Download Role of cardiac structural and functional abnormalities in the

Clinical Science (1999) 97, 259–267 (Printed in Great Britain)
Role of cardiac structural and functional
abnormalities in the pathogenesis of
hyperdynamic circulation and renal
sodium retention in cirrhosis
Florence WONG*, Peter LIU†, Lesley LILLY*, Arieh BOMZON‡
and Laurence BLENDIS*§
*Division of Gastroenterology, The Toronto Hospital, University of Toronto, Toronto, Ontario, Canada, †Division of Cardiology,
The Toronto Hospital, University of Toronto, Toronto, Ontario, Canada, ‡Department of Pharmacology, Technion Medical School,
Haifa, Israel, and §Institute of Gastroenterology, Ichilov Hospital, Tel Aviv, Israel
A
B
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The aim of this study was to assess the relationship between subtle cardiovascular abnormalities
and abnormal sodium handling in cirrhosis. A total of 35 biopsy-proven patients with cirrhosis
with or without ascites and 14 age-matched controls underwent two-dimensional echocardiography and radionuclide angiography for assessment of cardiac volumes, structural
changes and systolic and diastolic functions under strict metabolic conditions of a sodium intake
of 22 mmol/day. Cardiac output, systemic vascular resistance and pressure/volume relationship
(an index of cardiac contractility) were calculated. Eight controls and 14 patients with non-ascitic
cirrhosis underwent repeat volume measurements and the pressure/volume relationship was reevaluated after consuming a diet containing 200 mmol of sodium/day for 7 days. Ascitic cirrhotic
patients had significant reductions in (i) cardiac pre-load (end diastolic volume 106p9 ml ;
P 0.05 compared with controls), due to relatively thicker left ventricular wall and septum
(P 0.05) ; (ii) afterload (systemic vascular resistance 992p84 dyn:s:cm−5 ; P 0.05 compared
with controls) due to systemic arterial vasodilatation ; and (iii) reversal of the pressure/volume
relationship, indicating contractility dysfunction. Increased cardiac output (6.12p0.45 litres/
min ; P 0.05 compared with controls) was due to a significantly increased heart rate. Pre-ascitic
cirrhotic patients had contractile dysfunction, which was accentuated when challenged with
a dietary sodium load, associated with renal sodium retention (urinary sodium excretion
162p12 mmol/day, compared with 197p12 mmol/day in controls ; P 0.05). Cardiac output
was maintained, since the pre-load was normal or increased, despite a mild degree of ventricular
thickening, indicating some diastolic dysfunction. We conclude that : (i) contractile dysfunction
is present in cirrhosis and is aggravated by a sodium load ; (ii) an increased pre-load in the preascitic patients compensates for the cardiac dysfunction ; and (iii) in ascitic patients, a reduced
afterload, manifested as systemic arterial vasodilatation, compensates for a reduced pre-load and
contractile dysfunction. Cirrhotic cardiomyopathy may well play a pathogenic role in the
complications of cirrhosis.
Key words : cardiomyopathy, cirrhosis, hyperdynamic circulation, sodium retention.
Abbreviations : E\A ratio, E velocity is early maximal ventricular filling velocity, and A velocity is late diastolic or atrial velocity ;
EDV, end diastolic volume ; EF, ejection fraction ; ESV, end systolic volume.
Correspondence : Dr Florence Wong, Room 220, 9th Floor, Eaton Wing, Toronto Hospital, 200 Elizabeth Street, Toronto M5G
2C4, Ontario, Canada.
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F. Wong and others
INTRODUCTION
In cirrhosis, cardiac function, in the absence of intrinsic
cardiac disease or clinically evident dilated alcoholic
cardiomyopathy, appears to be normal, as indicated by
the conventional ejection fraction (EF) [1]. Cardiac
output seems to increase appropriately when challenged
with an increased pre-load following a transjugular
intrahepatic portosystemic stent shunt [2,3] or after
peritoneovenous shunting [4]. However, occasional cases
of unexpected death due to heart failure have been
reported following liver transplantation [5], transjugular
intrahepatic portosystemic stent shunt [6] and surgical
portocaval shunts [7]. This raises the possibility of cardiac
dysfunction related to cirrhosis. Indeed, in animal studies,
the cardiac pre-load reserve, a parameter of cardiac
contractile function, has been documented to be significantly lowered in cirrhotic rats [8]. In another study,
cirrhotic rats have also been found to have abnormalities
in cardiac β-adrenergic receptors and conduction pathways [9]. These findings suggest that cirrhotic cardiomyopathy does occur. This is supported by reports of
mechanical, electrophysiological and structural cardiac
changes [10–13] and decreased cardiac performance,
especially in response to stress [10,11,14], in patients with
cirrhosis of non-alcoholic aetiologies.
The clinical significance of cirrhotic cardiomyopathy
has never been evaluated. Could cirrhotic cardiomyopathy, as a result of ‘ forward failure ’, play a role in
the pathogenesis of the abnormal sodium and water
homoeostasis and hyperdynamic circulation that
accompany cirrhosis ? Thus the aims of the present study
were to assess (i) cardiac structural and functional
abnormalities in cirrhosis, and (ii) the possible relationship between these abnormalities and abnormal sodium
handling in these patients.
MATERIALS AND METHODS
Ethical approval for the study was granted by the Ethics
Committee of The Toronto Hospital. All control subjects
and patients with cirrhosis gave informed consent for the
study.
Patients
A total of 35 patients (32 males and 3 females ; mean age
52p4 years) with biopsy-proven cirrhosis were recruited
from the Liver Clinics of The Toronto Hospital. Of
these, 16 patients had no history of ascites or diuretic use.
Absence of ascites was confirmed by ultrasound before
enrolment. These patients were therefore termed preascitic cirrhotic patients. The remaining 19 patients had
obvious ascites clinically. Twenty-four patients had
alcoholic cirrhosis, but had been abstinent from alcohol
for at least 6 months before entering the study. Cirrhosis
# 1999 The Biochemical Society and the Medical Research Society
was related to hepatitis C infection in four patients and to
hepatitis B infection in another three. One patient had
both alcoholic cirrhosis and hepatitis C infection, while
the remaining three patients had cirrhosis due to α "
antitrypsin deficiency, haemochromatosis and steatohepatitis respectively. All patients were stable and had
been free of gastrointestinal bleeding within the previous
3 months. Cardiovascular disease was excluded by a
normal examination by a cardiologist, a normal ECG and
chest X-ray. Intrinsic renal disease was excluded by
history, examination of the urinary sediment and confirmation of normal-sized kidneys on ultrasound. Fourteen age-matched healthy individuals with no history of
cardiac or renal disease served as controls. Demographics
of all study subjects and results of baseline liver function
tests, including the Pugh score, in all cirrhotic patients are
given in Table 1.
Study design
Both cardiac structure and function were assessed. Left
ventricular systolic and diastolic chamber dimensions,
interventricular septal thickness and left ventricular
relative wall thickness were measured during twodimensional echocardiograph examination as assessments
of cardiac structure [15]. Cardiac systolic or contractile
function was assessed non-invasively using radionuclide
angiography. The parameters measured were left ventricular volumes, EF and the pressure\volume relationship, a highly reproducible and reliable measure of left
ventricular contractility [16,17]. Diastolic function was
assessed using two-dimensional echocardiograph by
measuring (i) the E\A ratio (E velocity is early maximal
ventricular filling velocity, and A velocity is late diastolic
or atrial velocity), an assessment of the atrial contribution
of the ventricular volume, (ii) deceleration time, and (iii)
isovolumic relaxation time. An increase in the deceleration time of the venous return [13,18] and an increase
in the ventricular relaxation time suggest impedance to
ventricular filling, i.e. increased ventricular stiffness or
diastolic dysfunction.
