Sodium and left ventricular mass in untreated hypertensive and normotensive subjects GUILHEM
DU CAILAR,
Department
of Medicine, H6pital Lapeyronie, 34059 Montpellier
JEAN
RIBSTEIN,
JEAN-PIERRE
Du Cailar, Guilhem, Jean Ribstein, Jean-Pierre Daures, and Albert Mimran. Sodium and left ventricular massin untreated hypertensive and normotensive subjects.Am. J. Physiol. 263 (Heart Circ. Physiol. 32): Hl77-Hl81, 1992.To determine whether urinary sodiumexcretion (a rather rough
estimate of sodium intake) can influence left ventricular mass independently of arterial pressure,91 untreated subjects with essentialhypertension and 50 normotensive subjectsof similar agewere studied.Left ventricular massindex (M-mode echocardiography) waspositively correlated with urinary sodiumexcretion in hypertensive (r = 0.22, P < 0.01) aswell asnormotensive subjects(r = 0.22, P < 0.05), and systolic arterial pressurewas correlated only in hypertensive subjects (r = 0.23, P < 0.01). When hypertensive subjectswere divided into groupswith appropriate or inappropriate left ventricular massby reference to a theoretical optimal left ventricular massfor each subject’s level of systolic arterial pressure,left ventricular masswas appropriate in 68% and inappropriate in 32% of subjects.Urinary sodiumexcretion washigher in subjectswith inappropriate left ventricular masscomparedwith thosewith appropriate left ventricular mass.In conclusion, sodium excretion may be an important modulator of the influence of arterial pressureon the left ventricle in normotensive subjectsand subjectswith essential hypertension. hypertension; normal subjects OF ARTERIAL PRESSURE is not the sole determinant in the development of cardiac hypertrophy (4). Among other factors, age and body mass index (7) as well as humoral factors such as angiotensin and catecholamines were identified (12). Experimental studies conducted in rats with 2-kidney,1 -clip hypertension have shown that the shift from normal to low-sodium intake was associated with a consistent reversibility of cardiac hypertrophy, despite the absence of arterial pressure decrease (9). Similar observations were made in deoxycorticosterone acetate-salt hypertensive rats (3). Two recent studies conducted in hypertensive humans have suggested that sodium intake, estimated by 24-h urinary sodium excretion, may contribute to left ventricular changes associated with hypertension (1, 14). Left ventricular hypertrophy is an appropriate response to pressure overload to normalize myocardial wall stress; however, its mechanisms as well as eventual modulating factors remain unknown. In the present study, the influence of dietary sodium intake (assessed by the estimate of urinary sodium excretion) on the relationship between left ventricular geometry and arterial pressure was assessed in normal subjects and subjects with untreated mild to moderate essential hypertension. In addition, to identify a potential trophic effect of sodium on the myocardial response to elevated arterial pressure, the influence of sodium was analyzed in subjects with “appropriate” and “inappropriate” left ventricular mass, defined by reference to a theoretical optimal left ventricular mass for each subject’s level of systolic arterial pressure (5).
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0363-6135/92
$2.00
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SUBJECTSAND
DAURES,
AND ALBERT
MIMRAN
Cedex, France METHODS
Studies were conducted in 91 untreated subjects (63 males aged 15-64 yr, and 28 femalesaged 25-61 yr) with uncomplicated borderline (27%) or mild to moderate (73%) essential hypertension defined according to the 1988 Joint National Committee criteria (8). The known duration of hypertension was 3-41 mo. Subjects had no electrocardiographic signs of valvular, primary myocardial, or coronary artery disease.Subjects with impaired renal function (glomerular filtration rate estimated by the clearance of ggmTc-diethylenetriaminopentaacetic acid, below the limits found in normal subjectsof similar age in our laboratory) were excluded. The control population consistedof 50 normal subjects (29 malesand 21 femalesaged25-61 yr) without a positive family history of hypertension (defined as one or both parents with diastolic arterial pressure higher than 95 mmHg or treated hypertension). Normotensive and hypertensive female subjects taking oral contraceptive therapy were excluded. In addition, overweight subjects defined as those with a body massindex [weight (kg)/height2 (m2)] >_27.8 for malesand 27.3 for females (13) were not included in the study. Subjects came to the ward with two consecutive 24-h urine collections for the measurementof urinary concentrations of sodium, potassium,creatinine, and protein. After a 30-min rest period in which the subject was in the supine position, arterial pressurewas measuredusing an automatic device (Dynamap 845XT, Critikon, France). In each subject, at least 10 measurementsof arterial pressurewere obtained, and the average of these values was considered. Subsequently, a blood samplewas withdrawn for the determination of hematocrit and plasmaconcentrations of sodium,potassium,creatinine, and plasmarenin activity (radioimmunoassay technique, CEA-Sorin kit, Saclay, France). Echocardiographic measurements. An ATL Ultramark 4 system (Advanced Technology Laboratories, Bellevue, WA) with an ATL 3.00 MHz mechanicaltransducer was used.The same operator obtained all echocardiogramswith the subject in the left lateral position, M-mode studies of the left ventricle were guided by two-dimensional echocardiograghyusing an optimal long-axis view below the tip of the mitral leaflets. M-mode tracings were analyzed using a digitized table (Edelman Software Products, Houston, TX) by two readerswho had no knowledge of arterial pressure and sodium intake. Measurement points weretaken at the peak of the R wave on the simultaneous electrocardiogram,on an averageof three cycles per recording. Interventricular septal thickness (IVSTd) and posterior wall thickness (PWTd) at end diastole were measuredaccording to the “Penn” convention (measurementsexcluding the thickness of the endocardial echoes).Relative wall thickness (RWT) at end diastolewascalculatedasthe ratio of twice the posterior left ventricular wall thickness to left ventricular diastolic internal dimension (LVIDd). Fractional shortening was assessed as a measureof left ventricular performance. Left ventricular mass (LVM) was calculated by the Penn-cube method according to Devereux et al. (2): LVM (g) = 1.04 [(LVIDd + PWTd + IVSTd)3 - (LVID,)“] - 13.6, where all ventricular dimensions are expressed in centimeters. Left ventricular mass index (LVMI) wascalculated as LVM per body surface area. A theoretically optimal left ventricular masswascalculatedto
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H178
SODIUM
EXCRETION
1 :LEFT
ANI:
allow each subject to achieve a normal value of peak systolic stress,according to the method describedby Ganau et al. (5). Peak systolic wall stresswascalculated using the formula: peak systolic stress= pressurex radius/thickness, where radius and thicknesscorrespondto LVIDJZ and PWTd, respectively. Subsequently,peak systolic stresswascalculatedas [ 1,333x SAP x WIW2) 1/PWTd, with SAP being systolic arterial pressure (mmHg) and 1,333the conversion factor from millimeters of Hg to dynes. In the presently reported 50 normotensive controls, calculated peak systolic stress was 467.4 t 12 (SD) x 10” dyn/cm? With the assumptionthat posterior wall and interventricular septal thicknesseswere equivalent in normotensive (0.80 t 0.11 vs. 0.81 t 0.11 cm, respectively) and hypertensive subjects(0.99 t 0.20 vs. 0.96 t 0.18 cm, respectively) (Table 1) and using the value of PWTd extracted from the peak systolic stressformula, estimation of optimal left ventricular masswas 1.04 x [(1.333 x LVIDd x SAP/467 + LVIDJ3 - LVIDd3]. Statistical methods. Resultswere analyzed using BMDP statistical software (University of California, Berkeley), and data wereexpressedasmeanst SD. Comparisonbetweengroupswas carried out by unpaired Student’s t test, nonparametric Kruskal-Wallis test, and stepwisediscriminant analysis.Linear nonparametric correlation coefficients between left ventricular massand other variables (demographic,hemodynamic, and humoral) were calculated. Variables that exhibited significant univariate correlation with left ventricular masswere further usedas independent variables in a stepwisemultiple regression analysis. RESULTS
As shown in Table 1, normotensive and hypertensive subjects did not differ with respect to age, body mass index, heart rate, and urinary sodium and potassium excretion. Interventricular septal thickness and posterior wall thickness at end diastole as well as left ventricular mass and left ventricular mass index were significantly higher in hypertensive than normotensive subjects. Left ventricular internal dimension at end diastole was similar in both groups. The prevalence of left ventricular hypertrophy (X27 and 110 g/m2 in males and females, respectively, as determined in our control population) was 26% in the hypertensive group. Of interest, arterial pressure was 148 t 16 to 94 t 12 mmHg in subjects without left
VENTRICULAR
MASS
ventricular hypertrophy and 152 t 15 to 97 t 11 mmHg (NS) in subjects with left ventricular hypertrophy. Determinants of left ventricular mass. Results of univariate correlations are summarized in Table 2. When the whole population was considered, left ventricular mass index was positively correlated with both systolic arterial pressure and urinary sodium excretion. In addition, PWTd was correlated with systolic and diastolic arterial pressure and natriuresis, whereas LVIDd was only correlated with urinary sodium excretion. When normotensive and hypertensive subjects were analyzed separately, it appeared that left ventricular mass index was positively correlated with urinary sodium excretion in both groups. The intercept with the ordinate axis was higher in hypertensive than normotensive subjects (P < O.Ol), whereas the slopes of the regression lines were not significantly different between the two groups (Fig. 1). Of interest, in normotensive subjects, urinary sodium excretion was positively correlated with left ventricular internal diameter at end diastole, whereas no such correlation was detected in hypertensive subjects. Only in the hypertensive group was urinary sodium excretion correlated with both left ventricular mass index and posterior wall thickness at end diastole. No significant correlation between urinary sodium excretion and arterial pressure was detected in either group. Multiple regression analysis (Table 3) showed that body mass index, urinary sodium excretion, and systolic arterial pressure were independent predictors of left ventricular mass in both normal and hypertensive subjects as well as the entire population. In the whole population and subjects with essential hypertension, the strongest predictors of left ventricular mass were body mass index and urinary sodium excretion. Thus multivariate analysis demonstrated the independence of urinary sodium excretion as a determinant of left ventricular mass in each population. Characteristics of subjects with appropriate and inappropriate left ventricular mass. Cluster analysis was used
to subdivide the hypertensive
population
according to the
Table 1. Clinical and echocardiographic characteristics of hypertensive and normal subjects Hypertensives
Clinical
Sex (male/female) Age, yr Body mass index, kg/m2 Systolic arterial pressure, mmHg Diastolic arterial pressure, mmHg Heart rate, beats/min Hematocrit, % Urinary sodium excretion, mmo1/24 h Urinary potassium excretion, mmo1/24 h
Normotensives
P Values
data
62/29 37klO 23.7t2.6 151t14 96dO 65t9 44.6k3.6 155266 67229 Echocardiographic indexes
29/21 37&11 22.9k2.5 122&9 73t7 67tlO 42.3k4.3 135252 58t20
Interventricular septal wall thickness, cm 0.96t0.18 0.81t0.11 Left ventricular posterior wall thickness, cm 0.99-to.20 0.8OkO. 11 Left ventricular end-diastolic diameter, cm 4.70t0.44 4.67t0.43 Left ventricular mass, g 195t52 143t40 Left ventricular mass index, g/m2 109-e25 83t20 Relative wall thickness 0.42t0.08 0.36t0.06 Fractional shortening, % 42&O. 1 40to. 1 Values are means t SD; n = 91 hypertensive subjects and 50 normal subjects. NS, not significant.
