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Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease
European Journal of Internal Medicine 24 (2013) 172–176
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease☆ Manuela Merli a,⁎, Angela Calicchia b, Alessandra Ruffa a, Pierpaolo Pellicori c, Oliviero Riggio a, Michela Giusto a, Carlo Gaudio b, Concetta Torromeo b a b c
Gastroenterologia, Dipartimento Medicina Clinica, Sapienza Università di Roma, Italy Dipartimento di Scienze Cardiovascolari, Nefrologiche e Geriatriche, Sapienza Università di Roma, Italy Department of Academic Cardiology, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Kingstone upon Hull, UK
a r t i c l e
i n f o
Article history: Received 1 May 2012 Received in revised form 12 July 2012 Accepted 14 August 2012 Available online 5 September 2012 Keywords: Liver cirrhosis Diastolic dysfunction Heart Cirrhotic cardiomiopathy Cardiac load
a b s t r a c t Background: Cirrhotic cardiomiopathy is described as the presence of cardiac dysfunction in cirrhotic patients. The aim of the study was to investigate factors associated with cardiac dysfunction in cirrhotic patients. Patients and methods: Seventy-four cirrhotic patients and twenty-six controls performed a conventional echocardiography and Tissue Doppler Imaging (TDI) for systolic and diastolic function. Results were analyzed by using the Guidelines of American Society of Echocardiography. Results: In patients with cirrhosis, left ventricular end-diastolic diameter was increased (p b 0.001) , peak systolic velocities were decreased (11.3 ± 2.7 vs 13.9 ± 1.4 cm/s; p b 0.001) and left atrial volumes were increased (32.7 ± 8.3 vs 24 ± 8.5 ml, p b 0.001) as well as cardiac mass (90.6 ± 23 vs 70.5 ± 22 g/m 2, p b 0.001). Forty-seven cirrhotic patients (64%) showed diastolic dysfunction at rest: grade I in 37 and grade II in 10 patients. Systolic and/or diastolic dysfunction were not influenced by a more severe liver impairment. Diastolic dysfunction was more prevalent in patients with ascites vs those without (77% vs 56%; p = 0.04). Conclusion: A mild diastolic dysfunction at rest is frequent in cirrhotic patients but cardiac load conditions are confounding factors in this diagnosis. We did not identify an association between severity of liver disease and cardiac dysfunction. © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Historically, liver cirrhosis has not been associated with any cardiac abnormalities, despite the fact that a hyperdynamic state leading to increased cardiac output and decreased systemic vascular resistance has been described in patients with cirrhosis more than 50 years ago [1]. In the last 20 years a number of evidences suggested that cirrhosis regardless of its etiology, is associated with the development of hemodynamic changes and major cardiovascular anomalies. Overall these alterations are known as cirrhotic cardiomyopathy [2–4]. According to the 2005 World Congress of Gastroenterology, cirrhotic cardiomyopathy is defined as “a cardiac dysfunction in patients
Abbreviations: decTime, deceleration time; EF, ejection fraction; IVRT, isovolumetric ventricular relaxation time; LAESV, left atrial end-systolic volume; LVEDD, left ventricular end diastolic diameter; LVEDV, left ventricular end diastolic volume; LVESD, left ventricular end systolic diameter; MAP, mean arterial pressure; PWDT, posterior wall diastolic thickness; SWDT, septal wall diastolic thickness; SWST, septal wall systolic thickness; TDI, tissue Doppler imaging. ☆ Disclosure: The authors have nothing to disclose No conflict of interest exist. ⁎ Corresponding author at: Gastroenterologia, Dipartimento di Medicina Clinica, “Sapienza” Università di Roma, Viale dell'Università 37, 00185 Roma, Italy. Tel.: +39 0649972001; fax: +39 064453319, +39 064440806. E-mail address: [email protected] (M. Merli).
with cirrhosis characterised by impaired contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiological abnormalities in the absence of other known cardiac disease” [5]. Systolic dysfunction, in cirrhotic patients, is characterized by a blunted increase in cardiac output and decreased contractility with exercise, pharmacological stress, and volume challenge [6]. Moreover cirrhotic patients have severe chronotropic incompetence, defined as significantly reduced cardiac response to exercise due to autonomic dysfunction with blunted sensitivity to sympathetic activation [7]. Diastolic dysfunction in cirrhotic patients has been associated with increased left ventricular wall thickness, subendocardial oedema, fibrosis and altered collagen structure, ultimately leading to altered relaxation [8]. Electrophysiological abnormalities have been related to plasma membrane and fluidity changes, adrenergic and post receptor signalling pathway defects and/or ion channel dysfunction [2]. The main electrophysiological changes in cirrhosis are prolongation at electrocardiography of the QTc interval and impaired electromechanical coupling likely as a result of potassium and calcium ion channel defects [9,10]. The criteria adopted for the diagnosis of diastolic dysfunction in cirrhotic patients need, however, to be interpreted with caution. Previous studies have based the diagnosis of diastolic dysfunction mainly on 2D-Doppler echocardiography parameters [11–13]. It is however well known that the E/A ratio is strongly influenced by loading
0953-6205/$ – see front matter © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2012.08.007
M. Merli et al. / European Journal of Internal Medicine 24 (2013) 172–176
conditions, and decompensated cirrhotic patients are frequently suffering a condition of fluid retention. Moreover it has not been completely defined how many parameters need to be altered for the diagnosis of diastolic dysfunction, therefore different criteria have been utilized in different studies. