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Elevated Circulating Cardiac Troponin I in Patients With Cirrhosis DOMINIQUE PATERON,1,2 PASCALE BEYNE,3 THIERRY LAPERCHE,4 DAMIEN LOGEARD,4 PASCALE LEFILLIATRE,1,2 PHILIPPE SOGNI,1,2 RICHARD MOREAU,1,2 PHILIPPE LANGLET,1,2 ANNIE ELMAN,1,2 JACQUES BERNUAU,2 DOMINIQUE VALLA,1,2 SERGE ERLINGER,2 AND DIDIER LEBREC1,2

It has been shown that certain patients with cirrhosis have asymptomatic cardiac abnormalities that have not yet been explained. Thus, cardiac troponin I, a specific marker of myocardial injury, has been measured in patients with cirrhosis without previous cardiac disease. Thirty-two consecutive patients (age 49 ⴞ 11) with cirrhosis and normal ECG were selected, 22 of which were alcoholic. Hemodynamic investigations were performed. Left ventricular function and mass were evaluated by echocardiography. Serum creatine kinase MB mass, myoglobin, and cardiac troponin I concentrations were measured. Cardiac troponin I concentrations were elevated in 10 patients (32%) (range 0.06-0.25 ␮g/L) whereas creatine kinase MB mass and myoglobin were normal in all patients. Abnormal troponin I values were not related to the severity of cirrhosis, to the degree of portal hypertension, or to other hemodynamic values. In contrast, elevated serum cardiac troponin I concentrations were related to a decreased stroke-volume index (P F .05) and a decreased left ventricular mass (P F .05). These results show a high prevalence of slightly elevated serum cardiac troponin I in patients with cirrhosis, especially in those with alcoholic cirrhosis. Elevated troponin I is associated with subclinical left ventricular myocardial damage. These findings may be linked to a lack of left ventricular adaptation in certain patients with cirrhosis and alcoholic cardiomyopathy. (HEPATOLOGY 1999;29:640-643.) In patients with cirrhosis, hyperkinetic circulation characterized by increased cardiac outpout is common1 and induces an increase in left ventricular work. Certain patients with cirrhosis have subclinical cardiomyopathy related to either hyperdynamic unloaded heart failure with evidence of abnormal ventricular function or alcoholic intoxication.2,3 Because a latent impairment of cardiac function may occur in patients with cirrhosis, cardiovascular status should be carefully evaluated, especially in patients undergoing liver transplanta-

Abbreviations: ECG, electrocardiogram; CK-MB, creatine kinase-MB. From the 1Laboratoire d’He´modynamique Splanchnique et de Biologie Vasculaire INSERM and 2Service d’He´patologie, 3Service de Biochimie, 4Service de Cardiologie, Hoˆpital Beaujon, Clichy, France. Received March 25, 1998; accepted October 16, 1998. A part of this study was presented at the 48th Annual Meeting of the American Association for the Study of Liver Diseases in Chicago November 7-11, 1997 and published in abstract form (HEPATOLOGY 1997;26:208A). Dr. Pateron held a fellowship from the Fondation pour la Recherche Me´dicale. Address reprint requests to: Dr D. Pateron, INSERM, Hoˆpital Beaujon, 92118 Clichy, France. Fax: 33-1-47-30-17-11. Copyright r 1999 by the American Association for the Study of Liver Diseases. 0270-9139/99/2903-0004$3.00/0

tion, surgical portosystemic shunts, or intrahepatic portosystemic shunts.4 Recently, it has been shown that elevated serum troponin concentrations reflect cardiac injury.5 Troponin is a thin-filament–associated protein of the myocyte with three components: troponin I, troponin C, and troponin T. A specific cardiac isoform of troponin I exists in cardiac muscles that inhibits actin and myosin interaction in the absence of calcium.6 Cardiac troponin I can be selectively measured and has been shown to be highly specific for myocardial injury, especially myocardial ischemia.7 This study was designed to evaluate the prevalence of elevated cardiac troponin I in patients with cirrhosis with normal electrocardiogram (ECG) and without known cardiac disease, and to determine the relationship between elevated serum cardiac troponin I and cardiac dysfunction. PATIENTS AND METHODS Patients. Over a period of 11 months, 115 patients with histologically proven cirrhosis who underwent transvenous liver biopsy, 32 were selected because they had no previous cardiac disease, no ECG abnormalities and all patients gave written informed consent to the study. Cirrhosis was caused by alcohol in 22 patients, hepatitis C virus in four patients, hepatitis B virus in five patients, and sclerosing cholangitis in one patient. Nineteen patients were not abstinent (⬎80 g/day). Twelve patients had ascites. Eight patients were classified Child-Pugh C, 17 Child-Pugh B, and 7 Child-Pugh A. The remaining 83 patients were not included because of ECG abnormalities (n ⫽ 35), previous cardiac disease (n ⫽ 29), and no consent (n ⫽ 19). 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 SwanGanz catheter placed in the pulmonary artery. Stroke volume index was calculated according to the following formula: stroke volume index ⫽ 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. With this

