- Email: [email protected]
High salt intake and cardiovascular disease: is there a connection?
662
Chrysant
23. Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS. Tissue distribution and quantitative analysis of estrogen receptor-alpha (ER␣) and estrogen receptorbeta (ER) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology 1997;138:4613 24. Jefferson WN, Couse JF, Banks EP, Korach KS, Newbold RR. Expression of estrogen receptor beta is developmentally regulated in reproductive tissues of male and female mice. Biol Reprod 2000;62:310 25. vom Saal F, Timms B, Montano M, et al. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci 1997;94:2056 26. Welshons WV, Nagel SC, Thayer KA, Judy BM, vom Saal FS. Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxy-
Nutrition Volume 16, Numbers 7/8, 2000
27. 28.
29.
30.
chlor and other xenoestrogens increases adult prostate size in mice. Toxicol Ind Health 1999;15:12 Thigpen JE, Setchell KD, Goelz MF, Forsythe DB. The phytoestrogen content of rodent diets (letter). Environ Health Perspect 1999;107:A182 Boettger-Tong H, Murthy L, Chiappetta C, et al. A case of a laboratory animal feed with high estrogenic activity and its impact on in vivo responses to exogenously administered estrogens. Environ Health Perspect 1998;106:369 Newbold RR, Hanson RB, Jefferson WN, et al. Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis 1998;19:1655 North K, Golding J. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. BJU Int 2000;85:107
High Salt Intake and Cardiovascular Disease: Is There a Connection? George S. Chrysant, MD From the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA INTRODUCTION Several epidemiologic studies in the past have demonstrated a positive association between high salt intake and the incidence of hypertension.1,2 Dahl1 found an almost linear relationship between salt intake and blood pressure in five different populations, whereas Gleibermann2 found a similar association in 27 different populations. In contrast, low salt intake (⬍30 mmol Na⫾/d), documented in more than 20 different primitive populations, has been associated with low blood pressure and the lack of rise of blood pressure with age.3 Migration of these populations toward the sea or to urbanized centers, where the consumption of salt is high, is associated with elevation of their blood pressure. Page et al.4 have described six separate primitive populations in the Solomon Islands who prepare their meals in salty, coastal waters, resulting in salt intakes of 150 –230 mmol Na⫾/d. These people have the highest blood pressures among the primitive populations. However, all these studies have been criticized for poor data collection and lack of statistical analysis. Based on these studies, a threshold of sodium intake of 30 mmol/d has been proposed to maintain normotension in the Western acculturated societies.4 – 6 Sodium intake of this magnitude is difficult to maintain by any Westernized society, as the average daily consumption of sodium in the US has been estimated to be 160 mmol. However, recent large, observational studies have questioned the association of salt intake and blood pressure.7 This multinational, multicenter study, which involved 11 000 adult men and women in 39 countries and 52 centers failed to show a significant relationship between 24-h urinary sodium excretion and blood pressure in the 48 acculturated populations, whereas it showed a positive correlation between body mass index and alcohol consumption in these populations.7 A significant association between 24-h sodium excretion and blood pressure emerged when the data from four centers of nonacculturated populations (Yanomamo and Xingu tribes in Brazil, as well as tribes in Kenya and Papua, New Guinea) were added. These populations had extremely low salt and alcohol intakes, as
Correspondence to: George S. Chrysant, MD, Department of Medicine, University of Alabama at Birmingham, 1808 Seventh Avenue South, Birmingham, AL 35294 – 0012, USA.
