Cardiac alterations in cirrhosis: reversibility after liver transplantation

Article Outline

• Abstract
• 1. Introduction
• 2. Patients and methods
  • 2.1. Patients
  • 2.2. Study protocol
  • 2.3. Echocardiography
  • 2.4. Radionuclide ventriculography
  • 2.5. Statistics
• 3. Results
  • 3.1. Cirrhotic patients and controls
  • 3.2. Pre and post-transplantation
• 4. Discussion
• Acknowledgements
• References
• Copyright

Background/Aims

Liver cirrhosis induces cardiac alterations. We aimed to define these alterations and assess their reversibility after transplantation.

Methods

Cirrhotic patients (n=40) and controls (n=15) underwent echocardiography and stress ventriculography. Fifteen cirrhotics were reevaluated 6–12 months after transplantation.

Results

Cirrhotics had higher left ventricular wall thickness (9.6±1.2 vs. 8.8±1.2mm; P<0.05) and ejection fraction (73±6 vs. 65±4%, P<0.001) than controls. Basal diastolic function was similar. During stress, cirrhotics presented lower increases of heart rate, left ventricular ejection fraction, stroke volume and cardiac index (P<0.05 for all), and diastolic dysfunction with lower ventricular peak filling rate (P=0.001). Exercise capacity was reduced (48±21 vs. 76±24W; P<0.001). Ascitic patients exhibited more diastolic dysfunction at rest and during stress compared to non-ascitic patients. Liver transplantation caused regression of ventricular wall thickness (10.2±1.3 vs. 9.5±1.2mm; P<0.05), improvement of diastolic function, and normalization of systolic response and exercise capacity during stress (significant increases in heart rate, ventricular ejection fraction, stroke volume and cardiac index; P<0.05 for all).

Conclusions

Cardiac alterations in cirrhosis present with mild increases in ventricular wall thickness, diastolic dysfunction that worsens with ascites and physical stress, and abnormal systolic response to stress limiting exercise capacity. Liver transplantation reverses these alterations.

Keywords: Complications of cirrhosis, Portal hypertension, Transplantation, Ascites, Nuclear cardiology, Cardiac alterations

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1. Introduction 

The hyperdynamic circulatory syndrome of patients with portal hypertension is associated with a variety of cardiovascular alterations [1]. In addition, the heart in patients with cirrhosis presents with structural and functional abnormalities that have been termed cirrhotic cardiomyopathy [2], [3]. These include changes in ventricular wall size, systolic and diastolic dysfunction.

The cause of these cardiac alterations in portal hypertension is not clear and probably both continuous mechanical stress and neurohumoral factors play a role in this condition [2], [3], [4]. If these alterations were a consequence of factors present in cirrhotic patients, it would be expected that the cardiac abnormalities would disappear after liver transplantation. However, no single study has extensively examined this issue so far [4]. The aim of this study was to define the cardiac alterations of cirrhotic patients by using echocardiography and radionucleotide stress ventriculography, and exploring their reversibility after liver transplantation.

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2. Patients and methods 

2.1. Patients 

Forty patients were included in the study, 20 patients had alcoholic liver cirrhosis and the others had non-alcoholic liver cirrhosis (14 with chronic hepatitis C, three with chronic hepatitis B and three with other etiologies). The diagnosis of liver cirrhosis was based on clinical, analytical, imaging and endoscopic findings in all patients, and confirmed with liver biopsy in 15 of them. Alcoholic liver cirrhosis was defined by a history of chronic alcohol intake (>80g/day for men and >60g/day for women during more than 10 years) plus exclusion of other etiologies of chronic liver disease. At the time of inclusion, alcoholic patients had been abstinent for at least 6 months. Non-alcoholic cirrhotic patients had consumed <40g/day of alcohol for men and 20g/day for women. Both groups of patients were matched by age, sex distribution and liver function (Table 1). Patients who participated in the study had a hemoglobin level >10g/dl, normal serum creatinine, absence of pulmonary, heart and thyroid disease, and absence of hypertension, diabetes and hemochromatosis. Patients with recent (<2 weeks) episodes of gastrointestinal bleeding and infection were also excluded. Also patients who were taking vasoactive drugs (β-blockers, nitrates, etc.) were not included in the study. Alcoholic cardiomyopathy was reasonably excluded by clinical history (absence of cardiac symptoms), the absence of cardiomegaly and echocardiographic findings.

