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Plasma renin activity in men with relation to the presence of ischaemic heart disease
41
Atherosclerosis,
27 (1877)
@ Elsevier/North-Holland
41-48
Scientific
PLASMA RENIN ACTIVITY PRESENCE OF ISCHAEMIC
A. SLAB+,
0. HOFMAN,
Publishers,
Ltd.
IN MEN WITH RELATION HEART DISEASE
R. REISENAUER
TO THE
and J. URBANEK
4th Department of Internal Medicine and Biophysicul Institute, Charles University, Department of Internal Medicine, Prague 7, and the Research Institute for Endocrinology, Prague (Czechoslovakia)
(Received (Revised, (Accepted
2 July, 1976) received 24 September, 27 September, 1976)
1976)
Summary Plasma renin activity (PRA) stimulated by upright posture was measured, in 300 men aged 45-64 years, by a radio-immunoassay of angiotensin I. The subjects examined were divided into six groups, comparable in mean age, each containing 50 subjects: group 1, normotensives without manifest atherosclerosis; group 2, .normotensives with angina pectoris definite; group 3, normotensives with a history of a transmural myocardial infarction; groups 4 to 6, patients with benign essential hypertension, without manifest atherosclerosis in group 4, with angina pectoris in group 5 and with a history of myocardial infarction in group 6. Significant differences in mean PRA were found between corresponding groups of hypertensives and normotensives, the values in hypertensives being lower. The percentage of low renin values was higher in hypertensives with ischaemic heart disease than in other groups. An analysis of 3-year cardiovascular mortality revealed no significant difference in mortality due to ischaemic heart disease between high-renin and low renin sub-groups. Key words:
Cardiovascular mortality -Essential Plasma renin activity -Risk factors
hypertension
-- Ischaemic
heart
disease
-
Introduction The problem of plasma renin values, possibly bearing a relationship to the prognosis of essential hypertension, has not yet been definitely solved. Several
42
prospective studies are now in progress, with the aim of comparing cardiovascular morbidity and mortality in hypertensives without complications at entry, according to their initial values of plasma renin activity (PRA). Since 1973, we have been following up six groups of men aged 45-64 years, consisting of normotensive subjects and patients with benign essential hypertension, either without manifest atherosclerosis, or with ischaemic heart disease. We report here some characteristics of these groups, as well as the 3-year cardiovascular mortality in relation to initial PRA values. Materials and Methods Three-hundred men aged 45-64 years were examined, half of them normotensives, the other half patients with essential hypertension. The material is relatively unselected, since two of the authors examined all subjects fulfilling the specified diagnostic criteria, as they attended, for examination, the respective general outpatient departments [l]. According to the criteria mentioned, six groups were formed, each containing 50 subjects. Normotensive subjects, i.e. those who had never had a blood pressure recorded higher than 155/90 mm Hg, were without manifest atherosclerosis in group 1, with angina pectoris definite in group 2, and with a history of clinically proved myocardial infarction (at least six months after the acute phase) in group 3. Patients with benign essential hypertension, with a diastolic blood pressure of 100 mm Hg or more on three occasions, were grouped in a similar fashion into those without manifest atherosclerosis in group 4, with angina pectoris in group 5, and with a history of myocardial infarction in group 6. Angina pectoris definite was defined according to the WHO criteria [2]. The diagnosis of a transmural myocardial infarction was made from the hospital records, in the presence of serial electrocardiographic evidence of infarction (Q waves that satisfied the criteria for classification in the l-l or l-2 categories of the Minnesota Code [2]. An increase in serum enzymes was also proved in many cases. All hypertensive subjects had been examined at the medical department before the start of the study, to exclude secondary causes of hypertension, the workup including renal function tests, radio-isotope nephrography, intravenous pyelography, and renal angiography, when needed. Subjects with signs of cardiac or renal insufficiency, as well as those with retinopathy, were not included. In each subject, 142 data were collected from history, clinical examination, ECG, chest X-ray, fundoscopy, urinary analysis, and biochemical examinations including PRA. Urinary sodium excretion was examined only in those subjects whom a quantitative collection of urine was guaranteed. All medicaments had been suspended 3 weeks before the examination. Blood pressure was measured three times with the subject in the sitting position and the lowest value was recorded. A mercury manometer with a 14-cm cuff was used, the diastolic readings reported being the fifth phase. Plasma cholesterol, blood glucose and serum creatinine were determined by current methods, electrolytes by internal standard flame photometry. PRA was determined in peripheral venous blood, taken after 3 h upright at 11 a.m., with sodium in the diet unrestricted. Radio-immunoassay of angio-