well as low body mass index and blood pressure. Another large study, of 11 629 Scottish men and women, is the Scottish Heart Health Study.8 This study also did not find any significant correlation between sodium intake and blood pressure after correcting for confounding variables, including body mass index and alcohol consumption. In contrast to these large observational studies, prospective randomized intervention trials provide a firmer association between salt intake and blood pressure. Three recent metaanalyses of such trials have shown a small but consistent association between salt intake and blood pressure. These metaanalyses included 108 trials in hypertension and 96 trials in normotensive subjects.9 –11 The sodium reduction averaged to a 24-h urinary sodium excretion of 100 mmol and was associated with a mean decrease in systolic blood pressure of 4.9 mm Hg for systolic and 2.4 mm Hg for diastolic blood pressure in hypertensive subjects. The blood pressure reductions in normotensive subjects were much smaller, 2.0 mm Hg for systolic and 1.5 mm Hg for diastolic. Most of the studies analyzed were of short duration to approximately 4 wk. Another multicenter trial, which included sodium restriction, weight loss, and behavioral modification (TOHP) in mild hypertensive patients, showed that after 6 mo of intervention, salt restriction and weight loss resulted in 3.7/2.7 and 2.9/1.6 mm Hg decreases in blood pressure, respectively. The combination of salt restriction and weight loss had a greater effect, lowering blood pressure by 4.0/2.8 mm Hg.12–14 However, all of these studies have not analyzed the results according to the salt sensitivity of hypertensive patients.
EFFECTS OF SALT IN SALT-SENSITIVE HYPERTENSIVE PATIENTS Blood pressure that is sensitive to salt intake is not universal among all individuals exposed to high salt intake and salt restriction. Salt sensitivity is defined by a rise or fall of diastolic blood pressure by at least 5 mm Hg from baseline in response to high or low salt intake.15 It has been reported that dietary salt restriction lowers the blood pressure in 30 – 60% of hypertensive subjects and in 25– 49% of normotensive subjects.16 –18 Sensitivity to dietary salt appears to be greater in black hypertensive patients,16,17,19 –21 elderly hypertensive patients,16,19,22 obese,23,24 and female hyper-
Nutrition Volume 16, Numbers 7/8, 2000 tensive patients.25,26 Possible pathophysiologic mechanisms accounting for this salt sensitivity include low plasma renin activity,16,18,27,28 increased sympathetic nervous system activity,29 –31, and insulin resistance in the obese32,33 and in women using oral contraceptives.34 Salt-sensitive hypertensive patients demonstrate a clinically significant blood pressure reduction to salt restriction. A recent large multicenter study showed that moderate salt restriction of 80 –100 mmol/d sodium in salt-sensitive hypertensive patients resulted in a decrease in systolic and diastolic blood pressure of 10 and 7 mm Hg, respectively, and there were no racial, age, gender, or weight differences in the response of blood pressure to salt restriction.15 These blood pressure reductions are similar to those obtained with the use of antihypertensive drugs. In addition, these levels of salt restriction should be easy to maintain. However, even in this well-supervised study, there was a drift of salt intake toward higher levels as the time progressed. The problem therefore is modification of the eating habits of patients, and with the food industry to reduce salt content in baby foods.
SALT AND TARGET ORGAN DAMAGE High salt intake has been associated with left ventricular hypertrophy (LVH) in patients with essential hypertension. Whether this association with LVH occurs independently of blood pressure is debatable at present. Because LVH has been implicated in an increase in cardiovascular morbidity and mortality, the finding of a link between sodium intake and LVH would be clinically relevant. Such a link is supported by present observational and interventional studies. An echocardiographic study of the heart in 50 hypertensive patients showed that salt-sensitive hypertensive patients exposed to high salt intake (260 mmol sodium/d) for 1 wk demonstrated an increase in left ventricular mass in salt-sensitive patients compared to salt-resistant patients, although the blood pressures of both groups were similar.35 Another study of 68 untreated mild to moderate hypertensives studied by M-mode and two-dimensional echocardiography of the heart showed a positive correlation between sodium intake and LVH, which was independent of blood pressure.36 An interesting finding of this study was that the higher prevalence of LVH was in the group with higher angiotensin II levels, suggesting that the failure to suppress the renin-angiotensin-aldosterone system (RAAS) by salt intake may contribute to the development of LVH in individuals consuming high-salt diets. Normally, sodium is linked with RAAS in a negative-feedback loop. Subjects unable to suppress RAAS by high sodium intake would have two independent but related stimuli for LVH: increased blood pressure and increased angiotensin II and aldosterone levels, both of which have trophic effects on the heart and blood vessels. Salt-sensitive subjects more often fail to suppress the RAAS in response to a salt load than do salt-resistant subjects.36 Another study showed a positive relationship between salt restriction and reversion of LVH in hypertensive patients.37 However, in this study it was difficult to separate the effect of decrease in blood pressure or salt intake from the reduction of LVH. Along with its adverse effects on the heart, high sodium intake exerts adverse hemodynamic effects on the kidney. Several investigators have demonstrated decreased renal blood flow and glomerular filtration rate, and an increase in filtration fraction and renal vascular resistance with high salt intake both in salt-sensitive animals and in humans.38 – 41 Weir et al.41 also showed that high salt intake by salt-sensitive hypertensive patients increases protein excretion, which could have long-term detrimental effects on the kidney.
