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(Circulation. 1997;95:581-587.)
© 1997 American Heart Association, Inc.

Articles

Baseline Sodium-Lithium Countertransport and 6-Year Incidence of Hypertension

The Gubbio Population Study

Martino Laurenzi, MD, MPH; Massimo Cirillo, MD; Walter Panarelli, MD; Maurizio Trevisan, MD; Rose Stamler, MA; Alan R. Dyer, PhD; Jeremiah Stamler, MD; for the Gubbio Study Research Group

the Center for Epidemiological Research, Merck Sharp & Dohme Italy, Rome (M.L.); the Department of Preventive Medicine, Northwestern University Medical School, Chicago, Ill (M.L., M.C., R.S., A.R.D., J.S.); the Division of Nephrology, Medical School, 2nd Naples (Italy) University (M.C.); the Department of Preventive Medicine, State University of New York, Buffalo (M.T.); and Gubbio (Italy) Civil Hospital (W.P.).

Correspondence to Jeremiah Stamler, MD, Department of Preventive Medicine, Northwestern University Medical School, 680 N Lake Shore Drive, Suite 1102, Chicago, IL 60611-4402. E-mail hwe216@nwu.edu.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Sodium-lithium countertransport (Na-Li CT) activity is high in persons with hypertension. This study investigated whether high Na-Li CT relates to development of hypertension.

Methods and Results At the baseline visit of the Gubbio Population Study, 4210 people of the 5376 surveyed were 18 to 74 years old; of these, 1599 were hypertensive (systolic pressure 140 mm Hg, or diastolic pressure 90 mm Hg, or on antihypertensive drug therapy). Of the 2611 nonhypertensives, 302 did not have Na-Li CT measured and 580 did not participate in 6-year follow-up. This analysis, therefore, deals with data collected on 1729 men 18 to 74 years old and women 18 to 74 years old who at baseline were nonhypertensive and had Na-Li CT measurement. Compared with individuals who were nonhypertensive at baseline and follow-up, individuals with incident hypertension at follow-up (systolic pressure 140 mm Hg, or diastolic pressure 90 mm Hg, or on antihypertensive drug therapy) had higher baseline values of Na-Li CT, blood pressure, age, body mass index, plasma cholesterol, and alcohol intake (P<.05). Baseline Na-Li CT was positively associated (P<.05) with development of hypertension in quartile analysis, with highest incidence of hypertension among men and women with Na-Li CT in the highest quartile (for men, 376 and for women, 311 µmol Li·L red blood cells^-1·h^-1). In univariate logistic regression, incidence of hypertension was related to baseline value of Na-Li CT, blood pressure, age, body mass index, plasma cholesterol, and alcohol intake (P<.05). In multiple logistic regression analysis, individuals with baseline Na-Li CT higher by 127 µmol (pooled SD for men and women) had 1.23 times greater risk of incident hypertension with control for sex and baseline age, body mass index, systolic pressure, and other confounders (P<.001).

Conclusions Na-Li CT is a predictor of hypertension risk in adults.

Key Words: hypertension • sodium-lithium countertransport • Gubbio Population Study

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Sodium-lithium countertransport is a membrane transport system usually measured as sodium-dependent Li efflux from Li-loaded RBCs.^{1 2} Canessa et al³ in 1980 first showed that average values of Na-Li CT are elevated in RBCs of hypertensive compared with nonhypertensive individuals. Since then, several reports, including those from population-based studies, confirmed the existence of a positive association between Na-Li CT and blood pressure/hypertension.^{4 5 6 7 8 9 10 11} Na-Li CT activity relates in some studies to Na-proton exchange activity^{12 13 14 15 16} and to indices of Na reabsorption at the renal tubular level¹⁷ ; however, the physiological role of this transport system is not yet well defined. Unsolved key questions are (1) Does high Na-Li CT activity exist before development of hypertension? and (2) Is high Na-Li CT activity in nonhypertensive individuals an index of increased risk of future development of hypertension? Only one prospective study has presented data on this matter; the Utah Study reported that for its whole cohort, baseline Na-Li CT activity did not relate to 7-year incidence of being placed on antihypertensive drugs, as ascertained by a questionnaire answered by 67% of originally nonhypertensive participants.¹⁸

