SOME OBSERVATIONS ON

CARDIAC DYSFUNCTION AND ITS

COURSE IN PATIENTS OF
CIRRHOSIS OF LIVER

RAHUL ARORA
JR-2
 Chief Supervisor
PROF. RAVI MISRA
M.D.
Professor
Department of Medicine

DR. VIVEK KUMAR PROF. SANJAY MEHROTRA

M.D. M.D.
Assistant Professor Professor
Department of Medicine Department of Medicine
 AIM OF STUDY
To study cardiac dysfunction in patients of cirrhosis
of liver and to correlate it with severity of cirrhosis of
liver and to study its course during treatment in
these patients
 OBJECTIVES OF STUDY

 To evaluate cardiac dysfunction in patient of

cirrhosis of liver.

 To correlate cardiac dysfunction with degree of

severity of cirrhosis of liver as by CHILD
PUGH’S classification.

 To study course of cardiac dysfunctions in

cirrhotic patients during treatment of the patient
and follow these patients at regular interval to
study the course of cardiac dysfunction
 INTRODUCTION
 Cirrhotic cardiomyopathy is defined as “a chronic
cardiac dysfunction in patients with cirrhosis
characterized by blunted contractile responsiveness
to stress and / or altered diastolic relaxation with
electrophysiological abnormality in absence of known
cardiac disease”. (Ma and Lee, 1996)
 Liver cirrhosis is associated with abnormal
hemodynamics , characterized by :
 reduced splanchnic and systemic vascular resistance,
 low mean arterial pressure, and
 increased cardiac output (Moller and Henriksen,
2001)

 PATHOGENESIS (Ward et al., 2001)

 Decrease of β-adrenergic function,
 An increase of nitric oxide synthesis,
 Abnormalities in plasma membrane fluidity, and
 Augmented synthesis of endocannabinoids
 Characteristic features of cirrhotic cardiomyopathy
The characteristic features of cirrhotic cardiomyopathy
include:
(a) an attenuated systolic or diastolic response to
stress stimuli,
(b) structural or histological changes in cardiac
chambers,
(c) electrophysiological abnormalities, and
(d) serum markers suggestive of cardiac stress (Al-
Hamoudi, 2010)

Cardiovascular complications-
Two major cardiovascular complications-
1. Cirrhotic cardiomyopathy ;and
2. Hyperdynamic circulation-
have been shown to exist in cirrhotic patients (Lee et
al., 2007). .The exact prevalence of cirrhotic
cardiomyopathy remains unclear.
 STUDY DESIGN
PATIENT PRESENTED IN OPD / EMERGENCY

PATIENT SELECTION

CLINICAL EXAMINATION, USG , OGD, LIVER BIOPSY ,LFT

,S.PROTEIN / ALBUMIN , PT / INR

DIAGNOSIS OF CIRRHOSIS

APPLY EXCLUSION CRITERIA

SUBJECTS OF STUDY

ECG , ECHO ,CARDIAC MARKER

CORRECTION OF COMPLICATION

ECG / ECHO
 MATERIAL AND METHODS
PLAN OF WORK
 A minimum of 40 consecutive patients of hepatic
cirrhosis admitted in medical wards ;and
 Patient of age limit and sex matched controls were
included in study.
 The controls were healthy persons with no history of
alcohol intake and no known cardio vascular or related
problems in whom clinical examination, biochemical
and other investigations were with in normal limits.
 The diagnosis of cirrhosis was made on basis of
clinical evaluation, biochemical and ancillary
investigation like USG, upper GI endoscopy.
 A detailed clinical history with specific reference to
CVS problems, alcohol intake and smoking was taken.
A complete general and systemic examination
particularly for stigmata of chronic liver disease and
cardio vascular status was carried out.
 Inclusion Criteria :
 All patients of cirrhosis of liver admitted in medical
wards of Gandhi Memorial and Associated Hospitals
of C.S.M. Medical University, Lucknow with
evidence of Hepatocellular dysfunction with portal
hypertension as evidenced by coarse echotexture
of liver with increased portal vein diameter >13 mm
on ultrasonography alongwith presence of
esophageal or gastric varices on endoscopy and/or
presence of cirrhosis of liver on biopsy (if possible)
shall be subjects of present study
 Exclusion Criteria :
 Established clinical cases of coronary artery disease with
overt florid evidence of stable angina, unstable angina or
myocardial infarction, congenital heart disease, rheumatic
heart disease, hypertension, thyroid gland disorders, diabetes
mellitus or baseline ECG abnormalities (e.g. left bundle
branch block, left ventricular hypertrophy and strain or pre -
excitation)

 Liver diseases associated with pregnancy.