43
tensin I according to Haber et al. [3] was used. Blood was drawn into prechilled plastic tubes containing Na2-EDTA, and immediately centrifuged at 2-4°C. Plasma was incubated at 37°C and pH 5.6-5.8 for 3 h, in the presence of enzymic inhibitors (dimercaptol, &hydroxyquinoline). A similar aliquot of plasma was held at 0°C. Angiotensin I in the samples was determined by using labelled angiotensin I and rabbit antiserum from the commercial kit supplied by Sorin. Antibody-bound peptide was separated and counted in a well scintillation counter. The results, were expressed in ng of angiotensin I, formed in 1 ml of plasma during 1 h of incubation. The coefficient of variation of duplicates was f 5% and the between-assay reproducibility was + 12%. The statistical significance of the differences between groups was tested by Student’s t test for quantitative values. (The prerequisite of a normal distribution was fulfilled in all tests.) For qualitative characteristics, the test of the differences of relative values was used. The level of probability chosen was 0.05. PRA values determined in our subjects were divided into the following three intervals: low values, less than 0.5 ng/ml . h, medium values O-5-2.49 ng/ml * h, high values 2.5 ng/ml - h and more. This classification was done independently of urinary sodium excretion which, whenever determined, exceeded 100 mequiv. in 24 h. Follow-up examinations of all subjects were performed once a year. In this year, all 300 subjects were either examined or reliable information about their death was obtained. The cause of death was determined from the official death certificate or according to the findings of the post-mortem examination. The diseases were coded according to the Eight Revision of the International Classification of Diseases, Injuries, and Causes of Death. The causes of death found were divided into the following three groups: 1, ischaemic heart disease, 2, other cardiovascular diseases (cerebrovascular diseases, pulmonary embolism); 3, other causes (not cardiovascular). Results Table 1 sums up some characteristics of the subjects examined in groups l-6. As can be seen, there was no significant difference between groups in mean values of age. Neither was there any difference in systolic blood pressure between the groups of normotensives, or between those of hypertensives. Mean weight was significantly higher in hypertensives than in normotensives, the highest value being in hypertensives without manifest atherosclerosis. The known duration of hypertension was longer in hypertensives with IHD than in those without manifest atherosclerosis, as could be expected. Diastolic blood pressure was similar in all groups of normotensives. Its mean value was significantly higher in hypertensives without manifest atherosclerosis than in those with a history of myocardial infarction, the difference between groups 4 and 5 closely approaching the limit of significance. In normotensives, plasma cholesterol was significantly higher in both groups with IHD than in normotensives without manifest atherosclerosis. A similar difference could not be proved between the groups of hypertensives. On the other hand, significant differences in mean blood glucose levels were found in hypertensives only. Serum creatinine was higher in hypertensives than in
duration
Known
glucose
creatinine
sodium
potassium
rain
a Numbers
brackets
(%)
+
2.5
(%)
(%)
between
activity
plasma
. h)
0.5-2.49
<0.5
renin
Intervalsof
@g/ml
Plasma
h)
excretion
pressure
activity
sodium
(mequiv./24
Urinary
(mequiv./I)
Serum
(mequiv./l)
Serum
(mg/dl)
Serum
(mg/dI)
Blood
(yrs)
of
a
pressure
cholesterol
Hg)
blood
Hg)
blood
(mg/dI)
Plasma
(mm
Diastolic
(mm
Systolic
hypertension
(kg)
(YLS)
of subjects
CHARACTERISTICS
1
Weight
Age
Number
Item
SOME
TABLE
GROUPS
2
0.06
0.4
0.03
6.8
7.8
0.9
1.3
0.07
0.3
0.02
2.8
6.9
0.8
1.6
= numbers
of subjects
for urinary
sodium
16.0
16.0
14.0
1.54
18.0
0.18
186.3
4.8
140.2
1.16
104.3
277.8
83.5
133.4
80.4
66.0
t
f 18.7
-r
_+
*
+
+
+
+
1.3
56.6
18.0
1.63
178.8
4.9
141.7
1.11
97.6
272.2
82.9
134.0
i
80.7
0.8
0.8
0.06
0.4
0.03
5.6
7.7
1.0
1.5
1.4
0.14
excretion.
i
i 29.1
?
+
?
?
+
+
i
r
?-
50 (18)
66.0
% 0.13
+ 16.8
t
i
i
+
1-
+
?;
?
(15)
55.1
50
68.0
18.0
1.39
145.2
4.8
141.1
1.13
105.1
246.3
83.4
131.1
?
79.0
1.4
+_ 0.1
(18)
55.2
50
4.0
78.0
3 8.0
1.02
201.4
4.5
141.5
1.15
96.2
258.1
114.5
0.07
0.4
0.03
2.4
6.1
1.2
2.6
0.6
1.8
0.7
with
t
0.09
f 20.1
+
_+
+
?
?
i
?
+
5.4 187.2
f
I
(17)
87.5
55.3
50
sclerosis
athero-
infarction
definite
sclerosis
athero-
Without manifest
Subjects
4
SE)
myocardial
f
With past
(MEAN
pectoris
With
3
EXAMINED
Without
angina
SUBJECTS
subjects
OF
manifest
Normotensive
1
Group
OF
-
6.0
58.0
36.0
1.12
220.0
4.6
141.8
1.22
110.0
161.1+
111.9
184.3
7.3
84.3
56.2
0.05
0.4
0.02
6.1
6.8
1.2
2.6
0.8
1.8
c
0.12
+_ 21.6
i
k
+
*
f
t
+
?
?
50 (17)
definite
0.8
angina
pectoris
With
ess. hypertension
5
8.0
60.0
32.0
1.05
157.6
4.7
141.3
1.18
111.7
257.4
111.4
181.8
?
i
i
*
i
f
f
t
+
i
+
?r
(18)
7.9
82.4
56.2
50
infarction
0.06
0.3
0.03
6.3
7.1
1.1
2.1
0.8
1.4
0.9
0.11
17.4
past
myocardial
With
6
1:5,
4:6
(within
2:4,
4:5
1:5,
1:4,
1~4,
1:4.
1:5,
4:5,
1:2,
3:4
2:5,
2:4,
1:5.
1:5,
2:5
4:6
1:3,
3:5,
2:5,
5:6
2:4,
3:4
hypertensive)
4:6
4:5
3:4,
2:5.
3:6
3:4.
normotensives
normotensives
2:4.