A prior aim of the Gubbio Population Study^{9 19 20 21 22} was to investigate prospectively whether baseline Na-Li CT was significantly and independently related to incidence of hypertension. This report bases its findings on 6-year follow-up of the nonhypertensive population sample of 1729 men and women 18 to 74 years old at baseline.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Cohort
The Gubbio Population Study is an ongoing cross-sectional and prospective investigation in the hill town of Gubbio, north central Italy.^{9 19 20 21 22} The baseline examination was done between 1983 and 1986; 5376 individuals of both sexes 5 years old were surveyed at the Gubbio Center for Preventive Medicine. The second examination—6-year follow-up—was performed between 1989 and 1992; 5288 individuals were surveyed, of whom 3727 had been baseline participants. Of the 1649 individuals who attended at baseline and not at follow-up, 418 were dead at the time of follow-up; therefore, the response rate at follow-up for surviving baseline participants was 75.2%.

Individuals with baseline ages of 18 to 74 years and with valid baseline Na-Li CT measurement were selected for analysis in this study if they were nonhypertensive at baseline examination (SBP <140 mm Hg, DBP <90 mm Hg, and no treatment with antihypertensive drugs). At baseline, 4210 individuals were in this age stratum, of whom 1599 were hypertensive (SBP 140 mm Hg, or DBP 90 mm Hg, or regular treatment with antihypertensive drugs). Of the 2611 nonhypertensives, 302 did not have valid measurement of baseline Na-Li CT, ie, either Na-Li CT was not measured or the measurement was rejected at baseline due to technical inadequacy⁹ ; another 580 of these nonhypertensives did not participate in the follow-up examination. Therefore, the cohort for this article is made up of 1729 individuals who at baseline were nonhypertensive, 18 to 74 years old, and with valid Na-Li CT; they are 66.2% of the entire target cohort and 74.9% of those with valid baseline Na-Li CT measurement.

Data Collection
At baseline, data were collected, as previously reported,^{9 19 20 21 22} for sex, age, weight, height, SBP, DBP, pulse rate, antihypertensive treatment status, habitual alcohol intake, plasma cholesterol, and urinary ratio of Na to K concentration in first-voided morning spot urine (taken as an index of dietary salt and K intake).²³ Baseline Na-Li CT was measured in RBCs according to slight modifications⁹ of the method of Canessa et al.³ At second examination, data were collected as at the baseline visit for blood pressure and antihypertensive treatment. At baseline and follow-up examination, hypertension was defined as SBP 140 mm Hg, or DBP 90 mm Hg, or regular treatment with antihypertensive medication.

Statistics
In univariate analyses, differences in means between two groups were analyzed by unpaired Student's t test, assuming that the variances were not equal in the two groups compared; differences in proportions between two groups were tested by ² analysis with Yates' correction for continuity. ANOVA was used to test differences in means when groups were more than two and/or when analyses were adjusted for covariates. Quantile analysis of baseline Na-Li CT was used to test whether the relationship of Na-Li CT to incident hypertension and other variables was continuous and progressive; quantile analysis was based on quartiles instead of quintiles used for cross-sectional data,⁹ since the cohort size was reduced because of exclusion of persons hypertensive at baseline examination. Test for linearity was used to assess whether means of variables (Pearson's ²) and proportions (Mantel-Haenszel test) increase or decrease progressively across quartiles; in these tests, the null hypothesis was that means or proportions are equal across quartiles. Scheffe's test was used for multiple comparisons among quartiles. Univariate and multivariate logistic regressions were done with incident hypertension as dependent variable. Two-tailed values of P.05 were considered statistically significant in all analyses. Exponentiation of the logistic regression coefficient was used to estimate relative risk of incident hypertension with 1 SD higher baseline Na-Li CT.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Descriptive Statistics
Of surviving individuals at baseline with measured Na-Li CT, nonhypertensive, and 18 to 74 years old, those included in the present analysis (n=1729) and those not included (n=580) had no significantly different values (mean±SD) in baseline Na-Li CT (women, 260±117 and 268±123 µmol·L RBCs^-1·h^-1, P=.352; men, 309±138 and 313±135 µmol·L RBCs^-1·h^-1, P=.683); different values for baseline age (women, 40.8±13.8 and 36.0±15.5 years, P<.001; men, 40.9±14.4 and 38.3±15.7 years, P=.009); similar values for baseline SBP (women, 117.3±11.0 and 116.5±11.3 mm Hg, P=.275; men, 120.8±9.7 and 120.3±9.9 mm Hg, P=.432); and different values for baseline DBP in women but not in men (women, 71.1±8.2 and 69.5±9.4 mm Hg, P=.009; men, 73.2±8.7 and 73.2±8.5 mm Hg, P=.993). In ANOVA done separately for men and women, baseline values of Na-Li CT, SBP, and DBP were not significantly different between those included in the present analysis and those not included after adjustment for differences in baseline age (data not shown).