 Patients with severe anemia and other conditions which could

alter cardiovascular status.

 Patients with malignancy, Hb <8 gm, and abdominal

paracentsis (with in 7 days).

 Any substance abuse, mental illness or conditions, which in

the opinion of investigator would make it difficult for the
potential participant to participate in the intervention.
All patients in the study will be subjected to the
following:
1) Full clinical history taking including manifestations of
liver cell failure, cardiovascular complaints and
manifestations of heart failure.
2) Detailed clinical examination paying special attention
to signs of hyperdynamic circulation.
3) Electrocardiogram studies ( ECG ), for prolonged Q-T
interval or any other evident changes
4) Echocardiographic studies for systolic and diastolic
functions.
5) Laboratory work up including; CBC, coagulation
profile, renal function tests & liver Function tests.
6) Troponin I and PRO-BNP assay.
 TABLE 1: CIRCULATORY CHANGES IN PATIENTS WITH CIRRHOSIS

SYSTEMIC CIRCULATION
Plasma volume ↑ PULMONARY CIRCULATION
Pulmonary blood flow ↑
Total blood volume ↑
Pulmonary vascular resistance ↓ (↑)
Non-central blood volume ↑ RENAL CIRCULATION
Central and arterial blood volume →↓ (↑) Renal blood flow ↓
Renal vascular resistance ↑
Cardiac output (→) ↑
CEREBRAL CIRCULATION
Arterial blood pressure →↓ Cerebral blood flow ↓ →
Heart rate ↑ CUTANEOUS AND SKELETAL
Systemic vascular resistance ↓
MUSCLE CIRCULATION
Cutaneous blood flow →↑
HEART Skeletal muscular blood flow →
Left atrial volume ↑
Left ventricular volume → (↓)
Right atrial volume→↑↓
Right ventricular volume →↑↓
Right atrial pressure →↑
Right ventricular end-diastolic pressure →
Pulmonary artery pressure →↑
Pulmonary capillary wedge pressure →
Left ventricular end-diastolic pressure →
Tables 2 and 3 summarise various studies done to show blunted
cardiovascular response to various physiologic and pharmacologic
stimuli in patients with cirrhosis.

Table 2: Abnormal Cardiovascular Responses to Physiologic Stimuli in

Patients With Cirrhosis

Stimulus Expected or Normal Response Observed Response Source

Exercise ↑ Cardiac output; no change in Blunted inotropic Gould et al, Kelbaek
pulmonary wedge pressure response; Increased et al,
Pulmonary wedge Gould et al,
pressure
Eating ↑Splanchnic blood flow; no Earlier onset of Lee et al
change in cardiac output splanchnic hyperemia;
decreased cardiac output
Upright Tachycardia; stable blood Blunted tachycardiac Lunzer et al,
titling pressure response Bernardi et al,
Fluctuations in blood Lunzer et al
pressure
Valsalva Bardycardia Blunted bradycardiac Lunzer et al
maneuver response
Deep Physiologic sinus arrhythmia No change in heart rate Decaux et al
respirations
Cold Bradycardia Blunted bradycardiac Lunzer et al
stimulation response
Table 3: Abnormal Cardiovascular Responses to Drug Infusions in
Patients With Cirrhosis

Drug Expected or Normal Observed Response Source

Response
Angiotensin II ↑ Stroke work index (SWI); Blunted ↑ SWI; ↑ Limas et al
no change in pulmonary pulmonary wedge
wedge pressure pressure

Tyramine ↑ Blood pressure Blunted pressure Mashford et al

response
Isoproterenol Tachycardia Blunted tachycardiac Lenz et al,Ramond
hydrochloride response et al

Dobutamine ↑ Stroke volume No change in stroke Milkulic et al

volume
Ouabain ↑ Ventricular contractility No change in Limas et al
contractility
 ELECTROCARDIOGRAPHY
Bernardi et al. detected QTc interval prolongation (>440
ms) in a significantly higher proportion of cirrhotic
patients than healthy subjects (46.8% versus 5.4%).
This abnormality was irrespective of the etiology of
cirrhosis (42.9% in alcoholic versus 47.1% in non-
alcoholic cirrhosis). However, the frequency was
dependent on the degree of hepatic failure according to
the Child-Pugh classification .