3:4,
differences groups
hypertensive)
(within
4:6
1:4.
between
Significant
4:6
and and
%
45
normotensives. There was no difference in serum sodium concentrations, mean serum potassium being lower in hypertensives than in normotensives. Urinary sodium excretion was highest in hypertensives without manifest atherosclerosis and those with angina pectoris. Mean PRA values were significantly lower in groups of hypertensives than in corresponding groups of normotensives (group 4 < 1, 5 < 2, 6 < 3). On the other hand, we found no significant difference between subjects without manifest atherosclerosis and those with IHD, either in normotensives, or in hypertensives. In patients with essential hypertension complicated by ischaemic heart disease (groups 5 and 6), there were more PRA values of less than 0.5 ng/ml * h in comparison with other groups, the difference being significant for group 5 and the total of groups 5 + 6. In the course of three years, 32 men died (i.e. 10.7%). There were no cardiovascular deaths in normotensives without manifest atherosclerosis (Table 2). The combined group of normotensives with IHD (group 2 + 3) had a mortality of 11% due to IHD. Two patients with benign essential hypertension without manifest atherosclerosis at entry died of cerebrovascular accident. Total cardiovascular mortality in hypertensives with IHD at entry (groups 5 + 6) amounted to 15%, two-thirds of the deaths having been caused by IHD. No significant relationship of cardiovascular mortality to initial PRA TABLE
2
THREE-YEAR Group
MORTALITY
PRA (w/ml
*h)
ACCORDING
Number
of
subjects
at
entry -~
TO Cause
INITIAL
PRA
VALUES
Other
cardio-
of death
IHD
Not
n
7%
m
%bofn
cardio-
“BSC.
vase . __~ m
Total
-___ %ofn
m %ofn
m
%ofn
1
11.1
1
11.1
1
2.9
1
2.9 _a
2
4.0
2
4.0
2
11.1
2
3.0
8
12.1
3
18.8
2
2.0
13
13.0
___ 1
5
34
0.5-2.49 2.5
+
Total 2+3
<0.5 0.5-2.49 2.5
+
14.0
50
00.0
-_ -
_a _a
18
18.0
2
11.1
66.0
6
9.1
16.0
3
18.8
00.0
11
11.0
3
18.0
39
78.0
2
+
1
100.0
:b
_c 1
,;:;
2
4.0a
a,c
L
z
1
-
-
2
4.0
5
14.7
8.8
2
5.9
_
3
5.lb
-
-
10 -
17 -
10.0
5
5.0b
--
-
15
15.0
+
a Significant
difference
between
groups
1 and
b Significant
difference
between
groups
2 + 4 and
c Significant
difference
between
sub-groups.
PRA,
renin
activity;
IHD,
ischaemic
4.
heart
5;:;
11.9
5
Total
plasma
_
:b
_c
4.0
50
-
1
0.5-2.49 2.5
-
66
5
Total 5+6
7
100
0.5-2.49 2.5
68.0
16
Total 4
18.0
9
5 + 6. disease;
groups
1-6
see in Table
1.
a.c
0
46
values could be proved either in normotensive patients with IHD, or hypertensives with IHD. The only statistically significant within-group difference was that in group 4, the incidence of cerebrovascular accident in the high-renin subgroup being higher than in the low-renin one. Discussion Interrelationships between blood pressure and atherosclerosis are well known (see in [4]). Although essential hypertension affects predominantly arterioles and small arteries, its adverse influence on atherosclerosis of large vessels has been proved. While mechanical factors play a major role in the development of hypertensive vascular diseases, the contribution of humoral influences seems to be likewise important. Among others, the participation of the renin-angiotensin system is suspected [ 51. Several experimental data suggest the possibility of the renin-angiontensin system being involved in atherogenesis [6,7] and in development of cardiac hypertrophy [ 81. In clinical medicine, attention has been focused on the possible relationship of plasma renin to ischaemic heart disease, since the publications by Brunner et al. [9,10]. The majority of clinical investigators, while analyzing their experience in this respect, were unable to confirm any favourable prognostic significance of low PRA values with regard to vascular accidents in essential hypertension [ll-201. Nevertheless, there is no definite answer yet to the question of increased plasma renin activity acting as a risk factor for ischaemic heart disease. It is our conviction that plasma renin activity, as a global clinical test, gives better information on the rate of angiotensin formation in vivo than the more selective methods determining the components of the reninangiotensin system. Actual values of PRA are determined by various regulatory mechanisms, some of them probably unknown until now. Among the regulatory mechanisms, sodium balance certainly plays an important role. As it is difficult to maintain sodium balance under out-patient conditions [21], we could not take it into due consideration. We have serious doubts about the validity of 24-h sodium excretion as a method for estimating sodium balance. In our attempt to assess PRA as a risk factor for ischaemic heart disease, we tried to examine PRA under conditions as close as possible to the normal conditions of life of the subjects examined (out-patient conditions, diet, posture). We are, of course, aware of the paramount importance of day-today variability of PRA values under the given conditions for any prognostic purpose. In this respect, conclusive information is not available. According to Genest’s experience [12], there is a considerable variability of PRA values on repeated examinations. In 76 of 300 subjects reported here, control examinations of PRA were performed after a time interval varying from four weeks to six months. The values of these control examinations failed to fit into the same renin sub-groups in more than 20% of cases. Our finding of lower mean PRA values in hypertensives may be explained in two possible ways. A. negative feedback mechanism can be assumed to decrease renin secretion in benign essential hypertension. On the other hand, lower values of PRA in hypertensives might be caused by lower adrenergic stimulation or by certain functional disturbances, especially in the kidneys [ 221. This latter
47