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method, left ventricular hypertrophy is defined for a calculated mass 134 g/m2 in men and 110 g/m2 in women. Biochemical Tests. Blood samples were obtained for measurement of cardiac troponin I, creatine kinase-MB mass (CK-MB) and myoglobin. Serial samples were obtained in the right jugular vein during the procedure before right-sided heart catheterization. Assays of cardiac troponin I, CK-MB, and myoglobin were performed by a biochemist who was blinded to the clinical and echocardiographic data. Cardiac troponin I was assayed by an immunoenzymometric assay, which uses two specific monoclonal antibodies on the access analyzer (Sanofi Diagnostics, Pasteur, France). The lower detection limit of this assay is 0.03 µg/L.10 Each sample was measured in duplicate and the mean value was used. The intra-assay and interassay variation coefficient ranged from 6% to 10% and from 9% to 13%, respectively. In a control group of eight hospitalized patients without known cardiac, liver, and renal disease, cardiac troponin I was undetectable. The cardiac troponin I immunoenzymometric assay has no detectable cross-reactivity with human skeletal muscle troponin I.5,11 CK-MB and myoglobin were also measured in samples with commercially available reagents on the access analyzer. The upper reference limits are 4 µg/L for CK-MB and 70 µg/L for myoglobin. Statistical Analysis. Results were expressed as mean ⫾ SD. Unpaired Student’s t test was used for statistical comparisons. Correlations were examined by a linear regression test. Results were considered to be significant at P ⬍ .05. ␹2 test with Yates correction, if necessary, was used for the comparison of percentages. RESULTS

Ten patients (31%) had elevated serum cardiac troponin I (0.06, 0.07, 0.07, 0.08, 0.08, 0.09, 0.10, 0.11, 0.16, and 0.25 µg/L, respectively). Serum CK-MB and myoglobin were normal in all patients (1.9 ⫾ 1.0 µg/L and 38 ⫾ 18 µg/L, respectively). The clinical and biological values of patients with and without elevated serum cardiac troponin I were not significantly different between the two groups (Table 1). The percentage of alcoholic cirrhosis and the percentage of nonabstinent were higher in the group of patients with elevated serum cardiac troponin I concentrations than in the other group but the differences were not significant (90% vs. 59% and 80% vs. 50%, respectively). The hepatic venous pressure gradient was not related to serum cardiac troponin I concentrations (Table 2). Cardiac outpout and arterial and pulmonary pressures were not significantly different between patients with and without elevated serum cardiac troponin I concentrations (Table 2). The stroke volume index was significantly lower in patients with elevated serum cardiac

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TABLE 2. Hemodynamic Values of Patients With and Without Elevated Cardiac Troponin I

Mean arterial pressure (mmHg) Heart rate (beats/min) Right atrial pressure (mmHg) Cardiac index (L/min/m2) Stroke volume index (mL/beats/m2) Mean pulmonary pressure (mmHg) Pulmonary wedged pressure (mmHg) Wedged hepatic venous pressure (mmHg) Free hepatic venous pressure (mmHg) Hepatic venous pressure gradient (mmHg)

Patients With Elevated Troponin I (n ⴝ 10)

Patients With Undetectable Troponin I (n ⴝ 15)

83 ⫾ 10 81 ⫾ 19 7.0 ⫾ 2.9 3.8 ⫾ 0.9 45 ⫾ 14 17 ⫾ 3 11 ⫾ 3 32 ⫾ 6 13 ⫾ 5 19 ⫾ 5

79 ⫾ 10 69 ⫾ 13 8.3 ⫾ 3.1 3.9 ⫾ 0.9 58 ⫾ 14* 18 ⫾ 7 11 ⫾ 3 29 ⫾ 6 11 ⫾ 4 18 ⫾ 5

NOTE. Mean ⫾ SD. *Significantly different P ⬍ .05.

troponin I than in patients without (Table 2). Echocardiographic values were not significantly different between patients with and without elevated serum cardiac troponin I, except the left-ventricular–mass index, which was significantly lower in patients with elevated cardiac troponin I than in patients with undetectable cardiac troponin I (Table 3). Ten patients (31%) had cardiac hypertrophy based on echocardiography, only one of these patients had elevated serum cardiac troponin I concentration. DISCUSSION