SALT RESTRICTION AND CARDIOVASCULAR RISK Although salt restriction has been regarded as free from adverse effects, a few studies have examined the potential deleterious
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cardiovascular effects of salt restriction. Alderman et al.42 studied salt restriction in 2937 mildly to moderately hypertensive participants at a work site. They found that the incidence of myocardial infarction was inversely related to urinary sodium excretion. This was true for men and not true for women. However, there was no relationship between urinary sodium excretion and stroke, noncardiovascular morbidity, or non-cardiovascular mortality. Another large study, the National Health and Nutrition Examination Survey (NHANES I), showed similar findings in 11 346 participants.43 There were 3923 deaths, 1970 of which were cardiovascular, and the death rate was inversely related to urinary sodium excretion. However, both of these studies have been criticized by several authors for a number of important limitations, such as single random urinary samples for sodium excretion and the unreliability of dietary recall for salt and calorie consumption. Although these data are insufficient to justify the conclusion that dietary sodium reduction per se increases cardiovascular morbidity and mortality, they are provocative. It is well known that salt restriction activates the RAAS, which may adversely influence cardiovascular outcomes. Plasma renin and aldosterone levels are increased in a dose-dependent fashion in response to sodium restriction in both hypertensive and normotensive subjects.11,44 Plasma renin activity (PRA) has been invoked as an independent risk factor for cardiovascular events, such as myocardial infarction and stroke.45 A 5-y follow-up of 219 untreated patients with moderate to severe hypertension with low, normal, or high PRA showed an incidence of myocardial infarction or stroke of 0%, 11%, and 14% for patients with low, normal, or high PRA, respectively.45 In another study it was shown that baseline PRA was highly predictive of myocardial infarction.46 In 1717 patients with mild hypertension, followed-up for 8 y, the incidence of myocardial infarction was 3.2-fold higher in patients with high PRA, compared with those with low PRA. However, this positive relationship between PRA and myocardial infarction has not been observed by other investigators and no clear association between PRA and myocardial infarction or sudden death has been documented in normotensive men.47 Also, myocardial infarction or stroke is rare in primitive populations consuming low-salt diets.4 Additional adverse effects of salt restriction include the activation of the sympathetic nervous system,11 elevation of low-density lipoprotein cholesterol and triglycerides,48,49 decrease in nutrient intake,49 and increase in circulating insulin levels.50 All these adverse metabolic changes may increase the cardiovascular morbidity and mortality.51 These adverse hormonal and metabolic adverse effects of salt restriction can be prevented when low dietary salt intake is combined with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in hypertensive patients.52, 53 This combination produces a synergistic effect with significant blood pressure reduction.54,55
SUMMARY AND RECOMMENDATIONS Based on current knowledge, moderate salt restriction (80 –100 mmol/d sodium) is recommended for all hypertensive patients, especially those that are salt sensitive, such as blacks, the elderly, obese, and diabetics.51 Additional benefits include reduced diuretic-induced hypokalemia,54, 55 better blood pressure control with low-dose diuretics, and preventing target organ damage, most notably LVH. Increased use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, if the first are not tolerated, is recommended as a preferred treatment in hypertensive patients due to the significant cardiovascular protection afford by these drugs.56, 57 Hypertensive patients who are unable to maintain a low-salt diet should be treated, preferably, with calcium channel blockers, as these agents have been shown to be more effective with unrestricted salt intake.58