The study was performed with all study subjects
consuming a metabolic diet containing 22 mmol of
sodium and 1.0 litre of fluid per day. Control subjects and
pre-ascitic patients do not retain sodium while on this
sodium intake, whereas the ascitic patients retain sodium
avidly even on this low-sodium diet. This was to permit
correlation of cardiac abnormalities with the extent of
sodium retention. The control subjects and pre-ascitic
cirrhotic patients were then asked to consume a highsodium diet of 200 mmol\day together with a 1.5
litre\day fluid restriction, since pre-ascitic cirrhotic
patients have been shown to have subtle sodium retention
after remaining on this diet for 7 days [19]. This would
permit the relationship between cardiac function and the
state of sodium retention to be assessed at an earlier stage
of liver cirrhosis.
Cardiac dysfunction in cirrhosis
Table 1
Baseline demographics of control subjects and patients with cirrhosis
n
Age (years)
Sex (male/female)
Prothrombin time (s)
Albumin (g/l)
Bilirubin (µmol/l)
Pugh score
Aetiology of cirrhosis
Alcohol
Hepatitis C virus
Alcohol plus hepatitis C virus
Hepatitis B virus
α1-Antitrypsin deficiency
Haemochromatosis
Steatohepatitis
Controls
Pre-ascitic
cirrhosis
Ascitic
cirrhosis
14
48p3
14/0
10–13
40p2
10p2
–
16
50p6
16/0
12.1p1.0
36p3
19p4
6.4p0.3
19
55p3
16/3
14.1p0.9
31p2
37p6
8.8p1.1
10
3
0
0
1
1
1
14
1
1
3
0
0
0
Protocol
The study began with all study subjects being maintained
on a sodium-restricted diet of 22 mmol\day, with a 1 litre
fluid restriction per day. Day 1 of the study was the first
day of the diet. All diuretics were withheld from the
ascitic patients. All study subjects were monitored by
daily weighing and 24 h urine collections to determine
their urinary sodium excretion. Urinary creatinine concentrations were used as an indicator of completeness of
the urine collections.
On day 7 of the study, both control subjects and
cirrhotic patients, after having fasted and remained supine
for at least 6 h, underwent radionuclide angiography for
measurement of total central blood volume and cardiac
chamber volume in the Nuclear Cardiology Department.
The technique for measurement of central blood volume
has been described previously [1]. Automatic blood
pressure and pulse monitoring (Dinamap, model 845XT ;
Critikon, Tampa, FL, U.S.A.) was performed regularly
during radionuclide angiography. The peak systolic
blood pressure, together with the end systolic volume
(ESV), were used to calculate the peak systolic pressure\
ESV relationship, a surrogate index of cardiac contractility [16,17]. Quality assurance studies in our Nuclear Cardiology Laboratory have established the standard error of the ventricular volume calculation to be less
than 5 ml [20]. On the same afternoon, all subjects
underwent a two-dimensional echocardiological examination for measurement of cardiac chamber dimensions
and parameters of diastolic function.
After completion of the above baseline studies, the
control subjects and pre-ascitic cirrhotic patients were
placed on a diet containing 200 mmol of sodium and 1.5
litres of fluid per day for a further 7 days. Radionuclide
angiography was repeated and the pressure\volume
relationship was re-evaluated to assess cardiac contractile
function with sodium loading.
Laboratory analysis
Urinary sodium concentrations were determined by
flame photometry. Urinary creatinine was measured by
the Jaffe reaction.
Calculations
Total central blood volume, pulmonary vascular
volumes, left end diastolic volume (EDV) and left ESV
were measured directly during radionuclide angiography
based on actual cardiopulmonary and blood sample
radioactivities. The left-sided systolic stroke volume was
calculated as EDVkESV. Cardiac output and systemic
vascular resistance were then calculated from standard
formulae using stroke volume, heart rate and mean
arterial pressure [5].