concept seems to be supported by our finding of more patients with angina pectoris or myocardial infarction and hypertension having plasma renin activities of less than 0.5 ng/ml * h. The fact that we were unable to find any significant difference in PRA between groups without manifest atherosclerosis and those with IHD cannot be taken as circumstantial evidence against the possible prognostic significance of PRA, because PRA values before and after coronary events should not be compared. With the exception of the well-known negative correlation between PRA and urinary sodium excretion (r = -0.7), we were unable to prove any meaningful significant correlations between PRA values and the other quantitative characteristics given in Table I. In our groups of subjects aged 45+4 years we did not find a significant correlation between PRA and age, as others did for broader age ranges [ 23-251. In analyzing the cardiovascular mortality, we saw marked differences between our groups, although absolute numbers of deaths were small. There were no deaths due to IHD in subjects without manifest atherosclerosis at entry, the mortality of both normotensives and hypertensives with IHD being rather high. Notwithstanding, we found no difference in mortality due to IHD in relation to PRA values. This may be taken as evidence against the prognostic value of PRA, while not excluding the possible influence of the renin-angiotensin system in atherogenesis. The difficulty in recognizing PRA as a risk factor probably lies in the fact that it belongs to factors exerting their influence in the initial phase of atherogenesis. In conclusion, our follow-up study failed to prove any prognostic significance of plasma renin as regards mortality due to ischaemic heart disease. References 1 Slab+, A., Hofman, 0.. UrbBnek, J. and Reisenauer, R., Plasma renin activity and the ischaemic heart disease, Cas. Lek. Ces., 114 (1975) 1325 (in Czech, summary in English). 2 Rose. G.A. and Blackbum, H., Cardiovascular survey methods, World Health Organization Monograph Series No. 56. 1968, p, 188. 3 Haber, E., Koemer, T.. Page, L.B., Kliman, B. and Purnode. A., Application of a radioimmunoassay of angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects, J. Clin. Endocrinol.. 29 (1969) 1349. 4 Slab?, A., Reisenauer, R. and Reinis, Z., Arterial blood pressure and the manifestation of atherosclerosis in a rural population of North Bohemia, Atherosclerosis, 14 (1971) 79. 5 Hollenberg, N.K., Epstein, M., Basch, R.I., Couch, N.P.. Hickler. R.B. Merrill. J.P., Renin secretion in essential and accelerated hypertension, Amer. J. Med., 47 (1969) 855. 6 Constantinides, P. and Robinson, M.. Ultrastructural injury of arterial end&helium, Part 2 (Effects of vasoactive amines). Arch. Path., 88 (1969) 106. 7 Robertson. A.L. and Khairallab, P.A., Effects of angiotensin II and some analogues on vascular permeability in the rabbit, Circ. Res., 31 (1972) 923. in spontaneously 8 Sen. S., Tarazi, R.C., Khairallah, P.A. and Bumpus, F.M., Cardiac hype&why hypertensive rats. Circ. Res., 35 (1974) 775. 9 Brunner, H.R., Laragh, J.H., Baer, L.. Newton, M.A., Goodwin, F.T., Krakoff, L.R., Bard. R.H. and Biihler, F.R., Essential hypertension - Renin and aldosterone. heart attack and stroke, New Engl. J. Med., 286 (1972) 441. 10 Brunner, H.R., Sealey. J.E. and Laragh, J.H., Renin as a risk factor in essential hypertension -More evidence, Amer. J. Med., 55 (1973) 295. 11 Doyle, A.E., Jerums, G.. Johnston, C.I. and Louis. W.J.. Plasma renin levels and vascular complications in hypertension, Brit. Med. J., 2 (1973) 206. 12 Genest, J.. Boucher. R., Kuchel, 0. and Nowaczynski, W., Rrnin in hypertension - How important as a risk factor?Canad. Med. Ass. J., 109 (1973) 475.
48 13 14 15 16 17 18 19 20 21 22 23
24
25
Hollander. W., Hypertension, antihypertensive drugs and atherosclerosis, Circulation, 48 (1973) 1112. Kaplan, N.M.. The prognostic implications of plasma renin in essential hypertension, J. Amer. Med. Ass., 231 (1975) 167. Kern. D.C., Kramer, N.J., Gomez-Sanchez, C., White M., and Kaplan, N.M., The low-renin state Definition and implications, J. Clin. Invest., 52 (1973) 46a. Mroczek. W.J., Finnerty, F.A. and Catt, K.J., Lack of association between plasma-renin and history of heart-attack or stroke in patients with essential hypertension, Lancet, 2 (1973) 464. Mroczek, W.J.. Davidov, M.E.. Finnerty, F.A. and Catt, K.J.. Plasma renin activity and vascular disease in essential hypertension, Angiology, 27 (1976) 91. Schalekamp. M.A. and Birkenhlger. W.H., Renin levels in hypertension (Letter to the Editor). New Engl. J. Med., 286 (1972) 1319. Spark, R.F., Low renin hypertension and the adrenal cortex, New Engl. J. Med., 287 (1972) 343. Stroobandt, R., Fagard. R. and Amery, A.K.. Are patients with essential hypertension and low renin ‘protected against stroke and heart attack?, Amer. Heart J., 86 (1973) 781. Woods, J.W., Pittman, A.W., Pulliam. C.C., Werk, E.E., Waider. W. and Allen, C.A.. Renin profiling in the treatment of hypertension, New Engl. J. Med., 294 (1976) 1137. Brown. J.J.. Lever, A.F., Robertson, J.I.S. and Schalekamp, M.A., Renal abnormality of essential hypertension, Lancet, 2 (1974) 320. Biihler. F.R.. Patel. U. and Marbet. G.. Ambulante und stationlre Bestimmung des Renln-NatriumIndex zur Unterteilung und gezielten Behandlung der essentiellen Hypertonie, Schweiz. Med. Wschr., 104 (1974) 1802. Schalekamp, M.A.D.H., Krauss, X.H., Schalekamp-Kuyken, M.P.A.. Kolsters, G. and BirkenhZger, W.H.. Studies on the mechanism of hypernatriuresis in essential hypertension in relationship to measurements of plasma renin concentration, body fluid compartments and renal functions, Clin. Sci., 41 (1971) 219. Tuck, M.L., Williams. G.H., Cain, J.P., Sullivan, J.M. and Dluhy, R.G., Relation of age, diastolic pressure and known duration of hypertension to presence of low renin essential hypertension, Amer. J. Cardiol., 32 (1973) 637.
