Download Haemodynamics in Essential Hypertension

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Clinical Science (1980)59,343~354s
STATE OF THE A R T REVIEW
Haemodynamics in essential hypertension
P. LUND-JOHANSEN
Medical Department A , University of Bergen, School of Medicine, Bergen, Norway
Introduction
The arterial blood pressure is mainly determined
by the cardiac output and the total peripheral
resistance. The blood pressure and the cardiac
output are measured and the total peripheral
resistance is calculated by dividing mean arterial
blood pressure by cardiac output. This
calculation is valid only for laminar flow in rigid
straight tubes, but still this calculation is currently
used to estimate the complex total peripheral
resistance in man, although this means a rough
approximation (Peterson, 1961).
In an extensive review of the haemodynamics
of hypertension, Freis (1960) stated that
according to the prevailing concept the primary
and cardinal haemodynamic disturbance in
practically all forms of hypertension was an
increase in total peripheral resistance, probably
caused by neurogenic or humoral mechanisms.
The cardiac output was normal as long as heart
failure was not present and, from a pathogenetic
point of view, the heart was not of much interest.
However, in the late 1950s and the early 1960s
a few observations in experimental and human
hypertension seemed to indicate that an increased
cardiac output could play an important role in the
starting phase of hypertension. The total peripheral resistance could become increased later
as a sort of autoregulatory phenomenon.
Ledingham & Cohen (1963) demonstrated that in
some rats with experimental renal hypertension
the cardiac output was increased when the
pressure started to rise, although the total
peripheral resistance was still normal. After some
time the cardiac output fell and the total
peripheral resistance increased, maintaining the
Key words: antihypertensive drugs, cardiac
output, exercise, haemodynamics, hypertension.
Correspondence: Professor P. Lund-Johansen,
Medical Department A, University of Bergen,
5016 Haukeland sykehus, Bergen, Norway.
12
elevated arterial pressure. From Czechoslovakia, Hejl (195’?), Widimsky, Fejfarova &
Fejfar (1957) and Fejfar & Widimsky (1961)
reported increased cardiac output in the majority
of young patients with essential hypertension.
The calculated total peripheral resistance was
numerically normal.
These observations generated great interest in
the haemodynamics of essential hypertension,
and today it is well documented that the
haemodynamic pattern varies and depends upon
the age of the subject and the stage of the
hypertensive
disorder
(reviews: Frohlich,
Tarazi & Dustan, 1969; Sannerstedt, 1970; LundJohansen, 1973; Birkenhager & Schalekamp,
1976). In recent years, functional disturbances of
the heart and resistance vessels together with
morphological changes in the left ventricle (diagnosed by echocardiography) have been demonstrated surprisingly early, e.g. in subjects in their
twenties with mild hypertension.
This review will first discuss the function of the
heart and the resistance vessels during rest and
various stress conditions, and then the pathophysiological mechanisms responsible for the
alterations in function. Finally the possibility of
reversing the haemodynamic abnormalities by
drug therapy will be briefly reviewed.
Central haemodynamics at rest
Early hypertension
It is difficult to find subjects with documented
early essential hypertension. Most studies have
been made in young adults with ‘borderline’ (here
defined as patients with some readings above and
some below 90 mmHg) or mild hypertension.
When groups of borderline hypertensive subjects
are compared with age-matched normotensive
controls, the cardiac index at rest supine is
usually increased. The heart rate is also increased and the stroke index usually normal
P . Lund-Johansen
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T \ R L I 1. Mean values f o r cardiac index, mean arterial blood pressure, total peripheral resistance index, heart rate and stroke
index in subjects with labile or mild essential hypertension in the supine position at rest
M e a n values for control groups are in parentheses.
Reference
Bello. Sevy & Harakal (1965)
Lund-Johansen (1967)
Frohlich, Tarazi & Dustan
(1969)
Safar el nl. (1970)
Julius er a/. ( I97 I b)
No.
