Journal of Znternal Medicine 1992 : 231 : 521-529
Responses of atrial natriuretic factor to long-term sodium restriction in mild to moderate hypertension A. JULA, T. RONNEMAA, I. TIKKANEN* & H. KARANKO From the Rehabilitation Research Centre of the Social lnsurance Institution. Turku. and the * Minerva Institute jor Medical Research, Helsinki, Finland
Abstract. Jula A, Ronnemaa T, Tikkanen I, Karanko H (Rehabilitation Research Centre of the Social Insurance Institution, Turku, and Minerva Institute for Medical Research, Helsinki, Finland). Responses of atrial natriuretic factor to long-term sodium restriction in mild to moderate hypertension. Journal of Znternal Medicine 1992: 231 : 521-529. The effects of long-term sodium restriction on plasma atrial natriuretic factor (ANF) concentrations, and the role of baseline plasma ANF concentration as an indicator of changes in haemodynamics and left ventricular hypertrophy during this treatment were studied in 40 middle-aged previously untreated mildly to moderately hypertensive men and women in a 6-month controlled randomized study. The main emphasis of the treatment programme was to reduce daily sodium intake to less than 70 mmol. Mean sodium excretion decreased from 148 f 74 mmol 24 h-' to 79 k 71 mmol 24 h-' in the treatment group, but remained unchanged in the control group (173 f 68 mmol 24 h-' vs. 186 62 mmol 24 h-': P < 0.01 for the difference in changes between the groups). Mean plasma ANF concentrations in the treatment group were 52.4 f20.7 (median 50) pgml-' at baseline and 38.7k26.3 (median 42) pgml-' at 6 months, and the corresponding values in the control group were 55.5 f 2 0 . 5 (median 50) pg ml-' and 46.1 f32.4 (median 50) pg ml-I, respectively ( P = NS for the difference in changes). The ANF concentration decreased from 70 k 14 pg ml-' to 32 k 26 pg ml-' in treated subjects with a high baseline plasma ANF concentration (> 50 pg ml-'), but increased from 37f 11 pg ml-I to 45 f 2 7 pg ml-' in subjects with a low baseline plasma ANF concentration (,< 50 pg d-l)(difference in changes P < 0.001).Compared with treated subjects with low baseline plasma ANF levels and with controls, treated subjects with high baseline plasma ANF levels showed a decrease (P < 0.05) in interventricular septal and left posterior wall thicknesses, in relative wall thickness, and in peripheral resistance. These results suggest that in mildly to moderately hypertensive subjects long-term sodium restriction decreases high plasma ANF concentrations concomitantly with regression of concentric left ventricular hypertrophy, probably as a result of changes in haemodynamics.
Keywords: atrial natriuretic factor, hypertension, left ventricular hypertrophy, sodium restriction, total peripheral resistance.
Introduction Atrial natriuretic factor (ANF), a peptide hormone that is primarily synthesized and stored in atrial cardiocytes. has potent acute natriuretic, diuretic Abbreviations: ANF = atrial natriuretic factor, IVST = interventricular septal thickness, LVIDd = left ventricular internal dimension in diastole, LVM = left ventricular mass, LVMI = left ventricular mass index, PRA = plasma renin activity, PWT = posterior wall thickness, R W T = relative wall thickness, TPR = total peripheral resistance.
and vasodilatory effects [l]. It is released via atrial stretch, secondary to a n increase in central blood volume, caused by saline infusion [ 2 4 ] , water immersion [S] and change from upright to supine posture [6-81. In contrast, short-term sodium restriction decreases ANF secretion in both normotensive [4] and hypertensive [9-111 subjects. To our knowledge no one has examined the responses of ANF release to long-term sodium restriction. Plasma ANF concentrations are increased in some hypertensive subjects [12-14]. Among hypertensive
52 1
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individuals high plasma ANF is associated with higher blood pressure [13, 141, left ventricular hypertrophy [14, 161, increased left atrial size [15, 161 and, according to some [ 7, 15, 171 but not all studies [14, 161, with more advanced age. However, redistribution of blood from peripheral to central venous space, which has been shown to occur particularly in low-renin hypertensives [18, 191, could also be partly responsible for increased ANF secretion due to increased right atrial stretch. We wanted to examine the effects of long-term moderate sodium restriction on plasma ANF concentration in untreated subjects suffering from mild to moderate uncomplicated essential hypertension. In addition, we wanted to detect factors associated with high baseline plasma ANF levels, and to determine whether high plasma ANF concentrations predict changes in haemodynamics and characteristics of left ventricular hypertrophy during longterm sodium restriction.
subjects dropped out of the treatment group and one dropped out of the control group. For anatomical reasons, echocardiography could not be successfully performed in three patients. Thus the population with regard to echocardiographic data consisted of 1 6 subjects in the treatment group and 1 7 subjects in the control group.
Treatment programme The main aim of the non-pharmacological treatment programme was to reduce daily sodium intake to less than 70 mmol. Patients also received instructions on how to reduce their intake of saturated fat, to increase the ratio of polyunsaturated to saturated fatty acids in their diet, and to lose weight if necessary. The controls did not receive any instructions regarding non-pharmacological treatment of hypertension. Antihypertensive medication was not used in either group.
Measurements
Patients and methods Patients Forty subjects (18 men and 2 2 women, aged 35-55 years) with mild to moderate essential hypertension (World Health Organization stages 1-11) were recruited from the occupational health service of three industrial plants and two government offices. The subjects had diastolic blood pressure consistently in the range 90-110 mmHg and/or systolic blood pressure consistently in the range 160-200 mmHg during the run-in period. The diagnosis of uncomplicated essential hypertension was based on physical examination, routine biochemical tests and exercise electrocardiogram. The patients had no cardiomyopathy or significant valvular disease according to physical examination and echocardiography, and they were not on oral contraceptives or any other regular drug treatment. The patients had not been treated for hypertension earlier, or had been without treatment for at least 1 year before the onset of the study. The study subjects were divided into two groups that were comparable with regard to sex, age and occupational status. Randomization into a control group and a treatment group was carried out between the two groups. Thus to avoid contamination of controls, control and treatment subjects were never derived from the same source. Two
Diet was monitored at baseline and at 3 and 6 months by means of 7-d dietary records, 24-h urine samples for sodium, potassium and creatinine content, and weight measurement. Blood samples for determination of plasma renin activity (PRA), plasma aldosterone and ANF were taken at the clinic, after a night’s rest and before rising, at baseline and at 6 months. For plasma noradrenaline and adrenaline sampling, a cannula was inserted into the left median cubital vein and 5 ml of blood were drawn after a 15-min rest in the supine position and after 5 min in the sitting position. Two-dimensionally controlled M-mode echocardiographic studies were performed at baseline and 6 months from the same intercostal space using an ATL MARK I11 ultrasonoscope and a real-time scanhead (720A) with a 3-Mhz transducer. All echo studies were performed by the same investigator, who also read and coded the tracings blindly, in random order, after the study period. The cardiac dimensions were measured from M-mode echocardiograms according to the recommendations of the American Society of Echocardiography [20], digitized and processed using a Hewlett Packard 9845B minicomputer and a Hewlett Packard 9874A digitizing table, and averaged from at least five heart cycles. Leading edge to leading edge convention was used. Relative wall thickness was determined as the ratio of end-diastolic posterior wall thickness and
ATRIAL NATRIURETIC FACTOR AND SODIUM RESTRICTION
523
Table 1. Comparison of treatment and control subjects Variable Sex (women/men)
Treatment group (n = 19)
P-valuet
12/8
Control group (n = 17) 9/8
4 4 . 7 f 5.6
42.5 f 3.8
Age ( y e a 4 Systolic blood pressure (mmHg) Baseline 1-6 months
151.9 f 17.9 133.3f 11.8***
< 0.01
143.9f10.4 136.6f 10.4**
Diastolic blood pressure (mmHg) Baseline 1-6 months
9 8 . 4 f 7.6 88.4+6.7***
< 0.001
96.1 k 4 . 1 9 2 . 6 k 5.4"
Weight (kg) Baseline 6 months
75.2k15.4 73.6+15.1**
< 0.01
76.1 f 15.3 76.8 f 15.3
Body mass index (kg m-') Baseline 6 months
26.1f4.5 25.5+4.4**
< 0.01
25.7f 3.3 26.0 & 3.3
148 f 7 4 7 9 + 71**
< 0.01
173f68 186 f6 2
Sodium excretion (mmol 2 4 h-l) Baseline 6 months Potassium excretion (mmol 2 4 h-') Baseline 6 months
76 k 2 3 88 f2 4
NS
79 21 83t-21
Plasma renin activity (ng A1 ml-' h-') Baseline 6 months
0.70+0.60 1.10 0.56'