IMPLICATION
Patients with QTc interval prolongation exhibited high
mortality, more likely due to the advanced hepatic
disease than to a higher incidence of sudden cardiac
death in this special group of patients.
MECHANISM OF ACTION
 Electro physiological changes including prolonged
repolarization and impaired cardiac excitation –
contraction coupling have been demonstrated in
cirrhotic patients. Repolarization prolongation is
manifested by a prolonged QT interval on the
electrocardiogram. Rate corrected prolongation of the
QT (more than 440 msec) is found in 30 – 60 % of
patients with cirrhosis (Bal and Thuluvath, 2003).

 The impaired membrane fluidity of cardiomyocyte, by

compromising the function of the calcium and
potassium pumps, may be related with the
repolarization phase abnormality and QT interval
prolongation.1
 Finally, increased plasma estrogen levels in
cirrhosis have also been implicated in the increased
incidence of QT interval prolongation. Nevertheless, it is
well-known that this ECG abnormality is more frequent
in females and QT prolongation has been considered
to be a hormone dependent finding.2

 QT interval prolongation is also considered by some

authors to be a phenomenon that is reversible during
the post-transplant period.3
 ELEVATED LEVELS OF MARKERS OF CARDIAC
DYSFUNCTION IN CIRRHOSIS

 Serum troponin I levels, a specific marker of myocardial

injury are reported to be elevated in 32% of patients with
cirrhosis .

 Both subclinical ventricular myocardial injury and strain

have been suggested as a cause of this phenomenon.5

 Increases in troponin I levels occur in the absence of

increases in creatine kinase. This suggests that the
troponin I levels are increased in the absence of
myocardial cell plasma membrane injury and represent a
stress rather than injury related response. This also
suggests that any additional cardiac stress in cirrhotics
with elevated troponin I levels could lead to myocardial
failure.6
 PRO - BNP
 Recently it has been shown that BNP is released from
cardiac ventricles in response to ventricular volume
expansion and pressure overload, suggesting that BNP
levels are a more sensitive and specific indicator of
ventricular disorders than other natriuretic
peptides.

 Data from heart failure investigations suggest that the

increased release of BNP is a compensatory
response elicited by ventricular remodeling aimed
at reducing systemic pressure load hypertrophy
through sodium and water diuresis.

 Thus BNP has become a specifics marker of ventricular

damage rather than just an indicator of volume
overload.

 In 1991, La Villa et al reported increased levels of

BNP in decompensated cirrhotic patients. 139
 Iwao T et al in 2000 also reported increased natriuretic
peptides in compensated cirrhotic patients.140

 In 2001 Wong designed a study to clarify the role of

natriuretic peptides as markers of cardiac dysfunction in
cirrhosis.

 They evaluated the levels of N-terminal pro-atrial

natriuretic peptide and brain natriuretic peptide and
their relationship with cardiac structure and function in
patients with cirrhosis.

 All high levels of brain natriuretic peptide were

correlated significantly with septal thickness (P < 0.01),
left ventricular diameter at the end of diastole (P = 0.02)
and deceleration time (P < 0.01).
 They concluded that elevated levels of brain
natriuretic peptide are related to interventricular septal
thickness and the impairment of diastolic function in
asymptomatic patients with cirrhosis and that levels of
brain natriuretic peptide may prove to be useful as a
marker for screening patients with cirrhosis for the
presence of cirrhotic cardiomyopathy, and thereby
identifying such patients for further investigations.