Table 1. Clinical features of cirrhotic patients and controls

Fifteen age and sex matched control individuals with no history of vascular, cardiac and pulmonary disease were included as controls (Table 1). The majority of these controls were chronic healthy HBsAg carriers with normal liver function and liver biopsy (n=8) and the rest were healthy individuals (n=7). All patients and controls had a normal chest X-ray. All ECG recordings were normal in controls and patients, except for the presence of a prolonged QTc interval (>440ms) in 8 (20%) of the 40 cirrhotic patients studied. The study protocol was approved by the ethics committee of the hospital and written informed consent was obtained from all patients and controls.

2.2. Study protocol 

The study was carried out with patients and controls on a low-salt diet (70mmol/day) for 7 days prior to performing the cardiac studies. Paracentesis were not allowed for 2 weeks before the study. All study subjects underwent an echocardiographic study and a radionuclide stress ventriculography on 2 consecutive days, 4h after their usual breakfast. Data were adjusted for the subjects' body surface area, in which patients with clinical ascites at the time of the study was calculated using the weight they reached after total paracentesis. In a subgroup of 15 cirrhotic patients (six with alcoholic and nine with non-alcoholic cirrhosis), a second study was repeated between 6 and 12 months (mean 9±2 months) after liver transplantation. This subgroup of 15 patients was also matched by age and sex with the control group. These 15 patients had normal liver function, had no evidence of liver cirrhosis, 12 received tacrolimus-based and three cyclosporin-based immunosuppresion, two developed arterial hypertension after transplantation, and no patient had diabetes. None of these patients developed significant cardiac events in the immediate postoperative period. Four of these 15 patients (26%) had a prolonged QTc interval in the ECG before liver transplantation.

2.3. Echocardiography 

A complete transthoracic echocardiography was performed using a commercial cardiac ultrasound machine (General Electrics: ViVid 7). Patients were supine resting for 30min before starting the procedure. Standard echocardiographic recordings were obtained by M-mode, two-dimensional mode and Doppler. The following parameters were calculated: heart rate (HR), mean arterial pressure (MAP=systolic pressure+2× diastolic pressure/3), left ventricular systolic diameter (LVSD), left ventricular diastolic diameter (LVDD), left atrial diameter (LAD), left ventricular ejection fraction (LVEF), stroke volume index (SVI), cardiac index (CI=SVI×HR), and systemic vascular resistance index (SVRI=MAP×80/CI). LVSD, LVDD and LAD were assessed by M-mode. LVEF was measured by biplane two-dimensional mode using the Simpson's method. SVI was calculated as the product of the velocity time integral times the area in the LV outflow tract adjusted by the body surface area. Diastolic function was assessed by measuring the E/A ratio (E velocity=early maximal ventricular filling velocity, A velocity=late diastolic or systolic atrial velocity), which reflects the degree of impairment of diastolic ventricular relaxation, E wave deceleration time (EDT) (time period during which the ventricle inflow decelerates completely), and LAD. An increase in EDT and LAD, and a decreased E/A ratio suggest left ventricular abnormal relaxation. LV wall thickness was assessed by measuring the left ventricular posterior wall thickness (LVPWT) and the interventricular septal thickness (IST). The LV mass was also calculated by using the formula: 0.8×[1.05×(LVDD+IST+LVPWT)³−LVDD³]/m². Criteria for LV hypertrophy were LV mass >130g/m² for men and >110g/m² for women.

All echocardiographic studies were performed by the same observer (L.D.) and interpreted with a second observer (A.E.). The inter-observer coefficients of variability in the Echocardiography Laboratory are 5% for M-mode and 10% for two-dimensional and Doppler values [5].