+
NS
0.65k0.37 0.86+0.57*
Plasma aldosterone ( p o l I-') Baseline 6 months
297f125 363 f 132
NS
243 & 66 279t-99
*** P < 0.001, ** P < 0.01. * P < 0.05 compared to baseline.
t Significance of difference in change from baseline between treatment and control groups. Mean values SD are shown.
+
half of the end-diastolic left ventricular internal dimension. Left ventricular mass was calculated from end-diastolic wall thickness and cavity dimensions using the formula described by Troy et al. [21]. Left ventricular volumes were estimated by the cubefunction formula and used to calculate stroke volume as the difference between end-diastolic and endsystolic left ventricular volumes : cardiac output was calculated as stroke volume x heart rate. Total peripheral resistance was estimated by dividing mean arterial pressure (diastolic blood pressure added by one-third of the difference between systolic and diastolic blood pressures) with cardiac output and expressed as dynes s ~ m - End-systolic ~. wall stress was calculated from systolic blood pressure and from endsystolic left ventricular diameter and posterior wall thickness using a previously described and validated formula [22, 231. Blood pressure was measured by a single trained nurse using a mercury sphygmomanometer. Measurements were made with subjects
in the supine position, immediately after recording the left ventricular echocardiogram. The average of two measurements taken at approximately 2-min intervals was used to calculate peripheral resistance and end-systolic wall stress. The coefficient of variation in mild to moderate hypertensives ( n = 38) was 5.1 % for interventricular septa1 thickness, 6.5 % for posterior wall thickness, 3.6 % for left ventricular internal diameter, 5.8 % for left ventricular mass, 9.6% for cardiac output, 11.4% for total peripheral resistance and 17.6% for end-systolic wall stress. Out-patient clinic blood pressures were measured by a single trained technician using a Hawksley random zero sphygmomanometer. Measurements were made with subjects in the sitting position, always in the morning and in the same quiet room throughout the study. Blood pressure was the mean value of two measurements taken with a 2-min interval. During the run-in period, blood pressure was measured three times at weekly intervals, and
A. JULA et al.
524
= Plasma samples were centrifuged under refrigeration and stored at - 70 "C. Radioimmunoassay was used to determine PRA (Phadebas Angiotensin I-test, Pharmacia Diagnostics, Stockholm, Sweden), plasma aldosterone (Aldosterone RIA, Abbott Laboratories, Chicago, IL, USA) and plasma ANF [24]. Plasma noradrenaiine and adrenaline were measured with a radioenzymatic technique [2 5, 261. The inter-assay coefficient of variation was 7.7% for PRA, 10.9% for aldosterone, 9.9% for ANF, 12.7% for adrenaline and 9.6 % for noradrenaline, respectively.
I 800 I600
T
E, v)
1400
I200 1000
n
a
r = 0.41
Statistical methods
P < 0.05
0
I
I
I
I
1
20
40
60
80
I
100
Plasma ANF Concentration (pg m1-I)
Fig. 1 . Correlation of plasma ANF concentrations with total peripheral resistance at baseline (all hypertensives combined).
0
O
I
O o o C
-' 'ooo[
c
0
800
5
-0-
e 00
8
Results
0
400
0
n a
I-
r = 0.44
P < 0.01 0
I
Statistical analysis of the data was performed using SAS computer programs (SAS Institute, Cary, NC, USA). Analysis of variance was used to test the significance of the difference between the study group at baseline, and repeated-measures analysis of variance was used to test the significance of the difference in changes within and between the study groups. Pearson' s correlation coefficient was calculated to indicate the correlations between plasma ANF levels and other variables at baseline during unrestricted sodium intake.
I
1
I
I
20
40
60
80
I
100
No significant differences in baseline characteristics were found between treatment and control subjects (Table 1). The net decrease (difference in changes between treatment and control group) was 11.2 mmHg (P < 0.01) in out-patient clinic systolic blood pressure and 6.5 mmHg (P < 0.001) in outpatient clinic diastolic blood pressure during the 6-month follow-up.
Plasma ANF concentration (pg m1-l)
Fig. 2. Correlation of plasma ANF concentrations with total peripheral resistance index at baseline (all hypertensives combined).
the mean value of the last two measurements was taken to represent baseline blood pressure. Blood pressure was measured monthly during the followup. Diastolic blood pressure was defined as the disappearance of the fifth phase of Korotkoff sounds.
Biochemical assays For the measurement of PRA. aldosterone, ANF and catecholamines, blood was collected into ice-cold tubes containing 6 mg Na,EDTA ml-' of blood.
Dietary changes A marked decrease in 24-h urine sodium (68 f9 7 mmol, P < 0.01) and a small decrease in weight ( 1 . 6 f 2 . 1 kg, P < 0.01) was noted at 6 months in the treatment group, whereas no changes were observed in the controls (Table 1). Energy intake from fat decreased from 41 L- 6% to 37 f4 % (P < 0.05) in the treatment group, but remained unchanged in the control group (43 f3 % at baseline vs. 4 3 f6 % at 6 months). The decrease in fat intake of treatment subjects consisted of approximately equal reductions in the intake of saturated and monounsaturated fatty acids, whereas the intake of polyunsaturated fatty acids remained unchanged.