Statistical analysis
All results are expressed as meanspS.E.M. Regression
analysis was used to determine the relationship between
systolic arterial blood pressure and ESV during ingestion
of the low-sodium diet. Differences between the three
study groups were assessed by analysis of variance, while
the differences between the control subjects and the preascitic patients during the period of the high-sodium diet
were assessed using the unpaired Student’s t test. A P
value of 0.05 was considered statistically significant.
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F. Wong and others
RESULTS
Diet of 22 mmol of sodium/day
At the end of 7 days on the low-sodium diet, mean
urinary sodium excretion was similar between the control
subjects (21p2 mmol\day) and the pre-ascitic cirrhotic
patients (19p2 mmol\day), but significantly reduced in
the patients with ascites (5p1 mmol\day ; P 0.05
compared with controls and pre-ascitic cirrhotics). Mean
urinary creatinine levels during intake of the low-sodium
diet in the male subjects were 20.1p0.4 mmol\day for
the controls, 18.2p1.2 mmol\day for the pre-ascitic
cirrhotic patients and 13.4p1.4 mmol\day for the ascitic
cirrhotic patients (normal range 9–22 mmol\day). The
mean urinary creatinine output for the female patients, all
of whom had ascites, was 8.1p1.0 mmol\day (normal
range 5–15 mmol\day). These levels represented complete daily urine collections.
Assessment of cardiac function
The controls and the pre-ascitic cirrhotics had similar
values for systolic blood pressure, mean arterial blood
pressure and heart rate. In contrast, the ascitic patients
had a significantly lower systolic blood pressure (P
0.05), a normal but slightly lower mean arterial pressure
and a significantly higher heart rate (P 0.05) (Table 2).
Table 2 Baseline haemodynamic and cardiac chamber volume measurements in control
subjects and patients with cirrhosis while on a diet containing 22 mmol of sodium/day
Significance of differences : *P
0.05 compared with controls ; †P
n
Heart rate (beats/min)
Systolic blood pressure (mmHg)
Mean arterial pressure (mmHg)
Diastolic blood pressure (mmHg)
EF ( %)
Stroke volume (ml)
EDV (ml)
ESV (ml)
Central blood volume (ml)
Cardiac output (litres/min)
Systemic vascular resistance (dyn:s:cm−5)
0.05 pre-ascitics compared with ascitics.
Controls
Pre-ascitic
cirrhosis
Ascitic
cirrhosis
14
64p3
121p4
87p3
70p3
58.5p1.6
83p9
142p16
59p4
1612p121
5.13p0.37
1309p112
16
62p3
122p4
90p2
74p2
60.8p2.3
94p12
156p18
62p8
2011p204*
5.83p0.36
1233p121
19
78p3*†
109p3*†
82p5
69p3
65.1p1.3*
72p5†
106p9*†
37p6*†
2144p216*
6.12p0.45*
992p84*†
Table 3 Systolic and diastolic functions and cardiac dimensions in control subjects and
patients with cirrhosis while on a diet containing 22 mmol of sodium/day
Measurements were obtained from a two-dimensional echocardiograph. Significance of differences : *P
compared with controls ; †P 0.05 compared with pre-ascitics.
n
Left atrial size (mm)
Left ventricular size at end
diastole (mm)
Left ventricular size at end
systole (mm)
E/A ratio
Deceleration time (ms)
Isovolumic relaxation time (ms)
Interventricular septal
thickness (mm)
Left ventricular relative wall thickness ( %)
# 1999 The Biochemical Society and the Medical Research Society
0.05, **P
0.01
Controls
Pre-ascitic
cirrhosis
Ascitic
cirrhosis
14
31p2
47p2
16
41p2*
50p2
19
40p1*
41p1*†
31p2
30p1
25p1*
1.3p0.4
172p8
63p11
8.5p1.1
1.2p0.3
218p12*
88p3*
10.5p0.9*
0.9p0.1*
214p11*
86p4*
10.9p0.1*
35p3
42p4
51p6**
Cardiac dysfunction in cirrhosis
being significantly higher than in the pre-ascitic patients
and the controls (Table 2). Keeping in mind that the EF
is a ratio between stroke volume and the EDV, the higher
EF in the ascitic cirrhotic patients was due to a lower
stroke volume divided by a much reduced EDV. This was
also associated with significantly smaller left-ventricular
dimensions in the ascitic patients, both at the end of
diastole and at the end of systole (Table 3). When the
systolic blood pressure was correlated with the leftventricular ESV in the control subjects, a normal physiological relationship of a positive correlation was observed,
i.e. the higher the systolic blood pressure, the greater the
ESV (Figure 1a). In contrast, in both the pre-ascitic and
ascitic patients, the pressure\volume relationship was
reversed, with the larger cardiac volumes being associated
with lower systolic blood pressure (Figures 1b and 1c).
(b) Diastolic function. The isovolumic relaxation time
was significantly prolonged in both the pre-ascitic and
ascitic patients (Table 3). This was associated with a
significantly prolonged deceleration time in both patient
groups (Table 3). The E\A ratio, a measure of the atrial
contribution to the EDV, was significantly decreased in
the ascitic patients only (P 0.05 compared with
controls) (Table 3). The left atrial diameter was significantly increased in both the pre-ascitic and ascitic patients
compared with the controls (Table 3).
Assessment of cardiac structure
The interventricular septal thickness was significantly
increased in the pre-ascitic and ascitic patients compared
with the controls (Table 3). The left-ventricular relative
wall thickness was also significantly greater in the ascitic
patients, but not in the pre-ascitic patients, when compared with the controls (Table 3).
Figure 1 Single-beat systolic pressure/volume relationship
in (a) healthy controls, (b) pre-ascitic cirrhotic patients and
(c) ascitic cirrhotic patients while on a diet containing
22 mmol of sodium/day
The stroke volume and cardiac chamber volumes were
similar between the controls and the pre-ascitic cirrhotic
patients, but with the latter tending towards increased
chamber volumes. The ascitic cirrhotic patients, however,
had lower values of stroke volume, EDV and ESV, with
the EDV and ESV being significantly decreased compared with both controls and pre-ascitic patients (P
0.05) (Table 2). The significantly higher heart rate in the
ascitic patients resulted in a significantly increased cardiac
output when compared with the controls (P 0.05), and
the low normal mean arterial pressure resulted in a
significantly reduced systemic vascular resistance compared with both the controls and the pre-ascitic cirrhotic
patients (P 0.05) (Table 2).
(a) Systolic function. The EF was in the normal range
in all three study groups, with that in the ascitic patients
Diet of 200 mmol of sodium/day
Eight control subjects and 14 pre-ascitic cirrhotic patients
consented to sodium loading for 7 days. This subset of
pre-ascitic cirrhotic patients had significantly higher
EDV and stroke volume values, a trend demonstrated by
the group as a whole (Table 2). At the end of 7 days on the
high-sodium diet, the mean 24 h urinary sodium excretion in the pre-ascitic cirrhotic patients was
162p12 mmol, significantly lower than that in the
control subjects (197p12 mmol ; P 0.05), who, unlike
the cirrhotics, remained in sodium balance. The control
subjects had a weight gain of 2.2p0.4 kg at the end of the
sodium loading period, while that in the pre-ascitic
patients was 3.8p0.3 kg. There was a significant increase
in total central blood volume, EDV and ESV in the
control subjects (Table 4). In contrast, the pre-ascitic
cirrhotic patients only had a significant increase in ESV,
and the changes in EDV and central blood volume were
not statistically significant.
