous dose prior to leaving the hospital followed by

subsequent oral daily doses of folate, vitamin B6 and vitamin B12 for

6 months exhibited increased rather than decreased risk of in-stent

restenosis and the need for target-vessel revascularization. The

results of ongoing intervention trials will be critical to our

understanding of the potential folate/cardiovascular disease

relationship.

Back to the question of what can we learn from these experiences.

First, given the experience of the past 10 years it should be clear

that there are no easy answers when it comes to cardiovascular

disease and nutrition. No, although on face value this does seem to

be the lesson, blindly accepting this premise carte blanche would be

dangerous. The scientific community needs to form hypotheses

collectively, test them meticulously in the most rigorous manner

possible, evaluate the data objectively and on this basis reassess

public health recommendations on a regular basis. Second, identifying

underlying biochemical mechanisms, a priori, ensures the safety of

nutrient interventions. No, as we have learned, understanding the

biological basis for decreased disease risk does not guarantee

positive outcomes to targeted intervensions. Unanticipated

confounding factors operating in uncontrolled environments intervene

and are difficult to anticipate. In addition, the atherogenic process

starts early in development; unsuccessful interventions in adults may

be successful if initiated earlier in life. Third, food is a mixture

of compounds that we should be able to sort out, identify the

putative compounds and test their efficacy. Maybe, although we have

to allow for the possibility that synergistic/antagonistic effects of

certain combinations may determine outcome. In addition, we need to

understand more about why one dietary pattern is associated with

decreased cardiovascular disease risk and another is not. Our

tendency to is look for the supposed operative compound. Perhaps we

should focus more on what is excluded, rather than included, among

different dietary patterns.

What more do we need to avoid unexpected and disappointing

outcomes in the future? We need to develop more sophisticated

approaches to address nutrient-/disease-related issues that focus

less on individual outcomes and take a more expansive approach. We

need to widen our understanding of nutrient–gene interactions and

take these into consideration when addressing issues related to

nutrient/disease risk. We need to be cautious in what we say and

claim about preliminary findings so as not to put the carriage in

front of the horse and for all intents and purposes let the market,

rather than the scientific community, determine direction.

Al Pater.