II
25
Mean arterial
blood pressure
(mmHg)
108 (91)
Cardiac
index
(Imin-’m
l)
Total peripheral
resistance index
(kPasl-’mz)
Heart rate
(beatshin)
Stroke index
(ml stroke-’ m
9
102 (84)
106 (93)
4.10 (3.29)
4.14 (3.45)
3.53 (3.05)
Zll (221)
197 (195)
240 (244)
81 (74)
75 (63)
77 (68)
51 (44)
56 (55)
46 (45)
23
71
105 (86)
100 (83)
4.09 (3.15)
3.79 (3.31)
210 (222)
222 (209)
80 (72)
76 (67)
51 (44)
50 (50)
(Eich, Peters, Cuddy, Smulyan & Lyons, 1962;
Bello, Sevy & Harakal, 1965; Julius & Conway,
1968; Kuramoto, Murata, Yazaki, Ikeda &
Nakao, 1968; Frohlich ef al., 1969; Frohlich,
Kozyl, Tarazi & Dustan, 1970; Safar, Fendler,
Weil, Idatte, Beuve-Mery & Milliez, 1970; Julius,
Pascual, Sannerstedt & Mitchell, 197 lb). The left
ventricular ejection rate is increased (Frohlich et
al., 1969, 1970). Only one study (in older
patients with more severe, but labile, hypertension) demonstrated normal heart rate and
increased stroke volume (Finkielman, Worcel &
Agrest, 1965). The calculated total peripheral
resistance is not significantly higher than in
controls. Individual variations are great, however, and a continuous spectrum of cardiac
outputs from high to low might be found
(Messerli, de Carvalho, Christie & Frohlich,
1978). Also in young adults with established, but
mild, hypertension [all readings above 140/90
mmHg, but without complications, in World
Health Organization stage I (Expert Committee,
1962)l a similar haemodynamic pattern has been
found (Sannerstedt, 1966; Lund-Johansen,
1967). Table 1 shows haemodynamic data from
five different laboratories obtained in adults
below 40 years with average mean arterial blood
pressure 100-108 mmHg at the time of the study.
A high heart rate and cardiac index have also
been demonstrated in a large proportion of
adolescents (12-25 years) and children with mild,
labile essential hypertension (Davignon, Rey,
Payot, Biron & Mongeau, 1977; Dustan &
Tarazi, 1977), but some subjects with a high
resistance are also found at this stage.
The increased cardiac output and heart rate in
patients supposed to be in the ‘starting phase’ of
essential hypertension gave rise to the concept of
the ‘hyperkinetic’ circulatory system, an important factor in the autoregulation theory
(Guyton, Coleman, Cowley, Norman, Manning
& Liard, 1973). However, four independent
studies showed that the oxygen uptake during
2)
rest was increased as well (Eich, Cuddy, Smulyan
1966; Sannerstedt, 1966; LundJohansen, 1967; Julius & Conway, 1968), and
when the cardiac output was plotted against the
oxygen consumption it was found to be normal,
and so was the arteriovenous oxygen difference.
These results showed that there is really no true
‘luxury’ perfusion in ‘early’ essential hypertension and no need for any ‘protection’ of the
tissues against overflow through increase in
vascular resistance. (During muscular exercise
the cardiac output is definitely not increased; see
below.) A true hyperkinetic circulatory system
has been demonstrated by Gorlin (1962) in
subjects with tachycardia and ‘cardiac awareness’. In these subjects the arteriovenous oxygen
difference was abnormally low (2.9 vs 4.0 ml of
oxygen/100 ml of blood in normals) and the
cardiac index was 5.7 vs 3.9 1 min-I m-2 in
controls. Some of these patients had slightly
elevated blood pressure, but whether they
developed hypertension later is not known.
In elderly subjects with mild hypertension the
cardiac output is usually low (Lund-Johansen,
1980b), but exceptions are seen and Kuwajima
(1979) has reported a selected group of elderly
subjects with mild hypertension and cardiac
index values above 4.0 1 min-’ m-*.
& Lyons,
Late hypertension
In adults with moderate essential hypertension
of several years’ duration and in WHO stage I or
11, the dominating haemodynamic disturbance is
an increase in total peripheral resistance. The
cardiac output is usually lower than in normotensive controls and lower than in younger
hypertensive stage I subjects. The heart rate is
usually higher than in controls and the stroke
volume is normal or low (Glazer, 1963; Bello et
al., 1965; Bello, Sevy, Harakal & Hillyer, 1967;
Amery, 1969; Frohlich et al., 1970; Frohlich &
Pfeffer, 1975; Chau, Safar, Weiss, London,
Haemodynamics in essential hypertension
Simon, Lehner & Milliez, 1977; de Leeuw, Kho,
Falke, Birkenhager & Wester, 1978).
Severe hypertension
In patients with more severe hypertension and
complications (WHO stage 111) the characteristic finding is a pronounced increase in total
peripheral resistance and a markedly decreased
cardiac output and stroke volume (Glazer, 1963;
Bello et al., 1965; Sannerstedt, 1966; Bello et al.,
1967; Lund-Johansen, 1967; Frohlich et al.,
1969; 1970; Terasawa, Kuramoto, Lie Hon
Ying, Suzuki & Kuramochi, 1972; Frohlich,
1973).
In patients with severe hypertension refractory
to triple drug treatment very high resistance
values were found (Anderson, Hansson &
Sivertsson, 1978).