NS NS NS
0.001 0.001 NS co.05 NS NS 0.002 0.002 NS 0.0001
0.001 0.001 NS
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SODIUM
Table 2. Univariate
correlations
EXCRETION
AND
LEFT
between echocardiographic All LVM
Subjects
LVIDd
H179
MASS
indexes and clinical parameters
(n = 141)
LVMI
VENTRICULAR
Normotensive PWTd
LVM
Subjects
(n = 50)
LVIDd
PWTd
LVMI
Hypertensive LVM
LVMI
Subjects
(n = 91)
LVIDd
PWTd
0.01 0.21" 0.03 0.17 0.01 0.01 0.18 0.27* 0.07 0.19 Age, yr 0.19* 0.16 0.18 Body mass index, kg/m* 0.36* 0.18 0.27* 0.29* 0.32* 0.03 0.26* 0.38" 0.19 0.23* 0.31" Systolic arterial pressure, mmHg 0.50* 0.20* 0.11 0.56" 0.40* 0.19 0.28* 0.35* 0.21* 0.23* 0.09 0.21* 0.14 0.29* 0.15 0.11 0.22* 0.12 0.11 0.23 0.19 0.16 0.18 0.01 Diastolic arterial pressure, mmHg 0.11 0.24* 0.22* 0.12 0.21" Urinary sodium excretion, mmo1/24 h 0.33* 0.21" 0.23* 0.23* 0.41* 0.22* 0.43* 0.01 0.13 0.11 0.09 0.12 0.09 0.15 0.17 0.16 0.09 0.10 Urinary potassium excretion, mmo1/24 h 0.11 LVM, left ventricular mass (g); LVMI, left ventricular mass index (g/m*); LVIDd, left ventricular internal diameter at end diastole (cm); PWTd, posterior wall thickness at end diastole (cm). * P < 0.05.
200 -
y=O.llx+68
Normotensive Subjects
.
N $ i
Table 3. Multivariate analysis of systolic arterial pressure, body mass index, and urinary sodium excretion as determinants of left ventricular mass
r = 0.22
p < 0.05
160 .
Variables
120 -
SE
4.58 1.14 0.20
1.62 0.21 0.06
P Value
All subjects
Body mass index, kg/m* Systolic arterial pressure, mmHg Urinary sodium excretion, mmo1/24 h Multiple r = 0.37
go:; .
g 40. a 0 E b 200, 2 .
P
1
1
.
loo
I
.
200
I
.
300
y =0.08x r = 0.22
Essemtid Hypertension
z
.s MOE
+ 97
p < 0.01
0
O@ *O*
I 400
Normotensive
subjects
Body mass index, kg/m* Systolic arterial pressure, mmHg Urinary sodium excretion, mmo1/24 h Multiple r = 0.34 Hypertensive
s e
0.20 1.35 0.24
1.60 0.52
6.35 0.64 0.16
2.22 0.33 0.08
0.10
NS
0.01 0.02 0.001
patients
Body mass index, kg/m* Systolic arterial pressure, mmHg Urinary sodium excretion, mmo1/24 h Multiple r = 0.20 NS, not significant.
l
0.006 0.000 1 0.002 0.0001
0.006 0.04 0.03 0.0001
s 0
.
40 ’
0
Urinary
1
I
loo
1
1
200
1
1
J
300
Sodium Excretion
400
mmo1/24h
Fig. 1. Univariate correlations between left ventricular mass index and natriuresis in normal subjects and subjects with essential hypertension.
ratio of the left ventricular mass calculated by the Penn convention to the theoretically optimal left ventricular mass. Sixty-two subjects with a ratio cl.1 were defined as subjects with appropriate left ventricular mass (68% of the hypertensive population), whereas 29 subjects (32%) with a ratio z 1.1 were classified as subjects with inappropriate left ventricular mass. As summarized in Table 4, urinary sodium excretion was significantly higher in subjects with inappropriate left ventricular mass, whereas urinary potassium excretion, glomerular filtration rate, hematocrit, and plasma renin activity were similar in the two groups. Interestingly, systolic and diastolic arterial pressures were higher in subjects with appropriate left ventricular mass compared with those with inappropriate left ventricular mass. DISCUSSION
In agreement with previous investigations (1, 14), the present study confirmed the existence of an independent
relationship between 24-h urinary sodium excretion and left ventricular mass index in normotensive as well as hypertensive nonobese subjects. In addition, urinary sodium excretion was higher in a subgroup of hypertensive subjects in whom left ventricular mass was “inappropriate” to the level of arterial pressure than in subjects with “appropriate” left ventricular mass. These results suggest that a possible trophic effect of sodium on cardiac mass may be superimposed on the level of arterial pressure in essential hypertension. In the present study two consecutive measurements of 24-h urinary sodium excretion were used as an estimate of sodium intake (lo), which equals urinary excretion under normal circumstances except for a negligible loss of sodium in sweat and feces (11). The regression lines of the correlation between urinary sodium excretion and left ventricular mass index had similar slopes in normotensive and hypertensive subjects; however, the intercept with the ordinate axis was higher in the hypertensive than the normotensive group. This clearly indicates that for a given level of natriuresis, hypertensive subjects have a higher left ventricular mass index than normotensive subjects, thus emphasizing the role of both sodium and arterial pressure in the genesis of cardiac hypertrophy. In contrast with the hypertensive population, urinary sodium excretion was positively correlated with left ventricular diastolic internal dimension in the normotensive
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HMO
SODIUM
EXCRETION
AND LEFT VENTRICULAR
MASS
Table 4. Comparison between the characteristics of patients with appropriate and inappropriate left ventricular mass Left
Ventricular
Mass P Values
Appropriate
Inappropriate
data 62 40/22 37.2Hl l.Blt0.9 23.6t2.5 154t15
29 2217 36.4H3 2.08t1.3 24.1k2.4 144k13
Clinical
Number Sex (male/female) Age, yr
Duration of hypertension, yr Body mass index, kg/m2 Systolic arterial pressure, mmHg Diastolic arterial pressure, mmHg Mean arterial pressure, mmHg Heart rate, beats/min Hematocrit, % Glomerular filtration rate, ml. min-l 1.73 mm2 Plasma renin activity, ng ml+ h-l Urinary sodium excretion, mmo1/24 h Urinary potassium excretion, mmo1/24 h
97t_8 115k14
67t12
group, whereas posterior wall thickness at end diastole was positively correlated with sodium excretion only in the hypertensive group. This suggests that the impact of sodium on left ventricular mass may be primarily due to an effect on wall thickness in hypertensive subjects, whereas it may affect ventricular mass through a change in chamber volume via modification of circulating fluid (preload) in normotensive subjects. It is believed that chronic pressure overloading of the heart leads to normalization of myocardial wall stress, i.e., appropriate hypertrophy (6). In contrast, in hypertrophic myocardiopathy, inappropriate hypertrophy probably resulting from factors other than mechanical overload is observed (15, 16). In subjects with hypertension, it may be difficult to ascertain whether left ventricular hypertrophy is a consequence of high blood pressure, a manifestation of a coexistent primary hypertrophic cardiomyopathy, or a direct effect of trophic factors. In the present study, subjects with inappropriate left ventricular mass were characterized by a higher concentric left ventricular hypertrophy, despite a lower mean arterial pressure and similar known duration of hypertension compared with subjects with appropriate ventricular mass. Fractional shortening was not significantly different between groups. Thus the difference in left ventricular mass between the two groups cannot be explained by a difference in myocardial contractility or pressure overloading (although 24-h measurements of arterial pressure were not undertaken). Interestingly, in subjects with inappropriate ventricular mass, urinary sodium excretion was higher than in subjects with adapted ventricular mass. Plasma renin activity (and presumably circulating angiotensin II level) was similar in both groups; however, it may be inappropriate for the level of sodium intake in
128t25
NS
1.51k1.4
NS
183t63 73t21
0.01 NS
0.94&O. 1 0.90t0.2
1.12kO.2 1.12t0.2
0.001 0.001
4.80t0.4
4.56t0.4
0.005
42.1kO.l 0.39&O. 1 182&48 104&24
39.9kO.l
Echocardiographic
Interventricular septal wall thickness, cm Left ventricular posterior wall thickness, cm Left ventricular end-diastolic diameter, cm Fractional shortening, % Relative wall thickness Left ventricular mass, g Left ventricular mass index, g/m2 Values are means & SD.