ATRIAL NATRIURETIC FACTOR A N D SODIUM RESTRICTION
525
Table 2. Comparison of treated hypertensive subjects with high plasma baseline ANF ( > 50 pg ml-') and low plasma baseline ANF ( < 50 pg ml-') concentrations
Variable
High ANF (n = 9)
Sex (women/men) Age (years)
P-valuet
614 43.2 C 6.0
613
46.3
IAW ANF ( n = 10)
+ 5.1
Systolic blood pressure (mmHg) Baseline 1-6 months
159.7 & 14.8 138.1 11.7***
+
NS
144.XC 18.2 129.0f 10.7**
Diastolic blood pressure (mmHg) Baseline 1-6 months
101.4k7.0 90.2 5.2**
NS
95.7+ 7.5 86.7 7.7***
+
+
Weight (kg) Baseline 6 months
72.1 & 14.3 69.6 f 12.7**
NS
78.0f16.6 77.3 C 16.8
Body mass index (kg m-') Baseline 6 months
25.2C4.5 24.3 C 4.1 *
NS
26.8k4.5 26.6 4.6
156+70 70 C 82'
NS
140k81 87C62
83 25 95+18
NS
69k21 82 27
Plasma renin activity (ng Al ml-' h-') Baseline 6 months
0.66 k 0 . 3 2 1.19+0.51
NS
0.74C0.80 1 .02 0.62
Plasma aldosterone (pmol I-') Baseline 6 months
287+ 145 362 77
NS
306C 112 363 I72
Sodium excretion (mmol 24h-') Baseline 6 months Potassium excretion (mmol 24 h-') Baseline 6 months
Plasma atrial natriuretic factor (pg ml-') Baseline 6 months
+
70+14 32 26**
+
< 0.001
+ +
37+ 11 45 k 27
*** P < 0.001, ** P < 0.01, * P < 0.05 compared with baseline.
t Significance of difference in change from baseline between high and low ANF subgroups. Mean values C SD are shown.
Renin and aldosterone PRA increased slightly (P < 0.05) in the treatment and control groups (Table l),while no significant increases in plasma aldosterone levels were observed.
Atrial natriuretic factor At baseline, treatment and control subjects combined showed a significant correlation between ANF and total peripheral resistance (Fig. 1)and total peripheral resistance index (Fig. 2), but not between ANF and supine mean arterial pressure ( r = 0.21), supine systolic blood pressure ( r = 0.27). and out-patient clinic diastolic ( r = 0.23) and systolic ( r = 0.30) blood pressure. No associations were found between
plasma ANF and age ( r = 0.02), PRA ( r = -0.20), plasma aldosterone ( r = -0.01), plasma adrenaline and noradrenaline at supine rest ( r = 0.08 and r = 0.12, respectively) and adrenaline and noradrenaline in the sitting position ( r = 0.05 and r = 0.09, respectively), body mass index ( r = -0.27), and 24-h urine sodium ( r = -0.20), as well as between plasma ANF and left atrial diameter indexed by body surface area ( r = -0.04), left ventricular mass indexed by body surface area ( r = -0.21), and enddiastolic interventricular ( r = - 0.08) and posterior wall thicknesses ( r = - 0.08). Mean plasma atrial natriuretic factor concentrations were 5 2 . 4 k 2 0 . 7 (median, 50) pg ml-' at baseline and 3 8 . 7 k 2 6 . 3 (median, 42) pgml-' at 6 months in the treatment group, and 55.5 k 20.5
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A. JULA et al.
Table 3. Changes in left ventricular characteristics in treated subjects with high plasma baseline atrial natriuretic factor concentrations (ANF> 50 pg m1-l) compared with treated subjects with low plasma baseline ANF ( < 50 pg m1-l) and with controls Treatment group
Variable
Control group
Difference in changes High AN!? vs. low ANF
High ANF vs. controls
Low ANF vs. controls
High ANF (n = 7)
Low ANF (n = 9)
(n = 17)
LVIDd (mm)
Baseline 6 months
47.5 f 3.3 50.6+4.1*
50.3 f3.7 49.7f4.2
51.6f4.8 50.8 5 . 0
+
< 0.05
< 0.05
NS
IVST (mm)
Baseline 6 months
11.5 f 1.6 10.3f1.7
11.0f 1.1 11.5f 1.7
11.5f 1.7 12.1 f 1 . 7
< 0.05
< 0.05
NS
PWT (mm)
Baseline 6 months
10.0f I .2 9.2k1.0
9 . 6 f 0.9 10.1 f 1.3
9.8+ 1.3 10.2 f 1.4
< 0.05
< 0.05
NS
RWT
Baseline 6 months
0 . 4 2f 0 . 0 7 0.37+0.06*
0.38 f0.05 0.41f0.06
0.38 f0.05 0.41 f0.06
< 0.05
< 0.01
NS
Baseline 6 months
2 3 4 f41 225 f 32
242+45 255 62
268 f66 276f68
NS
NS
NS
Baseline 6 months
I 3 2 f1 4 129f11
129+16 135f22
142f31 146f33
NS
NS
NS
LVM (8) LVMI (g m-')
~~
~
+
~
LVIDd = left ventricular internal dimension in end-diastole, IVS = interventricular septal thickness in end-diastole, PWT = posterior wall thickness in end-diastole, RWT = relative wall thickness, LVM = left ventricular mass, LVMI = left ventricular mass index, TPR = total peripheral resistance. * P < 0.05. compared with baseline. Mean values fSD are shown.
(median, 50) pg ml-' and 46.1 32.4 (median, 50) pg ml-', respectively, in the control group. The changes within or between the study groups were not statistically significant. Subjects in the treatment and control groups were classified as subjects with high or low ANF concentrations according to the baseline median plasma ANF concentration of the study population. Treated subjects with a high plasma ANF concentration ( > 5 0 p g ml-') showed a decrease in ANF concentration ( P < 0.01) during sodium restriction, while no change was observed in subjects with a low plasma ANF concentration (Table 2) and in controls with a high plasma ANF concentration ( 7 3 f 1 4 pg ml-' at baseline vs. 6 7 f 2 9 pg ml-' at 6 months). The changes in sodium excretion, PRA and plasma aldosterone were similar in treated subjects with high and low baseline plasma XNF concentrations. The two groups did not differ significantly in blood pressure responses to sodium restriction, but baseline blood pressure values tended to be higher in treated subjects with high baseline plasma ANF concentrations (Table 4). However, interventricular septal and left posterior wall thicknesses, relative wall thickness and peripheral resistance decreased significantly, and cardiac output
tended to increase, in subjects with high baseline ANF concentrations compared with treated subjects with low ANF concentrations and with controls (Tables 3 and 4).
Discussion Several pathways may lead to increased plasma ANF levels in hypertension. Impaired diastolic function, often seen before the development of left ventricular hypertrophy [27, 281, can result in increased left atrial pressure and wall tension. Central venous volume, which has been shown to be increased particularly in low-renin hypertensives [181, could lead to increased plasma ANF concentrations via raised right atrial stretch. Recent findings suggest that some of the circulating ANF may also originate from cardiac ventricles [29, 301. It has been suggested that catecholamines may increase ANF secretion via direct stimulatory effects on cardiac alpha and beta2-receptors [ 311, although recent findings indicate that this only occurs via changes in haemodynamics [32, 331. In a study of all hypertensive subjects at baseline during unrestricted sodium intake, we observed a marked association between plasma ANF concentrations and total peripheral resistance, confirming
ATRIAL NATRIURETIC FACTOR AND SODIUM RESTRICTION
527
Table 4. Changes in haemodynamics in treated subjects with high baseline plasma atrial natriuretic factor concentrations (ANF > 50 pg rn1-l) compared with treated subjects with low baseline plasma ANF ( < 5 0 pg m1-l) and with controls Treatment group Low ANF (n = 9)
Control group
Difference in changes
(n
High ANF vs. low ANF
High ANF vs. controls
Low ANF vs. controls
17)
Variable
High ANF (n = 7 )
MAP (mmHg) Baseline 6 months
108.2f 12.27 99.1 f 12.5*
9 5 . 4 f 14.9 89.9+9.9
9 5 . 6 f 7.1 95.1 f8.9
NS
< 0.05
NS
SBP (mmHg) Baseline 6 months
151.4f 18.6$ 137.7 f I 7.4*'
130.8f 19.5 120.7 17.4
1 3 1 . 8 k 12.0 129.8 f 14.6
NS
< 0.01
NS
TPR (dynes s cm-') Baseline 6 months
1571+212§ 1262k296
ll79+308 1 3 1 7 k 358
1240k283 1342 i383
< 0.05
< 0.05
NS
0.06
0.06
NS
NS
NS
=
CO (ml min-') Baseline 6 months
5 . 7 + 1.2 6 . 6 f 1.8
6.8k1.1 5.9 f 1.9
6.6 f2 . 0 6.2 2.3
ESWS ( 1 O3 dynes cmP) Baseline 6 months
7 6 + 23 80f23
75+26 72f26
81 k 2 0 7 4 f 18
+
NS
MAP = supine mean arterial pressure. SBP = supine systolic blood pressure, TPR = total peripheral resistance, CO = cardiac output, ESWS = end-systolic wall stress. P < 0.05, ** P < 0.01. compared with baseline. t P = 0.08. $ P = 0.06, 4 P = 0 . 0 2 for the difference at baseline between subjects in high and low ANF subgroups. Mean values fSD are shown.