When the pressure\volume relationship was reexamined in the control subjects, they showed a physio# 1999 The Biochemical Society and the Medical Research Society
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F. Wong and others
Table 4 Effects of sodium loading on systemic haemodynamics and cardiac volume measurements in control subjects and
patients with pre-ascitic cirrhosis
The low-sodium diet contained 22 mmol of sodium/day, and the high-sodium diet contained 200 mmol of sodium/day. Significance of differences : *P
with controls ; †P 0.05 compared with low-sodium diet.
Controls (n l 8)
Heart rate (beats/min)
Systolic blood pressure (mmHg)
Mean arterial pressure (mmHg)
EDV (ml)
ESV (ml)
Stroke volume (ml)
EF ( %)
Central blood volume (ml)
0.05 compared
Pre-ascitic cirrhosis (n l 14)
Low sodium
High sodium
Low sodium
High sodium
67p3
119p4
84p4
142p9
55p3
81p5
57.4p2.5
1525p111
67p2
128p3†
87p3
164p8†
75p4†
94p3†
58.9p2.6
1891p107†
63p4
121p4
89p4
162p12*
61p5
97p8*
62.7p3.6
1901p94*
62p3
125p3
89p2
164p11
73p4†
94p6
61.1p2.5
2110p124
On analysing the responses of the individual cirrhotic
patients to sodium loading, eight patients showed a
normal systolic pressure increase associated with the
increase in the ESV, whereas the remaining six patients
had an abnormal response, with a reduction in their
systolic blood pressure in association with an increase in
ESV (Figure 2b). Those pre-ascitic cirrhotic patients who
showed an abnormal response to sodium loading had a
significantly higher mean peak systolic blood pressure
(131p5 mmHg) compared with those who showed a
normal response (114p4 mmHg ; P l 0.02).
DISCUSSION
Figure 2 Individual single-beat systolic pressure/volume
relationships before and after sodium loading with 200 mmol
of sodium/day in (a) healthy controls and (b) pre-ascitic
cirrhotic patients
logical cardiovascular response, i.e. the increase in cardiac
volume after sodium loading was associated with an
increase in the systolic blood pressure (Figure 2a). This
normal response was observed in all control subjects
(Figure 2a). In contrast, the pre-ascitic cirrhotic patients,
as a group, showed a minimal increase in systolic blood
pressure, despite a significant increase in ESV (Table 4).
# 1999 The Biochemical Society and the Medical Research Society
Cirrhotic patients demonstrated both structural and
functional cardiac abnormalities, resulting in systolic and
diastolic dysfunction, which appeared to correlate with
the severity of the liver disease.
Cardiac systolic performance is governed by the preload, the afterload and cardiac contractility. The preload, in turn, is best expressed non-invasively as the
EDV, which is determined by both the volume of the
venous return and the stiffness or the diastolic function of
the heart. The pre-load in the pre-ascitic cirrhotic patients
was normal or even increased, despite evidence of
diastolic abnormalities. In contrast, the patients with
ascitic cirrhosis, who also had diastolic dysfunction,
demonstrated significantly reduced cardiac pre-load or
EDV. Could the difference in pre-load between the preascitic and ascitic cirrhotic patients simply be a function
of the severity of the diastolic dysfunction ? Indeed, the
ascitic patients had a thicker left ventricular wall and a
lower E\A ratio, indicating greater impedance to venous
inflow. An increased venous return, indirectly reflected
by a significantly increased central blood volume in the
pre-ascitic cirrhotic patients, appeared to have been able
to maintain the pre-load. In contrast, the same increase in
Cardiac dysfunction in cirrhosis
central blood volume in the ascitic cirrhotic patients
resulted in a smaller pre-load in the presence of a stiffer
left ventricle. In other words, the pre-ascitic cirrhotic
patients would have had a reduced pre-load if it were not
for their intravascular volume expansion, and the ascitic
cirrhotic patients were relatively ‘ under-volumed ’ for
their degree of diastolic dysfunction. That is, the stiff
heart has prevented adequate filling of the ventricle. This
does not mean that the ascitic cirrhotic patients had a
reduced total blood volume, but rather that the blood
volume was maldistributed elsewhere, such as the
splanchnic vascular bed, rather than to the heart.