2.4. Radionuclide ventriculography 

A complete description of the technique of cardiac measurements using radionuclide ventriculography has been already published [6]. In summary, red blood cells were labelled with 900MBq of Tc-99m pertechnetate using an in vivo–in vitro technique. The detection was performed in an ELSCINT SP-4 gammacamera with low energy general purpose collimator and 15% window over technetium photo peak.

After performing the ventriculography at rest in a supine semi-recumbent position, patients initiated a graded multi-level bicycle ergonometry in the same position, starting at zero workload, and increasing by 10W every 1min. Patients were encouraged to exercise until they reached the maximal workload they could maintain steadily without intolerable symptoms, and a second ventriculogram was obtained during 4–5min of exercise. ECG, HR and blood pressure were monitored during the procedure.

The acquisition data were processed with an automatic method calculating the LVEF and the LV end diastolic volume (LVEDV). The intra and inter-observer variability of the technique is around 2% [6]. After then, the program calculated other associated values: LV end systolic volume (LVESV), SVI and CI. Diastolic function was explored by measuring the LV peak filling rate (PFR) and the time to reach the PFR (TPFR). A decrease in PFR and increase in TPFR suggest left ventricular diastolic dysfunction; the physiologic response to stress is an increased PFR and a reduction in TPFR.

2.5. Statistics 

Data are expressed as mean±SE. Frequency data were compared using the χ² test. Comparison of quantitative data between groups was done by using the t test or the paired-t test when necessary (pre and post-transplant comparisons) and ANOVA test when comparing more than two groups. The response to stress for each parameter analyzed during the ventriculography is expressed as the percentage of increment (Δ) with respect to the basal value. The two way repeated measures ANOVA was utilized to analyze differences between basal and under stress results among the different groups studied. A P value of <0.05 was required for statistical significance. The SigmaStat 3.00 statistical package was used.

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3. Results 

3.1. Cirrhotic patients and controls 

As shown in Table 2, the echocardiographic findings of patients with and without ascites and controls demonstrated a basal hyperdynamic state in the cirrhotic group (higher HR, SVI, LVEF, and CI, with lower MAP and SVRI). Measures of LV thickness were not different between patients with and without ascites. However, we observed a mild increase of these parameters in the whole group of 40 cirrhotic patients compared to controls with a higher LVPWT (9.6±1.2 vs. 8.8±1.2mm; P=0.02) and LVPWT+IST (20.2±1.7 vs. 19.1±1.9mm; P=0.04) (data not shown). Criteria for LV hypertrophy were found in 10 of the 40 patients (25%). Ascitic patients exhibited an important diastolic dysfunction at rest compared to non-ascitic patients (higher LAD and EDT).

Table 2. Comparison of echocardiographic findings in cirrhotic patients with and without ascites and controls

	Controls (N=15)	Patients without ascites (N=21)	Patients with ascites (N=19)	P
HR (beats/min)	67±8	73±14*	79±11*	0.01
MAP (mm Hg)	97±8	88±11*	81±9*	<0.001
SVI (mL/m2)	40±4	53±11*	48±8*	<0.001
LVEF (%)	65±4	74±5*	72±7*	<0.001
CI (L/minm2)	2.6±0.5	3.7±0.9*	3.5±0.5*	<0.001
SVRI (dins/cm5m2)	2984±552	2032±656*	1880±304*	<0.001
LVSD (mm)	29±3	28±3	24±5*#	0.006
LVDD (mm)	48±3	48±5	46±5	0.4
LAD (mm)	39±4	39±6	43±6*#	0.04
IST (mm)	10.3±1	10.5±0.9	10.5±0.8	0.5
LVPWT (mm)	8.8±1.2	9.6±1.3	9.6±1	0.05
LVPWT+IST (mm)	19.1±1.9	20.2±1.7	20.1±1.6	0.1
E/A ratio	1.2±0.4	1.1±0.3	1±0.3	0.4
EDT (ms)	222±40	215±40	255±50*#	0.02

*P<0.05 between patients and controls; #P<0.05 between patients; HR, heart rate; MAP, mean arterial pressure; SVI, stroke volume index; LVEF, left ventricular ejection fraction; CI, cardiac index; SVRI, systemic vascular resistance index; LVSD, left ventricular systolic diameter; LVDD, left ventricular diastolic diameter; LAD, left atrial diameter; LVPWT, left ventricular posterior wall thickness; IST, interventricular septal thickness, EDT, E deceleration time.

