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Introduction
The effect of high sodium intake on the risk of
cardiovascular disease has been debated. Much of this effect is thought
to be mediated through raised blood pressure, although
experimental data indicate that other mechanisms might also
be involved. High sodium intake is associated with
mortality and risk of coronary heart disease, independent of other
cardiovascular risk factors, including blood
pressure[1]. The cardioprotective effects of dietary potassium have been
hypothesized as the basis for low cardiovascular disease rates
in populations consuming "primitive" diets and in
vegetarians in industrialized
cultures[2]. Although numerous epidemiologic and clinical studies have shown the significant
association between the urinary sodium excretion and
urinary potassium excretion with the morbidity and mortality
of coronary heart disease[3], there is little information
available about the association between the angiographic
characteristics of coronary atherosclerosis estimated by
conventional coronary angiography and the serum sodium level.
The Gensini score assigns a severity score for a stenosed
vessel depending on the degree of luminal narrowing and
the importance of its location[4]. So we took advantage of
the large sample size epidemiologic study to evaluate the
association between the angiographic characteristics of
coronary atherosclerosis and the serum sodium level.
Materials and methods
Experimental patients The study population consisted
of 896 consecutive patients (684 males and 212 females) who
underwent coronary angiography for suspected or known
coronary atherosclerosis at the First Affiliated Hospital of
Nanjing Medical University (Nanjing, China) from 2004 to
2005. Patients with spastic angina pectoris (ie
acetylcholine-positive) were excluded. Patients with infectious
processes within 2 weeks before catheterization, heart failure
(Killip class ³2 after acute myocardial infarction), hepatic
dysfunction, vascular disease (aortitis treated with
predniso-lone), familial hypercholesterolemia, thyroid dysfunction, or
adrenal dysfunction were also excluded. This study was
approved by the Ethics Committee of the First Affiliated
Hospital of Nanjing Medical University, and informed
consent was obtained from each patient.
Coronary angiography and echocardiography
The coronary arteries were cannulated by the Judkins
technique[5] with 5F catheters, and coronary angiography was performed from
several projections. The severity of coronary
atherosclerosis was defined by the Gensini score system, based on the
hypothesis that the severity of coronary heart disease should
be considered as a consequence of the functional
significance of the vascular narrowing and the extent of the area
perfused by the involved vessel or vessels. Therefore, the
Gensini score was computed by assigning a severity score
to each coronary stenosis according to the degree of luminal
narrowing and its geographic importance. The reduction in
the lumen diameter and the roentgenographic appearance of
concentric lesions and eccentric plaques were evaluated
(reductions of 25%, 50%, 75%, 90%, 99%, and complete
occlusion were given Gensini scores of 1, 2, 4, 8, 16, and 32,
respectively). Each principal vascular segment was assigned
a multiplier in accordance with the functional significance of
the myocardial area supplied by that segment: the left main
coronary artery, ×5; the proximal segment of left anterior
descending coronary artery (LAD), ×2.5; the proximal
segment of the circumflex artery, ×2.5; the mid-segment of the
LAD, ×1.5; the right coronary artery, the distal segment of
the LAD, the posterolateral artery and the obtuse marginal
artery, ×1; and others,
×0.5[4]. Left ventricular ejection
fraction (LVEF) is an important parameter in the assessment of
cardiac mortality and morbidity. It also provides important
diagnostic, therapeutic, and prognostic information for
patients with known or suspected coronary heart disease.
Currently, left ventricular angiography is considered the gold
standard for the measurement of LVEF. However, it is
associated with risks, and its invasive nature does not allow for it
to be repeated on a frequent basis. Therefore, non-invasive
techniques for the assessment of LVEF are commonly used
in clinical practice. To evaluate the heart function of the
patients, LVEF was assessed by 2-D echocardiography.
Cigarette smoking and alcohol intake Cigarette
smoking and alcohol intake were assessed by means of a
standardized questionnaire. The patients' smoking status was
classified as never smoking and smoking (including formerly
smoked and currently smoking). Patients who reported
consuming alcohol at least 50 g/week were regarded as current
drinkers. Alcohol intake status was classified as never
drinking and drinking (including formerly drank and currently
drinking).