A few exceptions from this pattern have been
reported with a high cardiac index in some
patients with severe hypertension (Ibrahim,
Tarazi, Dustan, Bravo & Gifford, 1975).
In patients with hypertension and left ventricular strain on ECG the cardiac index is
decreased (Olivari, Fiorentini, Polese & Guazzi,
1978), and when heart failure is present, very low
cardiac output and very high total peripheral
resistance have been reported, together with
increased pressures in the pulmonary circulation
(Werka & Lagerlaf, 1949; Varnauskas, 1955;
Taylor, Donald & Bishop, 1957), and reduced
left
ventricular
ejection
fraction
and
circumferential fibre shortening (Strauer, 1979).
Regional circulation at rest
Large systematic studies of the circulatory
pattern in various parts of the body in hypertensive subjects of different ages and in various
stages are lacking. The increased calculated total
peripheral resistance in established essential
hypertension is not shared equally in all parts of
the body (Brod, Fencl, Hejl, Jirka & Ulrych,
1962; Brod, 1973).
In early essential hypertension renal blood flow
is increased (Hollenberg & Adams, 1971) and
there is a correlation between cardiac output and
renal blood flow (Messerli et al., 1978). In
established hypertension the renal blood flow is
usually reduced and the renal vascular resistance
increased (Brod et al., 1962; de Leeuw et al.,
1978; Messerli et al., 1978). In the splanchnic
area the resistance is also increased, as in the rest
of the body (Messerli, Genest, Nowaczynski,
Kuchel, Honda & Latour, 1975; Messerli et al.,
1978).
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In the skeletal muscles the blood flow is
increased in the early stage, and the total
peripheral resistance is increased (Conway, 1963;
Amery, Bossaert & Verstracle, 1969), but there is
no correlation between central and peripheral
haemodynamics (Fantini, Nuzzaci, Padeletti,
Michelucci, Arcangeli & Forti, 1977).
Hand
blood
flow
during
maximal
vasodilatation (obtained by heating and exercise
during ischaemia) is increased in young subjects
(19-22 years) with mild hypertension. The
resistance in the hand vessels is normal if cardiac
output is increased, but elevated if cardiac output
is normal (Sivertsson, Sannerstedt & Lundgren,
1976).
Strauer (1979) has demonstrated that the
coronary reserve is reduced in patients even in the
early stages of hypertension. In more severe
hypertension a great reduction in the coronary
reserve was found and an increase in coronary
vascular resistance during rest.
Pulmonary circulation
As long as heart failure is not present, it has
been assumed that the pulmonary circulation is
normal in essential hypertension. However,
recently it has been shown that even in patients
with moderate hypertension without clinical signs
of heart failure, there is often an increase in the
pulmonary artery pressure as well, and vascular
resistance is increased both in the pulmonary and
the systemic circulation (Atkins, Mitchell &
Pettinger, 1977; Olivari et al., 1978; Ferlinz,
1980). Also there is involvement of the right
ventricle with reduced ejection fraction demonstrating functional disturbances on both the left
and the right side of the heart (Guazzi, Fiorentini,
Olivari & Polese, 1979).
Haemodynamics during sleep, exercise and stress
Haemodynamics during sleep
Continuous intra-arterial recordings have
shown that blood pressure decreases markedly
during sleep (Millar-Craig, Bishop & Raftery,
1978). Bristow, Honour, Pickering & Sleight
(1969) found that the pressure fall was mainly
due to a marked decrease in total peripheral
resistance, and the cardiac output showed only a
small decrease (6%). However, in another study
by Khatri & Freis (1969) the dominant changes
were in the cardiac output.
Studies in cats have shown that vasodilatation
is mainly responsible for the fall in blood pressure
(Zanchetti, Baccelli, Guazzi & Mancia, 1973).
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P . Lund-Johansen
The sensitivity of the baroreceptor reflex
during sleep is increased (Bristow et al., 1969)
and could possibly contribute to the reduction in
pressure.
Haemodynamics during dynamic exercise
Borderline and mild hypertension. In patients
with borderline hypertension the blood pressure
increases during exercise, parallel to the rise in
normotensive age-matched controls. Cardiac
output is no longer increased, and rises as in
normals. The total peripheral resistance falls, but
not to the same low levels as in controls (Levy,
Tabakin & Hanson, 1967; Julius & Conway,
1968).
We have studied central haemodynamics
during standardized exercise on an ergometer
bicycle at 50, 100 and 150 W in more than 200
males with mild to moderate essential hypertension, the majority in WHO stage I, and in
normotensive age-matched controls (LundJohansen, 1967, 1973, 1980b). During exercise
the ‘hyperkinetic’ circulatory pattern found in
young hypertensive subjects (1 7-29 years) at rest
disappears. The cardiac output is then no longer
higher than in controls; on the contrary, it tends
to be subnormal. At 150 W the cardiac output
related to oxygen consumption is significantly
lower than in age-matched controls. The heart
rate during exercise is slightly increased and the
stroke volume subnormal. The total peripheral
resistance falls, but not to the same low levels as
in normotensive subjects. In patients 10 years
older a similar pattern is found.
Late and severe hypertension. In patients in
WHO stage I1 and 111, the cardiac output during
exercise is markedly lower than in age-matched
controls, mainly due to a subnormal stroke index.
In these patients the stroke index is often already
low at rest. The total peripheral resistance is
markedly increased at rest as well as during
exercise (Varnauskas, 1955; Taylor et al., 1957;
Sannerstedt, 1966; Amery, Julius, Whitlock &
Conway, 1967; Lund-Johansen, 1967).
Haemodynamics during isometric exercise
Isometric exercise induces marked increase in
the blood pressure and heart rate (Chrysant,
1978). Patients with borderline hypertension and
high cardiac output demonstrate greater increase
in mean arterial pressure and heart rate than
patients with low cardiac output (Messerli et al.,
1978).
Haemodynamics during emotional stress
Brod (1974) has demonstrated that during
emotional stress the blood pressure increase is
associated with vasoconstriction in the kidneys,
in the skin and probably also in the splanchnic
area, whereas vasodilatation takes place in the
muscles. The net balance between these vascular
areas will determine the total peripheral resistance. Andren, Hansson, Bjorkman & Jonsson
(1980) have shown that industrial noise raises
blood pressure through increase in total peripheral resistance.
Long-term changes in central haemodynamics
From cross-sectional observations it seems likely
that the circulatory pattern in hypertension would
undergo a change with time from the typical ‘high
blood flow-normal resistance pattern’ in young
age towards ‘low blood flow-high resistance
pattern’ in old age.
Unfortunately there are few systematic followup studies in untreated hypertensive subjects.
Table 2 summarizes the most important findings
in six studies (Eich et al., 1966; Eliasch,
Varnauskas & Werka, 1971; Birkenhager,
Schalekamp, Krauss, Kolsters & Zaal, 1972;
Lund-Johansen, 1977; Weiss, Safar, London,
Simon, Levenson & Milliez, 1978; Julius, Quadir
& Gajendragadkar, 1979). Only two include
strictly untreated patients and have been
performed with the same experimental conditions
at both studies.
In our series (Lund-Johansen, 1977, 1979a) 77
patients who had been investigated haemodynamically in 1964-1966 were restudied
clinically, and 33 of the 34 untreated patients also
haemodynamically after about 10 years. The
blood pressure during rest sitting was on average
150/92 mmHg in age group I (17-29 years) in
the first study, and was not significantly increased during the follow-up period. Individual
data showed that the blood pressure increase was
seen mainly in the few patients who had a high
total peripheral resistance in study 1. During
exercise at 150 W there was a significant increase
in the mean arterial pressure in both age groups.
The oxygen consumption, which was originally
increased in age group I, had fallen to values
close to those seen in age group I1 10 years
before. The cardiac output had decreased 15 and
23% during rest in age groups I and I1
respectively ( 15 and 14% during 150 W exercise).
In both age groups there was decrease in
stroke index of about 12%. The heart rate
showed small changes in age group I; in group I1
there was a significant decrease at rest and also
during exercise. The total peripheral resistance
increased by about 24-35% in both groups.
Julius et al. (1979) reported rather similar
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Haemodynamics in essential hypertension
TABLE
2. Haemodynamic follow-up studies in essential hypertension showing changes in cardiac output (CO) and peripheral
resistance (TPR)
1, Decrease; t, increase. SAP, D A P , Systolic and diastolic arterial pressure.
Reference
No. of
patients
Therapy
Study 1
Study 2
Eich el al. (1966)
68
41
In some
Eliash el al. (197 1)
83
20
Birkenhager el a/. (1972)
15
15
Sympathectomy
in some
Inall
Weiss el al. (1978)
37
37
0
Lund-Johansen (1977)
(untreated group)
Julius el al. (1979)
34
35
0
24
24
Innine
Experimental
condition
during study 1
and study 2
Different.
Rest only
Different?
Rest only
Same
Rest only
Same
Rest only
Same
Rest and exercise
Same
Rest only
Follow-up
time
(years)
Haemodynamic changes
in study 2
About 4
COlTPRt
8-17
C0lTPRtB.P. unchanged
1 4
COlTPRt
About 4
COlTPRtSAPtDAP unchanged
9-10
C0lTPRTB.P. unchanged
5-6
C0lTPRtB.P. unchanged
'Study 1: ward patients (study 2: outpatients).
tStudy 2: heart catheterization (study 2: less-invasive methods).
findings in patients with mild borderline hypertension (blood pressure only 141/88 mmHg)
followed for 5-6 years.