earlier observations [15]. No correlation was found between left atrial diameter and plasma ANF concentrations. However, left atrial diameter may not be sufficiently sensitive to reflect small increases in left atrial load in subjects with mild to moderate hypertension. No significant inverse association, as would have been expected, was found between plasma ANF concentrations and PRA. This may be explained by increased sympathetic drive, which has been shown to occur particularly in high-renin hypertensives [34]. On the other hand, increased sympathetic activity may lead to increased ANF release through haemodynamic changes. Thus both low-renin and some high-renin hypertensives could have increased ANF secretion. We found no association between plasma ANF and resting catecholamine levels, suggesting that the latter do not directly regulate ANF secretion. Plasma ANF concentrations have been shown to be increased in subjects with left ventricular hypertrophy, estimated by electrocardiographic criteria, which are applicable to patients with severe forms of hypertension [14, 161. In accordance with earlier observations [15], we found no direct link between increased plasma ANF concentrations and left ven-
tricular hypertrophy, assessed by echocardiography, in our subjects with mild to moderate untreated hypertension. Strict short-term sodium restriction has been shown to decrease plasma ANF concentrations [9-111. However, the haemodynamic changes that regulate ANF release may be vastly different after long-term moderate sodium restriction. We found that long-term moderate sodium restriction decreased plasma ANF concentrations only in those hypertensive subjects who had high concentrations at baseline. The decrease in ANF was accompanied by a reversal in left ventricular wall thicknesses and relative wall thickness, as well as by a decrease in total peripheral resistance. Left ventricular enddiastolic diameter increased during sodium restriction in subjects with high baseline plasma ANF concentrations, possibly as a result of improved left ventricuIar distensibility, which in turn may lead to improved left atrial emptying and decreased atrial wall tension and ANF release. These findings suggest that a 6-month moderate sodium restriction decreases concentric left ventricular hypertrophy and ANF release in subjects with high plasma ANF concentrations, probably via reduced overall pressure
528
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load and relaxation of the left ventricle. The increase in left ventricular end-diastolic diameter explains why, despite the decrease in wall thicknesses, the calculated left ventricular mass did not decrease significantly even in subjects with high baseline ANF concentrations. In summary, plasma ANF concentrations were related to haemodynamics, but not to factors characteristic of left ventricular hypertrophy. However, high plasma ANF concentrations predicted decrease of ANF, reversal of concentric left ventricular hypertrophy and decrease in total peripheral resistance during moderate, long-term sodium restriction.
References 1 Needleman P. Greenwald JE. Atriopeptin: a cardiac hormone intimately involved in fluid, electrolyte. and blood-pressure homeostasis. N E n g l / Med 1986: 314: 828-34. 2 Lang RE, Tholken H. Ganten D, Luft FC. Ruskoaho H. Unger Th. Atrial natriuretic factor - a circulating hormone stimulated by volume loading. Nature 1985 314: 264-6. 3 Yamaji T. Ishibashi M. Takaku F. Atrial natriuretic factor in human blood. / Clin Invest 1985: 76: 1705-9. 4 Sagnella. GA. Shore AC. Markandu ND. MacGregor GA. Etrects of changes in dietary sodium intake and saline infusion on immunoreative atrial natriuretic peptide in human plasma. Lancet 1985; 2: 1208-11. 5 Epstein M, Loutirenhiser RD. Friedland E. Aceto RM. Camargo MJF. Atlas SA. Increases in circulating atrial natriuretic factor during immersion-induced central hypervolemia in normal humans. / Hypertens 1986; 4 (Suppl. II): 11-S93-9. 6 Hollister AS. Tanaka I. Onrot J. Biaggioni I. Inagami T. Modulation of plasma atrial natriuretic factor levels in human subjects by sodium loading and posture change (abstract). Circulation 1985: 72 (Suppl. 111): 102. 7 Haller BGD. Ziist H. Shaw S. Gnadinger MP. Uehlinger DE. Weidmann. P. Etrects of posture and ageing on circulating atrial natriuretic peptide levels in man. / Hypertens 1987: 5 :
551-6. 8 Weil J, Strom TM. Heim JM et al. Influence of diurnal rhythm, posture and right atrial size on plasma atrial natriuretic peptide levels. Z Kardiol 1988: 77 (Suppl. 2): 36-40. 9 Sagnella GA. Markandu ND. Buckley MG et al. Plasma atrial natriuretic peptide in essential hypertension : effects of changes in dietary sodium. BMJ 1987: 295: 417-8. 10 Ogihara T. Hara H, Shima J. Iinuma K. Kumahara Y. Changes in the plasma hANP level during long-term salt loading in patients with essential hypertension. Clin Exp Hypertens [A] 1988; 10: 105-17. 11 Matsubara H. Mori Y. Takashima H. Inada M. Simultaneous measurement of a-human atrial natriuretic factor (hANF) and NH,-terminal fragment of pro-hANF in essential hypertension. Am Heart 1989; 118: 494-9. 12 Sugawara A. Nakao K. Sakamoto M et al. Plasma concentration of atrial natriuretic polypeptide in essential hypertension. Lancet 1985; 2: 1426-7. 13 Sagnella GA. Markandu ND. Shore AC. MacGregor GA. Raised circulating levels of atrial natriuretic peptides in essential hypertension. Lancet 1986; 1: 179-81.