Laboratory measurements The 12-h fasting blood
samples were drawn in the morning. Thereafter, the blood
samples were centrifuged, and serums were separated,
collected, and analyzed. All laboratory measurements were
conducted at the Central Clinical Laboratory in the First
Affiliated Hospital of Nanjing Medical University. The
concentrations of potassium, sodium, and chlorine were
measured with an ion selective electrode analyzer (Medica
EasyLyte PLUS, Bedford, MA, USA). The level of total
chole-sterol, triglyceride, fasting blood glucose, urea, creatinine,
and uric acid were determined by enzymatic procedures on
an automated auto analyzer (AU 2700 Olympus, 1st Chemical,
Tokyo, Japan). The laboratory was monitored for precision
and accuracy of glucose and lipid measurements by the
agency's surveillance program. Measurements on
agency-assigned quality control samples showed no consistent bias
over time within or between surveys.
Statistical methods Data analysis was performed using
the Statistical Package for Social Science (SPSS for Windows,
version 10.0, SPSS, Chicago, IL, USA). Patients were
classified into 4 groups with sodium level using the quartile
values as cut-off points so that each group had about an equal
number of patients to minimize any bias that may have been
produced in the statistical analysis. Data of body mass
index (BMI) and uric acid were normally distributed
parameters and presented as mean±SD; comparisons were
analyzed by one-way ANOVA. Skewed data, including age,
blood pressure, potassium, chlorine, total cholesterol,
triglyceride, fasting blood glucose, urea, creatinine, LVEF,
and the Gensini score were expressed as the median and
quartile range; comparisons were analyzed by the
Kruskal-Wallis test. Categorical variables, including sex, smoking,
and drinking were compared among the groups of patients
by χ2-test. The Spearman two-way test and partial
correlation were used to assess the relation between 2 quantitative
variables. We assessed the independent correlation of the
sodium level with the multiple linear regression analysis. We
used the multinomial logistic regression analysis to study
the relation between quartiles of sodium level and the Gensini
score. Differences were considered significant at
P<0.05, and all P-values were 2-tailed.
Results
Clinical and biochemical characteristics in patients
grouped according to sodium level Table 1 shows the
clinical and biochemical characteristics in patients grouped
according to sodium concentration, quartile values of which
were used as cut-off points. The frequency distribution of
smoking status (P=0.334) and drinking status
(P=0.133) was similar among the 4 groups; however, the frequency
distribution of gender (P=0.000) differed among the groups. The
level distribution of BMI (P=0.455), total cholesterol
(P=
0.646), triglyceride (P=0.070), urea
(P=0.823), creatinine (P=
0.130), and uric acid (P=0.519) were similar among the 4
groups, whereas those of age (P=0.011), systolic blood
pressure (SBP; P=0.001), diastolic blood pressure (DBP,
P=
0.035), fasting blood glucose (P=0.000), potassium
(P=0.025), chlorine (P=0.000), LVEF, and the Gensini score
(P=0.000) differed significantly among the groups.
Hyponatremia and hypernatremia of the patients
To
assess gender and age as risk factors for hyponatremia and
hypernatremia and describe the prevalence of hyponatremia
and hypernatremia in this study population, the binary
logistic regression analysis was performed. In this
regression analysis, hyponatremia was defined as the serum
sodium concentration less than 136 mmol/L and was coded
as 1 (or otherwise coded as 0), and hypernatremia was
defined as the serum sodium concentration greater than 145
mmol/L and was coded as 1 (or otherwise coded as 0). Age
(classified in 4 groups with age levels using quartile values
as cut-off points) and gender (male was set 1, female was set
2) were set as the independent variables, and hyponatremia
and hypernatremia were employed as the dependent variables, respectively. The results are summarized in Table
2. The results indicated that females were at greater risk of
hyperna-tremia, and increasing age was a risk factor for
hyponatremia.
Spearman correlations and partial correlations between
sodium and the Gensini score, anthropometric
measure-ments, and biochemical characteristics in patients
Tables 3 and 4 show the results of the Spearman correlations and
partial correlations (controlling for gender, smoking status,
and drinking status) between sodium and the Gensini score,
anthropometric measurements, and biochemical
characteristics in the patients. The results in Tables 3 and 4 indicated
that the concentration of sodium significantly correlated with
the Gensini score, potassium level, chlorine, and glucose,
whereas the sodium level had no significant correlation with
age, BMI, SBP, DBP, total cholesterol, triglyceride, urea,
creatinine, LVEF, and uric acid, respectively.