Baseline characteristics for 1729 men and women included in the analysis are given by sex in Table 1. Duration of follow-up and baseline values of Na-Li CT, blood pressure, pulse rate, body mass index, plasma cholesterol, and indices of alcohol intake were significantly different for men and women.

View this table: [in this window] [in a new window]   Table 1. Descriptive Statistics for Selected Variables at Baseline in Nonhypertensive Men and Women 18 to 74 Years Old

Incidence of Hypertension
Incidence of hypertension was similar for the two sexes (12.6% and 13.1% for women and men, respectively; P=.806) and was higher with greater age for both men and women (Figure); no women with baseline age of 18 to 24 years were hypertensive at follow-up. Among 118 women and 104 men with incident hypertension, 34 and 25, respectively, were regular users of antihypertensive drug treatment at follow-up.

View larger version (33K): [in this window] [in a new window]   Figure 1. Six-year incidence of hypertension by sex and baseline age in 929 women and 800 men who were 18 to 74 years old, nonhypertensive, and with valid sodium-lithium countertransport determination at baseline. At baseline and follow-up, hypertension was defined as SBP 140 mm Hg, or DBP 90 mm Hg, or regular antihypertensive drug treatment. No women 18 to 24 years old at baseline became hypertensive during the next 6 years.

Table 2 shows baseline values by sex for two blood pressure strata, those nonhypertensive at baseline and follow-up (NN in table) and those nonhypertensive at baseline and hypertensive at follow-up (NH in table). Baseline Na-Li CT, blood pressure, age, body mass index, plasma cholesterol, and indices of alcohol intake were significantly higher in NH than in NN for both sexes.

View this table: [in this window] [in a new window]   Table 2. Baseline Values of Na-Li CT (Mean) and Other Variables (Mean±SD or %) in NN Group Compared With NH Group

Baseline Na-Li CT, Other Variables, and Incidence of Hypertension
Univariate Analyses
Tables 3 and 4 show, for the two sexes separately, percent incidence of hypertension, percentage of persons on regular antihypertensive drug treatment, follow-up duration, and baseline values of selected variables by quartile of baseline Na-Li CT. In the last two columns, the tables show probability values for differences among quartiles (ANOVA or ² analysis) and for tests of linearity (Pearson's ² and Mantel-Haenszel test). Mean age at baseline did not differ among the four strata. Duration of follow-up, baseline values of body mass index, and plasma cholesterol were significantly higher with higher level of baseline Na-Li CT, and there was a similar trend for alcohol intake. In men only, baseline age was linearly higher with higher levels of baseline Na-Li CT. Differences in hypertension incidence were significant for women and borderline significant for men. In both sexes, incidence of hypertension was highest in quartile 4. In analyses for men and women combined, incidence of hypertension by Na-Li CT quartile was 10.0%, 11.3%, 11.3%, and 18.6%, respectively (P<.001 for Pearson's ², P<.001 for Mantel-Haenszel test of linearity).

View this table: [in this window] [in a new window]   Table 3. Quartiles of Baseline Na-Li CT, Incidence of Hypertension, and Other Variables (Mean or %), Women

View this table: [in this window] [in a new window]   Table 4. Quartiles of Baseline Na-Li CT, Incidence of Hypertension, and Other Variables (Mean or %), Men

On the basis of this observation, a post hoc categorical grouping of participants according to baseline Na-Li CT was used in some statistical analyses, ie, those in quartiles 1 to 3 (with Na-Li CT <376 µmol·L RBCs^-1·h^-1 for men and <311 µmol·L RBCs^-1·h^-1 for women) and those in quartile 4. The incidence of hypertension was almost twofold higher in quartile 4 than in quartiles 1 to 3 for both sexes (women, 18.8% and 10.5%, P<.001; men, 18.4% and 11.3%, P=.010). The difference between quartile 4 and quartiles 1 to 3 strata remained significant with control for baseline age and duration of follow-up (women, 10.6% and 17.6%, P=.008; men, 18.1% and 11.1%, P=.021).