14 Montorsi P. 'I'onolo G. Polonia J. Hepburn I). Richards AM. Correlates of plasma atrial natriuretic factor in health and hypertension. Hypertension 1 98 7 : 10 : 570-6. 15 Ganau A, Devereux. RB. Atlas SA et al. Plasma atrial natriuretic factor in essential hypertension : relation to cardiac size. function and systemic hemodynamics. / Art1 Coll Car-did 1989: 14: 715-24. 16 Stimpel M. Kaufmann W, Wambach. G. Atriales natriuretisches Peptid (ANP) bei essentieller Hypertonie : Humoraler Marker fur Kochsalzsensitivitat und hypertensive Herzkrankheit in klinisch-asymptomatischen Stadium ? Z Kardiol 1988: 77 (Suppl. 2): 92-8. 17 Larochelle P. Cusson JR. Gutkowska J et a/. Plasma atrial natriuretic factor concentrations in essential and renovascular hypertension. EM/ 1987: 294: 1249-52. 18 Julius S. Esler M. Increased central blood volume: a possible pathophysiological factor in mild low-rcnin essential hypertension. Clin Sci Mol Med 1976; 51 : 207s-10s. 19 Julius S. Interaction between renin and the autonomic nervous system in hypertension. Am Heart / 1988: 116: 611-6. 20 Sahn DJ. DeMaria A. Kisslo. J. Weyman A. Recommendations regarding quantitation in M-mode echocardiography : results of a survey of echocardiographic measurements. Circulatiori 1978: 58: 1072-83. 21 Troy BL. Pombo J. Rackley. CE. Measurement of left ventricular wall thickness and mass by echocardiography. Circulatiort 1972; 45: 602-11. 22 Grossman W. Jones D. McLaurin LP. Wall stress and patterns of hypertrophy in the human left ventricle. / Clin lrrvest 19 75 : 56: 56-64. 23 Reichek N, Wilson J. Sutton M St J, Plappert TA. Goldberg S. Hirshfeld JW. Non-invasive determination of left ventricular end-systolic stress: validation of the method and initial application. Circulation 1982 : 65: 99-1 08. 24 Tikkanen I. Metsarinne K. Fyhrquist F. Leidenius R. Plasma atrial natriuretic peptide in cardiac disease and during infusion in healthy volunteers. Lancet 1983: 2: 66-9. 25 Da Prada M. Ziircher G. Simultaneous radioemymatic determination of plasma and tissue adrenaline. noradrenaline and dopamine within the femtomole range. LiJe Sci 1976 : 19 : 1 1 6 1-74. 26 Vuori 1. Marniemi J. Rahkila P. Vainikka M. The effect of a sixday ski-hike on plasma catecholamine concentrations and their response to submaximal exercise. Med Biol 1979; 57: 362-6. 27 Inouye 1. Masic B, Loge D et al. Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension. Am / Cardiol 1984: 53: 120-6. 28 Phillips RA. Goldman ME, Ardeljan M et al. Determinants of abnormal left ventricular filling in early hypertension. / Am Coll Cardiol 1989: 14: 979-85. 29 Day ML. Schwartz D. Wiegand RC e l al. Ventricular atriopeptin : unmasking of messenger RNA and peptide synthesis by hypertrophy or dexamethasone. Hypertension 1987: 9 : 485-91. 30 Edwards BS. Ackerman DM. Lee ME, Reeder GS. Wold LE. Burnett JC Jr. Identification of atrial natriuretic factor within ventricular tissue in hamsters and humans with congestive heart failure. J Clin invest 1988: 8 1 : 82-6. 31 Keller N. Sykulski R. Thamsborg G. Storm T, Larsen J . Atrial natriuretic peptide during exercise in patients with coronary heart disease before and after single dose atenolol and acebutolol. Acta Med Scand 1988 ; 223: 305-1 1 .
A T R I A L N A T R I U R E T I C F A C T O R A N D SODIUM R E S T R I C T I O N
32 Uehlinger DE.%man T.Weidmann P, Shaw S, Gnadinger MP. Pressure dependence of atrial natriuretic peptide during norepinephrine infusion in humans. Hypertension 1987: 10: 249-53. 33 Shenker Y. Bates ER, Egan BH. Harnmond J. Grekin RJ. Fifect of vasopressors on atrial natriuretic factor and hernodynamic function in humans. Hypertension 1988 : 12: 20-5. 3 4 Esler M. Julius S, Zweifler A et a!. Mild high-renin essential
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hypertension. Neurogenic human hypertension ? N Engl 1 Med 1 9 7 7 : 296: 405-11. Received 18 June 1991, accepted 1 8 October 1991. Correspondence: Dr Antti Jula. Rehabilitation Research Centre of the Social Insurance Institution. Peltolantle 3, 20720 Turku, Finland.
Responses of atrial natriuretic factor to long-term sodium restriction in mild to moderate hypertension A. JULA, T. RONNEMAA, I. TIKKANEN* & H. KARANKO From the Rehabilitation Research Centre of the Social lnsurance Institution. Turku. and the * Minerva Institute jor Medical Research, Helsinki, Finland
Abstract. Jula A, Ronnemaa T, Tikkanen I, Karanko H (Rehabilitation Research Centre of the Social Insurance Institution, Turku, and Minerva Institute for Medical Research, Helsinki, Finland). Responses of atrial natriuretic factor to long-term sodium restriction in mild to moderate hypertension. Journal of Znternal Medicine 1992: 231 : 521-529. The effects of long-term sodium restriction on plasma atrial natriuretic factor (ANF) concentrations, and the role of baseline plasma ANF concentration as an indicator of changes in haemodynamics and left ventricular hypertrophy during this treatment were studied in 40 middle-aged previously untreated mildly to moderately hypertensive men and women in a 6-month controlled randomized study. The main emphasis of the treatment programme was to reduce daily sodium intake to less than 70 mmol. Mean sodium excretion decreased from 148 f 74 mmol 24 h-' to 79 k 71 mmol 24 h-' in the treatment group, but remained unchanged in the control group (173 f 68 mmol 24 h-' vs. 186 62 mmol 24 h-': P < 0.01 for the difference in changes between the groups). Mean plasma ANF concentrations in the treatment group were 52.4 f20.7 (median 50) pgml-' at baseline and 38.7k26.3 (median 42) pgml-' at 6 months, and the corresponding values in the control group were 55.5 f 2 0 . 5 (median 50) pg ml-' and 46.1 f32.4 (median 50) pg ml-I, respectively ( P = NS for the difference in changes). The ANF concentration decreased from 70 k 14 pg ml-' to 32 k 26 pg ml-' in treated subjects with a high baseline plasma ANF concentration (> 50 pg ml-'), but increased from 37f 11 pg ml-I to 45 f 2 7 pg ml-' in subjects with a low baseline plasma ANF concentration (,< 50 pg d-l)(difference in changes P < 0.001).Compared with treated subjects with low baseline plasma ANF levels and with controls, treated subjects with high baseline plasma ANF levels showed a decrease (P < 0.05) in interventricular septal and left posterior wall thicknesses, in relative wall thickness, and in peripheral resistance. These results suggest that in mildly to moderately hypertensive subjects long-term sodium restriction decreases high plasma ANF concentrations concomitantly with regression of concentric left ventricular hypertrophy, probably as a result of changes in haemodynamics.
Keywords: atrial natriuretic factor, hypertension, left ventricular hypertrophy, sodium restriction, total peripheral resistance.
Introduction Atrial natriuretic factor (ANF), a peptide hormone that is primarily synthesized and stored in atrial cardiocytes. has potent acute natriuretic, diuretic Abbreviations: ANF = atrial natriuretic factor, IVST = interventricular septal thickness, LVIDd = left ventricular internal dimension in diastole, LVM = left ventricular mass, LVMI = left ventricular mass index, PRA = plasma renin activity, PWT = posterior wall thickness, R W T = relative wall thickness, TPR = total peripheral resistance.
and vasodilatory effects [l]. It is released via atrial stretch, secondary to a n increase in central blood volume, caused by saline infusion [ 2 4 ] , water immersion [S] and change from upright to supine posture [6-81. In contrast, short-term sodium restriction decreases ANF secretion in both normotensive [4] and hypertensive [9-111 subjects. To our knowledge no one has examined the responses of ANF release to long-term sodium restriction. Plasma ANF concentrations are increased in some hypertensive subjects [12-14]. Among hypertensive
52 1
522
A. J U L A et al.
individuals high plasma ANF is associated with higher blood pressure [13, 141, left ventricular hypertrophy [14, 161, increased left atrial size [15, 161 and, according to some [ 7, 15, 171 but not all studies [14, 161, with more advanced age. However, redistribution of blood from peripheral to central venous space, which has been shown to occur particularly in low-renin hypertensives [18, 191, could also be partly responsible for increased ANF secretion due to increased right atrial stretch. We wanted to examine the effects of long-term moderate sodium restriction on plasma ANF concentration in untreated subjects suffering from mild to moderate uncomplicated essential hypertension. In addition, we wanted to detect factors associated with high baseline plasma ANF levels, and to determine whether high plasma ANF concentrations predict changes in haemodynamics and characteristics of left ventricular hypertrophy during longterm sodium restriction.
subjects dropped out of the treatment group and one dropped out of the control group. For anatomical reasons, echocardiography could not be successfully performed in three patients. Thus the population with regard to echocardiographic data consisted of 1 6 subjects in the treatment group and 1 7 subjects in the control group.