62&17 44.7t3.4
120t28 1.87k1.4 146t69 65t31
l
93t5 108k12
44.6t3.7
l
l
NS NS NS NS 0.01 0.01 0.01 0.03 NS
indexes
0.50&O.
223t51 122&25
NS 1
0.001
0.001 0.002
subjects with inappropriate ventricular mass. Because angiotensin II is a known growth promoter (12), it could be speculated that sodium may act as a modulator of the effect of endogenous angiotensin II on the heart. It has been suggested that the trophic effects of increased dietary sodium may result from potentiation of the known effect of the sympathetic nervous system activity on the myocardium (12). Unfortunately this issue was not addressed in the present study. Nevertheless an effect of sodium on myocardial growth directly or through an influence on chamber volume (at an early stage in the development of hypertension) cannot be excluded. In conclusion, estimation of urinary sodium excretion may be an important factor in the assessment of the consequences of hypertension on the left ventricle. When estimating the effect of antihypertensive agents on left ventricular mass, urinary sodium excretion should be considered as a possible mechanism of the eventual resistance of left ventricular hypertrophy to treatment or the cause of the lack of relationship between changes in left ventricular mass and arterial pressure associated with antihypertensive therapy. Address for reprint requests: A. Mimran, Dept. of Medicine, Hopital Lapeyronie, 34059 Montpellier Cedex, France. Received 16 May 1991; accepted in final form 28 February 1992. REFERENCES Daniels, S. D., A. R. Meyer, and J. Loggie. Determinants of cardiac involvement in children and adolescents with essential hypertension. Circulation 82: 1243-1248A 1990. Devereux, B., and N. Reichek. Echocardiographic determination of left ventricular mass in man. Circulation 55: 613-618,1977. Fields, N. G., B. Yuan, and F. H. H. Leenen. Sodium-induced cardiac hypertrophy. Cardiac sympathetic activity versus volume load. Circ. Res. 68: 745-755, 1991.
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SODIUM
EXCRETION
AND LEFT VENTRICULAR
E. D., and R. C. Tarazi. Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy? Am. J. Cardiot. 44: 959-963, 1979.
4. Frohlich,
11. Michelsen,
5. Ganau, A., R. B. Devereux, P. L. Schnall, S. Santucci,
Sodium and potassium intakes and excretions of normal men consuming sodium chloride or a 1:l mixture of sodium and potassium chlorides. Am. J. Clin. Nutr. 30: 2033-2037, 1977. 12 Morgan, H. E, and K. M. Baker. Cardiac hypertrophy, mechanical, neural and endocrine dependence. Circdution 83: 13-25,
T. G. Pickering, M. C. Spitzer, and
M. J. Roman, J. H. Laragh.
Relation of left ventricular hemodynamic load and contractile performance to left ventricular mass in hypertension. Circulation 81: 25-36, 6. Grossman,
1990. W.,
D. Jones,
and patterns of hypertrophy Invest. 56: 56-64, 1975. 7. Hammond, H. Laragh.
I. W.,
Wall stress in the human left ventricle. J. Clin. and
R. B. Devereux,
L. P. McLaurin.
M.
H. Alderman,
and
J.
Relation of blood pressure and body build to left ventricular mass in normotensive and hypertensive employed adults. J. Am. Colt. Cardiol. 12: 996-1004, 1988.
8. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch. Intern. Med. 148: 1023-1027, 1988. 9. Lindpaintner, K., and S. Sen. Role of sodium in hypertensive cardiac hypertrophy. Circ. Res. 57: 610-617, 1985. 10. Luft, F. C., N. S. Fineberg, and R. S. Sloan. Estimating dietary sodium intake in individuals receiving a randomly fluctuating intake. Hypertension Dallas 4: 805-808, 1982.
O.,
H181
MASS D.
Makdani,
J.
L. Gill,
and
R.
L. Frank.
l
1991.
13. National
Institute of Health Consensus Development Health implications of obesity: health implications obesity. Ann. Intern. Med. 103: 1073-1077, 1985. Panel.
14. Schmieder, S. Nunez.
R. E., F. H. Messerli,
G. E. Garavaglia,
and
of B.
Salt intake as a determinant of cardiac involvement in essential hypertension. Circulation 78: 95 l-956, 1988. Sugishita, Y., K. Iida, K. Yukisada, and I. Ito. Cardiac de15* terminants of regression of left ventricular hypertrophy in essential hypertension with antihypertensive treatment. J. Am. Coil. Cardiol. 15: 665-671, 1990. Sugishita, Y., K. Iida, K. Yukisada, and I. Ito. Classification 16. of hypertrophied hearts in essential hypertension: evaluation by left ventricular wall stress and adrenergic responses. Br. Heart J. 59: 244-252,
1988.