 In 2005 Yildiz R and colleagues conducted similar

study and inferred that increased levels of BNP are
more likely related to the severity of disease in
non-alcoholic cirrhotic patients. Also, advanced
cirrhosis is associated with more advanced
cardiac dysfunction and BNP has prognostic value
in progression of cirrhosis.
 CONCLUSION :elevated circulating levels of
proBNP and BNP in patients with cirrhosis
most likely reflects increased cardiac
ventricular generation of these peptides and
thus indicates the presence of cardiac
dysfunction, rather than being caused by the
hyperdynamic circulatory changes found in
these patients.
 DIASTOLIC DYSFUNCTION

• Diastolic dysfunction refers to the disturbance in

ventricular relaxation, where the time period during which
the myocardium loses its ability to generate force and
shorten and return to an unstressed length and force is
prolonged, slowed or incomplete (Zile and Brutsaert,
2002).

• Significance of diastolic dysfunction in cirrhotic

cardiomyopathy has been brought to the forefront with
several reports of unexpected heart failure following
liver transplantation and transjugular intrahepatic
portosystemic stent-shunt (TIPS) (Huonker et al., 1999;
Liu and Lee, 2005; Al Hamoudi and Lee, 2006).
 Researchers have also found that even though
most patients with cirrhosis may not all show a
clear depression in systolic functioning, most of
these patients do show some depression in
diastolic functioning as marked by a stiff,
noncompliant ventricle (Finucci et al., 1996). This
is consistent with the fact that in many myocardial
diseases that result in heart failure, there is
evidence of diastolic dysfunction before the
occurrence of overt systolic contractile failure
(Lee, 2003). However, the mechanisms behind the
development of diastolic dysfunction in cirrhotic
cardiomyopathy remain to be elucidated.
 DIASTOLIC DYSFUNCTION AND CIRRHOTIC
CARDIOMYOPATHY

•Abnormalities of ventricular filling pattern and

consequent variation in the ratio of early (E) and late (A)
phase of ventricular filling, as recorded by Doppler
echocardiography, are used as markers of diastolic
dysfunction.
•Studies evaluating ventricular diastolic filling in patients with
cirrhosis have provided supportive evidence of the presence
of diastolic dysfunction, which was marked by a reduction in
E/A ratio (Pozzi et al., 1997; Valeriano et al., 2000).
• Patients with cirrhosis have hemodynamic changes that are
characterized by an expanded blood volume that increases
the cardiac preload, decreases peripheral resistance and
reduces afterload, thus contributing to the persistent increase
in cardiac output, with overloading and impaired contractility
as the outcome (Moller and Henriksen, 2002
RESULTS AND
OBSERVATIONS
NUMBER OF PATIENTS ENROLLED IN
STUDY

MALE
FEMALE
32
SEVERITY OF CIRRHOSIS

10%

15%
CHILD A
CHILD B
CHILD C
75%
ECG CHANGES IN CIRRHOTIC PATIENT

19%
PROLONGED QT
INTERVAL
T WAVE
55% INVERSION
26% WNL
PRO-BNP LEVEL IN CIRRHOTIC
PATIENT
CHILD A 468.2 40-1237
CHILD B 878 44.53-3010
CHILD C 1820.7 247-5010

PRO-BNP
2000

1500

1000
PRO-BNP
500

0
CHILD A CHILD B CHILD C
TROP –I LEVEL IN CIRRHOTIC
PATIENT
CHILD A 0.03-0.107 0.087
CHILD B 0.09-0.237 0.1464
CHILD C 0.03-0.549 0.2275

TROP I
0.25

0.2

0.15
TROP I
0.1

0.05

0
CHILD A CHILD B CHILD C
ECHOCARDIOGRAPHY
 hyperdynamic circulation
 raised lvef % as compared to control
 fractional shortening decreased
 only few patients have decrease ef
which improved in some patients on
follow up
 grade 1 diastolic dysfunction, with
prolonged deceleration time with e/a
ratio <1
 left atrial dimension increased
 ECHO