Although in the present study, the number of patients was relatively low, the patients were carefully selected. Indeed, only 28% of patients with cirrhosis who underwent transvenous liver biopsy were included, and exclusion criteria were rigorously determined to avoid including patients with potentially increased cardiac troponin I resulting from cardiovascular abnormalities. Thirty-one percent of the patients with cirrhosis in the present study had an increase in serum cardiac troponin I concentrations without any clinical or ECG signs of cardiac ischemia. These results are supported by a similar percentage (30%) in another series of patients with cirrhosis in a preliminary study.12 The prevalence of elevated cardiac troponin I in patients with cirrhosis is higher than that observed in our 8 controls and in 145 healthy subjects in which serum cardiac troponin I concentrations were not detectable.13

TABLE 1. Clinical and Biological Characteristics of Patients

Male/female (number of patients) Age (yrs) Cirrhosis (number of patients) Alcohol Virus B Virus C Sclerosing cholangitis Nonabstinent (number of patients) Ascites (number of patients) Prothrombin (% of normal value) Serum albumin (g/L) Serum bilirubin (µmol/L) NOTE. Mean ⫾ SD.



7/3 51 ⫾ 11

16/6 50 ⫾ 7

9 0 0 1 8 4 49 ⫾ 11 34 ⫾ 7 100 ⫾ 84

13 5 4 0 11 8 53 ⫾ 14 36 ⫾ 5 41 ⫾ 39

TABLE 3. Echographic Values of Patients With and Without Elevated Cardiac Troponin I

Parameter (Normal Values)

Left atrial diameter (mm) Left ventricular diastolic diameter (mm) Left ventricular systolic diameter (mm) Left ventricular posterior wall thickness (mm) Interventricular septum thickness (mm) Ventricular mass index (males ⬍ 137; females ⬍ 110 g/m2) NOTE. Mean ⫾ SD. *Significantly different P ⬍ .05.



37 ⫾ 6 48 ⫾ 6 32 ⫾ 12 9.0 ⫾ 1.7 8 ⫾ 1.5

37 ⫾ 4 52 ⫾ 5 30 ⫾ 4 9.2 ⫾ 1.3 9.4 ⫾ 2.2

99 ⫾ 19

120 ⫾ 21*

642 PATERON ET AL.

The sensitive monoclonal antibody used in this study provides a highly heart-specific measurement of cardiac troponin I,5 with less than 0.1% cross-reactivity with skeletal troponin. Moreover, cardiac troponin I was not increased in patients with renal diseases in whom other biochemical tests such as CK-MB and myoglobin may be increased.14 Elevated cardiac troponin I is known to be a marker of myocyte injury and is therefore a valuable tool for the diagnosis of myocardial infarction.7,13,15,16 Elevated cardiac troponin I concentrations have also been observed in other clinical conditions such as reperfusion therapy monitoring,17 myocarditis, and in patients with cardiac contusions,18,19 thus confirming its cardiospecificity. The level of significance of cardiac troponin I elevations depends on the assay cut-off value. In acute myocardial infarction, for example, cardiac troponin concentrations are much higher than the upper limit of reference, and in one study on acute myocardial infarction, the mean concentration of cardiac troponin I using this assay ranged from 1.2 to 278 µg/L.20 Moreover it has been shown that high concentrations of cardiac troponin I are specific for myocardial infarction.5,7,17 In the present study, most cardiac troponin I elevations were moderate. Similar slight increases in cardiac troponin I have been observed in cardiac diseases such as unstable angina.21 Moderate cardiac troponin I increases could reflect troponin leakage from the cell resulting from a low level of subendocardial ischemia, which is undetectable by other biochemical methods.15 In the present study, serum CK-MB or myoglobin concentrations, two less specific and less sensitive biochemical tests of cardiac injury, were not increased, which may be explained by the lower sensitivity of these tests. In cirrhosis, cardiac contractile function has been shown to be abnormal.2-4,22,23 Certain echocardiographic studies have shown a significant increase in left ventricular end diastolic volume index and elevated left ventricular stroke volume index in these patients.24 In fact, ventricular hyporesponsiveness has been shown to occur in patients with cirrhosis under physiological stress, resulting in tissue oxygen consumption increases that may not be satisfied by cardiac function. For example, one study has shown that cardiac stroke index does not increase but may even decrease in some patients with cirrhosis during exercise.4 Most cardiomyopathies have been observed in alcoholic cirrhosis but nonalcoholic cirrhosis may be also associated with latent cardiomyopathy.4,25 In the present study, elevated cardiac troponin I concentrations were mainly observed in patients with alcoholic cirrhosis because only one patient had another cause of cirrhosis. Thus, asymptomatic alcoholic cardiomyopathy might play a role in the increased troponin I. Elevated cardiac troponin I concentrations in the present study were not correlated with portal pressure, pulmonary circulation modifications, or liver tests, which suggests that elevated serum cardiac troponin I is not related to the severity of liver disease or the degree of portal hypertension. In contrast, certain associations were found between increased cardiac troponin I concentrations and cardiac function. For example, significant decreases in stroke volume index in patients with elevated cardiac troponin I were observed, whereas these patients had a high heart rate to maintain the elevated cardiac index. This may be related to an enhanced sympathetic nervous activity in cirrhosis in which the plasma catecholamine levels are elevated.26

