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REGULATORY STATUS OF SALT AND ESTABLISH FOOD LABELING REQUIREMENTS REGARDING SALT AND SODIUM

The long-standing debate on the health impact of salt on health has been characterized by claims that salt reduction would improve health, in spite of the considerable body of documented evidence indicating these claims may lack scientific merit[1]^{,[2],[3],[4],[5],[6],[7],[8],[9],[10]}. Even experts on the Institute of Medicine panel on dietary reference intakes for electrolytes and water acknowledge that there is a gap in knowledge on the health consequences of dietary salt restriction[11]^,[12]. Nevertheless, ongoing salt reduction advocacy efforts and general media attention to this issue may induce the food industry and consumers to significantly cut back on salt utilization/consumption. The potential negative health impacts of a population-wide reduction in sodium intake as described in the scientific literature is the primary subject of this supplemental statement.

The renin-angiotensin-aldosterone system (RAAS) plays an critical role in regulating blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure. As the name implies, there are three important components to this system: 1) renin, 2) angiotensin, and 3) aldosterone. Renin, an enzyme which is primarily released by the kidneys, stimulates the formation of angiotensin in blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex. More recently, there has been a paradigm shift in our understanding of the actions of aldosterone. Indeed, seldom has there been such a renewed interest in the study of a compound that was isolated more than a half century ago, as we see ongoing now with aldosterone.

Traditionally our view has been that the primary action of aldosterone was its action on renal epithelial cells in the distal tubule and collecting duct in order to promote sodium re-absorption and potassium excretion. The more malignant role of aldosterone in the patho-physiological consequences of the activated renin-angiotensin-aldosterone system on vascular condition and chronic heart failure went unnoticed. There is now evidence for vascular synthesis of aldosterone aside from its secretion by the adrenal cortex. More recently, this hormone has been found to be involved in vascular smooth muscle cell hypertrophy and hyperplasia, as well as in vascular matrix impairment and endothelial dysfunction[13].

The latest observations indicate that some of the most significant impacts of aldosterone on cardiovascular and renal disease result from specific actions at critical sites including the heart, kidneys, and vasculature. Indeed, aldosterone is considered a crucial hormone for the body’s cardiovascular system[14]. Clinical studies indicate that aldosterone, completely independent of angiotensin II and elevated blood pressure, plays a role in cardiovascular disease. In addition to its role in fluid and electrolyte balance and circulatory homeostasis, aldosterone is a critical mediator of vascular injury through its effects on endothelial function as well as through increasing hypertrophy of vascular smooth muscle cells, generation of reactive oxygen species and inhibition of norepinephrine uptake.

The addition of aldosterone antagonists to the regimens of patients with left ventricular systolic dysfunction and ongoing symptoms of heart failure, despite optimal ongoing treatment with ACE inhibition and beta-blockers can substantially reduce overall mortality and the rate of sudden death in this vulnerable population. This result indicates that the aldosterone level may be a more important predictor of cardiovascular disease risk than is blood pressure.

Aldosterone interacts with mineralocorticoid receptors to facilitate thrombosis, reduce vascular compliance and impair the baroreceptor function. It also interacts with mineralocorticoid receptors to cause myocardial and vascular fibrosis and left ventricular hypertrophy[15]^,[16].

This more recent information explains many of the unexpected results that have been observed in the past.

For instance, in an analysis of 219 patients with essential hypertension in the early 1970s, heart attacks and strokes were observed when the plasma enzyme, renin was elevated. It was concluded that renin may be a risk factor for heart attacks[17]. In 1991, Alderman et al reported on the relationship of reduced salt related high renin levels with increased myocardial infarction rates^[18]. This relationship was once again confirmed in 1997[19].

A short time later, in 58 trials of hypertensive persons, reducing sodium intake to 118 mmol/24 h (urinary sodium excretion) lowered systolic blood pressure (SBP) by 3.9 mm Hg and diastolic blood pressure (DBP) by 1.9 mm Hg. In 56 trials of normotensive persons, reducing sodium intake to 160 mmol/24 h lowered SBP by 1.2 mm Hg and DBP by 0.26 mm Hg. On the surface, this appeared to be a positive outcome, however, another consequence of this drop in sodium consumption was a significant 360% increase in the levels of plasma renin and a 320% increase in the level of aldosterone. These increases were proportional to the degree of sodium reduction and were accompanied by a significant decrease in body weight, and an increase in noradrenaline, cholesterol, and low-density lipoprotein cholesterol levels[20].