8%

30% NORMAL

DIASTOLIC
DYSFUNCTION
SYSTOLIC
DYSFUNCTION
62%
 E/A
1.2

0.8

0.6
E/A

0.4

0.2

0
CHILD A CHILD B CHILD C
 References
1. Liu H, Lee SS: Cardiopulmonary dysfunction in
cirrhosis. J Hepatol Gastroenterol 1999; 14: 600-
608.
2. Lehmann MH: QT prolongation in end-stage liver
disease: a result of altered sex hormone
metabolism? Hepatology 1997; 26: 244
3. Mochamad R, Forsey PR, Davies MK, Neuberger
JM: Effect of liver transplantation on QT interval
prolongation and autonomic dysfunction in end-
stage liver disease. Hepatology 1996; 23: 1128-
1134
4. Pateron D, Beyne P, Laperche T et al. Elevated
circulating cardiac troponin I in patients with
cirrhosis. Hepatology 1999; 29: 640–3
5. Nunes JP. Cardiac troponin I in systemic diseases. A
possible role for myocardial strain. Rev Port Cardiol.
2001; 20: 785-8
6.Karasu Z, Mindikodlu AL, Van Theil D H. Cardiovascular
problems in cirrhotic patients. The Turkish Journal of
Gastroenterology 2004; 15: 126-132
7.Wong, Gut 2001; 49:268-275 doi:10.11 36/gut.49.2.268.
8. Moller S and Henriksen JH. Cirrhotic cardiomyopathy: A
pathophysiological review of circulatory dysfunction in
liver disease. Heart 2002;87:9-15.
9. Bal JS and Thuluvath PJ. Prolongation of QTc interval:
relationship with etiology and severity of liver disease,
mortality and liver transplantation, Liver Int. 2003;
23:243-8.
10. Waleed K. Al-hamoudi, Cardiovasular change in
cirrhosis : Pathogenesis and clinical
implications, The Saudi Journal of Gastroenterology,
Volume 16, Number 3, July 2010
11.Moller S and Henriksen JH. Cardiovascular
dysfunction in cirrhosis. Pathophysiologic evidence of a
cirrhotic cardiomyopathy. Scand J Gastroenterol 2001;
36: 786–794.
12. Ma Z. and Lee SS. Cirrhotic cardiomyopathy:
getting to the heart of the matter. HEPATOLOGY 1996;
24: 451–459.
13. Ward CA, Liu H and Lee SS. Altered cellular
calcium regulatory systems in a rat model of cirrhotic
cardiomyopathy. Gastroenterology 2001; 121: 1209–
1218.
14.Ceolotto G, Papparella I, Sticca A, et al. An
abnormal gene expression of the β-adrenergic system
contributes to the
pathogenesis of cardiomyopathy in cirrhotic rats
MOLECULAR MECHANISM
 Pathogenic Mechanisms of Cirrhotic Cardiomyopathy
1.1 β-Adrenergic Receptor Signalling
In view of the relationship between the β-adrenergic receptor and cardiac
contractility, this system has been subjected to detailed study in cirrhotic
cardiomyopathy.
The G-protein subunits, Gs and Gi2α, are significantly decreased, in both content
and function, without any change to the Gβ subunit. cAMP generation was also
shown to be attenuated in BDL. This decrease of cAMP is due to impairment of
adenylyl cyclase activity, which is partly secondary to decreased G-protein
stimulation of the catalytic subunit of the enzyme, and also due in part to an
inhibitory effect of jaundice (Ma et al., 1999).
.1.2 Membrane Fluidity
Membrane fluidity represents the freedom with which lipid and protein molecules
are able to move in the plasma membrane lipid bilayer. Several studies have
demonstrated that in cirrhosis, the plasma membrane fluidity in cells from the heart
(Ma et al., 1994), erythrocytes (Kakimoto et al., 1995), kidneys (Imai et al., 1992)
and liver (Reichen et al., 1992) is abnormal, and in some cases have reduced
fluidity due to an increase in membrane cholesterol content. & play an integral role
in diminished β-adrenergic receptor functioning through interference with G-protein
coupling (Ma et al., 1997) and cAMP production (Ma et al., 1994). This suggests
that alterations in plasma membrane fluidity play an important role in the β-
adrenergic receptor dysfunction and thus in the pathogenesis of cardiac
contractility in cirrhosis.
1.3 Endocannabinoids
By definition, endogenous cannabinoids or endocannabinoids are endogenous
ligands capable of binding to and functionally activating cannabinoid receptors- CB1
and CB2.
Since their discovery, anandamide and 2-arachidonoylglycerol have been implicated
in a variety of physiological and pathological processes.
arterial hypotension observed in cirrhotic rat models (Batkai et al., 2001; Ros et al.,