HEPATOLOGY March 1999

Hyperdynamic circulatory changes may induce high cardiac output failure similar to that found in chronic volume overload of the heart2 and result in the left ventricular hypertrophy, which precedes heart failure.27 A study performed in rats showed that heart weight in CCl4 induced cirrhosis was higher than in controls.28 A recent study showed an increase in ventricular wall thickness in patients with cirrhosis, which may be a result of cardiac overload.29 In contrast, in the present study, left ventricular mass was low in patients with elevated serum cardiac troponin I concentrations suggesting another mechanism such as damage to cardiac myocytes by alcohol. Elevated troponin I concentrations are usually observed in ischemic cardiac diseases. Although cirrhosis appears to be associated with few coronary diseases and myocardial infarctions in autopsy studies,30 there is no information on the coronary microcirculation in these patients. Moreover histological investigations in certain patients with cirrhosis have shown myocardial hypertrophy and changes including cardiomyocyte edema, fibrosis, exudation, and nuclear vacuolation.22 These histological injuries could induce and explain mild cardiac troponin I increases.31 Thus, measurement of cardiac troponin I could help identify patients with myocyte injuries who may have function disorders and prevent adaptation under certain clinical conditions that result in acute hemodynamic disturbance such as during liver transplantation or intrahepatic portosystemic shunts. Acknowledgment: The authors thank Drs. J. Heller and C. Chageau for their medical contribution and Mrs C. Bertin and V. Schifano for their excellent technical assistance. We also thank Sanofi Diagnostics Pasteur for the gift of reagents. REFERENCES 1. Valla D, Poynard T, Bercoff E, Bataille C, Goldfarb G, Lebrec D. Le syndrome d’hypercine´sie circulatoire syste´mique chez les malades atteints de cirrhose. Gastroenterol Clin Biol 1984;8:321-324. 2. Ma Z, Lee SS. Cirrhotic cardiomyopathy: getting to the heart of the matter. HEPATOLOGY 1996;24:451-459. 3. Kelbaek H, Eriksen J, Brynjolf I, Raboel A, Lund JO, Munck O, Bonnevie O, et al. Cardiac performance in patients with asymptomatic alcoholic cirrhosis of the liver. Am J Cardiol 1984;54:852-855. 4. Grose RD, Nolan J, Dillon JF, Errington M, Hannan WJ, Bouchier IAD, Hayes PC. Exercise-induced left ventricular dysfunction in alcoholic and non-alcoholic cirrhosis. J Hepatol 1995;22;326-332. 5. Adams JE, Bodor GS, Davila-Roman VG, Delmez JA, Apple FS, Ladenson JH. Cardiac troponin I: a marker with high specificity for cardiac injury. Circulation 1993;88:101-106. 6. Nairn AC, Perry SV. Calmodulin and myosin light-chain kinase of rabbit fast skeletal muscle. Biochem J 1979;1:89-97. 7. Bodor GS, Porter S, Landt Y, Ladenson JH. Development of monoclonal antibodies for an assay of cardiac troponin-I and preliminary results in suspected cases of myocardial infarction. Clin Chem 1992;38:22032214. 8. Lebrec D. Methods to evaluate portal hypertension. Gastroenterol Clin North Am 1992;21:41-59. 9. Devereux R, Reichek N. Echographic determination of left ventricular mass in man. Circulation 1977;55:613-618. 10. Ossendorf M, Eberle B, Ehrenthal W, Rupprecht HJ, Mayer E, Kumpmann K, Hafner G, et al. Analytical and clinical evaluation of the access troponin I immunoassay. Clin Lab 1997;43:627-636. 11. Bodor GS, Porterfield D, Voss EM, Smith S, Apple FS. Cardiac troponin-I is not expressed in fetal and healthy or diseased adult human skeletal muscle tissue. Clin Chem 1995;41:1710-1715. 12. Therapondos G, Plevris JN, Dollinger MM, Gulliver-Sloan FH, Flapan AD, Hayes PC. Subclinical myocardial damage in patients with liver cirrhosis prior to liver transplantation. J Hepatol 1997;26(Suppl 1):294. 13. Larue C, Calzolari C, Bertinchant JP, Leclercq F, Grolleau R, Pau B. Cardiac-specific immunoenzymometric assay of troponin I in the early phase of acute myocardial infarction. Clin Chem 1993;39:972-979.

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