Table 5 gives univariate logistic regression analyses on the relation of baseline values of Na-Li CT (expressed both as continuous and categorical variables) and other variables to incidence of hypertension. In both sexes, statistically significant positive associations were observed for baseline Na-Li CT, blood pressure, age, body mass index, plasma cholesterol, and alcohol intake. The log, exponential, or quadratic transformation of baseline Na-Li CT did not improve statistical significance of its regression coefficient for hypertension incidence in these models.

View this table: [in this window] [in a new window]   Table 5. Univariate Logistic Regression Coefficients of Baseline Na-Li CT and of Other Variables With Incidence of Hypertension

Multivariate Analyses
In multiple logistic regression (Table 6), baseline values of Na-Li CT (continuous variable, µmol·L RBCs^-1·h^-1), blood pressure, age, and body mass index were significantly related to incidence of hypertension with baseline SBP or DBP in the analysis. In the two alternative models shown in Table 6, regression coefficients (and their standard errors, not shown) were similar for the several independent variables. The log, exponential, or quadratic transformation of Na-Li CT did not improve the statistical significance of its regression coefficient for hypertension incidence in these models. When the analyses were done separately for men and women, regression coefficients were positive for both sexes and were significant in women (in the model with baseline SBP, +0.0028±0.0009, P=.002; in the model with baseline DBP, +0.0024±0.0009, P=.009) but not in men (in the model with baseline SBP, +0.0010±0.0009, P=.265; in the model with baseline DBP, +0.0009±0.0008, P=.247).

View this table: [in this window] [in a new window]   Table 6. Multiple Logistic Regression Coefficients of Baseline Na-Li CT and Other Variables (Independent Variables) With Incidence of Hypertension at Follow-up (Dependent Variable) in Men and Women

In multivariate models with baseline Na-Li CT used as a categorical variable (0/1=quartiles 1 to 3/quartile 4) in the place of the continuous variable (Table 7), Na-Li CT was positively related to incidence of hypertension with baseline SBP or DBP included in the analysis. In the two alternative models, regression coefficients (and their standard errors, not shown) were similar for the several independent variables to those in models with baseline Na-Li CT used as a continuous variable (Table 6).

View this table: [in this window] [in a new window]   Table 7. Multiple Logistic Regression Coefficients of Baseline Na-Li CT (Categorical Variable*) and Other Variables (Independent Variables) With Incidence of Hypertension at Follow-up (Dependent Variable) in Men and Women

On the basis of exponentiation of the coefficient shown in Table 6 (model with use of SBP and continuous Na-Li CT), individuals with baseline Na-Li CT higher by 127 µmol·L RBCs^-1·h^-1 (pooled SD of baseline Na-Li CT for men and women) had 1.23 greater risk of incident hypertension (95% CI, 1.12 to 1.35). On the basis of exponentiation of the coefficient shown in Table 7 (model with SBP and categorical Na-Li CT), individuals in quartile 4 had 1.63 greater risk of incident hypertension than individuals in quartiles 1 to 3 (95% CI, 1.36 to 1.94).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Longitudinal data from the present study show for the first time that Na-Li CT activity is a significant predictor of incidence of hypertension in adult nonhypertensives. Incidence of hypertension was also related to baseline values of blood pressure, age, and body mass index. The relation between baseline Na-Li CT and incidence of hypertension remained significant in multivariate analyses for the whole cohort. Exponentiation of logistic coefficients from multivariate models indicated that a nonhypertensive individual had 1.23 times the risk of having hypertension at 6-year follow-up if his or her Na-Li CT was higher by 127 µmol (1 SD). At least in men, the association between baseline Na-Li CT and hypertension incidence appeared to be well described by a nonlinear post hoc model in which high Na-Li CT (quartile 4) is compared with low-normal (quartiles 1 to 3 combined). This could reflect the nonnormal distribution of Na-Li CT⁷ and/or the need for longer follow-up to detect a small increase in risk of incident hypertension in persons with lower-order elevations of Na-Li CT.

