(Hypertension. 1996;27:1305-1311.)
© 1996 American Heart Association, Inc.
Articles |
Sodium-Lithium Countertransport and Blood Pressure Change Over Time
The Gubbio Study
From the Division of Nephrology, Medical School, Second Naples (Italy) University (M.C.); Department of Preventive Medicine, Northwestern University Medical School, Chicago, Ill (M.C., M.L., A.R.D., R.S., J.S.); Center for Epidemiologic Research, Merck Sharp & Dohme–Italy, Rome (M.L.); Gubbio (Italy) Civil Hospital (W.P.); and Department of Preventive Medicine, State University of New York, Buffalo (M.T.).
Correspondence to Jeremiah Stamler, MD, Department of Preventive Medicine, Northwestern University Medical School, 680 N Lake Shore Dr, Suite 1102, Chicago, IL 60611.
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Abstract |
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Abstract Sodium-lithium countertransport activity in red blood cells relates to blood pressure (BP) and the prevalence of hypertension. This study investigated in adults the relation of sodium-lithium (Na-Li) countertransport to BP change from baseline to 6-year follow-up. In the Gubbio Population Study, 4210 men and women were 18 to 74 years old at baseline (1983-1986), and 3766 had a valid baseline Na-Li countertransport measurement; of these, 2729 were reexamined at 6 years of follow-up (1989-1992) and made up the study cohort. At baseline, data collection included age, height, weight, BP, pulse rate, drug treatment, alcohol intake, ratio of sodium to potassium in spot urine, plasma cholesterol, and Na-Li countertransport in red blood cells. At 6-year follow-up, data for age, BP, and drug treatment were collected as at baseline. From baseline, average BP declined for people on antihypertensive medication at follow-up and for those with baseline BP greater than or equal to 140/90 mm Hg (systolic/diastolic) and did not change or increased for the remaining participants. In quartile and correlation analyses controlled for sex, baseline BP, and antihypertensive treatment, BP change related significantly and directly to baseline Na-Li countertransport. In multiple linear regression analyses done for the entire cohort with control for other confounders, the regression coefficient of baseline Na-Li countertransport to BP change over time was positive and borderline significant. The Na-Li countertransport coefficient was positive and significant when analyses were done with the use of a categorical value of baseline Na-Li countertransport (quartile 4 and quartiles 1 through 3 combined). In both models, the Na-Li countertransport coefficient was the strongest for people with baseline BP greater than or equal to 120/80 mm Hg or for people with baseline age of 45 years or older. In conclusion, Na-Li countertransport significantly relates to BP change over time in adults.
Key Words: population study • blood pressure • sodium-lithium countertransport • Gubbio population study
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Introduction |
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In most societies, blood pressure (BP) increase with age during adulthood is a common phenomenon, leading to an epidemic prevalence of high-normal and high BP levels among middle-aged and older individuals.1 2 3 4 5 6 7 8 Dietary salt is one factor responsible for these BP changes with age, but mechanisms for its influence have not been well defined.4 5 6 7 8 Altered cellular sodium homeostasis is believed to play a role in the pathogenesis of BP elevation.9 In particular, activity of sodium-lithium (Na-Li) countertransport in red blood cells relates to BP and hypertension, as shown in several clinical and population-based studies.10 11 12 13 14 15 16 17 18 Na-Li countertransport is a membrane transport system involving a one-to-one exchange of sodium for lithium and is usually measured as sodium-dependent lithium efflux in lithium-loaded red blood cells. Na-Li countertransport activity relates to sodium-proton exchange19 20 21 22 23 and to indexes of sodium reabsorption at the renal tubular level,24 but its physiological role is not yet defined. It is not known whether high Na-Li countertransport activity precedes the development of high BP and whether Na-Li countertransport activity relates to the degree of BP increase with age.9 25 Clarification of these issues is one of the aims of the Gubbio Population Study,16 26 27 28 29 30 in which a prospective design was used for investigation of whether baseline Na-Li countertransport is related to BP change over time.
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Methods |
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Study Cohort
The Gubbio Population Study is an ongoing cross-sectional and prospective investigation in the hill town of Gubbio in north central Italy.16 26 27 28 29 30 A baseline examination was done between 1983 and 1986; 5376 individuals 5 years old and older of both sexes were surveyed at the Gubbio Center for Preventive Medicine. A 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%.
