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

PROF. SANJAY MEHROTRA M.D.

Professor Department of Medicine

DR. VIVEK KUMAR M.D.Assistant ProfessorDepartment 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.

SYSTEMIC CIRCULATION

Plasma volume ↑

Total blood volume ↑

Non-central blood volume ↑

Central and arterial blood volume →↓ (↑)

Cardiac output (→) ↑

Arterial blood pressure →↓

Heart rate ↑

Systemic vascular resistance ↓

HEART

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 →

TABLE 1: CIRCULATORY CHANGES IN PATIENTS WITH CIRRHOSIS

PULMONARY CIRCULATIONPulmonary blood flow ↑Pulmonary vascular resistance ↓ (↑)RENAL CIRCULATIONRenal blood flow ↓Renal vascular resistance ↑CEREBRAL CIRCULATIONCerebral blood flow ↓ →CUTANEOUS AND SKELETAL MUSCLE CIRCULATIONCutaneous blood flow →↑Skeletal muscular blood flow →

Stimulus Expected or Normal Response Observed Response SourceExercise ↑ Cardiac output; no change in

pulmonary wedge pressureBlunted inotropic response; Increased Pulmonary wedge pressure

Gould et al, Kelbaek et al,

Gould et al,

Eating ↑Splanchnic blood flow; no change in cardiac output

Earlier onset of splanchnic hyperemia; decreased cardiac output

Lee et al

Upright titling

Tachycardia; stable blood pressure

Blunted tachycardiac response

Fluctuations in blood pressure

Lunzer et al, Bernardi et al, Lunzer et al

Valsalva maneuver

Bardycardia Blunted bradycardiac response

Lunzer et al

Deep respirations

Physiologic sinus arrhythmia No change in heart rate Decaux et al

Cold stimulation

Bradycardia Blunted bradycardiac response

Lunzer et al

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

Drug Expected or Normal Response

Observed Response Source

Angiotensin II ↑ Stroke work index (SWI); no change in pulmonary wedge pressure

Blunted ↑ SWI; ↑ pulmonary wedge pressure

Limas et al

Tyramine ↑ Blood pressure Blunted pressure response

Mashford et al

Isoproterenol hydrochloride

Tachycardia Blunted tachycardiac response

Lenz et al,Ramond et al

Dobutamine ↑ Stroke volume No change in stroke volume

Milkulic et al

Ouabain ↑ Ventricular contractility No change in contractility

Limas et al

Table 3: Abnormal Cardiovascular Responses to Drug Infusions in Patients With Cirrhosis

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 . IMPLICATIONPatients 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

32

8

NUMBER OF PATIENTS ENROLLED IN STUDY

MALEFEMALE

10%15%

75%

SEVERITY OF CIRRHOSIS

CHILD ACHILD BCHILD C

19%

26%55%

ECG CHANGES IN CIRRHOTIC PATIENT

PROLONGED QT INTERVALT WAVE IN-VERSIONWNL

PRO-BNP LEVEL IN CIRRHOTIC PATIENT

CHILD A CHILD B CHILD C0

500

1000

1500

2000

PRO-BNP

PRO-BNP

CHILD A 468.2 40-1237

CHILD B 878 44.53-3010

CHILD C 1820.7 247-5010

TROP –I LEVEL IN CIRRHOTIC PATIENT

CHILD A CHILD B CHILD C0

0.05

0.1

0.15

0.2

0.25TROP I

TROP I

CHILD A 0.03-0.107 0.087

CHILD B 0.09-0.237 0.1464

CHILD C 0.03-0.549 0.2275

ECHOCARDIOGRAPHYhyperdynamic circulation raised lvef % as compared to controlfractional shortening decreasedonly 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

30%

63%

8%

ECHO

NORMALDIASTOLIC DYSFUNCTIONSYSTOLIC DYSFUNCTION

CHILD A CHILD B CHILD C0

0.2

0.4

0.6

0.8

1

1.2

E/A

E/A

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 Hepatology 2008;48:1913–23

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.

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.

Table 1: proposed diagnostic criteria and supporting criteria for cirrhotic cardiomyopathy

Hemodynamic Study. After an overnight fast, patients were placedin the supine position for at least 2 hours and were sedated withmeperidine hydrochloride, 50 mg intramuscularly. Arterial pressurewas monitored with an external sphygmomanometer (Dinamap,Critikon, Tampa, FL) and heart rate was monitored by continuousECG tracing. Mean right atrial, mean pulmonary artery, andpulmonary wedged pressures as well as wedged and free hepaticvenouspressures were measured as previously described.8 Cardiacoutput was measured by the thermodilution method with a Swan-Ganz catheter placed in the pulmonary artery. Stroke volume indexwas calculated according to the following formula: stroke volumeindex 5 cardiac output/heart rate per body mass.Echocardiography. All echocardiographic examinations were performedby using commercial devices (Vingmed 700 CFM, Sonos1500, Hewlett-Packard, Horten, Norway) and interpreted by thesame expert echocardiographer who was unaware of the hemodynamicand biochemical results using commercially available devices.A qualitative approach eliminated segmental abnormalities in leftventricular contraction. Quantitative analysis was performed bymeasuring the dimensions of the left ventricular internal cavity andseptal and posterior wall thickness by the long axis parasternalapproach. Left ventricular mass was calculated by using a previouslyvalidated method9 and corrected by body surface area.