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REFERENCES 1. Dahl LK. Salt and hypertension. Am J Clin Nutr 1972;25:23 2. Gleibermann L. Blood pressure and dietary salt in human populations. Ecol Food Nutr 1973;2:143 3. Hunt JC. Sodium intake and hypertension: a cause for concern. Ann Intern Med 1983;98:724 4. Page LB, Damon A, Moellering R Jr. Antecedents of cardiovascular disease in six Solomon Islands societies. Circulation 1974;49:1132 5. Morgan T, Nowson C. The role of sodium restriction in the management of hypertension. Can J Physiol Pharmacol 1986;64:786 6. Freis ED. Salt, volume, and the prevention of hypertension. Circulation 1976; 53:383 7. Intersalt Cooperative Research Group. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24-hour urinary sodium and potassium excretion. Br Med J 198;297:319 8. Smith WCS, Combie IK, Tavendale RT, et al. Urinary electrolyte excretion, alcohol consumption, and blood pressure in the Scottish Heart Health Study. Br Med J 1988;297:329 9. Cutler JA, Follman D, Allender PS. Randomized trials of sodium reduction. An overview. Am J Clin Nutr 1997;65:643S 10. Cook NR, Cohen J, Hebert PR, et al. Implications of small reductions in diastolic blood pressure for primary prevention. Arch Intern Med 1995;155:701 11. Graudal NA, Galloe AM, Garred P. Effects of sodium restriction on blood pressure, renin, aldosterone, catecholamines, cholesterol and triglycerides. JAMA 1998;279:1383 12. The Trials of Hypertension Prevention (TOHP) Collaborative Research Group. The effects of non-pharmacological interventions on blood pressure of persons with high normal levels. Results of the Trials of Hypertension Prevention (Phase 1). JAMA 1992;267:1213 13. Hebert PR, Bolt RJ, Borhani NO, et al., for the Trials of Hypertension Prevention (TOHP) Collaborative Research Group. Design of a multicenter trial to evaluate long-term lifestyle intervention in adults with high normal blood pressure levels: Trials of Hypertension Prevention (Phase II). Ann Epidemol 1995;5:130 14. The Trials of Hypertension Prevention Collaborative Research Group. Effect of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high normal blood pressure: the Trials of Hypertension Prevention, Phase II. Arch Intern Med 1997;157:657 15. Chrysant SG, Weir MR, Weder AB, et al. There are no racial, age, sex or weight differences in the effect of salt on blood pressure in salt-sensitive hypertensive patients. Arch Intern Med 1997;157:2489 16. Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension 1986;8(suppl II):127 17. Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension 1996;27:481 18. Sullivan JM, Ratts TE. Sodium sensitivity in human subjects: hemodynamic and metabolic correlates. Hypertension 1988;11:17 19. Luft FC, Miller JZ, Grim CE, et al. Salt sensitivity and resistance of blood pressure: age and race as factors in physiological responses. Hypertension 1991; 17(suppl 1):102 20. Grim CE, Luft FC, Miller JZ. Racial differences in blood pressure in Evans County Georgia: relationship to sodium and potassium intake and plasma renin activity. J Chronic Dis 1980;33:87 21. Sowers JR, Zemel MD, Zemel LP, et al. Salt sensitivity in blacks: salt intake and natriuretic substances. Hypertension 1988;12:485 22. Law MR, Frost CD, Walk NJ. By how much does dietary salt reduction lower blood pressure: analysis of observational data among populations. Br Med J 1991;302:811 23. Gillum RJ, Prineas RJ, Jeffery RW. Non-pharmacologic therapy of hypertension: the independent effects of weight reduction and sodium restriction in overweight borderline hypertensive patients. Am Heart J 1983;105:128 24. Rocchini AP, Key J, Bondie D, et al. The effects of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989;321:580 25. Myers J, Morgan T. The effects of sodium intake on the blood pressure related to age and sex. Clin Exp Hypertens 1983;5:99 26. Elliott P. Observational studies of salt and blood pressure. Hypertension 1991; 17(suppl I):3 27. Chrysant SG, Danisa K, Kem DC, et al. Racial differences in pressure, volume and renin interrelationships in essential hypertension. Hypertension 1979;1:136 28. Fujita T, Henry WL, Bartter FC, et al. Factors influencing blood pressure in salt sensitive patients with hypertension. Am J Med 1980;69:334 29. Campese VM, Romoff MS, Levitan D, et al. Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension. Kidney Int 1982;21:371 30. Koolen MI, Van Brummelen PV. Adrenergic activity and peripheral hemody-
31.