Multiple linear regression analysis with the Gensini
score as the dependent variable To examine the
independent associations between the Gensini score and the
concentration of sodium, the multiple linear stepwise regression
analysis was performed. In this model, the Gensini score
was employed as the dependent variable. The independent
variables included age, BMI, SBP, DBP, total cholesterol,
triglyceride, fasting blood glucose, urea, creatinine, uric acid,
sodium level, potassium level, chlorine, and LVEF. In the
final model (Table 5), LVEF (β=-0.228, P=0.010), age
(β=0.137, P=0.010), glucose level (β=0.129,
P=0.000), and sodium level (β=_0.106,
P=0.004) were significantly and independently
associated with the Gensini score.
Multinomial logistic regression analysis to study the
relation between quartiles of sodium level and the Gensini
score To evaluate the association between quartiles of
sodium level and the Gensini score, the multinomial logistic
regression analysis was conducted. In the analysis, the
Gensini score (categorized in quartiles) was employed as a
dependent variable; the sodium level (categorized in
quartiles) was set as a factor. The covariate variables
included age, BMI, SBP, DBP, total cholesterol, triglyceride,
fasting blood glucose, urea, creatinine, uric acid, potassium
level, and chlorine level. The result of the likelihood ratio
tests in the multinomial logistic regression analysis (Table 6)
indicated that age, fasting blood glucose level, and sodium
level (categorized in quartiles) was significantly associated
with the Gensini score (categorized in quartiles), respectively.
In addition, the parameter estimates of the multinomial
logistic regression analysis (data not shown) showed that in the
first quartile of the Gensini score (the group with the lowest
level), the odds ratio [95% confidence interval (CI)] of
sodium level (categorized in quartiles) was 0.387
(0.197-
0.761; P=0.006) in the first quartile, 0.413
(0.231-0.738; P=
0.003) in the second quartile, and 0.995 (0.560-1.768;
P=
0.986) in the third quartile. From these results, it can be
concluded that hyponatremia was the risk factor for the
higher Gensini score.
Discussion
The present study documents that the severity of
angio-graphic characteristics of coronary atherosclerosis estimated
by the Gensini score was significantly and negatively
associated with the serum sodium level, independent of the other
cardiovascular risk factors including age, gender, BMI, SBP,
DBP, total cholesterol, triglyceride, fasting blood glucose,
urea, creatinine, and uric acid. To the best of our knowledge,
this is the first study focused on the relationship between
the severity of angiographic characteristics of coronary
atherosclerosis and the serum sodium level; the actual
mechanism underlying the above relationship needs further study.
Under normal conditions, serum sodium concentrations
are finely maintained within the narrow range of 135_145
mmol/L despite great variation in water and salt intake.
Sodium and its accompanying anions, principally chloride
and bicarbonate, account for 86% of the extracellular fluid
osmolality, which is normally 285_295 mosm/kg. Disorders
of serum sodium are the most common electrolyte
disturbances in clinical medicine, yet they remain poorly
under-stood. There is little agreement on the prevalence of the
disturbances of sodium balance or on the importance of
gender and age as markers of risk[6]. Data from
303 577 samples on 120 137 patients were available for analysis, and the
results suggest that increasing age is a risk factor for
hyponatremia[7]. In the same study, gender was not set as
an important risk factor for disturbances of serum Na
concentration[7]. However, the results from the current study
indicated that females were at greater risk of hypernatremia.
The findings of this study should remind medical staff of the
risk factors for hyponatremia and hypernatremia, and that
increasing age is a risk factor for hyponatremia.