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DU CAILAR,
Department
of Medicine, H6pital Lapeyronie, 34059 Montpellier
JEAN
RIBSTEIN,
JEAN-PIERRE
Du Cailar, Guilhem, Jean Ribstein, Jean-Pierre Daures, and Albert Mimran. Sodium and left ventricular massin untreated hypertensive and normotensive subjects.Am. J. Physiol. 263 (Heart Circ. Physiol. 32): Hl77-Hl81, 1992.To determine whether urinary sodiumexcretion (a rather rough
estimate of sodium intake) can influence left ventricular mass independently of arterial pressure,91 untreated subjects with essentialhypertension and 50 normotensive subjectsof similar agewere studied.Left ventricular massindex (M-mode echocardiography) waspositively correlated with urinary sodiumexcretion in hypertensive (r = 0.22, P < 0.01) aswell asnormotensive subjects(r = 0.22, P < 0.05), and systolic arterial pressurewas correlated only in hypertensive subjects (r = 0.23, P < 0.01). When hypertensive subjectswere divided into groupswith appropriate or inappropriate left ventricular massby reference to a theoretical optimal left ventricular massfor each subject’s level of systolic arterial pressure,left ventricular masswas appropriate in 68% and inappropriate in 32% of subjects.Urinary sodiumexcretion washigher in subjectswith inappropriate left ventricular masscomparedwith thosewith appropriate left ventricular mass.In conclusion, sodium excretion may be an important modulator of the influence of arterial pressureon the left ventricle in normotensive subjectsand subjectswith essential hypertension. hypertension; normal subjects OF ARTERIAL PRESSURE is not the sole determinant in the development of cardiac hypertrophy (4). Among other factors, age and body mass index (7) as well as humoral factors such as angiotensin and catecholamines were identified (12). Experimental studies conducted in rats with 2-kidney,1 -clip hypertension have shown that the shift from normal to low-sodium intake was associated with a consistent reversibility of cardiac hypertrophy, despite the absence of arterial pressure decrease (9). Similar observations were made in deoxycorticosterone acetate-salt hypertensive rats (3). Two recent studies conducted in hypertensive humans have suggested that sodium intake, estimated by 24-h urinary sodium excretion, may contribute to left ventricular changes associated with hypertension (1, 14). Left ventricular hypertrophy is an appropriate response to pressure overload to normalize myocardial wall stress; however, its mechanisms as well as eventual modulating factors remain unknown. In the present study, the influence of dietary sodium intake (assessed by the estimate of urinary sodium excretion) on the relationship between left ventricular geometry and arterial pressure was assessed in normal subjects and subjects with untreated mild to moderate essential hypertension. In addition, to identify a potential trophic effect of sodium on the myocardial response to elevated arterial pressure, the influence of sodium was analyzed in subjects with “appropriate” and “inappropriate” left ventricular mass, defined by reference to a theoretical optimal left ventricular mass for each subject’s level of systolic arterial pressure (5).
THE LZVEL
0363-6135/92
$2.00
Copyright
SUBJECTSAND
DAURES,
AND ALBERT
MIMRAN
Cedex, France METHODS
Studies were conducted in 91 untreated subjects (63 males aged 15-64 yr, and 28 femalesaged 25-61 yr) with uncomplicated borderline (27%) or mild to moderate (73%) essential hypertension defined according to the 1988 Joint National Committee criteria (8). The known duration of hypertension was 3-41 mo. Subjects had no electrocardiographic signs of valvular, primary myocardial, or coronary artery disease.Subjects with impaired renal function (glomerular filtration rate estimated by the clearance of ggmTc-diethylenetriaminopentaacetic acid, below the limits found in normal subjectsof similar age in our laboratory) were excluded. The control population consistedof 50 normal subjects (29 malesand 21 femalesaged25-61 yr) without a positive family history of hypertension (defined as one or both parents with diastolic arterial pressure higher than 95 mmHg or treated hypertension). Normotensive and hypertensive female subjects taking oral contraceptive therapy were excluded. In addition, overweight subjects defined as those with a body massindex [weight (kg)/height2 (m2)] >_27.8 for malesand 27.3 for females (13) were not included in the study. Subjects came to the ward with two consecutive 24-h urine collections for the measurementof urinary concentrations of sodium, potassium,creatinine, and protein. After a 30-min rest period in which the subject was in the supine position, arterial pressurewas measuredusing an automatic device (Dynamap 845XT, Critikon, France). In each subject, at least 10 measurementsof arterial pressurewere obtained, and the average of these values was considered. Subsequently, a blood samplewas withdrawn for the determination of hematocrit and plasmaconcentrations of sodium,potassium,creatinine, and plasmarenin activity (radioimmunoassay technique, CEA-Sorin kit, Saclay, France). Echocardiographic measurements. An ATL Ultramark 4 system (Advanced Technology Laboratories, Bellevue, WA) with an ATL 3.00 MHz mechanicaltransducer was used.The same operator obtained all echocardiogramswith the subject in the left lateral position, M-mode studies of the left ventricle were guided by two-dimensional echocardiograghyusing an optimal long-axis view below the tip of the mitral leaflets. M-mode tracings were analyzed using a digitized table (Edelman Software Products, Houston, TX) by two readerswho had no knowledge of arterial pressure and sodium intake. Measurement points weretaken at the peak of the R wave on the simultaneous electrocardiogram,on an averageof three cycles per recording. Interventricular septal thickness (IVSTd) and posterior wall thickness (PWTd) at end diastole were measuredaccording to the “Penn” convention (measurementsexcluding the thickness of the endocardial echoes).Relative wall thickness (RWT) at end diastolewascalculatedasthe ratio of twice the posterior left ventricular wall thickness to left ventricular diastolic internal dimension (LVIDd). Fractional shortening was assessed as a measureof left ventricular performance. Left ventricular mass (LVM) was calculated by the Penn-cube method according to Devereux et al. (2): LVM (g) = 1.04 [(LVIDd + PWTd + IVSTd)3 - (LVID,)“] - 13.6, where all ventricular dimensions are expressed in centimeters. Left ventricular mass index (LVMI) wascalculated as LVM per body surface area. A theoretically optimal left ventricular masswascalculatedto