In five of our patients aged 40-49 years there
was an increase in the blood pressure at rest as
well as during exercise, together with marked
increase in total peripheral resistance and
decrease in cardiac output.
In conclusion, the follow-up studies have
demonstrated a decrease in cardiac output and
stroke volume and increase in total peripheral
resistance with time in the young patients with
borderline or mild hypertension. The blood
pressure changed little, but with some increase in
the few subjects with high total peripheral
resistance. A 10 year follow-up period is
probably too short to demonstrate rise in blood
pressure in groups of young hypertensive
patients. Widimsky & Jandova (1977) found that
during 20 years 37 out of 70 young borderline
hypertensive patients had become hypertensive.
In older patients with increased peripheral
resistance a rise in blood pressure was found by
Eich et al. (1966), and also in our study
(Lund-Johansen, 1979b).
Whether the changes in flow and resistance are
mainly due to the effects of aging or to the effects
of hypertension is still unknown. Cross-sectional
studies of central haemodynamics in normal
subjects have shown that over several decades
there is a decrease in cardiac output and stroke
index (Amery, Wasir, Bulpitt, Conway, Fagard,
Lijnen & Reybrouck, 1978). On the other hand,
haemodynamic studies in subjects in their
twenties, thirties and forties have usually not
demonstrated significant differences between the
groups (Lund-Johansen, 1967; Hanson, Tabakin
& Levy, 1968).
Pathophysiological mechanisms inducing or
maintaining haemodynamic alterations
Sympathetic nervous system
The increased cardiac output, heart rate and
oxygen consumption during rest in patients with
early essential hypertension could be due to
overactivity of the sympathetic nervous system.
To demonstrate such an overactivity has been
difficult and the role of the sympathetic nervous
system in the pathogenesis of essential hypertension is still unsettled (review in Chalmers,
1978). The excretion of catecholamines in 24 h
urine is not increased in patients with essential
hypertension studied under similar inpatient
conditions as age-matched controls (Bing,
Harlow, Smith & Townshend, 1977).
Elevated plasma catecholamines have been
reported (Engelman, Portnoy & Sjoerdsma,
1970), but the difference between normal subjects
and hypertensive patients could be due to
differences in age (Lake, Ziegler, Coleman &
Kopin, 1977).
Philipp, Distler & Cordes (1978) have studied
plasma catecholamines at rest and during
exercise in hypertensive patients and normotensive subjects (age 20-49 years), and also
reactivity to infused noradrenaline. Increased
resting plasma noradrenaline levels and increased reactivity to noradrenaline was found in
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P. Lund-Johansen
some but not all patients with essential hypertension. No correlation between basal plasma
noradrenaline concentrations and blood pressure
was found.
Julius and coworkers (Julius & Conway, 1968;
Julius & Esler, 1975; Julius, 1976) have studied
the central haemodynamics and the sympathetic
nervous system in a large group of young males
with very mild borderline hypertension and in
control subjects (age 18-35 years). On the day of
the study, the mean blood pressures were only
132/75 f 14/10 mmHg (controls 112/63 & 8/11
mmHg). When P-adrenoreceptor blockade was
achieved (by propranolol) the increased cardiac
output fell, but only after complete autonomic
blockade with propranolol plus atropine was the
difference between hypertensive patients and
normotensive subjects abolished. The heart rate
then became similar (about 100 beats/min),
showing that the intrinsic activity of the sinus
node was normal and that the increased cardiac
output and the increased heart rate were due to an
imbalance in the autonomic nervous system. Also
increased stroke volume became normal after
autonomic blockade. Thus the sympathetic tone
to the heart is too high and the parasympathetic
tone too low. The mechanism of this imbalance is
unknown. The autonomic blockade also revealed
an increased total peripheral resistance, which
remained increased in a number of patients after
a-adrenoreceptor blockade with phentolamine,
possibly reflecting structural changes already at
this stage.
A subset of patients with mild essential
hypertension and increased plasma renin activity
has been demonstrated. This group showed other
signs of increased sympathetic nervous activity:
raised plasma noradrenaline and normal blood
pressure by total autonomic blockade (atropine,
propranolol and phentolamine) (Esler, Julius,
Zweifler, Randall, Harburg, Gardiner & de
Quattro, 1977). On psychometric testing, the
patients exhibited suppressed hostility. It is
possible that these patients have hypertension of
psychosomatic origin. More or less opposite
findings have been made in patients with low
renin hypertension (Esler, Zweifler, Randall,
Julius, Bennett, Rydelek, Cohen & de Quattro,
1976).