Results from the present study are apparently different from those reported from the Utah Study, which concluded that high Na-Li CT in RBCs was not associated with increased risk of hypertension for the whole cohort, stratified according to Na-Li CT levels of both participants and their blood relatives.¹⁸ These seemingly disparate findings could be due to methodological differences between the two studies. Incidence of hypertension in the Utah Study was based exclusively on inception of antihypertensive medication ascertained by questionnaire, a procedure that yielded an underestimate of real incidence of hypertension. In fact, in the Gubbio population, <30% of individuals with incident hypertension were on regular antihypertensive drug treatment at follow-up. Another difference is that the Utah Study investigated persons from selected pedigrees with high cardiovascular risk,²⁴ whereas the cohort of the Gubbio Study was a sample of the whole population irrespective of family medical history. Finally, sample size, and hence statistical power, was smaller in the Utah than in the Gubbio Study.

The prospective findings from the Gubbio Population Study extend previous observations based on cross-sectional analyses of Na-Li CT and prevalent hypertension and support the hypothesis that the development of hypertension in humans is related to cellular Na transport, a hypothesis proposed 40 years ago.^{25 26} Several studies of circulating blood cells reported inconsistent findings on relationships of Na-K pump and Na-K-Cl cotransport to blood pressure,¹ but clinical and epidemiological studies almost unanimously found high average RBC Na-Li CT in people with elevated blood pressure, at least for white hypertensive persons.^{1 2 3 4 5 6 7 8 9 10 11} Whether high Na-Li CT of hypertensives reflects a high V_max and/or an elevated affinity for extracellular Na of the Na-binding site of the exchanger remains to be defined.^{27 28 29} The mechanism underlying the association of high Na-Li CT with hypertension remains speculative. Evidence that high Na-Li CT relates to risk of hypertension does not necessarily prove that Na-Li CT activity is relevant to the mechanism of hypertensive disease, because high Na-Li CT activity could be a marker of other processes related to a prohypertensive condition. Na-Li CT is heritable,^{30 31 32} but it also relates to environmental factors.^{19 33 34 35} The specific physiological role of Na-Li CT is not yet defined despite evidence that it relates to Na-proton exchange activity^{12 13 14 15 16} and to indices of renal tubular Na reabsorption rate.¹⁷ Theoretically, high Na-Li CT could reflect altered vascular smooth muscle function, wherein Na-proton exchange modulates growth and contraction,³⁶ and/or low renal Na excretion, two mechanisms potentially involved in blood pressure elevation.

The findings of the present study that baseline values of blood pressure, age, and body mass index were statistically independent predictors of hypertension incidence in both sexes confirm data from previous research indicating that a high-normal blood pressure is a hypertension-prone condition and that overweight is associated with increased risk of incident hypertension.^{37 38} The lack of significant associations with hypertension incidence for baseline values of other variables may be explained in several ways. For plasma cholesterol and alcohol intake, which were related to hypertension incidence in univariate analyses, lack of significant association in multivariate analyses controlled for baseline values of Na-Li CT may represent overadjustment, since plasma cholesterol and alcohol intake were both significantly related to Na-Li CT in the Gubbio population.^{9 19} In the case of baseline spot urine Na/K ratio, lack of significant association in univariate and multivariate analyses may reflect limited statistical power due to small sample size and/or regression-dilution bias due to use of a single spot instead of one or more 24-hour urine collections.²³

In summary, this longitudinal population-based study showed for the first time that the measurement of Na-Li CT in RBCs predicted incidence of hypertension in nonhypertensive adults. These data indicate that the risk of hypertension in the population relates to the status of Na homeostasis at the cellular level present before hypertensive disease becomes established.