0 1992 the American
Physiological
Society
HI77
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H178
SODIUM
EXCRETION
1 :LEFT
ANI:
allow each subject to achieve a normal value of peak systolic stress,according to the method describedby Ganau et al. (5). Peak systolic wall stresswascalculated using the formula: peak systolic stress= pressurex radius/thickness, where radius and thicknesscorrespondto LVIDJZ and PWTd, respectively. Subsequently,peak systolic stresswascalculatedas [ 1,333x SAP x WIW2) 1/PWTd, with SAP being systolic arterial pressure (mmHg) and 1,333the conversion factor from millimeters of Hg to dynes. In the presently reported 50 normotensive controls, calculated peak systolic stress was 467.4 t 12 (SD) x 10” dyn/cm? With the assumptionthat posterior wall and interventricular septal thicknesseswere equivalent in normotensive (0.80 t 0.11 vs. 0.81 t 0.11 cm, respectively) and hypertensive subjects(0.99 t 0.20 vs. 0.96 t 0.18 cm, respectively) (Table 1) and using the value of PWTd extracted from the peak systolic stressformula, estimation of optimal left ventricular masswas 1.04 x [(1.333 x LVIDd x SAP/467 + LVIDJ3 - LVIDd3]. Statistical methods. Resultswere analyzed using BMDP statistical software (University of California, Berkeley), and data wereexpressedasmeanst SD. Comparisonbetweengroupswas carried out by unpaired Student’s t test, nonparametric Kruskal-Wallis test, and stepwisediscriminant analysis.Linear nonparametric correlation coefficients between left ventricular massand other variables (demographic,hemodynamic, and humoral) were calculated. Variables that exhibited significant univariate correlation with left ventricular masswere further usedas independent variables in a stepwisemultiple regression analysis. RESULTS
As shown in Table 1, normotensive and hypertensive subjects did not differ with respect to age, body mass index, heart rate, and urinary sodium and potassium excretion. Interventricular septal thickness and posterior wall thickness at end diastole as well as left ventricular mass and left ventricular mass index were significantly higher in hypertensive than normotensive subjects. Left ventricular internal dimension at end diastole was similar in both groups. The prevalence of left ventricular hypertrophy (X27 and 110 g/m2 in males and females, respectively, as determined in our control population) was 26% in the hypertensive group. Of interest, arterial pressure was 148 t 16 to 94 t 12 mmHg in subjects without left
VENTRICULAR
MASS
ventricular hypertrophy and 152 t 15 to 97 t 11 mmHg (NS) in subjects with left ventricular hypertrophy. Determinants of left ventricular mass. Results of univariate correlations are summarized in Table 2. When the whole population was considered, left ventricular mass index was positively correlated with both systolic arterial pressure and urinary sodium excretion. In addition, PWTd was correlated with systolic and diastolic arterial pressure and natriuresis, whereas LVIDd was only correlated with urinary sodium excretion. When normotensive and hypertensive subjects were analyzed separately, it appeared that left ventricular mass index was positively correlated with urinary sodium excretion in both groups. The intercept with the ordinate axis was higher in hypertensive than normotensive subjects (P < O.Ol), whereas the slopes of the regression lines were not significantly different between the two groups (Fig. 1). Of interest, in normotensive subjects, urinary sodium excretion was positively correlated with left ventricular internal diameter at end diastole, whereas no such correlation was detected in hypertensive subjects. Only in the hypertensive group was urinary sodium excretion correlated with both left ventricular mass index and posterior wall thickness at end diastole. No significant correlation between urinary sodium excretion and arterial pressure was detected in either group. Multiple regression analysis (Table 3) showed that body mass index, urinary sodium excretion, and systolic arterial pressure were independent predictors of left ventricular mass in both normal and hypertensive subjects as well as the entire population. In the whole population and subjects with essential hypertension, the strongest predictors of left ventricular mass were body mass index and urinary sodium excretion. Thus multivariate analysis demonstrated the independence of urinary sodium excretion as a determinant of left ventricular mass in each population. Characteristics of subjects with appropriate and inappropriate left ventricular mass. Cluster analysis was used
to subdivide the hypertensive
population
according to the
Table 1. Clinical and echocardiographic characteristics of hypertensive and normal subjects Hypertensives
Clinical
Sex (male/female) Age, yr Body mass index, kg/m2 Systolic arterial pressure, mmHg Diastolic arterial pressure, mmHg Heart rate, beats/min Hematocrit, % Urinary sodium excretion, mmo1/24 h Urinary potassium excretion, mmo1/24 h
Normotensives
P Values
data
62/29 37klO 23.7t2.6 151t14 96dO 65t9 44.6k3.6 155266 67229 Echocardiographic indexes
29/21 37&11 22.9k2.5 122&9 73t7 67tlO 42.3k4.3 135252 58t20
Interventricular septal wall thickness, cm 0.96t0.18 0.81t0.11 Left ventricular posterior wall thickness, cm 0.99-to.20 0.8OkO. 11 Left ventricular end-diastolic diameter, cm 4.70t0.44 4.67t0.43 Left ventricular mass, g 195t52 143t40 Left ventricular mass index, g/m2 109-e25 83t20 Relative wall thickness 0.42t0.08 0.36t0.06 Fractional shortening, % 42&O. 1 40to. 1 Values are means t SD; n = 91 hypertensive subjects and 50 normal subjects. NS, not significant.