In response to physical stress, cirrhotic patients responded differently from controls (Table 3). Cirrhotic patients presented an insufficient increase in HR, SVI and CI, compared to controls. As shown, the LVEF had a mean negative increase, and an important diastolic dysfunction, especially in ascitic patients, was evident under stress conditions (PFR). Maximal workload was higher in the control group (Table 3).

Table 3. Comparison of stress ventriculography findings in cirrhotic patients with and without ascites and controls

*P<0.05 between patients and controls; #P<0.05 between patients; HR, heart rate; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; LVEF, left ventricular ejection fraction; SVI, stroke volume index; CI, cardiac index; PFR, peak filling rate; TPFR, time to PFR.

When patients with alcoholic cirrhosis were compared with patients with non-alcoholic cirrhosis no differences were found in any of the parameters evaluated (data not shown).

3.2. Pre and post-transplantation 

When data obtained from patients before and after liver transplantation were compared, striking differences were observed. Echocardiographic findings (Table 4) demonstrated a significant improvement in the basal hemodynamic status in the post-transplant period (lower HR, LVEF and CI and higher MAP and SVRI). At the same time, LV thickness diminished after liver transplantation, especially the LVPWT; also, the LV mass was significantly reduced. LAD also showed a significant decrease, probably reflecting an improvement in diastolic function.

Table 4. Comparison of echocardiographic findings in the same group of cirrhotic patients before and after liver transplantation

	Pre-Transplantation (N=15)	Post-Transplantation (N=15)	P
HR (beats/min)	76±11	65±10	0.003
MAP (mm Hg)	83±9	99±7	<0.001
SVI (ml/m2)	47±7	45±7	0.4
LVEF (%)	73±5	67±5	0.007
CI (L/minm2)	3.5±0.7	2.9±0.5	<0.001
SVRI (dins/cm5m2)	1944±536	2760±448	<0.001
LVSD (mm)	26±6	26±5	0.9
LVDD (mm)	49±6	47±5	0.03
LAD (mm)	44±6	41±5	0.04
IST (mm)	10.4±0.8	10.1±0.9	0.2
LVPWT (mm)	10.2±1.3	9.5±1.2	0.04
LVPWT+IST (mm)	20.7±1.9	19.6±1.8	0.06
LV mass (g/m2)	115±7.8	97±4.9	0.002
E/A ratio	1.1±0.3	1±0.3	0.2
EDT (ms)	241±60	232±20	0.6

HR, heart rate; MAP, mean arterial pressure; SVI, stroke volume index; LVEF, left ventricular ejection fraction; CI, cardiac index; SVRI, systemic vascular resistance index; LVSD, left ventricular systolic diameter; LVDD, left ventricular diastolic diameter, LAD, left atrial diameter; LVPWT, left ventricular posterior wall thickness; IST, interventricular septal thickness; EDT, E deceleration time.

The response to physical stress was also greatly improved during the post-transplant period as compared to the pretransplant situation (Table 5). Significant increases in HR, SVI, CI and LVEF (mainly due to an increase in LVEDV) were observed under stress conditions in the post-transplant evaluation. Also, diastolic function improved significantly after liver transplantation (PFR). Maximal workload tended to increase after transplantation.

Table 5. Comparison of stress ventriculography findings in the same group of cirrhotic patients before and after liver transplantation

HR, heart rate; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; LVEF, left ventricular ejection fraction; SVI, stroke volume index; CI, cardiac index; PFR, peak filling rate; TPFR, time to PFR.

In addition, in the four transplanted patients who presented a prolonged QTc interval in the ECG prior to transplantation, a disappearance of the ECG abnormality was observed after liver transplantation.