Atherosclerosis,
27 (1877)
@ Elsevier/North-Holland
41-48
Scientific
PLASMA RENIN ACTIVITY PRESENCE OF ISCHAEMIC
A. SLAB+,
0. HOFMAN,
Publishers,
Ltd.
IN MEN WITH RELATION HEART DISEASE
R. REISENAUER
TO THE
and J. URBANEK
4th Department of Internal Medicine and Biophysicul Institute, Charles University, Department of Internal Medicine, Prague 7, and the Research Institute for Endocrinology, Prague (Czechoslovakia)
(Received (Revised, (Accepted
2 July, 1976) received 24 September, 27 September, 1976)
1976)
Summary Plasma renin activity (PRA) stimulated by upright posture was measured, in 300 men aged 45-64 years, by a radio-immunoassay of angiotensin I. The subjects examined were divided into six groups, comparable in mean age, each containing 50 subjects: group 1, normotensives without manifest atherosclerosis; group 2, .normotensives with angina pectoris definite; group 3, normotensives with a history of a transmural myocardial infarction; groups 4 to 6, patients with benign essential hypertension, without manifest atherosclerosis in group 4, with angina pectoris in group 5 and with a history of myocardial infarction in group 6. Significant differences in mean PRA were found between corresponding groups of hypertensives and normotensives, the values in hypertensives being lower. The percentage of low renin values was higher in hypertensives with ischaemic heart disease than in other groups. An analysis of 3-year cardiovascular mortality revealed no significant difference in mortality due to ischaemic heart disease between high-renin and low renin sub-groups. Key words:
Cardiovascular mortality -Essential Plasma renin activity -Risk factors
hypertension
-- Ischaemic
heart
disease
-
Introduction The problem of plasma renin values, possibly bearing a relationship to the prognosis of essential hypertension, has not yet been definitely solved. Several
42
prospective studies are now in progress, with the aim of comparing cardiovascular morbidity and mortality in hypertensives without complications at entry, according to their initial values of plasma renin activity (PRA). Since 1973, we have been following up six groups of men aged 45-64 years, consisting of normotensive subjects and patients with benign essential hypertension, either without manifest atherosclerosis, or with ischaemic heart disease. We report here some characteristics of these groups, as well as the 3-year cardiovascular mortality in relation to initial PRA values. Materials and Methods Three-hundred men aged 45-64 years were examined, half of them normotensives, the other half patients with essential hypertension. The material is relatively unselected, since two of the authors examined all subjects fulfilling the specified diagnostic criteria, as they attended, for examination, the respective general outpatient departments [l]. According to the criteria mentioned, six groups were formed, each containing 50 subjects. Normotensive subjects, i.e. those who had never had a blood pressure recorded higher than 155/90 mm Hg, were without manifest atherosclerosis in group 1, with angina pectoris definite in group 2, and with a history of clinically proved myocardial infarction (at least six months after the acute phase) in group 3. Patients with benign essential hypertension, with a diastolic blood pressure of 100 mm Hg or more on three occasions, were grouped in a similar fashion into those without manifest atherosclerosis in group 4, with angina pectoris in group 5, and with a history of myocardial infarction in group 6. Angina pectoris definite was defined according to the WHO criteria [2]. The diagnosis of a transmural myocardial infarction was made from the hospital records, in the presence of serial electrocardiographic evidence of infarction (Q waves that satisfied the criteria for classification in the l-l or l-2 categories of the Minnesota Code [2]. An increase in serum enzymes was also proved in many cases. All hypertensive subjects had been examined at the medical department before the start of the study, to exclude secondary causes of hypertension, the workup including renal function tests, radio-isotope nephrography, intravenous pyelography, and renal angiography, when needed. Subjects with signs of cardiac or renal insufficiency, as well as those with retinopathy, were not included. In each subject, 142 data were collected from history, clinical examination, ECG, chest X-ray, fundoscopy, urinary analysis, and biochemical examinations including PRA. Urinary sodium excretion was examined only in those subjects whom a quantitative collection of urine was guaranteed. All medicaments had been suspended 3 weeks before the examination. Blood pressure was measured three times with the subject in the sitting position and the lowest value was recorded. A mercury manometer with a 14-cm cuff was used, the diastolic readings reported being the fifth phase. Plasma cholesterol, blood glucose and serum creatinine were determined by current methods, electrolytes by internal standard flame photometry. PRA was determined in peripheral venous blood, taken after 3 h upright at 11 a.m., with sodium in the diet unrestricted. Radio-immunoassay of angio-
43