NS NS NS
0.001 0.001 NS co.05 NS NS 0.002 0.002 NS 0.0001
0.001 0.001 NS
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SODIUM
Table 2. Univariate
correlations
EXCRETION
AND
LEFT
between echocardiographic All LVM
Subjects
LVIDd
H179
MASS
indexes and clinical parameters
(n = 141)
LVMI
VENTRICULAR
Normotensive PWTd
LVM
Subjects
(n = 50)
LVIDd
PWTd
LVMI
Hypertensive LVM
LVMI
Subjects
(n = 91)
LVIDd
PWTd
0.01 0.21" 0.03 0.17 0.01 0.01 0.18 0.27* 0.07 0.19 Age, yr 0.19* 0.16 0.18 Body mass index, kg/m* 0.36* 0.18 0.27* 0.29* 0.32* 0.03 0.26* 0.38" 0.19 0.23* 0.31" Systolic arterial pressure, mmHg 0.50* 0.20* 0.11 0.56" 0.40* 0.19 0.28* 0.35* 0.21* 0.23* 0.09 0.21* 0.14 0.29* 0.15 0.11 0.22* 0.12 0.11 0.23 0.19 0.16 0.18 0.01 Diastolic arterial pressure, mmHg 0.11 0.24* 0.22* 0.12 0.21" Urinary sodium excretion, mmo1/24 h 0.33* 0.21" 0.23* 0.23* 0.41* 0.22* 0.43* 0.01 0.13 0.11 0.09 0.12 0.09 0.15 0.17 0.16 0.09 0.10 Urinary potassium excretion, mmo1/24 h 0.11 LVM, left ventricular mass (g); LVMI, left ventricular mass index (g/m*); LVIDd, left ventricular internal diameter at end diastole (cm); PWTd, posterior wall thickness at end diastole (cm). * P < 0.05.
200 -
y=O.llx+68
Normotensive Subjects
.
N $ i
Table 3. Multivariate analysis of systolic arterial pressure, body mass index, and urinary sodium excretion as determinants of left ventricular mass
r = 0.22
p < 0.05
160 .
Variables
120 -
SE
4.58 1.14 0.20
1.62 0.21 0.06
P Value
All subjects
Body mass index, kg/m* Systolic arterial pressure, mmHg Urinary sodium excretion, mmo1/24 h Multiple r = 0.37
go:; .
g 40. a 0 E b 200, 2 .
P
1
1
.
loo
I
.
200
I
.
300
y =0.08x r = 0.22
Essemtid Hypertension
z
.s MOE
+ 97
p < 0.01
0
O@ *O*
I 400
Normotensive
subjects
Body mass index, kg/m* Systolic arterial pressure, mmHg Urinary sodium excretion, mmo1/24 h Multiple r = 0.34 Hypertensive
s e
0.20 1.35 0.24
1.60 0.52
6.35 0.64 0.16
2.22 0.33 0.08
0.10
NS
0.01 0.02 0.001
patients
Body mass index, kg/m* Systolic arterial pressure, mmHg Urinary sodium excretion, mmo1/24 h Multiple r = 0.20 NS, not significant.
l
0.006 0.000 1 0.002 0.0001
0.006 0.04 0.03 0.0001
s 0
.
40 ’
0
Urinary
1
I
loo
1
1
200
1
1
J
300
Sodium Excretion
400
mmo1/24h
Fig. 1. Univariate correlations between left ventricular mass index and natriuresis in normal subjects and subjects with essential hypertension.
ratio of the left ventricular mass calculated by the Penn convention to the theoretically optimal left ventricular mass. Sixty-two subjects with a ratio cl.1 were defined as subjects with appropriate left ventricular mass (68% of the hypertensive population), whereas 29 subjects (32%) with a ratio z 1.1 were classified as subjects with inappropriate left ventricular mass. As summarized in Table 4, urinary sodium excretion was significantly higher in subjects with inappropriate left ventricular mass, whereas urinary potassium excretion, glomerular filtration rate, hematocrit, and plasma renin activity were similar in the two groups. Interestingly, systolic and diastolic arterial pressures were higher in subjects with appropriate left ventricular mass compared with those with inappropriate left ventricular mass. DISCUSSION
In agreement with previous investigations (1, 14), the present study confirmed the existence of an independent
relationship between 24-h urinary sodium excretion and left ventricular mass index in normotensive as well as hypertensive nonobese subjects. In addition, urinary sodium excretion was higher in a subgroup of hypertensive subjects in whom left ventricular mass was “inappropriate” to the level of arterial pressure than in subjects with “appropriate” left ventricular mass. These results suggest that a possible trophic effect of sodium on cardiac mass may be superimposed on the level of arterial pressure in essential hypertension. In the present study two consecutive measurements of 24-h urinary sodium excretion were used as an estimate of sodium intake (lo), which equals urinary excretion under normal circumstances except for a negligible loss of sodium in sweat and feces (11). The regression lines of the correlation between urinary sodium excretion and left ventricular mass index had similar slopes in normotensive and hypertensive subjects; however, the intercept with the ordinate axis was higher in the hypertensive than the normotensive group. This clearly indicates that for a given level of natriuresis, hypertensive subjects have a higher left ventricular mass index than normotensive subjects, thus emphasizing the role of both sodium and arterial pressure in the genesis of cardiac hypertrophy. In contrast with the hypertensive population, urinary sodium excretion was positively correlated with left ventricular diastolic internal dimension in the normotensive
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HMO
SODIUM
EXCRETION
AND LEFT VENTRICULAR
MASS
Table 4. Comparison between the characteristics of patients with appropriate and inappropriate left ventricular mass Left
Ventricular
Mass P Values
Appropriate
Inappropriate
data 62 40/22 37.2Hl l.Blt0.9 23.6t2.5 154t15
29 2217 36.4H3 2.08t1.3 24.1k2.4 144k13
Clinical
Number Sex (male/female) Age, yr
Duration of hypertension, yr Body mass index, kg/m2 Systolic arterial pressure, mmHg Diastolic arterial pressure, mmHg Mean arterial pressure, mmHg Heart rate, beats/min Hematocrit, % Glomerular filtration rate, ml. min-l 1.73 mm2 Plasma renin activity, ng ml+ h-l Urinary sodium excretion, mmo1/24 h Urinary potassium excretion, mmo1/24 h
97t_8 115k14
67t12
group, whereas posterior wall thickness at end diastole was positively correlated with sodium excretion only in the hypertensive group. This suggests that the impact of sodium on left ventricular mass may be primarily due to an effect on wall thickness in hypertensive subjects, whereas it may affect ventricular mass through a change in chamber volume via modification of circulating fluid (preload) in normotensive subjects. It is believed that chronic pressure overloading of the heart leads to normalization of myocardial wall stress, i.e., appropriate hypertrophy (6). In contrast, in hypertrophic myocardiopathy, inappropriate hypertrophy probably resulting from factors other than mechanical overload is observed (15, 16). In subjects with hypertension, it may be difficult to ascertain whether left ventricular hypertrophy is a consequence of high blood pressure, a manifestation of a coexistent primary hypertrophic cardiomyopathy, or a direct effect of trophic factors. In the present study, subjects with inappropriate left ventricular mass were characterized by a higher concentric left ventricular hypertrophy, despite a lower mean arterial pressure and similar known duration of hypertension compared with subjects with appropriate ventricular mass. Fractional shortening was not significantly different between groups. Thus the difference in left ventricular mass between the two groups cannot be explained by a difference in myocardial contractility or pressure overloading (although 24-h measurements of arterial pressure were not undertaken). Interestingly, in subjects with inappropriate ventricular mass, urinary sodium excretion was higher than in subjects with adapted ventricular mass. Plasma renin activity (and presumably circulating angiotensin II level) was similar in both groups; however, it may be inappropriate for the level of sodium intake in
128t25
NS
1.51k1.4
NS
183t63 73t21
0.01 NS
0.94&O. 1 0.90t0.2
1.12kO.2 1.12t0.2
0.001 0.001
4.80t0.4
4.56t0.4
0.005
42.1kO.l 0.39&O. 1 182&48 104&24
39.9kO.l
Echocardiographic
Interventricular septal wall thickness, cm Left ventricular posterior wall thickness, cm Left ventricular end-diastolic diameter, cm Fractional shortening, % Relative wall thickness Left ventricular mass, g Left ventricular mass index, g/m2 Values are means & SD.