Thus, according to Julius and coworkers, most
of the haemodynamic abnormalities during rest in
borderline hypertension can be explained through
neurogenic mechanisms.
Muiesan, Agabiti-Rosei, Alicandri & Fariello
(1979) found a positive correlation between total
peripheral resistance and plasma catecholamines, and after blockade of GI- and P-receptors
with labetalol the reduction in total peripheral
resistance was directly related to previous catecholamine levels.
Miura, Kobayashi, Sakuma, Tomioka, Adachi
& Yoshinaga (1978) have reported a positive
correlation between plasma noradrenaline and
total peripheral resistance or cardiac index in
patients with early essential hypertension.
Variations in sympathetic activity could be
responsible for the variability of the blood
pressure in hypertension. However, Clement,
Mussche, Vanhoutte & Pannier (1980) did not
find a correlation between pressure variability
and plasma catecholamines.
Barorejlexes
These complex regulating systems will be mentioned only briefly. Studies in humans in whom
blood pressure has been increased stepwise by
injections of angiotensin have shown that the
slowing of the heart is less in hypertensive
subjects, even when hypertension is mild,
reflecting less efficient baroreflex control. With
increasing severity of hypertension the baroreflex
is less efficient (Gribbin, Pickering, Sleight &
Peto, 1971; Takeshita, Tanaka, Kuroiwa &
Nakamura, 1975). Thus disturbances in the
baroreflexes could play an important role in the
maintenance of the elevated blood pressure in
essential hypertension. This area is under current
investigation also by new non-pharmacological
methods,
i.e.
the
pressure-neck-chamber
(Mancia, Ludbrook, Ferrari, Gregorini &
Zanchetti, 1978).
Blood volume, its
capacitance vessels
distribution
and
the
In the early phase of essential hypertension, an
increased heart rate is partly responsible for the
increased cardiac output. But since the afterload
on the heart is elevated, an increase in cardiac
contractility must also be an important factor. An
increase in the total blood volume or changes in
the distribution of the blood volume, with a larger
fraction centrally (in the lungs and heart, the
so-called cardiopulmonary blood volume), could
also play a role. This would facilitate the filling of
the heart and contribute to maintenance of
normal cardiac output and stroke volume when
the afterload is high (Julius, 1976; Safar, Weiss,
London, Chau & Milliez, 1977; Dustan &
Tarazi, 1978).
It has been demonstrated that the total blood
volume is not increased in mild hypertension and
in moderate or severe hypertension it is often
Haemodynamics in essential hypertension
abnormally low (Frohlich et al., 1969; Julius,
Pascual, Reilly, London & Arbor, 1971a;
Dustan, Tarazi & Bravo, 1972; Tarazi, 1976).
However, the cardiopulmonary blood volume is
increased, indicating a shift of the blood from the
peripheral veins to the pulmonary capacitance
bed (Safar, Weiss, London, Simon & Chau,
1980), and a positive correlation between the
cardiopulmonary blood volume and cardiac
output has been found by Messerli et al. (1978).
The mechanism behind this shift of the blood is
not understood. A reduced venous distensibility
could play a role, and this is possibly reflected in
the augmented rise in central venous pressure
after rapid infusion of dextran, characteristic in
patients with established essential hypertension
(Ulrych, Hofman & Hejl, 1964; Lund-Johansen,
1967; London, Safar, Simon, Alexandre,
Levensson & Weiss, 1978; Safar, London,
Levenson, Simon & Chau, 1979a; Ulrych, 1979).
The mechanism behind the suspected reduced
distensibility of the total venous system in
hypertension is unknown. Functional and/or
structural alterations could be responsible
(Ulrych, 1979). Simon, Franciosa & Cohn,
(1979) have demonstrated a decreased venous
distensibility in the forearm in patients with
essential hypertension, but they found no
correlation between the reduced distensibility and
the haemodynamic parameters. Thus the pathophysiological role of this finding is uncertain, but
obviously the forearm represents a very small
part of the capacitance system and the results are
inconclusive.
Structural changes in the left ventricle and in the
resistance vessels
It has been shown in the spontaneously
hypertensive rat that hypertrophy and reduced
compliance of the left ventricle occur at a very
early stage in the development of hypertension
(Folkow, 1978; Hallback-Norlander, Noresson
& Thoren, 1979; Yamori, Mori, Nishio,
Ooshima, Horie, Ohtaka, Soeda, Saito, Abe,
Nara, Nakao & Kihara, 1979). Based on ECG
recordings and haemodynamic observations
during rest, it seems that reduced compliance and
left ventricular hypertrophy are rather late
phenomena in human hypertension. However,
when patients with mild hypertension exercise in
the semi-sitting position with legs and thighs
horizontally, facilitating venous return, the stroke
volume does not increase to the same high levels
as in normotensive controls (Lund-Johansen,
1967). This rather surprising finding was first
interpreted as a sign of incipient cardiac in-
349s
sufficiency (Lund-Johansen, 1970b), but today
restructuring of the left ventricle with reduced
compliance would seem more likely (Tarazi,
1979).