The afterload is largely determined by the impedance
to ventricular ejection, which is represented noninvasively as the systemic vascular resistance. Normally,
lower impedance should lead to a greater stroke volume.
Decreased afterload was evident in the ascitic, but not the
pre-ascitic, patients. The presence of excess vasodilators,
especially in decompensated cirrhosis, is thought to be
responsible for the systemic arterial vasodilatation [21],
which has been implicated in the hyperdynamic circulation and sodium retention in these patients [22].
Despite the many detrimental effects of systemic arterial
vasodilatation in cirrhosis, it seems that Nature has
provided the perfect solution to the development of
cirrhotic cardiomyopathy. The reduction in afterload has
probably helped to protect the cirrhotic heart from florid
decompensation, especially in ascitic patients.
Finally, cardiac contractility is best determined by a
pressure\volume relationship, simplified as the peak
systolic pressure\ESV ratio ; the greater the ratio, the
better the intrinsic contractility of the heart [23]. Contractility was abnormal in both the pre-ascitic and ascitic
cirrhotic patients, as estimated by the peak systolic
pressure\volume relationship. This seems paradoxical in
the presence of a ‘ normal ’ EF. One must keep in mind
that EF is an extensively load-dependent parameter. It is
simply a mathematical expression of the ratio between
the stroke volume and the EDV. In cirrhosis, the change
in stroke volume parallels the change in the EDV, thereby
maintaining the EF in the ‘ pseudonormal ’ range. Despite
the presence of contractile dysfunction, the pre-ascitic
cirrhotic patients were able to maintain a normal stroke
volume and mean arterial pressure because of their
normal pre-load and afterload. However, the response of
the pre-ascitic cirrhotic patients was abnormal when
challenged by a physiological stress, such as a highsodium diet ; an increased ESV due to the sodium load
resulted in overall unchanged systolic pressure rather
than an increase. It appears that, in a subset of pre-ascitic
cirrhotic patients who had a higher baseline systolic
pressure, the higher afterload had accentuated the contractile dysfunction in the presence of a physiological
stress. That is, they did not show the decrease in afterload
to protect the heart in conditions of stress. Whether these
pre-ascitic cirrhotic patients will develop further compli-
cations of cirrhotic cardiomyopathy will require further
studies. As a corollary of this observation, it seems
prudent to advise pre-ascitic cirrhotic patients with high
systolic blood pressure to consume a low-sodium diet.
The ascitic cirrhotic patients, unlike the pre-ascitic
patients, were unable to generate an adequate stroke
volume, despite a significantly reduced afterload. The
contractile dysfunction, coupled with a relative decrease
in the pre-load, was most probably responsible for this.
This decrease in stroke volume in the ascitic cirrhotic
patients was partly compensated by increased chronotropy, or the hyperdynamic circulation. A reduced
cardiac pre-load seems paradoxical in the presence of an
increased total central blood volume in the ascitic
cirrhotic patients. Preferential distribution of the central
blood volume to the right side of the circulation [24] and
to the dilated pulmonary circulation [1], coupled with
decreased compliance of the left ventricle, would have
reduced the venous return to the left ventricle.