When the 15 patients evaluated in the post-transplant period were compared with the control group, no differences were found in any of the parameters evaluated by echocardiogragraphy or stress ventriculography (data not shown). Differences in cardiac parameters between the patients transplanted for alcoholic cirrhosis and the patients transplanted for non-alcoholic cirrhosis were not observed.

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4. Discussion 

This study demonstrates that cirrhotic patients, independently of the etiology of cirrhosis, show a mild degree of increased ventricular wall thickness, a diastolic dysfunction that worsens with the presence of ascites and with physical stress, and insufficient and abnormal systolic response to stress. The study also proves that these alterations are completely reversible after liver transplantation. Our data also confirms prior reports [7], [8], [9] indicating that abstinent alcoholic cirrhotic patients, without overt cardiac failure, present cardiac alterations indistinguishable from those found in non-alcoholic patients. The similar nature of cardiac alterations in both groups of cirrhotic patients is supported by our observation of comparable improvement in cardiac function and structure after liver transplantation.

Systolic dysfunction under stress conditions was the first and most frequently described alteration [2], [7], [10], [11]. Cirrhotics show a baseline hyperdynamic systolic function in the context of a hyperdymanic circulatory state. This hyperdynamic systolic function is reflected by an elevated basal LVEF with lower LVSD. The systolic response to moderate exercise observed during ventriculography is clearly insufficient. Our cirrhotic patients were unable to increase adequately their HR, SVI and CI. In addition, their LVEF showed a mean negative increase compared to controls. As a consequence, cirrhotic patients presented a reduced exercise capacity reflected in a lower maximal workload. It could be argued that the reduced exercise capacity is a consequence of the physical effects of liver cirrhosis (muscle wasting, inactivity, presence of ascites), rather than the result of the cardiac dysfunction. However, recent data suggesting that cirrhotic patients have reduced maximal oxygen consumption with an early anaerobic threshold support the hypothesis of impaired cardiac response to stress as an important contributor to the reduced exercise capacity [8]. In addition, the observation that cirrhotic patients also present an altered systolic response to other physical (such as active tilting) and pharmacological stresses favors the hypothesis of primary cardiac dysfunction [12]. The cause of this systolic dysfunction is unknown; alterations in the β-adrenergic signaling and excess production of nitric oxide have been suggested [2], [4], [13], [14], [15].

One of the interesting findings in cirrhotic cardiomyopathy is a mild left ventricular hypertrophy. In fact, rather than true ventricular hypertrophy, ventricular walls of cirrhotic patients are just thicker than controls. Myocardial hypertrophy was already documented in old necropsic studies, although most patients suffered from alcoholic cirrhosis [16], [17]. Ventricular hypertrophy affects equally patients with or without alcoholic cirrhosis or patients with or without ascites [8], [18]. Myocardial hypertrophy could be due to continued mechanical stress (hemodynamic overload) or neuroendocrine activation (renin–angiotensin system, endothelin-1, sympathetic stimulation, etc.). Data from hearts from cirrhotic rats have been relevant for the understanding of ventricular hypertrophy in cirrhosis [19]. This study demonstrated that cardiac hypertrophy in cirrhotic rats was a consequence of cardiomyocyte enlargement without increase in the myocardial collagen content and fibrotic reaction. In addition, the severity of the hypertrophic response correlated closely with the magnitude of the increased CI. It is also known that neuroendocrine-induced myocardial hypertrophy is usually accompanied by fibrosis [20]. All these data suggest that the hypertrophic response is mainly caused by cardiomyocyte hypertrophy due to mechanical overload. However, it is not clear why cirrhotic hearts should increase in the context of a low afterload (arterial vasodilation), but we think that the continuous demand of maintaining for a long time a high cardiac output with an intense systolic contraction (high LVEF and SVI) might eventually induce some degree of cardiomyocyte enlargement. The rapid regression of left ventricular hypertrophy in our patients after liver transplantation also points out to regression of cardiomyocyte enlargement after amelioration of mechanical stress.