Of 4210 baseline examinees originally aged 18 to 74 years, 444 did not have a valid baseline Na-Li countertransport determination, either because Na-Li countertransport was not measured or because the baseline measurement was rejected because of high technical error.16 Of 3766 individuals with baseline age of 18 to 74 years and valid Na-Li countertransport determination, the target cohort for the present analysis, 2729 (72.4%) were reexamined and made up the cohort for this report.
Data Collection
As previously reported,16 at baseline data
collection included sex, age, weight, height, systolic and
diastolic BPs (SBP and DBP), pulse rate, antihypertensive
treatment status, habitual alcohol intake, plasma
cholesterol, and urinary ratio of sodium to potassium
concentration in first-voided morning spot urine, taken as a
possible index of dietary salt and potassium intakes.4 6
Baseline Na-Li countertransport was measured by the method of Canessa
et al10 with minor modifications.16 At second
examination, data for age, weight, BP, and antihypertensive treatment
were collected as at baseline. Hypertension was defined as SBP greater
than or equal to 140 mm Hg or DBP greater than or equal to 90 mm Hg, or
regular drug treatment with antihypertensive drug.
Statistics
Statistical evaluation of results involved Student's
t test for paired data; ANOVA; test for linearity;
2 analysis; McNemar's test; and
univariate, bivariate, and multivariate
linear regression and correlation analyses.
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Results |
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Descriptive Statistics
Of surviving individuals with baseline ages of 18 to 74 years and measured baseline Na-Li countertransport, those included in the present analysis (n=2729) and those not included (n=1037) had at baseline similar average ages (men: 45.7±15.4 and 45.4±17.6 years; women: 47.4±15.2 and 48.6±18.4 years) and Na-Li countertransport (men: 327±143 and 325±149 µmol/L red blood cells per hour; women: 274±125 and 283±126 µmol/L red blood cells per hour). Average SBP values of the two groups were similar in men (131.3±19.5 and 132.8±21.4 mm Hg) and different in women (131.6±23.0 and 136.9±27.2 mm Hg, P<.001); average DBP values of the two groups were similar in both sexes (men: 77.9±11.4 and 77.4±11.1 mm Hg; women: 76.9±11.9 and 76.7±13.3 mm Hg); prevalence rates of hypertension of the two groups were similar in men (34.7% and 38.5%) and different in women (38.2% and 48.0%, P<.001).
The duration of follow-up averaged about 6 years in men and women
(5.89±1.09 and 5.93±1.39 years). Table 1
shows
descriptive statistics on BP by sex and use of regular antihypertensive
drug treatment. Compared with baseline, follow-up BP was lower and
the percentage of individuals on antihypertensive drug treatment was
higher in analyses for all men and women. People who were
taking antihypertensive drugs at follow-up (Treated) had the
largest BP reduction. Table 2 shows descriptive baseline
statistics for Na-Li countertransport and other variables by
sex.
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Baseline BP and BP Change
As expected, in part because of regression to the
mean29 and effects of antihypertensive treatment, in
univariate correlation analyses, baseline SBP and
DBP were inversely correlated with BP change per year of follow-up
(r=-.430 to -.525, P<.001); ie, the
higher the baseline BP, the greater the decrease or less the increase
in BP at follow-up. Findings were similar with or without inclusion
of Treated people (data not shown). The Figure shows SBP
change per year of follow-up for untreated participants divided
into three strata of baseline BP7 : Optimal (SBP <120 and
DBP <80 mm Hg), Not-High (SBP 120 to 139 or DBP 80 to 89 mm Hg and
without hypertension), and High (hypertensive) (SBP 
140 or DBP 90
mm Hg). SBP change per year of follow-up was significantly
different in these three subgroups; similar data were observed for DBP
(not shown). On the basis of these observations, analyses of
relationships of baseline Na-Li countertransport and other baseline
variables to BP change were controlled or stratified for baseline
BP.
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Baseline Na-Li Countertransport, Other Baseline Variables, and
BP Change
Correlation Analysis Controlled for Baseline
BP
Table 3 gives partial correlation coefficients of
baseline values of selected variables with change per year of
follow-up in SBP and DBP for men and women, with
control for baseline level of SBP and DBP,
respectively. In analyses done in men and women combined, with
control for sex also, baseline values of body mass index, alcohol
intake, and Na-Li countertransport were significantly and positively
related to SBP and DBP change per year of follow-up. Correlation
coefficients for Na-Li countertransport and BP change were positive in
all analyses and significant or borderline significant, except
for the relation to DBP change in men. Baseline age was positively
related to SBP change and negatively to DBP change. Similar data (not
shown) were observed when Treated people were excluded from
analyses.