Such a restructuring could also partly explain
the reduction in the stroke index in untreated
hypertensive subjects followed for 10 years.
Recent studies of the left ventricular wall by
echocardiography have shown that increased
wall thickness is often found in patients with
relatively mild hypertension (WHO stage I and
with a normal ECG) (Dunn, Chandrazatna, de
Carvalho, Basta & Frohlich, 1977; Frohlich &
Tarazi, 1979; Safar, Lehner, Vincent, Plainfosse
& Simon, 1979b; Savage, Drayer, Henry,
Mathews, Ware, Gardin, Cohen, Epstein &
Laragh, 1979). Safar et al. (1979b) have found
increased thickness of the intraventricular septum
even in patients with borderline hypertension.
With sustained hypertension increased thickness
is found both in the intraventricular septum and
in the posterior wall of the left ventricle.
An increase in the thickness of the arteriolar
wall with a reduction in the arteriolar lumen is
found in the spontaneously hypertensive rat even
at an early stage (Folkow, 1978). In essential
hypertension, the functional disturbances in the
total peripheral resistance during exercise (LundJohansen, 1967) could well be explained by
similar changes.
Lack of complete normalization of total
peripheral resistance after a-receptor blockade by
phentolamine (Julius, 1976) or after combination
of heating and exercise during ischaemia
(Sivertsson & Hansson, 1976) could also be due
to structural changes. So could the increase in
total peripheral resistance with time in untreated
patients. However, obviously this evidence is only
indirect.
Regression
or
arrest o f
alterations by drug treatment
haemodynamic
An important question is whether the functional
and structural changes in the heart and in the
resistance vessels found in hypertension are
reversible. In hypertensive rats treated with
a-methyldopa, regression of left ventricular
hypertrophy has been demonstrated (Ferrario,
Spech, Tarazi & Doi, 1979), but somewhat
surprisingly other antihypertensive agents also
reducing the blood pressure did not induce such
regression (Tarazi, 1979). Thus it is likely that
factors other than blood pressure reduction alone
are of importance (Frohlich & Tarazi, 1979).
In humans systematic studies of cardiovascular morphology are obviously lacking and
only studies of function are available.
350s
P . Lund-Johansen
In subjects with secondary hypertension it has
been shown that after removal of a kidney with a
stenotic artery, or after correction of coarctation
of the aorta, the haemodynamic abnormalities
may be changed in the direction of normal (P.
Lund-Johansen, unpublished results).
In essential hypertension, conventional drug
therapy
induced different haemodynamic
responses. We have studied about 200 male
patients with mild to moderate hypertension
before and after 1 year on one of the commonly
used antihypertensive agents (a few studies have
also been made on drug combinations) (review in
Lund-Johansen, 1978).
It is beyond the scope of this review to discuss
these results in detail, and only a few findings will
be mentioned.
Thiazide diuretics. In 15 patients treated with
hydrochlorothiazide as the sole drug for 1 year,
the haemodynamic restudy showed a 15%
decrease in mean arterial pressure at rest and also
during exercise, associated with a significant drop
in total peripheral resistance. The heart rate was
unchanged and so was the stroke volume and the
cardiac output during exercise. Thus at least a
partial correction of the haemodynamic abnormalities was achieved. Whether the induced
reduction in total peripheral resistance is due to
functional or structural changes is not known
(Lund-Johansen, 1970a).
Sympathetic nervous system inhibitors. (a)
/3-Adrenoreceptor-blocking agents. The ‘betablockers’ induce a dramatic change in the
function of the heart pump. Heart rate is reduced,
often by 25-30% at rest and during exercise.
Blood pressure is usually decreased 15-20%. On
some beta-blockers, an increase in the posttreatment stroke volume has been observed,
partly compensating for the marked decrease in
the heart rate and as a consequence cardiac
output during exercise is reduced less than the
heart rate. However, on all seven beta-blockers
(atenolol, metoprolol, alprenolol, bunitrolol,
pindolol, timolol and penbutolol) studied in our
laboratory there was a significant decrease in
cardiac output, averaging 15-20% (LundJohansen, 1980a).
The calculated total peripheral resistance did
not fall below pre-treatment levels either at rest or
during exercise and sometimes it was increased.
There appeared to be some differences between
the cardioselective and non-cardioselective betablockers in this respect (Lund-Johansen, 1980a).