Basal diastolic dysfunction is also a common finding of cirrhotic cardiomyopathy [8], [9], [18]. In our cirrhotic patients altered diastolic function at rest was observed in ascitic patients (elevated LAD and EDT). In addition, cirrhotics as a group were unable to increase the peak filling rate (PFR), an indicator of diastolic function, compared to controls. The influence of ascites, especially tense ascites, in the deterioration of left ventricular diastolic function in cirrhotics was nicely assessed by Pozzi et al. [8], demonstrating a significant improvement of diastolic parameters after total paracentesis in patients with tense ascites. The further deterioration of diastolic function with the presence of ascites might be due in part to physical factors such as higher hemodynamic overload, and increased intrathoracic pressure and elevation of the diaphragm by abdominal fluid accumulation [21]. Another mechanism that could collaborate to diastolic dysfunction and ventricular stiffness is the ventricular hypertrophy detected in our patients. Cardiac hypertrophy is accompanied by deficient distensibility of ventricular walls in many cardiac diseases [22].

The most remarkable finding of the present study is the significant improvement of heart function parameters between 6 and 12 months after liver transplantation. In fact, all cardiac alterations detected before transplantation returned to normality: the hyperdynamic state disappeared, the basal systolic function normalized, the ventricular wall hypertrophy regressed, diastolic function improved at rest and during exercise, and finally, there was a normalization of the systolic response and the exercise capacity during physical stress. As a consequence of this, cardiac function in post-transplant patients could not be distinguished from controls. Prior studies had only demonstrated that the hyperdynamic circulatory state regressed soon after transplantation [23], [24], and that early postoperative myocardial depression recovers after prolonged follow-up [25]. Only one study followed with basal echocardiography a group of cirrhotic patients during 3 months after transplantation [26]. The authors observed a mild increase in ventricular wall thickness and diastolic dysfunction during this period; a control group was not studied. The authors partially attributed these alterations to tacrolimus administration (as opposed to cyclosporine), but the patients presented no cardiac clinical events. The differences with our results are important, but the frame period of both studies is different. Since, we did not performed sequential evaluations of heart parameters, this question remains unanswered. In our opinion, there is probably a fairly rapid amelioration of cardiac parameters soon after the hemodynamic overload regresses and most of the neuroendocrine activated systems return to normality. Finally, one aspect that merits especial attention is the relatively rapid disappearance of the mild ventricular hypertrophy. This event, actually, is a common finding in any cardiac condition in which the factor responsible for the continued ventricular overload is suppressed. Examples of this situation can be found in athlete's hearts undergoing deconditioning, aortic stenosis after valve replacement and hypertensive cardiomyopathy after effective antihypertensive therapy [27], [28], [29].

The mild cardiac alterations described here are not present with any clinical consecuences in stable cirrhotic patients, like the ones evaluated here. From that point of view, no special recommendations should be made and routine screening for this abnormalities is not advised. For some authors, these cardiac abnormalities define a type of high-output heart failure termed cirrhotic cardiomyopathy [2], while others may argue it is just a cardiac adaptation to an hyperdynamic state induced by cirrhosis. In our opinion, this subtle cardiac dysfunction is something else than a cardiac adaptation to cirrhosis, and it might have, as suggested, an important role in the hemodynamic deterioration observed in critical situations like infectious events (spontaneous bacterial peritonitis) and hepatorenal syndrome [30], [31].

In conclusion, our results show that cardiac alterations in cirrhosis are mild and independent of the etiology of cirrhosis, and consist of increased ventricular wall thickness, a diastolic dysfunction that worsens with the presence of ascites and physical stress, and a basal hyperdynamic systolic function with abnormal systolic response to stress conditioning limited exercise capacity. The study also proves that all these alterations are completely reversible between 6 and 12 months after liver transplantation.

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Acknowledgements 

The authors thank all members of medical and nursing staff of the Liver and Liver Transplantation Units, and the Nuclear Medicine Laboratory for their enthusiastic collaboration. We also wish to thank Dr Juli Carballo and Dr Lluís Castells for their help. The study was supported in part by grants FIS 98/1229 and C03/02 (Red Nacional de Investigación en Hepatología y Gastroenterología) from the Instituto de Salud Carlos III, Spain.

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