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Quartiles of Baseline Na-Li Countertransport and BP
Change
Table 4 shows baseline SBP and SBP change per year
of follow-up by quartiles of baseline Na-Li countertransport for
all men and women. Baseline BP was significantly different and linearly
higher, with higher baseline Na-Li countertransport in both sexes. With
control for baseline SBP, SBP change was different among quartiles,
with borderline significance in men and women and statistical
significance in analysis for the two sexes combined. This
finding reflected the smaller change (ie, lesser decrease) for Na-Li
countertransport quartile 4 (Q4) than quartiles 1 through 3 (Q1-3)
(adjusted SBP change was similar among Q1-3). When the comparison was
made by ANOVA between Q1-3 combined and Q4, significant differences
were observed also for men and women separately. Similar data were
observed for DBP change per year of follow-up adjusted for baseline
DBP (men and women combined with control also for sex: -0.389,
-0.359, -0.299, and -0.109 mm Hg/y, quartiles 1, 2,
3, and 4, respectively; P=.002 among all quartiles,
P<.001 for Q4 compared with Q1-3 combined).
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Findings were similar when Treated people were excluded from such analyses. BP changes per year of follow-up with adjustment for baseline BP were more positive (or less negative) than those observed with inclusion of Treated people for SBP (men and women combined, with control for sex and baseline SBP: -0.167, -0.287, -0.307, and +0.113 mm Hg/y, quartiles 1, 2, 3, and 4, respectively; P=.006 among all quartiles, P<.001 for Q4 compared with Q1-3 combined) and DBP (men and women combined, with control for sex and baseline DBP: -0.159, -0.189, -0.109, and +0.061 mm Hg/y, quartiles 1, 2, 3, and 4, respectively; P=.017 among all quartiles, P=.002 for Q4 compared with Q1-3 combined).
On the basis of these findings, a categorical grouping of individuals
was used in some post hoc statistical procedures, ie, those in Q1-3
(Na-Li countertransport <401 µmol/L red blood cells per hour in men,
<329 in women) and those in Q4 (Na-Li countertransport 401 µmol/L
red blood cells per hour in men, 329 in women).
Baseline Na-Li Countertransport and BP Change: Regression and
Quartile Analyses for Untreated People Stratified by
Baseline BP and for People on Antihypertensive Drug
Treatment
In regression analyses, for SBP change per year of
follow-up regressed on baseline Na-Li countertransport,
univariate coefficients were dissimilar among untreated
people stratified according to baseline BP (three strata, see above)
and for people on regular antihypertensive drug treatment at
follow-up examination. For the Optimal stratum (men and women
combined, n=838), the coefficient of SBP change per year of
follow-up regressed on Na-Li countertransport was not significant
and negative for both continuous (-0.000513, P=NS) and
categorical (-0.127, P=NS) Na-Li countertransport.
Coefficients for SBP change with Na-Li countertransport were positive
for both continuous and categorical Na-Li countertransport for the
strata Not-High (n=891, continuous Na-Li countertransport: +0.001219,
P<.05; categorical Na-Li countertransport: +0.512,
P<.01), High (n=494, continuous Na-Li countertransport:
+0.000442, P=NS; categorical Na-Li countertransport: +0.612,
P<.05), and Treated people (n=506, continuous
Na-Li countertransport: +0.001236, P=NS; categorical Na-Li
countertransport: +0.431, P=NS). In the
analysis with categorical Na-Li countertransport as independent
variable, the 95% confidence interval of the
univariate coefficient of SBP change per year of
follow-up for people in the Optimal stratum (-0.40/+0.15) did
not overlap that for people in the Not-High (+0.16/+0.87) and High
(+0.48/+1.18) strata. Findings were similar for DBP change per year of
follow-up and when analyses were done separately in men and
women (data not shown).