32. 33. 34. 35. 36.
37.
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40. 41.
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43.
44.
45. 46.
47.
48.
49.
50. 51. 52. 53. 54. 55.
56.
57.
58.
namics in relation to sodium sensitivity in patients with essential hypertension. Hypertension 1984;6:820 Mark AL, Lawton WJ, Abbound FM, et al. Effects of high and low sodium intake on arterial pressure and forearm vascular resistance in borderline hypertension. Circ Res 1975;36:194 Tuck ML. Role of salt in the control of blood pressure in obesity and diabetes mellitus. Hypertension 1991;17(suppl I):135 Prineas RJ. Clinical interaction of salt and weight change on blood pressure level. Hypertension 1991;17(suppl I):143 Staessen J, Bulpitt CJ, Fagard R, et al. Contraceptive pill use, urinary sodium and blood pressure. Acta Cardiol 1984;39:55 De La Sierra A, Lluch MM, Pare JC, et al. Increased left ventricular mass in salt-sensitive hypertensive patients. J Hum Hypertens 1996;10:795 Schmieder RE, Lagenfeld MRW, Friedrich A, et al. Angiotensin II related to sodium excretion modulates left ventricular structure in human essential hypertension. Circulation 1994;89:1304 Jula AM, Karank HM. Effects on left ventricular hypertrophy of long-term nonpharmacological treatment with sodium restriction in mild to moderate essential hypertension. Circulation 1994;89:1023 Chrysant SG, Walsh GM, Kem DC, Frohlich ED. Hemodynamic and metabolic evidence of salt sensitivity in spontaneously hypertensive rats. Kidney Int 1979; 15:33 Chrysant SG, Mandal AK, Nordquist JA. Renal functional and organic changes induced by salt and prostaglandin inhibition in spontaneously hypertensive rats. Nephron 1980;25:151 Campese VM, Pairse M, Karubian F, Bigazzi R. Abnormal renal hemodynamics in black salt sensitive patients with hypertension. Hypertension 1991;18:805 Weir MR, Dengel DR, Behrens MT, Goldberg AP. Salt-induced increases in systolic blood pressure affect renal hemodynamics and proteinuria. Hypertension 1995;25:1339 Alderman MH, Madhaven S, Cohen H, et al. Low urinary sodium is associated with greater risk of myocardial infarction among treated hypertensive men. Hypertension 1995;25:1144 Alderman MH, Cohen H, Madhaven S. Dietary sodium intake and mortality. The National Health and Nutrition Examination Survey (NHANES 1). Lancet 1998; 351:781 Kawasaki T, Delea CS, Bartter FC, Smith H. The effect of high-sodium and low sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med 1978;64:193 Brunner HR, Laragh JH, Baer L, et al. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med 1972;286:441 Alderman MH, Madhaven S, Ooi WL, et al. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098 The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1991;327:685 Ruppert M, Overlack A, Kolloch R, et al. Effects of severe and moderate salt restriction on serum lipids in nonobese normotensive adults. Am J Med Sci 1994;307(suppl I):587 McCarron DA, Weder AB, Egan BM, et al. Blood pressure and metabolic responses to moderate sodium restriction in isradipine-treated hypertensive patients. Am J Hypertens 1997;10:68 Lind L, Lithell H, Gustafsson IB, et al. Metabolic cardiovascular risk factors and sodium sensitivity in hypertensive subjects. Am J Hypertens 1992;5:502 Chrysant GS, Bakir S, Oparil S. Dietary salt reduction in hypertension. What is the evidence and why is it still controversial? Prog Cardiovas Dis 1999;42:23 Chrysant SG. Vascular remodeling: the role of angiotensin-converting enzyme inhibitors. Am Heart J 1998;135:S21 Todd PA, Fitton A. Peridopril: a review of its pharmacological properties and therapeutic use in cardiovascular disorders. Drugs 1991;42:90 Chrysant SG. Antihypertensive effects of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Arch Intern Med 1994;154:737 Chrysant SG, Wombolt DG, Feliciano N, Zheng H. Long-term efficacy and tolerability of valsartan and hydrochlorothiazide in patients with essential hypertension. Curr Ther Res 1998;56:762 McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure. Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study investigators. Circulation 1999;100:1056 The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145 Chrysant SG, Weder AB, McCarron DA, et al. Effects of isradipine or enalapril on blood pressure in salt-sensitive hypertensives during low and high dietary salt intake. Am J Hypertens (in press)
Chrysant
23. Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS. Tissue distribution and quantitative analysis of estrogen receptor-alpha (ER␣) and estrogen receptorbeta (ER) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology 1997;138:4613 24. Jefferson WN, Couse JF, Banks EP, Korach KS, Newbold RR. Expression of estrogen receptor beta is developmentally regulated in reproductive tissues of male and female mice. Biol Reprod 2000;62:310 25. vom Saal F, Timms B, Montano M, et al. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci 1997;94:2056 26. Welshons WV, Nagel SC, Thayer KA, Judy BM, vom Saal FS. Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxy-
Nutrition Volume 16, Numbers 7/8, 2000
27. 28.