tensin I according to Haber et al. [3] was used. Blood was drawn into prechilled plastic tubes containing Na2-EDTA, and immediately centrifuged at 2-4°C. Plasma was incubated at 37°C and pH 5.6-5.8 for 3 h, in the presence of enzymic inhibitors (dimercaptol, &hydroxyquinoline). A similar aliquot of plasma was held at 0°C. Angiotensin I in the samples was determined by using labelled angiotensin I and rabbit antiserum from the commercial kit supplied by Sorin. Antibody-bound peptide was separated and counted in a well scintillation counter. The results, were expressed in ng of angiotensin I, formed in 1 ml of plasma during 1 h of incubation. The coefficient of variation of duplicates was f 5% and the between-assay reproducibility was + 12%. The statistical significance of the differences between groups was tested by Student’s t test for quantitative values. (The prerequisite of a normal distribution was fulfilled in all tests.) For qualitative characteristics, the test of the differences of relative values was used. The level of probability chosen was 0.05. PRA values determined in our subjects were divided into the following three intervals: low values, less than 0.5 ng/ml . h, medium values O-5-2.49 ng/ml * h, high values 2.5 ng/ml - h and more. This classification was done independently of urinary sodium excretion which, whenever determined, exceeded 100 mequiv. in 24 h. Follow-up examinations of all subjects were performed once a year. In this year, all 300 subjects were either examined or reliable information about their death was obtained. The cause of death was determined from the official death certificate or according to the findings of the post-mortem examination. The diseases were coded according to the Eight Revision of the International Classification of Diseases, Injuries, and Causes of Death. The causes of death found were divided into the following three groups: 1, ischaemic heart disease, 2, other cardiovascular diseases (cerebrovascular diseases, pulmonary embolism); 3, other causes (not cardiovascular). Results Table 1 sums up some characteristics of the subjects examined in groups l-6. As can be seen, there was no significant difference between groups in mean values of age. Neither was there any difference in systolic blood pressure between the groups of normotensives, or between those of hypertensives. Mean weight was significantly higher in hypertensives than in normotensives, the highest value being in hypertensives without manifest atherosclerosis. The known duration of hypertension was longer in hypertensives with IHD than in those without manifest atherosclerosis, as could be expected. Diastolic blood pressure was similar in all groups of normotensives. Its mean value was significantly higher in hypertensives without manifest atherosclerosis than in those with a history of myocardial infarction, the difference between groups 4 and 5 closely approaching the limit of significance. In normotensives, plasma cholesterol was significantly higher in both groups with IHD than in normotensives without manifest atherosclerosis. A similar difference could not be proved between the groups of hypertensives. On the other hand, significant differences in mean blood glucose levels were found in hypertensives only. Serum creatinine was higher in hypertensives than in
duration
Known
glucose
creatinine
sodium
potassium
rain
a Numbers
brackets
(%)
+
2.5
(%)
(%)
between
activity
plasma
. h)
0.5-2.49
<0.5
renin
Intervalsof
@g/ml
Plasma
h)
excretion
pressure
activity
sodium
(mequiv./24
Urinary
(mequiv./I)
Serum
(mequiv./l)
Serum
(mg/dl)
Serum
(mg/dI)
Blood
(yrs)
of
a
pressure
cholesterol
Hg)
blood
Hg)
blood
(mg/dI)
Plasma
(mm
Diastolic
(mm
Systolic
hypertension
(kg)
(YLS)
of subjects
CHARACTERISTICS
1
Weight
Age
Number
Item
SOME
TABLE
GROUPS
2
0.06
0.4
0.03
6.8
7.8
0.9
1.3
0.07
0.3
0.02
2.8
6.9
0.8
1.6
= numbers
of subjects
for urinary
sodium
16.0
16.0
14.0
1.54
18.0
0.18
186.3
4.8
140.2
1.16
104.3
277.8
83.5
133.4
80.4
66.0
t
f 18.7
-r
_+
*
+
+
+
+
1.3
56.6
18.0
1.63
178.8
4.9
141.7
1.11
97.6
272.2
82.9
134.0
i
80.7
0.8
0.8
0.06
0.4
0.03
5.6
7.7
1.0
1.5
1.4
0.14
excretion.
i
i 29.1
?
+
?
?
+
+
i
r
?-
50 (18)
66.0
% 0.13
+ 16.8
t
i
i
+
1-
+
?;
?
(15)
55.1
50
68.0
18.0
1.39
145.2
4.8
141.1
1.13
105.1
246.3
83.4
131.1
?
79.0
1.4
+_ 0.1
(18)
55.2
50
4.0
78.0
3 8.0
1.02
201.4
4.5
141.5
1.15
96.2
258.1
114.5
0.07
0.4
0.03
2.4
6.1
1.2
2.6
0.6
1.8
0.7
with
t
0.09
f 20.1
+
_+
+
?
?
i
?
+
5.4 187.2
f
I
(17)
87.5
55.3
50
sclerosis
athero-
infarction
definite
sclerosis
athero-
Without manifest
Subjects
4
SE)
myocardial
f
With past
(MEAN
pectoris
With
3
EXAMINED
Without
angina
SUBJECTS
subjects
OF
manifest
Normotensive
1
Group
OF
-
6.0
58.0
36.0
1.12
220.0
4.6
141.8
1.22
110.0
161.1+
111.9
184.3
7.3
84.3
56.2
0.05
0.4
0.02
6.1
6.8
1.2
2.6
0.8
1.8
c
0.12
+_ 21.6
i
k
+
*
f
t
+
?
?
50 (17)
definite
0.8
angina
pectoris
With
ess. hypertension
5
8.0
60.0
32.0
1.05
157.6
4.7
141.3
1.18
111.7
257.4
111.4
181.8
?
i
i
*
i
f
f
t
+
i
+
?r
(18)
7.9
82.4
56.2
50
infarction
0.06
0.3
0.03
6.3
7.1
1.1
2.1
0.8
1.4
0.9
0.11
17.4
past
myocardial
With
6
1:5,
4:6
(within
2:4,
4:5
1:5,
1:4,
1~4,
1:4.
1:5,
4:5,
1:2,
3:4
2:5,
2:4,
1:5.
1:5,
2:5
4:6
1:3,
3:5,
2:5,
5:6
2:4,
3:4
hypertensive)
4:6
4:5
3:4,
2:5.
3:6
3:4.
normotensives
normotensives
2:4.