In quartile analyses, findings were dissimilar across these four strata for the relationship of baseline Na-Li countertransport to BP change. For people in the Optimal stratum, SBP change per year of follow-up (unadjusted values, men and women combined) was positive (indicating SBP increase) for all quartiles, with nonsignificant differences among Na-Li countertransport quartiles (+0.602, +0.351, +0.428, and +0.335 mm Hg/y, P=.324, quartiles 1, 2, 3, and 4, respectively). For people in the Not-High stratum, SBP change per year of follow-up was positive (indicating SBP increase) for Q4 and negative (indicating SBP decrease) for Q1-3, with significant differences among Na-Li countertransport quartiles (-0.360, -0.058, -0.370, and +0.253 mm Hg/y, P=.015). For people in the High stratum, SBP change per year of follow-up was negative (indicating SBP decrease) for all quartiles, with significant differences among Na-Li countertransport quartiles (-0.832, -1.663, -1.490, and -0.745 mm Hg/y, P=.035), ie, smallest decrease in Q4. For people in the Treated stratum, SBP change per year of follow-up was negative (indicating SBP decrease) for all quartiles, with nonsignificant differences among Na-Li countertransport quartiles (-1.874, -1.796, -1.229, and -1.142 mm Hg/y, P=.265), ie, smallest decrease in Q4. Findings were similar for DBP change per year of follow-up and when men and women were analyzed separately (data not shown).
Multiple Linear Regression Analyses
Table 5 shows multiple linear regression
coefficients for SBP and DBP change regressed on baseline Na-Li
countertransport (continuous variable, micromoles per liter of red
blood cells per hour), baseline values of other variables, sex, and
regular antihypertensive drug treatment at follow-up as independent
variables. In this table, a positive regression coefficient
indicates that a higher value of the independent variable is
associated with a greater increase (or smaller decrease) in
follow-up BP compared with baseline. The regression coefficient for
baseline Na-Li countertransport with BP change per year of
follow-up was positive and borderline significant with control for
sex, antihypertensive drug treatment at follow-up, and baseline
values of age, body mass index, BP, pulse, alcohol intake, spot urine
Na-K ratio, and plasma cholesterol. Log, or quadratic, or
exponential transformation of baseline Na-Li countertransport did not
improve the statistical significance of its regression coefficient. In
an additional analysis, the change in body weight over time
(kilograms per year of follow-up) was added to the independent
variables shown in Table 5; weight change was positively related to
SBP (0.385±0.052, P<.001) and DBP (0.324±0.032,
P<.001) change. Compared with data shown in Table 5, the
inclusion of this variable in the model did not significantly
change the coefficients and statistical significance of baseline Na-Li
countertransport (for SBP, 0.000633±0.000339,
P=.062; for DBP, 0.000393±0.000208, P=.059)
and other variables (data not shown).
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Table 6 shows multiple linear regression coefficients
for SBP and DBP change in post hoc analyses in which baseline
Na-Li countertransport was used as a categorical variable (Q4
compared with Q1-3) with values of other independent variables as
in the multivariate models shown in Table 5
. The
relation of categorical Na-Li countertransport to BP change per year of
follow-up was significant and positive with control for sex,
antihypertensive drug treatment at follow-up, and baseline values
of age, body mass index, BP, pulse, alcohol intake, spot urine Na-K
ratio, and plasma cholesterol. When weight change was added
to these models, it was significantly related to SBP and DBP change
(regression coefficients and SE in text above); findings on the
relationship to BP change for baseline Na-Li countertransport (SBP,
0.307±0.104, P=.003; DBP, 0.192±0.064, P=.003)
and other variables (data not shown) were similar to those shown in
Table 6.
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Analyses were also done with people stratified by BP status
(Optimal, baseline SBP <120 mm Hg and baseline DBP <80 mm Hg and no
antihypertensive drug at follow-up, n=838; Above-Optimal, SBP 120
mm Hg or DBP 80 mm Hg or on antihypertensive drug at follow-up,
n=1891). In both models, ie, with Na-Li countertransport as continuous
and categorical variable, the relationship of baseline Na-Li
countertransport to BP change was much stronger for Above-Optimal than
Optimal people. For the model with continuous Na-Li countertransport
with SBP change as dependent variable, the regression coefficient
was +0.001249±0.000443 for Above-Optimal people and
-0.000704±0.000441 for Optimal people; for the model with
categorical Na-Li countertransport, corresponding coefficients were
+0.521±0.136 and -0.174±0.135.
Analyses were also done with people stratified by baseline age
(<45 years, n=1205; 45 years, n=1524). In both models, ie, with
Na-Li countertransport as continuous and categorical variable, the
relationship of baseline Na-Li countertransport to BP change was much
stronger for older than younger people. For the model with continuous
Na-Li countertransport with SBP change as dependent variable, the
regression coefficient was +0.001037±0.000518 for people 45 years old
and older and -0.000022±0.000393 for people younger than 45
years; for the model with categorical Na-Li countertransport,
corresponding coefficients were +0.466±0.157 and
+0.065±0.122.