2002). M as a selective splanchnic vasodilator in cirrhosis acting predominately
through two receptors- one of which is CB1 (Domenicali et al., 2005).
Gaskari et al demonstrated a negative inotropic effect of anandamide in left
ventricular papillary muscles of cirrhotic rats).
1.4 Calcium Kinetics
Stimulation of the β-adrenergic pathway or excitation-contraction coupling leads to
the activation of numerous calcium related systems that are crucial for cardiac
contraction. Studies performed on the cellular calcium dynamic in our BDL
cardiomyocytes showed a significant decrease in receptor density and
electrophysiological function of voltage-gated L-type Ca2+ channel (ICa,L)
compared to control myoctes (Ward et al., 2001).
ICa,L protein expression is quantitatively decreased in BDL cardiomyocytes.
1.5 Nitric Oxide
Balligand et al found that the inhibition of NOS synthesis by L-NMMA significantly
increased the contractile response of rat ventricular myocytes to the β-agonist
isoproterenol without affecting baseline contractility (Balligand et al., 1993). In the BDL
cirrhotic model, baseline isoproterenol-stimulated papillary muscle contractile force
was shown to be lower than in the control groups. However, when the papillary
muscles were preincubated with the NOS inhibitor L-NAME, contractile force increased
significantly in the cirrhotic rats, whereas control muscles were unaffected (Liu et al.,
2000). This group also showed that cirrhotic cardiomyocytes have an increased iNOS
mRNA and protein expression, whereas eNOS shows no significant difference in
expression between the BDL and the sham control hearts.
 Table 1: proposed diagnostic criteria and supporting criteria for cirrhotic cardiomyopathy
Definition of the working group recommended in cirrhotic cardiomyopathy
Cardiac dysfunction in cirrhotic patients, in the absence of other known cardiac disease, blunt the
contractile response to stress, and / or
an entity characterized by impaired diastolic relaxation with electrophysiological abnormalities.
Diagnostic criteria
Systolic dysfunction
- Exercise, inadequate cardiac output to increase in volume changes, or pharmacologic stimuli
- Resting ejection fraction <55% of
Diastolic dysfunction
- E / A ratio <1.0 (age-adjusted)
- Prolonged deceleration time (> 200 ms)
- Prolonged isovolumetric relaxation time (> 80 ms)
Supportive criteria
- Electrophysiological abnormalities
- An abnormal response to chronotropic
- Electromechanical uncoupling / dyssynchrony
- Prolonged Q-Tc interval
- Enlarged left atrium
- Increased myocardial mass
- Increased BNP and pro-BNP
- Elevated troponin I
BNP, brain natriuretic peptide, the E / A ratio: ratio of early to late (atrial) phases of ventricular filling.
Hemodynamic Study. After an overnight fast, patients were placed
in the supine position for at least 2 hours and were sedated with
meperidine hydrochloride, 50 mg intramuscularly. Arterial pressure
was monitored with an external sphygmomanometer (Dinamap,
Critikon, Tampa, FL) and heart rate was monitored by continuous
ECG tracing. Mean right atrial, mean pulmonary artery, and
pulmonary wedged pressures as well as wedged and free hepaticvenous
pressures were measured as previously described.8 Cardiac
output was measured by the thermodilution method with a Swan-
Ganz catheter placed in the pulmonary artery. Stroke volume index
was calculated according to the following formula: stroke volume
index 5 cardiac output/heart rate per body mass.
Echocardiography. All echocardiographic examinations were performed
by using commercial devices (Vingmed 700 CFM, Sonos
1500, Hewlett-Packard, Horten, Norway) and interpreted by the
same expert echocardiographer who was unaware of the hemodynamic
and biochemical results using commercially available devices.
A qualitative approach eliminated segmental abnormalities in left
ventricular contraction. Quantitative analysis was performed by
measuring the dimensions of the left ventricular internal cavity and
septal and posterior wall thickness by the long axis parasternal
approach. Left ventricular mass was calculated by using a previously
validated method9 and corrected by body surface area.