In recent years, a role for an inadequate electrolyte
balance in determining an increased risk of metabolic syndrome
and associated vascular complications has been
claimed[8]. The current study is an interesting finding that on the
surface seems to go against conventional wisdom that excess
sodium is cardiotoxic. A recently reported prospective study
followed 1173 Finnish men and 1263 women aged 25_64 years
with complete data on 24 h urinary sodium excretion and
cardiovascular risk factors. The hazards ratios for coronary
heart disease, cardiovascular disease, and all-cause
mortality associated with a 100 mmol increase in 24 h urinary
sodium excretion were 1.51 (95% CI 1.14_2.00), 1.45
(1.14_1.84), and 1.26 (1.06_1.50), respectively, in both men and
women. These results provide direct evidence that high
sodium intake is associated with mortality and risk of
coronary heart disease, independent of other cardiovascular risk
factors, including blood pressure[1]. Unfortunately, the
available data about the relationship between serum sodium
concentration and coronary atherosclerosis/coronary artery
disease are minimal. However, there are a few prospective
studies of the relation of sodium intake to cardiovascular
morbidity, and mortality may support the hypotheses in this
manuscript. In roughly 3000 of the employed and
systematically-treated (mild and moderately-treated), well-controlled
hypertensive patients, urine was collected over a 24 h period
before the initiation of therapy and was used to relate to
events over an average of 4 years. There was a significant
inverse association of sodium intake to mortality, so an
increase in sodium intake of 66 mmol/24 h was associated with
a 36% reduction in coronary events[9]. This result was
independent of plasma renin activity. These data are consistent
with the finding in the same population of the significant
association of increased plasma renin activity with increased
coronary events [10]. There is a report of the general
population which links baseline sodium intake as assessed by 24 h
dietary recall to 22 year mortality in the National Health and
Nutrition Examination Survey Epidemiological
Follow-Up[11]. In 11 348 patients from this representative national sample,
there were nearly 4000 deaths, almost half of which were
cardiovascular related. Here, too, an inverse, albeit modest,
relation of salt intake to cardiovascular mortality was
observed. When the analysis was restricted to patients
without prevalent cardiovascular disease at entry, the results
were similar. Thus, the results from the above study are
consistent with those of our study where the serum sodium
level has an inverse association with the severity of
coronary atherosclerosis.
The mechanism which may account for the relationship
between the severity of angiographic characteristics of
coronary atherosclerosis and the serum sodium level was
unknown. However, rennin angiotensin system (RAS)
activation may play a key role. The sodium depletion
observed in the patients with greater coronary disease may
be a cause or a consequence of RAS activation. The
components of the RAS have been identified in the cardiac tissues
of humans and various animal species, and the existence of
a functional cardiac RAS continuously forming low levels of
angiotensin (Ang) II has been demonstrated in humans. The
vascular formation of AngII has also been demonstrated in
the experimental preparation of isolated vascular tissues and
in humans. Locally-formed AngII may directly or indirectly
affect the pathophysiology of
atherosclerosis[12]. The activation of the RAS may exert numerous adverse effects on
the cardiovascular system[13] (ie arterial hypertension, chronic
renal failure, and potentially, atherosclerosis). An additional
hemodynamic effect is mediated by the RAS. Under usual
circumstances, the RAS modulates volume and
vasoconstriction to maintain pressure. As part of this physiologic
process, there is an inverse relation of sodium intake and
RAS activity. Thus, a 100 mmol/24 h reduction in sodium
intake generates a 3-fold increase in plasma renin activity, a
measure of RAS activity [14]. Although this mechanism is
appropriate to sustain BP, an elevated RAS also has adverse
effects on the vascular endothelium and smooth muscle cells
and stimulates inflammatory agents. The net result is
atherogenic[15]. In fact, among hypertensive patients, all other things
being equal, an increased renin is associated with increased
myocardial infarction. Other untoward cardiovascular
effects of sodium restriction, linked to the RAS include the
generation of aldosterone and the sustained stimulation of
the sympathetic nervous system. The latter is perhaps
responsible for the increased insulin resistance that is known
to accompany low-sodium diets[16].
In a clinical study experimentally evaluating the
hypona-tremic response to acute hyperglycemia, it was demonstrated
that every 5.6 mmol/L increase in glucose was accompanied
with about a 1.6 mmol/L decrease in sodium
concentration[7]. The results from the above study are consistent with those
of our study; the inverse association of the sodium level
with the glucose concentration is shown in Table 1. As the
glucose concentration is increased in coronary artery
disease patients, and the correlation between glucose and
coronary artery disease severity is significant, this result
may be another reason which accounts for the inverse
relationship between the severity of angiographic
characteristics of coronary atherosclerosis and the sodium level.
The limitation of the present study is that it is only a
cross-sectional study rather than a prospective study, and
it can not provide information regarding the cause and
effect relationship between the serum sodium concentration
and coronary atherosclerosis. The patients' urinary sodium
level was not obtained, and the long-term prognosis value
of serum sodium concentration for coronary heart disease
needs further study.
In conclusion, the severity of angiographic
characteristics of coronary atherosclerosis estimated by the Gensini
score was significantly and negatively associated with the
serum sodium level; the actually mechanism underlying the
association needs further study.
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