In contrast with dilating alcoholic cardiomyopathy
[25–28], cirrhotic cardiomyopathy characterized by normal or increased EF and normal or decreased ventricular
volumes is increasingly being reported, in both nonascitic and ascitic patients [10,13,14,29]. Furthermore,
evidence of contractile dysfunction has been demonstrated at rest and after exercise [10,29], and in response
to tilting [14]. The major histological abnormality of the
myocardium in such patients was myocardial hypertrophy [30,31]. One possible explanation for this would be
myocardial adaptation to a chronically elevated blood
volume [1,32]. Alternatively, ventricular hypertrophy or
remodelling could be related to the trophic effects of
activated neurohormonal systems such as noradrenaline
[33], or angiotensin II with or without the synergistic
effects of endothelin-1 [34,35]. Pre-ascitic cirrhotic
patients tend to have normal or suppressed circulating
levels of neurohormones [32,36]. However, these may
not reflect the intra-organ concentrations, as seen with
the renal renin–angiotensin system in pre-ascitic patients
[24] and the disparity between the cardiac coronary sinus
and systemic levels of atrial natriuretic peptide in
cirrhosis [37]. Myocardial contractile dysfunction, in
contrast, may be related to the local effects of liberated
cytokines [38,39], with the generation of nitric oxide and
cGMP as intermediaries [40–43]. In 1992, Lewis and
colleagues [44] first reported a decrease in ESV in relation
to a higher mean arterial pressure in pre-ascitic cirrhotic
patients. Therefore it is of interest that we have found, in
the same subgroup of cirrhotic patients, a reversal of the
normal physiological response to sodium loading.
Perhaps the cardiac abnormalities may be explained by
overactivity of the vasoconstrictor systems in response to
increased nitric oxide production in cirrhosis.
Given that cardiomyopathy exists in cirrhosis, is there
a relationship between myocardial dysfunction, haemodynamic changes, hormonal status and sodium retention
# 1999 The Biochemical Society and the Medical Research Society
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F. Wong and others
in cirrhosis ? Cirrhosis, with the development of portal
hypertension, is associated with haemodynamic changes
and altered neurohormonal activities. The activated
hormonal systems, in turn, appear to play a pathogenic
role in the development of cirrhotic cardiomyopathy.
Increased production of nitric oxide, while involved in
the pathogenesis of myocardial contractile dysfunction,
also produces systemic arterial vasodilatation by virtue of
its vasodilator properties. The reduction in afterload thus
permits the heart to maintain a normal cardiac output
even in the presence of contractile dysfunction and a
reduced pre-load, as in the ascitic cirrhotic patients.
However, an inadequate cardiac response for the extent
of the decrease in the afterload may aggravate the sodium
handling abnormality that is already present in cirrhosis ;
in turn, sodium retention may aggravate myocardial
dysfunction, hastening the development of refractory
ascites. Thus a ‘ vicious cycle ’ may be set up. Therefore
manipulations of any link in this pathophysiological
chain may help to improve haemodynamic status, myocardial function and hence sodium handling in cirrhosis.
In summary, patients with decompensated cirrhosis
and ascites had a decreased pre-load, decreased afterload
and abnormal left-ventricular contractility. They showed
an inability to generate a normal stroke volume, and the
cardiac output was maintained by an increased heart rate.
Pre-ascitic cirrhotic patients, despite their contractile
dysfunction, were able to maintain a normal stroke
volume because of their normal or increased pre-load.
However, those patients with higher mean systolic
pressure were unable to increase cardiac performance
when challenged by a sodium load. In conclusion,
regardless of aetiology, cirrhosis is associated with
significant myocardial dysfunction. The pathophysiological changes leading to the development of cirrhotic
cardiomyopathy and its consequences may well be
involved in the pathogenesis of the hyperdynamic circulation and sodium\water retention which are so
commonly observed in these patients.
ACKNOWLEDGMENT
Special thanks are extended to Yasmin Allidina of the
Nuclear Cardiology Department for image analysis and
data entry. P.L. holds the Heart and Stroke Foundation
Chair of Cardiovascular Research, Toronto, Canada.
This study was partly supported by grants from The
Heart and Stroke Foundation of Ontario, Canada
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Received 14 January 1999/25 March 1999; accepted 7 May 1999
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