29.
30.
chlor and other xenoestrogens increases adult prostate size in mice. Toxicol Ind Health 1999;15:12 Thigpen JE, Setchell KD, Goelz MF, Forsythe DB. The phytoestrogen content of rodent diets (letter). Environ Health Perspect 1999;107:A182 Boettger-Tong H, Murthy L, Chiappetta C, et al. A case of a laboratory animal feed with high estrogenic activity and its impact on in vivo responses to exogenously administered estrogens. Environ Health Perspect 1998;106:369 Newbold RR, Hanson RB, Jefferson WN, et al. Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis 1998;19:1655 North K, Golding J. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. BJU Int 2000;85:107
High Salt Intake and Cardiovascular Disease: Is There a Connection? George S. Chrysant, MD From the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA INTRODUCTION Several epidemiologic studies in the past have demonstrated a positive association between high salt intake and the incidence of hypertension.1,2 Dahl1 found an almost linear relationship between salt intake and blood pressure in five different populations, whereas Gleibermann2 found a similar association in 27 different populations. In contrast, low salt intake (⬍30 mmol Na⫾/d), documented in more than 20 different primitive populations, has been associated with low blood pressure and the lack of rise of blood pressure with age.3 Migration of these populations toward the sea or to urbanized centers, where the consumption of salt is high, is associated with elevation of their blood pressure. Page et al.4 have described six separate primitive populations in the Solomon Islands who prepare their meals in salty, coastal waters, resulting in salt intakes of 150 –230 mmol Na⫾/d. These people have the highest blood pressures among the primitive populations. However, all these studies have been criticized for poor data collection and lack of statistical analysis. Based on these studies, a threshold of sodium intake of 30 mmol/d has been proposed to maintain normotension in the Western acculturated societies.4 – 6 Sodium intake of this magnitude is difficult to maintain by any Westernized society, as the average daily consumption of sodium in the US has been estimated to be 160 mmol. However, recent large, observational studies have questioned the association of salt intake and blood pressure.7 This multinational, multicenter study, which involved 11 000 adult men and women in 39 countries and 52 centers failed to show a significant relationship between 24-h urinary sodium excretion and blood pressure in the 48 acculturated populations, whereas it showed a positive correlation between body mass index and alcohol consumption in these populations.7 A significant association between 24-h sodium excretion and blood pressure emerged when the data from four centers of nonacculturated populations (Yanomamo and Xingu tribes in Brazil, as well as tribes in Kenya and Papua, New Guinea) were added. These populations had extremely low salt and alcohol intakes, as
Correspondence to: George S. Chrysant, MD, Department of Medicine, University of Alabama at Birmingham, 1808 Seventh Avenue South, Birmingham, AL 35294 – 0012, USA.