3:4,
differences groups
hypertensive)
(within
4:6
1:4.
between
Significant
4:6
and and
%
45
normotensives. There was no difference in serum sodium concentrations, mean serum potassium being lower in hypertensives than in normotensives. Urinary sodium excretion was highest in hypertensives without manifest atherosclerosis and those with angina pectoris. Mean PRA values were significantly lower in groups of hypertensives than in corresponding groups of normotensives (group 4 < 1, 5 < 2, 6 < 3). On the other hand, we found no significant difference between subjects without manifest atherosclerosis and those with IHD, either in normotensives, or in hypertensives. In patients with essential hypertension complicated by ischaemic heart disease (groups 5 and 6), there were more PRA values of less than 0.5 ng/ml * h in comparison with other groups, the difference being significant for group 5 and the total of groups 5 + 6. In the course of three years, 32 men died (i.e. 10.7%). There were no cardiovascular deaths in normotensives without manifest atherosclerosis (Table 2). The combined group of normotensives with IHD (group 2 + 3) had a mortality of 11% due to IHD. Two patients with benign essential hypertension without manifest atherosclerosis at entry died of cerebrovascular accident. Total cardiovascular mortality in hypertensives with IHD at entry (groups 5 + 6) amounted to 15%, two-thirds of the deaths having been caused by IHD. No significant relationship of cardiovascular mortality to initial PRA TABLE
2
THREE-YEAR Group
MORTALITY
PRA (w/ml
*h)
ACCORDING
Number
of
subjects
at
entry -~
TO Cause
INITIAL
PRA
VALUES
Other
cardio-
of death
IHD
Not
n
7%
m
%bofn
cardio-
“BSC.
vase . __~ m
Total
-___ %ofn
m %ofn
m
%ofn
1
11.1
1
11.1
1
2.9
1
2.9 _a
2
4.0
2
4.0
2
11.1
2
3.0
8
12.1
3
18.8
2
2.0
13
13.0
___ 1
5
34
0.5-2.49 2.5
+
Total 2+3
<0.5 0.5-2.49 2.5
+
14.0
50
00.0
-_ -
_a _a
18
18.0
2
11.1
66.0
6
9.1
16.0
3
18.8
00.0
11
11.0
3
18.0
39
78.0
2
+
1
100.0
:b
_c 1
,;:;
2
4.0a
a,c
L
z
1
-
-
2
4.0
5
14.7
8.8
2
5.9
_
3
5.lb
-
-
10 -
17 -
10.0
5
5.0b
--
-
15
15.0
+
a Significant
difference
between
groups
1 and
b Significant
difference
between
groups
2 + 4 and
c Significant
difference
between
sub-groups.
PRA,
renin
activity;
IHD,
ischaemic
4.
heart
5;:;
11.9
5
Total
plasma
_
:b
_c
4.0
50
-
1
0.5-2.49 2.5
-
66
5
Total 5+6
7
100
0.5-2.49 2.5
68.0
16
Total 4
18.0
9
5 + 6. disease;
groups
1-6
see in Table
1.
a.c
0
46
values could be proved either in normotensive patients with IHD, or hypertensives with IHD. The only statistically significant within-group difference was that in group 4, the incidence of cerebrovascular accident in the high-renin subgroup being higher than in the low-renin one. Discussion Interrelationships between blood pressure and atherosclerosis are well known (see in [4]). Although essential hypertension affects predominantly arterioles and small arteries, its adverse influence on atherosclerosis of large vessels has been proved. While mechanical factors play a major role in the development of hypertensive vascular diseases, the contribution of humoral influences seems to be likewise important. Among others, the participation of the renin-angiotensin system is suspected [ 51. Several experimental data suggest the possibility of the renin-angiontensin system being involved in atherogenesis [6,7] and in development of cardiac hypertrophy [ 81. In clinical medicine, attention has been focused on the possible relationship of plasma renin to ischaemic heart disease, since the publications by Brunner et al. [9,10]. The majority of clinical investigators, while analyzing their experience in this respect, were unable to confirm any favourable prognostic significance of low PRA values with regard to vascular accidents in essential hypertension [ll-201. Nevertheless, there is no definite answer yet to the question of increased plasma renin activity acting as a risk factor for ischaemic heart disease. It is our conviction that plasma renin activity, as a global clinical test, gives better information on the rate of angiotensin formation in vivo than the more selective methods determining the components of the reninangiotensin system. Actual values of PRA are determined by various regulatory mechanisms, some of them probably unknown until now. Among the regulatory mechanisms, sodium balance certainly plays an important role. As it is difficult to maintain sodium balance under out-patient conditions [21], we could not take it into due consideration. We have serious doubts about the validity of 24-h sodium excretion as a method for estimating sodium balance. In our attempt to assess PRA as a risk factor for ischaemic heart disease, we tried to examine PRA under conditions as close as possible to the normal conditions of life of the subjects examined (out-patient conditions, diet, posture). We are, of course, aware of the paramount importance of day-today variability of PRA values under the given conditions for any prognostic purpose. In this respect, conclusive information is not available. According to Genest’s experience [12], there is a considerable variability of PRA values on repeated examinations. In 76 of 300 subjects reported here, control examinations of PRA were performed after a time interval varying from four weeks to six months. The values of these control examinations failed to fit into the same renin sub-groups in more than 20% of cases. Our finding of lower mean PRA values in hypertensives may be explained in two possible ways. A. negative feedback mechanism can be assumed to decrease renin secretion in benign essential hypertension. On the other hand, lower values of PRA in hypertensives might be caused by lower adrenergic stimulation or by certain functional disturbances, especially in the kidneys [ 221. This latter
47