In his introduction of Dr. Michael H. Alderman as Editor-in-Chief of the American Journal of Hypertension, renowned hypertension researcher and founder of the American Society of Hypertension, Dr. John Laragh stated that Dr. Alderman rightly “questioned the popular wisdom of unselectively advising salt avoidance for all hypertensives, and for all normotensive people, - a popular public health strategy which will surely chronically raise all of their plasma renin values and may have other unintended adverse consequences.[21]”

One of the serious unintended adverse consequences of salt avoidance is the negative impact of increased aldosterone levels on vascular compliance (stiffness).

Vascular compliance has assumed increasing importance as a key marker of early disease of the vascular wall, a predictor of future vascular disease, and a way to monitor the effects of vasoactive agents on arterial wall stiffness[22]. A significant number of recent publications attribute increased arterial stiffness to reduced salt intakes[23]^,[24].

Shapiro, Boaz, Matas, Fux, and Shargorodsky investigated the association between excess aldosterone, reflected by an increased aldosterone-renin ratio (ARR) and pulse wave velocity (PWV) in young healthy adults to determine vascular compliance. In a single-center study, 60 subjects were evaluated for lipid profile, glucose, hs-CRP, renin and aldosterone. PWV was performed as a simple noninvasive recording and computer analysis of the two artery sites pressure waveform[25]. The ARR was significantly and positively associated with PWV and had the potential to exhibit the direct effects of aldosterone on the vascular wall. Most significantly, the participants received instructions to consume levels of sodium proportional to energy intake, corresponding to 2,300mg per day sodium per 2,100 kcal and to avoid foods notably high in sodium due to processing or foods with salt topically added – in other word to comply with the upper limit DV recommendations of the Institute of Medicine[26]. This study demonstrated that this level of recommended intake resulted in increased aldosterone and increased arterial stiffness. Even the upper DV limit of sodium consumption recommended by the IOM appeared insufficient to prevent elevation of aldosterone and its consequent potential for harm.

There are a number of reasonable conclusions that can be derived from the above data. In the first instance, there is clear evidence that a reduction in salt intake will elicit increased plasma aldosterone-renin output, thereby placing normotensive people at a greater risk for vascular damage and myocardial infarction. It appears likely that the derived IOM upper limit of sodium may not be sufficient to protect the a large part of the population from arterial stiffening.

Further evidence comes from the primitive Yanomamo Indians of Brazil who do notuse added salt in their diet. This group provide a unique opportunity to study the hormonal regulation of sodium metabolism in aculture with life-long restriction of dietary sodium. Results indicate that urinary excretion of sodium is very low, however, their plasma renin activitieswere elevated when compared to other societies[27]. Thesefindings suggest that the hormonal adjustments to life-long low sodiumintakes are similar to those achieved in acute sodium restriction ofcivilized man. It appears that there may be no level of reduced salt intake to which we can become fully acculturated to without inducing some increase in plasma renin and aldosterone, along with their negative consequences

Unintended adverse consequences are what we all strive to avoid. Just as John Adams stated “we are a government of laws and not men,” so too, is the functioning of our physiology – processes governed by scientific laws, and not the subjective opinions of men. We stand to be in great peril if we ignore the science.

Despite vigorous salt reduction advocacy and populist media attention to this issue, the science will eventually come to the forefront. It can only be hoped that no one suffers unintended consequences because of a rush to judgment. Fortunately, the FDA is taking a more cautious approach than the regulatory agencies in other countries and evaluating all the scientific data before rushing ahead with any policies. They did this once before, when they delayed the acceptance of thalidomide, while the rest of the world eagerly accepted it without a full review of the science.

At this point in time, there is no justification to change the GRAS status of salt and there is sufficient information to reconsider the IOM’s recommendations for the DV of salt. Prudence dictates that we tread very carefully in any consideration of a change in the regulatory status of salt to ensure that we do not do the population more harm than good.

[1] Alderman, M. H., “Evidence Relating Dietary Sodium to Cardiovascular Disease,” Journal of the American College of Nutrition, 25 (3), 256S–261S, (2006).

[2] Freedman, D. A., and Petitti, D. B., “Salt and Blood pressure - Conventional Wisdom Reconsidered,” Evaluation Review, 25(3), 267-287, (2001).

[3] Dole, V. P., Dahl, L. K., Cotzias, G. C., Dziewiatkowski, D. D., Harris, C., “Dietary treatment of hypertension. II. Sodium depletion as related to the therapeutic effect,” J Clin Invest 30, 584–595, (1951).

[4] Laragh, J. H., Sealey, J. E., “Renin-angiotensin-aldosterone system and the regulation of sodium, potassium, and blood pressure homeostasis,” In Windhager EE (ed): “Handbook of Physiology, Renal Physiology,” Vol. II. New York: Oxford University Press, pp 1409–1541, (1992).

[5] Feldman, R. D., Logan, A. G., Schmidt, N. D., “Dietary salt restriction increases vascular insulin resistance,” Clin Pharmacol Ther, 60, 444–451, (1996).