Treatment programme The main aim of the non-pharmacological treatment programme was to reduce daily sodium intake to less than 70 mmol. Patients also received instructions on how to reduce their intake of saturated fat, to increase the ratio of polyunsaturated to saturated fatty acids in their diet, and to lose weight if necessary. The controls did not receive any instructions regarding non-pharmacological treatment of hypertension. Antihypertensive medication was not used in either group.
Measurements
Patients and methods Patients Forty subjects (18 men and 2 2 women, aged 35-55 years) with mild to moderate essential hypertension (World Health Organization stages 1-11) were recruited from the occupational health service of three industrial plants and two government offices. The subjects had diastolic blood pressure consistently in the range 90-110 mmHg and/or systolic blood pressure consistently in the range 160-200 mmHg during the run-in period. The diagnosis of uncomplicated essential hypertension was based on physical examination, routine biochemical tests and exercise electrocardiogram. The patients had no cardiomyopathy or significant valvular disease according to physical examination and echocardiography, and they were not on oral contraceptives or any other regular drug treatment. The patients had not been treated for hypertension earlier, or had been without treatment for at least 1 year before the onset of the study. The study subjects were divided into two groups that were comparable with regard to sex, age and occupational status. Randomization into a control group and a treatment group was carried out between the two groups. Thus to avoid contamination of controls, control and treatment subjects were never derived from the same source. Two
Diet was monitored at baseline and at 3 and 6 months by means of 7-d dietary records, 24-h urine samples for sodium, potassium and creatinine content, and weight measurement. Blood samples for determination of plasma renin activity (PRA), plasma aldosterone and ANF were taken at the clinic, after a night’s rest and before rising, at baseline and at 6 months. For plasma noradrenaline and adrenaline sampling, a cannula was inserted into the left median cubital vein and 5 ml of blood were drawn after a 15-min rest in the supine position and after 5 min in the sitting position. Two-dimensionally controlled M-mode echocardiographic studies were performed at baseline and 6 months from the same intercostal space using an ATL MARK I11 ultrasonoscope and a real-time scanhead (720A) with a 3-Mhz transducer. All echo studies were performed by the same investigator, who also read and coded the tracings blindly, in random order, after the study period. The cardiac dimensions were measured from M-mode echocardiograms according to the recommendations of the American Society of Echocardiography [20], digitized and processed using a Hewlett Packard 9845B minicomputer and a Hewlett Packard 9874A digitizing table, and averaged from at least five heart cycles. Leading edge to leading edge convention was used. Relative wall thickness was determined as the ratio of end-diastolic posterior wall thickness and
ATRIAL NATRIURETIC FACTOR AND SODIUM RESTRICTION
523
Table 1. Comparison of treatment and control subjects Variable Sex (women/men)
Treatment group (n = 19)
P-valuet
12/8
Control group (n = 17) 9/8
4 4 . 7 f 5.6
42.5 f 3.8
Age ( y e a 4 Systolic blood pressure (mmHg) Baseline 1-6 months
151.9 f 17.9 133.3f 11.8***
< 0.01
143.9f10.4 136.6f 10.4**
Diastolic blood pressure (mmHg) Baseline 1-6 months
9 8 . 4 f 7.6 88.4+6.7***
< 0.001
96.1 k 4 . 1 9 2 . 6 k 5.4"
Weight (kg) Baseline 6 months
75.2k15.4 73.6+15.1**
< 0.01
76.1 f 15.3 76.8 f 15.3
Body mass index (kg m-') Baseline 6 months
26.1f4.5 25.5+4.4**
< 0.01
25.7f 3.3 26.0 & 3.3
148 f 7 4 7 9 + 71**
< 0.01
173f68 186 f6 2
Sodium excretion (mmol 2 4 h-l) Baseline 6 months Potassium excretion (mmol 2 4 h-') Baseline 6 months
76 k 2 3 88 f2 4
NS
79 21 83t-21
Plasma renin activity (ng A1 ml-' h-') Baseline 6 months
0.70+0.60 1.10 0.56'
+
NS
0.65k0.37 0.86+0.57*
Plasma aldosterone ( p o l I-') Baseline 6 months
297f125 363 f 132
NS
243 & 66 279t-99
*** P < 0.001, ** P < 0.01. * P < 0.05 compared to baseline.
t Significance of difference in change from baseline between treatment and control groups. Mean values SD are shown.
+
half of the end-diastolic left ventricular internal dimension. Left ventricular mass was calculated from end-diastolic wall thickness and cavity dimensions using the formula described by Troy et al. [21]. Left ventricular volumes were estimated by the cubefunction formula and used to calculate stroke volume as the difference between end-diastolic and endsystolic left ventricular volumes : cardiac output was calculated as stroke volume x heart rate. Total peripheral resistance was estimated by dividing mean arterial pressure (diastolic blood pressure added by one-third of the difference between systolic and diastolic blood pressures) with cardiac output and expressed as dynes s ~ m - End-systolic ~. wall stress was calculated from systolic blood pressure and from endsystolic left ventricular diameter and posterior wall thickness using a previously described and validated formula [22, 231. Blood pressure was measured by a single trained nurse using a mercury sphygmomanometer. Measurements were made with subjects
in the supine position, immediately after recording the left ventricular echocardiogram. The average of two measurements taken at approximately 2-min intervals was used to calculate peripheral resistance and end-systolic wall stress. The coefficient of variation in mild to moderate hypertensives ( n = 38) was 5.1 % for interventricular septa1 thickness, 6.5 % for posterior wall thickness, 3.6 % for left ventricular internal diameter, 5.8 % for left ventricular mass, 9.6% for cardiac output, 11.4% for total peripheral resistance and 17.6% for end-systolic wall stress. Out-patient clinic blood pressures were measured by a single trained technician using a Hawksley random zero sphygmomanometer. Measurements were made with subjects in the sitting position, always in the morning and in the same quiet room throughout the study. Blood pressure was the mean value of two measurements taken with a 2-min interval. During the run-in period, blood pressure was measured three times at weekly intervals, and
A. JULA et al.
524
= Plasma samples were centrifuged under refrigeration and stored at - 70 "C. Radioimmunoassay was used to determine PRA (Phadebas Angiotensin I-test, Pharmacia Diagnostics, Stockholm, Sweden), plasma aldosterone (Aldosterone RIA, Abbott Laboratories, Chicago, IL, USA) and plasma ANF [24]. Plasma noradrenaiine and adrenaline were measured with a radioenzymatic technique [2 5, 261. The inter-assay coefficient of variation was 7.7% for PRA, 10.9% for aldosterone, 9.9% for ANF, 12.7% for adrenaline and 9.6 % for noradrenaline, respectively.