concept seems to be supported by our finding of more patients with angina pectoris or myocardial infarction and hypertension having plasma renin activities of less than 0.5 ng/ml * h. The fact that we were unable to find any significant difference in PRA between groups without manifest atherosclerosis and those with IHD cannot be taken as circumstantial evidence against the possible prognostic significance of PRA, because PRA values before and after coronary events should not be compared. With the exception of the well-known negative correlation between PRA and urinary sodium excretion (r = -0.7), we were unable to prove any meaningful significant correlations between PRA values and the other quantitative characteristics given in Table I. In our groups of subjects aged 45+4 years we did not find a significant correlation between PRA and age, as others did for broader age ranges [ 23-251. In analyzing the cardiovascular mortality, we saw marked differences between our groups, although absolute numbers of deaths were small. There were no deaths due to IHD in subjects without manifest atherosclerosis at entry, the mortality of both normotensives and hypertensives with IHD being rather high. Notwithstanding, we found no difference in mortality due to IHD in relation to PRA values. This may be taken as evidence against the prognostic value of PRA, while not excluding the possible influence of the renin-angiotensin system in atherogenesis. The difficulty in recognizing PRA as a risk factor probably lies in the fact that it belongs to factors exerting their influence in the initial phase of atherogenesis. In conclusion, our follow-up study failed to prove any prognostic significance of plasma renin as regards mortality due to ischaemic heart disease. References 1 Slab+, A., Hofman, 0.. UrbBnek, J. and Reisenauer, R., Plasma renin activity and the ischaemic heart disease, Cas. Lek. Ces., 114 (1975) 1325 (in Czech, summary in English). 2 Rose. G.A. and Blackbum, H., Cardiovascular survey methods, World Health Organization Monograph Series No. 56. 1968, p, 188. 3 Haber, E., Koemer, T.. Page, L.B., Kliman, B. and Purnode. A., Application of a radioimmunoassay of angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects, J. Clin. Endocrinol.. 29 (1969) 1349. 4 Slab?, A., Reisenauer, R. and Reinis, Z., Arterial blood pressure and the manifestation of atherosclerosis in a rural population of North Bohemia, Atherosclerosis, 14 (1971) 79. 5 Hollenberg, N.K., Epstein, M., Basch, R.I., Couch, N.P.. Hickler. R.B. Merrill. J.P., Renin secretion in essential and accelerated hypertension, Amer. J. Med., 47 (1969) 855. 6 Constantinides, P. and Robinson, M.. Ultrastructural injury of arterial end&helium, Part 2 (Effects of vasoactive amines). Arch. Path., 88 (1969) 106. 7 Robertson. A.L. and Khairallab, P.A., Effects of angiotensin II and some analogues on vascular permeability in the rabbit, Circ. Res., 31 (1972) 923. in spontaneously 8 Sen. S., Tarazi, R.C., Khairallah, P.A. and Bumpus, F.M., Cardiac hype&why hypertensive rats. Circ. Res., 35 (1974) 775. 9 Brunner, H.R., Laragh, J.H., Baer, L.. Newton, M.A., Goodwin, F.T., Krakoff, L.R., Bard. R.H. and Biihler, F.R., Essential hypertension - Renin and aldosterone. heart attack and stroke, New Engl. J. Med., 286 (1972) 441. 10 Brunner, H.R., Sealey. J.E. and Laragh, J.H., Renin as a risk factor in essential hypertension -More evidence, Amer. J. Med., 55 (1973) 295. 11 Doyle, A.E., Jerums, G.. Johnston, C.I. and Louis. W.J.. Plasma renin levels and vascular complications in hypertension, Brit. Med. J., 2 (1973) 206. 12 Genest, J.. Boucher. R., Kuchel, 0. and Nowaczynski, W., Rrnin in hypertension - How important as a risk factor?Canad. Med. Ass. J., 109 (1973) 475.
48 13 14 15 16 17 18 19 20 21 22 23
24
25
Hollander. W., Hypertension, antihypertensive drugs and atherosclerosis, Circulation, 48 (1973) 1112. Kaplan, N.M.. The prognostic implications of plasma renin in essential hypertension, J. Amer. Med. Ass., 231 (1975) 167. Kern. D.C., Kramer, N.J., Gomez-Sanchez, C., White M., and Kaplan, N.M., The low-renin state Definition and implications, J. Clin. Invest., 52 (1973) 46a. Mroczek. W.J., Finnerty, F.A. and Catt, K.J., Lack of association between plasma-renin and history of heart-attack or stroke in patients with essential hypertension, Lancet, 2 (1973) 464. Mroczek, W.J.. Davidov, M.E.. Finnerty, F.A. and Catt, K.J.. Plasma renin activity and vascular disease in essential hypertension, Angiology, 27 (1976) 91. Schalekamp. M.A. and Birkenhlger. W.H., Renin levels in hypertension (Letter to the Editor). New Engl. J. Med., 286 (1972) 1319. Spark, R.F., Low renin hypertension and the adrenal cortex, New Engl. J. Med., 287 (1972) 343. Stroobandt, R., Fagard. R. and Amery, A.K.. Are patients with essential hypertension and low renin ‘protected against stroke and heart attack?, Amer. Heart J., 86 (1973) 781. Woods, J.W., Pittman, A.W., Pulliam. C.C., Werk, E.E., Waider. W. and Allen, C.A.. Renin profiling in the treatment of hypertension, New Engl. J. Med., 294 (1976) 1137. Brown. J.J.. Lever, A.F., Robertson, J.I.S. and Schalekamp, M.A., Renal abnormality of essential hypertension, Lancet, 2 (1974) 320. Biihler. F.R.. Patel. U. and Marbet. G.. Ambulante und stationlre Bestimmung des Renln-NatriumIndex zur Unterteilung und gezielten Behandlung der essentiellen Hypertonie, Schweiz. Med. Wschr., 104 (1974) 1802. Schalekamp, M.A.D.H., Krauss, X.H., Schalekamp-Kuyken, M.P.A.. Kolsters, G. and BirkenhZger, W.H.. Studies on the mechanism of hypernatriuresis in essential hypertension in relationship to measurements of plasma renin concentration, body fluid compartments and renal functions, Clin. Sci., 41 (1971) 219. Tuck, M.L., Williams. G.H., Cain, J.P., Sullivan, J.M. and Dluhy, R.G., Relation of age, diastolic pressure and known duration of hypertension to presence of low renin essential hypertension, Amer. J. Cardiol., 32 (1973) 637.