well as low body mass index and blood pressure. Another large study, of 11 629 Scottish men and women, is the Scottish Heart Health Study.8 This study also did not find any significant correlation between sodium intake and blood pressure after correcting for confounding variables, including body mass index and alcohol consumption. In contrast to these large observational studies, prospective randomized intervention trials provide a firmer association between salt intake and blood pressure. Three recent metaanalyses of such trials have shown a small but consistent association between salt intake and blood pressure. These metaanalyses included 108 trials in hypertension and 96 trials in normotensive subjects.9 –11 The sodium reduction averaged to a 24-h urinary sodium excretion of 100 mmol and was associated with a mean decrease in systolic blood pressure of 4.9 mm Hg for systolic and 2.4 mm Hg for diastolic blood pressure in hypertensive subjects. The blood pressure reductions in normotensive subjects were much smaller, 2.0 mm Hg for systolic and 1.5 mm Hg for diastolic. Most of the studies analyzed were of short duration to approximately 4 wk. Another multicenter trial, which included sodium restriction, weight loss, and behavioral modification (TOHP) in mild hypertensive patients, showed that after 6 mo of intervention, salt restriction and weight loss resulted in 3.7/2.7 and 2.9/1.6 mm Hg decreases in blood pressure, respectively. The combination of salt restriction and weight loss had a greater effect, lowering blood pressure by 4.0/2.8 mm Hg.12–14 However, all of these studies have not analyzed the results according to the salt sensitivity of hypertensive patients.
EFFECTS OF SALT IN SALT-SENSITIVE HYPERTENSIVE PATIENTS Blood pressure that is sensitive to salt intake is not universal among all individuals exposed to high salt intake and salt restriction. Salt sensitivity is defined by a rise or fall of diastolic blood pressure by at least 5 mm Hg from baseline in response to high or low salt intake.15 It has been reported that dietary salt restriction lowers the blood pressure in 30 – 60% of hypertensive subjects and in 25– 49% of normotensive subjects.16 –18 Sensitivity to dietary salt appears to be greater in black hypertensive patients,16,17,19 –21 elderly hypertensive patients,16,19,22 obese,23,24 and female hyper-
Nutrition Volume 16, Numbers 7/8, 2000 tensive patients.25,26 Possible pathophysiologic mechanisms accounting for this salt sensitivity include low plasma renin activity,16,18,27,28 increased sympathetic nervous system activity,29 –31, and insulin resistance in the obese32,33 and in women using oral contraceptives.34 Salt-sensitive hypertensive patients demonstrate a clinically significant blood pressure reduction to salt restriction. A recent large multicenter study showed that moderate salt restriction of 80 –100 mmol/d sodium in salt-sensitive hypertensive patients resulted in a decrease in systolic and diastolic blood pressure of 10 and 7 mm Hg, respectively, and there were no racial, age, gender, or weight differences in the response of blood pressure to salt restriction.15 These blood pressure reductions are similar to those obtained with the use of antihypertensive drugs. In addition, these levels of salt restriction should be easy to maintain. However, even in this well-supervised study, there was a drift of salt intake toward higher levels as the time progressed. The problem therefore is modification of the eating habits of patients, and with the food industry to reduce salt content in baby foods.
SALT AND TARGET ORGAN DAMAGE High salt intake has been associated with left ventricular hypertrophy (LVH) in patients with essential hypertension. Whether this association with LVH occurs independently of blood pressure is debatable at present. Because LVH has been implicated in an increase in cardiovascular morbidity and mortality, the finding of a link between sodium intake and LVH would be clinically relevant. Such a link is supported by present observational and interventional studies. An echocardiographic study of the heart in 50 hypertensive patients showed that salt-sensitive hypertensive patients exposed to high salt intake (260 mmol sodium/d) for 1 wk demonstrated an increase in left ventricular mass in salt-sensitive patients compared to salt-resistant patients, although the blood pressures of both groups were similar.35 Another study of 68 untreated mild to moderate hypertensives studied by M-mode and two-dimensional echocardiography of the heart showed a positive correlation between sodium intake and LVH, which was independent of blood pressure.36 An interesting finding of this study was that the higher prevalence of LVH was in the group with higher angiotensin II levels, suggesting that the failure to suppress the renin-angiotensin-aldosterone system (RAAS) by salt intake may contribute to the development of LVH in individuals consuming high-salt diets. Normally, sodium is linked with RAAS in a negative-feedback loop. Subjects unable to suppress RAAS by high sodium intake would have two independent but related stimuli for LVH: increased blood pressure and increased angiotensin II and aldosterone levels, both of which have trophic effects on the heart and blood vessels. Salt-sensitive subjects more often fail to suppress the RAAS in response to a salt load than do salt-resistant subjects.36 Another study showed a positive relationship between salt restriction and reversion of LVH in hypertensive patients.37 However, in this study it was difficult to separate the effect of decrease in blood pressure or salt intake from the reduction of LVH. Along with its adverse effects on the heart, high sodium intake exerts adverse hemodynamic effects on the kidney. Several investigators have demonstrated decreased renal blood flow and glomerular filtration rate, and an increase in filtration fraction and renal vascular resistance with high salt intake both in salt-sensitive animals and in humans.38 – 41 Weir et al.41 also showed that high salt intake by salt-sensitive hypertensive patients increases protein excretion, which could have long-term detrimental effects on the kidney.