[6] Miller, J. Z., Weinberger, M. H., Daugherty, S. A., Fineberg, N. S., Christian, J. C., Grim, C. E., “Heterogeneity of blood pressure response to dietary sodium restriction in normotensive adults,” J Chronic Dis, 40, 245–250, (1987).

[7] Midgley, J. P., Matthew, A. G., Greenwood, C. M. T., Logan, A. G., “Effect of reduced dietary sodium on blood pressure. A meta-analysis of randomized controlled trials,” JAMA 275, 1590–1597, (1996).

[8] Alderman, M. H., Madhavan, S., Cohen, H., Sealey, J. E., Laragh, J. H., “Low urinary sodium is associated with greater risk of myocardial infarction among treated hypertensive men,” Hypertension, 25, 1144–1152, (1995).

[9] Robertson, J. I. S., “Dietary salt and hypertension: a scientific issue or a matter of faith?” Journal of Evaluation in Clinical Practice, 9(1), 1–22, (2003).

[10] Taubes, G., The (Political) Science of Salt,” Science, 281(5379), 898 – 907,(1998).

[11] Institute of Medicine, “Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate.” Washington, DC: National Academies Press, (2004).

[12] Egan, B. M., “Reproducibility of BP responses to changes in dietary salt. Compelling evidence for universal sodium restriction?” Hypertension, 42, 457–458, (2003).

[13] Duprez, D., De Buyzere, M., Rietzschel, E. R., Clement, D. L., “Aldosterone and vascular damage,” Curr Hypertens Rep, 2(3), 327-34, (2000).

[14] Epstein, M., “The Role of Aldosterone in Hypertension: Pathogenesis and Therapy,” presented at the 17th Annual Scientific Meeting of the American Society of Hypertension, (2002).

[15] Struthers, A. D., MacDonald, T. M., “Review of aldosterone- and angiotensin II-induced target organ damage and prevention,” Cardiovasc Res, 61, 663-670, (2004).

[16] Duprez, D., “Aldosterone, the Underrecognised Factor in Cardiovascular Damage,” E-Journal of Cardiology Practice,” 3(24), 22 February, (2005) accessed at:

http://www.escardio.org/knowledge/cardiology_practice/ejournal_vol3/vol3n24.htm on 02/21/2008.

[17] Brunner, H. R., Laragh, J.H., Baer, L., et al, “Essential hypertension: renin and aldosterone, heart attack and stroke,” N Engl J Med, 286, 441-449, (1972).

[18] Alderman, M. H., Madhavan, S., Ooi, W. L., et al, “Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension,” N Engl J Med, 324, 1098-1104, (1991).

[19] Alderman, M. H., Ooi, W. L., Cohen, H., et al, “Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients,” Am J Hypertens, 10, 1-8, (1997).

[20] Graudal, N. A.., Galløe, A. M., abd P. Garred, “Effects of Sodium Restriction on Blood Pressure, Renin, Aldosterone, Catecholamines, Cholesterols, and Triglyceride - A Meta-analysis,” JAMA, 279,1383-1391, (1998).

[21] Laragh,J. H., “Dr. Michael H. Alderman Takes the Helm as Editor-in-Chief of the American Journal of Hypertension, Am J Hypertens 19, 1197–1198, (2006).

[22] Winer, N., Weber, M. A., and Sowers,J. R., “The effect of antihypertensive drugs on vascular compliance,” Current Hypertension Reports, 3(4), 297-304, (2001).

[23] Resnick, L. M., Militianu, D., Cunnings, A. J., Pipe, J. G., Evelhoch, J. L., Soulen, R. L., and Lester, M. A., “Acute vascular effects of the angiotensin II receptor antagonist olmesartan in normal subjects: relation to the Renin-Aldosterone system,” Am J Hypertens 17, 203–208, (2004).

[24] Resnick, L. M., Militianu, D., Cunnings, A. J., Pipe, J. G., Evelhoch, J. L., Soulen, R. L., et al, “Pulse waveform analysis of arterial compliance - relation to other techniques, age, and metabolic variables,” Am J

Hypertens, 13, 1243–1249, (2000).

[25] Shapiro, Y., Boaz, M., Matas, Z., Fux, A., & M. Shargorodsky, “The association between the renin-angiotensin-aldosterone system and arterial stiffness in young healthy subjects,” Clinical Endocrinology (OnlineAccepted Articles). doi:10.1111/j.1365-2265.2008.03176.x.

[26] Dietary Reference Intakes For Water, Potassium, Sodium, Chloride, and Sulfate, Institute of Medicine of The National Academies, The National Academies Press, Washington, D.C. (2005).

[27] Oliver, W. J., Cohen, E. L., and Neel, J. V., “Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a "no-salt" culture,” Circulation; 52, 146-151, (1975).