62&17 44.7t3.4
120t28 1.87k1.4 146t69 65t31
l
93t5 108k12
44.6t3.7
l
l
NS NS NS NS 0.01 0.01 0.01 0.03 NS
indexes
0.50&O.
223t51 122&25
NS 1
0.001
0.001 0.002
subjects with inappropriate ventricular mass. Because angiotensin II is a known growth promoter (12), it could be speculated that sodium may act as a modulator of the effect of endogenous angiotensin II on the heart. It has been suggested that the trophic effects of increased dietary sodium may result from potentiation of the known effect of the sympathetic nervous system activity on the myocardium (12). Unfortunately this issue was not addressed in the present study. Nevertheless an effect of sodium on myocardial growth directly or through an influence on chamber volume (at an early stage in the development of hypertension) cannot be excluded. In conclusion, estimation of urinary sodium excretion may be an important factor in the assessment of the consequences of hypertension on the left ventricle. When estimating the effect of antihypertensive agents on left ventricular mass, urinary sodium excretion should be considered as a possible mechanism of the eventual resistance of left ventricular hypertrophy to treatment or the cause of the lack of relationship between changes in left ventricular mass and arterial pressure associated with antihypertensive therapy. Address for reprint requests: A. Mimran, Dept. of Medicine, Hopital Lapeyronie, 34059 Montpellier Cedex, France. Received 16 May 1991; accepted in final form 28 February 1992. REFERENCES Daniels, S. D., A. R. Meyer, and J. Loggie. Determinants of cardiac involvement in children and adolescents with essential hypertension. Circulation 82: 1243-1248A 1990. Devereux, B., and N. Reichek. Echocardiographic determination of left ventricular mass in man. Circulation 55: 613-618,1977. Fields, N. G., B. Yuan, and F. H. H. Leenen. Sodium-induced cardiac hypertrophy. Cardiac sympathetic activity versus volume load. Circ. Res. 68: 745-755, 1991.
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SODIUM
EXCRETION
AND LEFT VENTRICULAR
E. D., and R. C. Tarazi. Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy? Am. J. Cardiot. 44: 959-963, 1979.
4. Frohlich,
11. Michelsen,
5. Ganau, A., R. B. Devereux, P. L. Schnall, S. Santucci,
Sodium and potassium intakes and excretions of normal men consuming sodium chloride or a 1:l mixture of sodium and potassium chlorides. Am. J. Clin. Nutr. 30: 2033-2037, 1977. 12 Morgan, H. E, and K. M. Baker. Cardiac hypertrophy, mechanical, neural and endocrine dependence. Circdution 83: 13-25,
T. G. Pickering, M. C. Spitzer, and
M. J. Roman, J. H. Laragh.
Relation of left ventricular hemodynamic load and contractile performance to left ventricular mass in hypertension. Circulation 81: 25-36, 6. Grossman,
1990. W.,
D. Jones,
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I. W.,
Wall stress in the human left ventricle. J. Clin. and
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8. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch. Intern. Med. 148: 1023-1027, 1988. 9. Lindpaintner, K., and S. Sen. Role of sodium in hypertensive cardiac hypertrophy. Circ. Res. 57: 610-617, 1985. 10. Luft, F. C., N. S. Fineberg, and R. S. Sloan. Estimating dietary sodium intake in individuals receiving a randomly fluctuating intake. Hypertension Dallas 4: 805-808, 1982.
O.,
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Makdani,
J.
L. Gill,
and
R.
L. Frank.
l
1991.
13. National
Institute of Health Consensus Development Health implications of obesity: health implications obesity. Ann. Intern. Med. 103: 1073-1077, 1985. Panel.
14. Schmieder, S. Nunez.
R. E., F. H. Messerli,
G. E. Garavaglia,
and
of B.
Salt intake as a determinant of cardiac involvement in essential hypertension. Circulation 78: 95 l-956, 1988. Sugishita, Y., K. Iida, K. Yukisada, and I. Ito. Cardiac de15* terminants of regression of left ventricular hypertrophy in essential hypertension with antihypertensive treatment. J. Am. Coil. Cardiol. 15: 665-671, 1990. Sugishita, Y., K. Iida, K. Yukisada, and I. Ito. Classification 16. of hypertrophied hearts in essential hypertension: evaluation by left ventricular wall stress and adrenergic responses. Br. Heart J. 59: 244-252,
1988.
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