SALT RESTRICTION AND CARDIOVASCULAR RISK Although salt restriction has been regarded as free from adverse effects, a few studies have examined the potential deleterious
Salt and Cardiovascular Disease
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cardiovascular effects of salt restriction. Alderman et al.42 studied salt restriction in 2937 mildly to moderately hypertensive participants at a work site. They found that the incidence of myocardial infarction was inversely related to urinary sodium excretion. This was true for men and not true for women. However, there was no relationship between urinary sodium excretion and stroke, noncardiovascular morbidity, or non-cardiovascular mortality. Another large study, the National Health and Nutrition Examination Survey (NHANES I), showed similar findings in 11 346 participants.43 There were 3923 deaths, 1970 of which were cardiovascular, and the death rate was inversely related to urinary sodium excretion. However, both of these studies have been criticized by several authors for a number of important limitations, such as single random urinary samples for sodium excretion and the unreliability of dietary recall for salt and calorie consumption. Although these data are insufficient to justify the conclusion that dietary sodium reduction per se increases cardiovascular morbidity and mortality, they are provocative. It is well known that salt restriction activates the RAAS, which may adversely influence cardiovascular outcomes. Plasma renin and aldosterone levels are increased in a dose-dependent fashion in response to sodium restriction in both hypertensive and normotensive subjects.11,44 Plasma renin activity (PRA) has been invoked as an independent risk factor for cardiovascular events, such as myocardial infarction and stroke.45 A 5-y follow-up of 219 untreated patients with moderate to severe hypertension with low, normal, or high PRA showed an incidence of myocardial infarction or stroke of 0%, 11%, and 14% for patients with low, normal, or high PRA, respectively.45 In another study it was shown that baseline PRA was highly predictive of myocardial infarction.46 In 1717 patients with mild hypertension, followed-up for 8 y, the incidence of myocardial infarction was 3.2-fold higher in patients with high PRA, compared with those with low PRA. However, this positive relationship between PRA and myocardial infarction has not been observed by other investigators and no clear association between PRA and myocardial infarction or sudden death has been documented in normotensive men.47 Also, myocardial infarction or stroke is rare in primitive populations consuming low-salt diets.4 Additional adverse effects of salt restriction include the activation of the sympathetic nervous system,11 elevation of low-density lipoprotein cholesterol and triglycerides,48,49 decrease in nutrient intake,49 and increase in circulating insulin levels.50 All these adverse metabolic changes may increase the cardiovascular morbidity and mortality.51 These adverse hormonal and metabolic adverse effects of salt restriction can be prevented when low dietary salt intake is combined with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in hypertensive patients.52, 53 This combination produces a synergistic effect with significant blood pressure reduction.54,55
SUMMARY AND RECOMMENDATIONS Based on current knowledge, moderate salt restriction (80 –100 mmol/d sodium) is recommended for all hypertensive patients, especially those that are salt sensitive, such as blacks, the elderly, obese, and diabetics.51 Additional benefits include reduced diuretic-induced hypokalemia,54, 55 better blood pressure control with low-dose diuretics, and preventing target organ damage, most notably LVH. Increased use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, if the first are not tolerated, is recommended as a preferred treatment in hypertensive patients due to the significant cardiovascular protection afford by these drugs.56, 57 Hypertensive patients who are unable to maintain a low-salt diet should be treated, preferably, with calcium channel blockers, as these agents have been shown to be more effective with unrestricted salt intake.58
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Nutrition Volume 16, Numbers 7/8, 2000
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