	Selected Abbreviations and Acronyms

 

DBP = diastolic blood pressure Na-Li CT = sodium-lithium countertransport RBC = red blood cell SBP = systolic blood pressure

	Acknowledgments

 
The Gubbio Population Study, made possible thanks to the people of Gubbio, was supported, planned, and carried out by the Center for Epidemiological Research, Merck Sharp & Dohme Italy (MSD-I), in cooperation with the Center for Preventive Medicine in Gubbio (CPM), the Institute of Internal Medicine and Metabolic Diseases, University of Naples, Italy (IIMMDUN), the Istituto Superiore di Sanita, Rome, Italy (ISS), and the Department of Preventive Medicine, Northwestern University Medical School, Chicago, Ill (DPMNUMS). Determination of erythrocyte Na-Li countertransport was done in the IIMMDUN laboratory; determination of plasma lipids was done in the ISS laboratory. The research was supervised and guided by a Scientific Policy Board, whose members were Prof P. Angeletti (Chairman, MSD-I, deceased), Dr L. Carratelli (MSD-I), Prof M. Mancini (IIMMDUN), Dr U. Mortari (MSD-I), Prof A. Menotti (ISS), Prof R. Stamler and Prof J. Stamler (DPMNUMS), and Prof A. Zanchetti, Institute of Internal Medicine, University of Milan, Italy. Thanks are expressed for their fine cooperation to the staff of the Gubbio Civil Hospital, particularly Dr M. Angeletti and Dr O. Cardoni, and the staff of the field survey team (CPM). The Gubbio Population Study was also funded by grant R01-HL-40397-02 from the National Heart, Lung, and Blood Institute.

Received May 6, 1996; revision received August 22, 1996; accepted September 4, 1996.

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				M. Cirillo, M. Laurenzi, M. Mancini, A. Zanchetti, and N. G. De Santo Low Muscular Mass and Overestimation of Microalbuminuria by Urinary Albumin/Creatinine Ratio Hypertension, January 1, 2006; 47(1): 56 - 61. [Abstract] [Full Text] [PDF]

				O. Vaccaro, V. Cuomo, M. Trevisan, M. Cirillo, W. Panarelli, M. Laurenzi, M. Mancini, G. Riccardi, and On behalf of the Gubbio Study Research Group Enhanced Na-Li countertransport: a marker of inherited susceptibility to type 2 diabetes Int. J. Epidemiol., October 1, 2005; 34(5): 1123 - 1128. [Abstract] [Full Text] [PDF]

				G. Zerbini, D. Gabellini, D. Ruggieri, and A. Maestroni Increased Sodium-Lithium Countertransport Activity: A Cellular Dysfunction Common to Essential Hypertension and Diabetic Nephropathy J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S81 - 84. [Abstract] [Full Text]

				G. Zerbini, A. Maestroni, D. Breviario, R. Mangili, and G. Casari Alternative Splicing of NHE-1 Mediates Na-Li Countertransport and Associates With Activity Rate Diabetes, June 1, 2003; 52(6): 1511 - 1518. [Abstract] [Full Text] [PDF]

				M. Cirillo, M. Laurenzi, W. Panarelli, M. Trevisan, and J. Stamler Prospective Analysis of Traits Related to 6-Year Change in Sodium-Lithium Countertransport Hypertension, March 1, 1999; 33(3): 887 - 893. [Abstract] [Full Text] [PDF]

				M. Pahor, M. B. Elam, R. J. Garrison, S. B. Kritchevsky, and W. B. Applegate Emerging Noninvasive Biochemical Measures to Predict Cardiovascular Risk Arch Intern Med, February 8, 1999; 159(3): 237 - 245. [Abstract] [Full Text] [PDF]

				M. Cirillo, L. Senigalliesi, M. Laurenzi, R. Alfieri, J. Stamler, R. Stamler, W. Panarelli, and N. G. De Santo Microalbuminuria in Nondiabetic Adults: Relation of Blood Pressure, Body Mass Index, Plasma Cholesterol Levels, and Smoking: The Gubbio Population Study Arch Intern Med, September 28, 1998; 158(17): 1933 - 1939. [Abstract] [Full Text]

				P. Strazzullo, A. Siani, F. P. Cappuccio, M. Trevisan, E. Ragone, L. Russo, R. Iacone, and E. Farinaro Red Blood Cell Sodium-Lithium Countertransport and Risk of Future Hypertension : The Olivetti Prospective Heart Study Hypertension, June 1, 1998; 31(6): 1284 - 1289. [Abstract] [Full Text] [PDF]

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