( b ) a-Adrenoreceptor-blocking agents. More
recently a-receptor blockers have been used with
success in treatment of hypertension. The areceptor blocker prazosin, which mainly acts at
the post-synaptic a-receptor, induces a reduction
in blood pressure through a significant decrease
in total peripheral resistance. The results have
been very consistent, with a reduction in resistance of about 22% at rest as well as during
exercise. In contrast to effects of other drugs
causing vasodilatation, the heart rate did not
increase. The stroke volume is higher than before
treatment and the post-treatment cardiac output
is increased. Thus, the post-synaptic a-receptor
blocker prazosin changes central haemodynamics in the direction of normal (LundJohansen, 1978).
Prolonged therapy f o r 5 years. Since it might
be possible that prolongation of treatment for
several years could induce greater normalization
of central haemodynamics, a group of patients
who had been on atenolol as the sole drug for 5
years were restudied after 5 years. The results did
not demonstrate any decrease in total peripheral
resistance or increase in cardiac output when 1
year and 5 year results were compared (LundJohansen, 1979a).
All these results show that neither ‘betablockers’ nor diuretics induce complete normality
of central haemodynamics in patients with mild
to moderate hypertension on long-term
treatment. The greatest improvement was seen on
prazosin. It is, of course, impossible to tell to
what extent these functional alterations reflect
structural changes and how they will effect
clinical prognosis.
Conclusion
In the 20 years which have passed since Freis’
(1960) review haemodynamics and cardiovascular structure have been followed almost
from birth to death in the spontaneously hypertensive rats, the animal model showing many
similarities with human essential hypertension. It
has been demonstrated that left ventricular
hypertrophy and increased total peripheral resistance occur very early and also that reversal of
those changes are possible at an early stage
(reviews in Folkow, 1978; Yamori ef al., 1979).
In man with essential hypertension the
question about the role of the cardiac output in
the starting phase is still open to discussion.
However, it is well documented that a large
fraction of young patients with borderline or mild
essential hypertension do have an increased
cardiac output and heart rate (compared with
normotensive age-matched controls), but the
cardiac output is not increased when related to
the oxygen consumption of the body. It is also
uncertain whether the majority of these subjects
Haemodynamics in essential hypertension
develop manifest hypertension after several
decades, although reduction in cardiac output
and increase in total peripheral resistance have
been demonstrated in 5-10 year follow-up
studies. Thus, it is difficult to use the increased
cardiac output as an argument in favour of total
body autoregulation and as being the important
factor for inducing an increase in total peripheral
resistance (still the cardinal haemodynamic disorder in established essential hypertension). The
increased cardiac output found in the early phase
of essential hypertension is probably neurogenic,
whereas the increased cardiac output in many
types of experimental hypertension is usually of
short duration and initiated by mechanisms very
dif€erent from those in essential hypertension
(Fletcher, Korner, Angus & Oliver, 1976;
Dustan 8c Tarazi, 1978; Ferrario, Page &
McCubbin, 1970; Ferrario & Page, 1978). The
high cardiac output is an inconsistent finding and,
for instance, in DOCA-hypertensive pigs blood
pressure increase is sometimes caused by increase in cardiac output, sometimes by increase
in total peripheral resistance (Miller, Bohr,
Schork & Terris, 1979). An excellent review of
cardiac output in experimental hypertension has
been given recently by Liard (1979).
An increase in total peripheral resistance is an
early phenomenon in essential hypertension and
is clearly demonstrated in subjects in their
twenties kith mild hypertension, more recently
also in some hypertensive children. Studies of the
regional circulation have also unveiled increased
resistance at an early stage, probably caused by
structural changes.
In man it has been shown that the stroke
volume during exercise is subnormal even at an
early stage, probably reflecting reduced
compliance in the left ventricle. Echocardiographic studies have demonstrated an increase in
the left ventricular wall in early hypertension
(with normal ECG and normal cardiac X-ray).
An increase in the cardiopulmonary blood
volume possibly contributes to maintaining the
resting cardiac output in spite of increase in the
afterload.
The recent demonstration of a reduction in the
coronary reserve in patients with mild hypertension is of great importance.
As a main conclusion, studies of the
haemodynamics in hypertension over the last 20
years have indicated that at an early stage
important disturbances are found in the heart as
well as in the resistance vessels and possibly also
in the capacitance vessels. Their cause is still
unknown. Studies of the effects of various
antihypertensive agents have demonstrated that
351s
these are able to normalize the haemodynamic
abnormalities to different extents, but which of
the different haemodynamic patterns will induce
the best clinical prognosis is still unknown. This
and many other important questions await an
answer in the next 20 years.
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