I 800 I600
T
E, v)
1400
I200 1000
n
a
r = 0.41
Statistical methods
P < 0.05
0
I
I
I
I
1
20
40
60
80
I
100
Plasma ANF Concentration (pg m1-I)
Fig. 1 . Correlation of plasma ANF concentrations with total peripheral resistance at baseline (all hypertensives combined).
0
O
I
O o o C
-' 'ooo[
c
0
800
5
-0-
e 00
8
Results
0
400
0
n a
I-
r = 0.44
P < 0.01 0
I
Statistical analysis of the data was performed using SAS computer programs (SAS Institute, Cary, NC, USA). Analysis of variance was used to test the significance of the difference between the study group at baseline, and repeated-measures analysis of variance was used to test the significance of the difference in changes within and between the study groups. Pearson' s correlation coefficient was calculated to indicate the correlations between plasma ANF levels and other variables at baseline during unrestricted sodium intake.
I
1
I
I
20
40
60
80
I
100
No significant differences in baseline characteristics were found between treatment and control subjects (Table 1). The net decrease (difference in changes between treatment and control group) was 11.2 mmHg (P < 0.01) in out-patient clinic systolic blood pressure and 6.5 mmHg (P < 0.001) in outpatient clinic diastolic blood pressure during the 6-month follow-up.
Plasma ANF concentration (pg m1-l)
Fig. 2. Correlation of plasma ANF concentrations with total peripheral resistance index at baseline (all hypertensives combined).
the mean value of the last two measurements was taken to represent baseline blood pressure. Blood pressure was measured monthly during the followup. Diastolic blood pressure was defined as the disappearance of the fifth phase of Korotkoff sounds.
Biochemical assays For the measurement of PRA. aldosterone, ANF and catecholamines, blood was collected into ice-cold tubes containing 6 mg Na,EDTA ml-' of blood.
Dietary changes A marked decrease in 24-h urine sodium (68 f9 7 mmol, P < 0.01) and a small decrease in weight ( 1 . 6 f 2 . 1 kg, P < 0.01) was noted at 6 months in the treatment group, whereas no changes were observed in the controls (Table 1). Energy intake from fat decreased from 41 L- 6% to 37 f4 % (P < 0.05) in the treatment group, but remained unchanged in the control group (43 f3 % at baseline vs. 4 3 f6 % at 6 months). The decrease in fat intake of treatment subjects consisted of approximately equal reductions in the intake of saturated and monounsaturated fatty acids, whereas the intake of polyunsaturated fatty acids remained unchanged.
ATRIAL NATRIURETIC FACTOR A N D SODIUM RESTRICTION
525
Table 2. Comparison of treated hypertensive subjects with high plasma baseline ANF ( > 50 pg ml-') and low plasma baseline ANF ( < 50 pg ml-') concentrations
Variable
High ANF (n = 9)
Sex (women/men) Age (years)
P-valuet
614 43.2 C 6.0
613
46.3
IAW ANF ( n = 10)
+ 5.1
Systolic blood pressure (mmHg) Baseline 1-6 months
159.7 & 14.8 138.1 11.7***
+
NS
144.XC 18.2 129.0f 10.7**
Diastolic blood pressure (mmHg) Baseline 1-6 months
101.4k7.0 90.2 5.2**
NS
95.7+ 7.5 86.7 7.7***
+
+
Weight (kg) Baseline 6 months
72.1 & 14.3 69.6 f 12.7**
NS
78.0f16.6 77.3 C 16.8
Body mass index (kg m-') Baseline 6 months
25.2C4.5 24.3 C 4.1 *
NS
26.8k4.5 26.6 4.6
156+70 70 C 82'
NS
140k81 87C62
83 25 95+18
NS
69k21 82 27
Plasma renin activity (ng Al ml-' h-') Baseline 6 months
0.66 k 0 . 3 2 1.19+0.51
NS
0.74C0.80 1 .02 0.62
Plasma aldosterone (pmol I-') Baseline 6 months
287+ 145 362 77
NS
306C 112 363 I72
Sodium excretion (mmol 24h-') Baseline 6 months Potassium excretion (mmol 24 h-') Baseline 6 months
Plasma atrial natriuretic factor (pg ml-') Baseline 6 months
+
70+14 32 26**
+
< 0.001
+ +
37+ 11 45 k 27
*** P < 0.001, ** P < 0.01, * P < 0.05 compared with baseline.
t Significance of difference in change from baseline between high and low ANF subgroups. Mean values C SD are shown.
Renin and aldosterone PRA increased slightly (P < 0.05) in the treatment and control groups (Table l),while no significant increases in plasma aldosterone levels were observed.
Atrial natriuretic factor At baseline, treatment and control subjects combined showed a significant correlation between ANF and total peripheral resistance (Fig. 1)and total peripheral resistance index (Fig. 2), but not between ANF and supine mean arterial pressure ( r = 0.21), supine systolic blood pressure ( r = 0.27). and out-patient clinic diastolic ( r = 0.23) and systolic ( r = 0.30) blood pressure. No associations were found between
plasma ANF and age ( r = 0.02), PRA ( r = -0.20), plasma aldosterone ( r = -0.01), plasma adrenaline and noradrenaline at supine rest ( r = 0.08 and r = 0.12, respectively) and adrenaline and noradrenaline in the sitting position ( r = 0.05 and r = 0.09, respectively), body mass index ( r = -0.27), and 24-h urine sodium ( r = -0.20), as well as between plasma ANF and left atrial diameter indexed by body surface area ( r = -0.04), left ventricular mass indexed by body surface area ( r = -0.21), and enddiastolic interventricular ( r = - 0.08) and posterior wall thicknesses ( r = - 0.08). Mean plasma atrial natriuretic factor concentrations were 5 2 . 4 k 2 0 . 7 (median, 50) pg ml-' at baseline and 3 8 . 7 k 2 6 . 3 (median, 42) pgml-' at 6 months in the treatment group, and 55.5 k 20.5
526
A. JULA et al.
Table 3. Changes in left ventricular characteristics in treated subjects with high plasma baseline atrial natriuretic factor concentrations (ANF> 50 pg m1-l) compared with treated subjects with low plasma baseline ANF ( < 50 pg m1-l) and with controls Treatment group
Variable
Control group
Difference in changes High AN!? vs. low ANF
High ANF vs. controls
Low ANF vs. controls
High ANF (n = 7)
Low ANF (n = 9)
(n = 17)
LVIDd (mm)
Baseline 6 months
47.5 f 3.3 50.6+4.1*
50.3 f3.7 49.7f4.2
51.6f4.8 50.8 5 . 0
+
< 0.05
< 0.05
NS
IVST (mm)
Baseline 6 months
11.5 f 1.6 10.3f1.7
11.0f 1.1 11.5f 1.7
11.5f 1.7 12.1 f 1 . 7
< 0.05
< 0.05
NS
PWT (mm)
Baseline 6 months
10.0f I .2 9.2k1.0
9 . 6 f 0.9 10.1 f 1.3
9.8+ 1.3 10.2 f 1.4
< 0.05
< 0.05
NS
RWT
Baseline 6 months
0 . 4 2f 0 . 0 7 0.37+0.06*
0.38 f0.05 0.41f0.06
0.38 f0.05 0.41 f0.06
< 0.05
< 0.01
NS
Baseline 6 months
2 3 4 f41 225 f 32
242+45 255 62
268 f66 276f68
NS
NS
NS
Baseline 6 months
I 3 2 f1 4 129f11
129+16 135f22
142f31 146f33
NS
NS
NS
LVM (8) LVMI (g m-')
~~
~
+
~
LVIDd = left ventricular internal dimension in end-diastole, IVS = interventricular septal thickness in end-diastole, PWT = posterior wall thickness in end-diastole, RWT = relative wall thickness, LVM = left ventricular mass, LVMI = left ventricular mass index, TPR = total peripheral resistance. * P < 0.05. compared with baseline. Mean values fSD are shown.