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Discussion |
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This study shows that activity of Na-Li countertransport in red blood cells related positively to BP change from baseline to 6-year follow-up in adult men and women with control for sex, baseline BP, and antihypertensive drug treatment. The relation was also present in multivariate analyses controlled for other correlates of BP. These data extend previous observations of a cross-sectional association between Na-Li countertransport and BP level15 16 and further support the hypothesis that BP in humans is related to cellular sodium transport.9
The BP changes over time in this population sample may reflect several mechanisms. First, baseline high and low BP values regress toward intermediate values because of regression toward the mean associated with repeated measurement.31 Second, BP may decrease from baseline because of dietary or antihypertensive drug treatment after baseline examination; the prevalence of antihypertensive drug treatment increased by about 60% in the Gubbio population from baseline to second examination. Third, BP usually increases over time in adults of industrialized societies because of the adverse influences of such factors as obesity, high salt and high ratio of sodium to potassium intakes, excess alcohol ingestion, and sedentary lifestyle.1 2 3 4 5 6 7 8 Baseline Na-Li countertransport related to BP change in people whose baseline BP was above optimal values (SBP/DBP, <120/<80 mm Hg), and findings were stronger for people aged 45 to 74 years than for those 18 to 44 years old. This observation suggests the operation of a sequence of influences whereby the mechanism or mechanisms hypothetically linking Na-Li countertransport to BP change become effective only after other factors have produced some elevation in BP.
The relation of Na-Li countertransport to BP change appeared to be reasonably described by a nonlinear model in which high Na-Li countertransport (highest 25% of the sex-specific distribution) was compared with Na-Li countertransport quartiles 1 through 3. Further analyses are needed for assessment of whether this finding is related to a non-normal distribution of Na-Li countertransport14 and/or to a too short duration of follow-up for detection of lower-order influences of Na-Li countertransport on BP change. Thus, a 6-year follow-up might be insufficient for observation of differential BP changes in people with Na-Li countertransport in the low, intermediate, and high parts of the distribution.
At present, it is possible only to speculate about the mechanism or mechanisms underlying the association between Na-Li countertransport and BP change. Na-Li countertransport has been regarded as an index of Na-H exchange activity and of renal tubular function,19 20 21 22 23 24 but its physiological role is not known.
Data from this study confirm that lifestyle indexes such as overweight and alcohol intake are significant predictors of BP change over time.1 32 In particular, baseline body mass index related to BP change in all analyses, in support of the concept that body weight control is important for the prevention and control of adverse BP levels. The lack of a significant relation between the Na-K ratio in spot urine and BP change probably reflects several problems: use of only one spot instead of 24-hour urine, small sample size, and overadjustment.4
In summary, the present study reports the novel finding that the activity of Na-Li countertransport in red blood cells is a significant predictor of BP change over time in adult men and women. On the basis of estimates from multivariate analyses, nonhypertensive men and women with SBP greater than or equal to 120 mm Hg or DBP greater than or equal to 80 mm Hg and with Na-Li countertransport in the highest quartile of the sex-specific distribution on average should experience over 10 years a change in SBP 5 mm Hg higher than individuals in Na-Li countertransport quartiles 1 through 3. The finding of a significant relation between Na-Li countertransport and BP change over time is concordant with the concept of an etiopathogenetic role for Na-Li countertransport in BP elevation, but it remains possible that Na-Li countertransport is merely a marker of a prohypertensive condition.
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Acknowledgments |
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The Gubbio Population Study, made possible thanks to the people of Gubbio, was supported, planned, and carried out by the Center for Epidemiologic 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 laboratory of IIMMDUN; determination of plasma lipids was done in the laboratory of ISS. The research was supervised and guided by a Scientific Policy Board, whose members have been Prof Piero Angeletti (Chairman, MSD-I, deceased), Dr Umberto Mortari (MSD-I), Dr Luigi Carratelli (MSD-I), Prof Mario Mancini (IIMMDUN), Prof Alessandro Menotti (ISS), Prof Rose Stamler, and Prof Jeremiah Stamler (DPMNUMS). Thanks are expressed for their fine cooperation to the staff of the Gubbio Civil Hospital, particularly Dr Mario Angeletti, Dr Ondina Cardoni, and the staff of the field survey team (CPM). The Gubbio Population Study has been funded also by Grant RO1-HL-40397-02 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Received December 12, 1995; first decision January 19, 1996; accepted February 21, 1996.
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