(median, 50) pg ml-' and 46.1 32.4 (median, 50) pg ml-', respectively, in the control group. The changes within or between the study groups were not statistically significant. Subjects in the treatment and control groups were classified as subjects with high or low ANF concentrations according to the baseline median plasma ANF concentration of the study population. Treated subjects with a high plasma ANF concentration ( > 5 0 p g ml-') showed a decrease in ANF concentration ( P < 0.01) during sodium restriction, while no change was observed in subjects with a low plasma ANF concentration (Table 2) and in controls with a high plasma ANF concentration ( 7 3 f 1 4 pg ml-' at baseline vs. 6 7 f 2 9 pg ml-' at 6 months). The changes in sodium excretion, PRA and plasma aldosterone were similar in treated subjects with high and low baseline plasma XNF concentrations. The two groups did not differ significantly in blood pressure responses to sodium restriction, but baseline blood pressure values tended to be higher in treated subjects with high baseline plasma ANF concentrations (Table 4). However, interventricular septal and left posterior wall thicknesses, relative wall thickness and peripheral resistance decreased significantly, and cardiac output
tended to increase, in subjects with high baseline ANF concentrations compared with treated subjects with low ANF concentrations and with controls (Tables 3 and 4).
Discussion Several pathways may lead to increased plasma ANF levels in hypertension. Impaired diastolic function, often seen before the development of left ventricular hypertrophy [27, 281, can result in increased left atrial pressure and wall tension. Central venous volume, which has been shown to be increased particularly in low-renin hypertensives [181, could lead to increased plasma ANF concentrations via raised right atrial stretch. Recent findings suggest that some of the circulating ANF may also originate from cardiac ventricles [29, 301. It has been suggested that catecholamines may increase ANF secretion via direct stimulatory effects on cardiac alpha and beta2-receptors [ 311, although recent findings indicate that this only occurs via changes in haemodynamics [32, 331. In a study of all hypertensive subjects at baseline during unrestricted sodium intake, we observed a marked association between plasma ANF concentrations and total peripheral resistance, confirming
ATRIAL NATRIURETIC FACTOR AND SODIUM RESTRICTION
527
Table 4. Changes in haemodynamics in treated subjects with high baseline plasma atrial natriuretic factor concentrations (ANF > 50 pg rn1-l) compared with treated subjects with low baseline plasma ANF ( < 5 0 pg m1-l) and with controls Treatment group Low ANF (n = 9)
Control group
Difference in changes
(n
High ANF vs. low ANF
High ANF vs. controls
Low ANF vs. controls
17)
Variable
High ANF (n = 7 )
MAP (mmHg) Baseline 6 months
108.2f 12.27 99.1 f 12.5*
9 5 . 4 f 14.9 89.9+9.9
9 5 . 6 f 7.1 95.1 f8.9
NS
< 0.05
NS
SBP (mmHg) Baseline 6 months
151.4f 18.6$ 137.7 f I 7.4*'
130.8f 19.5 120.7 17.4
1 3 1 . 8 k 12.0 129.8 f 14.6
NS
< 0.01
NS
TPR (dynes s cm-') Baseline 6 months
1571+212§ 1262k296
ll79+308 1 3 1 7 k 358
1240k283 1342 i383
< 0.05
< 0.05
NS
0.06
0.06
NS
NS
NS
=
CO (ml min-') Baseline 6 months
5 . 7 + 1.2 6 . 6 f 1.8
6.8k1.1 5.9 f 1.9
6.6 f2 . 0 6.2 2.3
ESWS ( 1 O3 dynes cmP) Baseline 6 months
7 6 + 23 80f23
75+26 72f26
81 k 2 0 7 4 f 18
+
NS
MAP = supine mean arterial pressure. SBP = supine systolic blood pressure, TPR = total peripheral resistance, CO = cardiac output, ESWS = end-systolic wall stress. P < 0.05, ** P < 0.01. compared with baseline. t P = 0.08. $ P = 0.06, 4 P = 0 . 0 2 for the difference at baseline between subjects in high and low ANF subgroups. Mean values fSD are shown.
earlier observations [15]. No correlation was found between left atrial diameter and plasma ANF concentrations. However, left atrial diameter may not be sufficiently sensitive to reflect small increases in left atrial load in subjects with mild to moderate hypertension. No significant inverse association, as would have been expected, was found between plasma ANF concentrations and PRA. This may be explained by increased sympathetic drive, which has been shown to occur particularly in high-renin hypertensives [34]. On the other hand, increased sympathetic activity may lead to increased ANF release through haemodynamic changes. Thus both low-renin and some high-renin hypertensives could have increased ANF secretion. We found no association between plasma ANF and resting catecholamine levels, suggesting that the latter do not directly regulate ANF secretion. Plasma ANF concentrations have been shown to be increased in subjects with left ventricular hypertrophy, estimated by electrocardiographic criteria, which are applicable to patients with severe forms of hypertension [14, 161. In accordance with earlier observations [15], we found no direct link between increased plasma ANF concentrations and left ven-
tricular hypertrophy, assessed by echocardiography, in our subjects with mild to moderate untreated hypertension. Strict short-term sodium restriction has been shown to decrease plasma ANF concentrations [9-111. However, the haemodynamic changes that regulate ANF release may be vastly different after long-term moderate sodium restriction. We found that long-term moderate sodium restriction decreased plasma ANF concentrations only in those hypertensive subjects who had high concentrations at baseline. The decrease in ANF was accompanied by a reversal in left ventricular wall thicknesses and relative wall thickness, as well as by a decrease in total peripheral resistance. Left ventricular enddiastolic diameter increased during sodium restriction in subjects with high baseline plasma ANF concentrations, possibly as a result of improved left ventricuIar distensibility, which in turn may lead to improved left atrial emptying and decreased atrial wall tension and ANF release. These findings suggest that a 6-month moderate sodium restriction decreases concentric left ventricular hypertrophy and ANF release in subjects with high plasma ANF concentrations, probably via reduced overall pressure
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load and relaxation of the left ventricle. The increase in left ventricular end-diastolic diameter explains why, despite the decrease in wall thicknesses, the calculated left ventricular mass did not decrease significantly even in subjects with high baseline ANF concentrations. In summary, plasma ANF concentrations were related to haemodynamics, but not to factors characteristic of left ventricular hypertrophy. However, high plasma ANF concentrations predicted decrease of ANF, reversal of concentric left ventricular hypertrophy and decrease in total peripheral resistance during moderate, long-term sodium restriction.
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hypertension. Neurogenic human hypertension ? N Engl 1 Med 1 9 7 7 : 296: 405-11. Received 18 June 1991, accepted 1 8 October 1991. Correspondence: Dr Antti Jula. Rehabilitation Research Centre of the Social Insurance Institution. Peltolantle 3, 20720 Turku, Finland.
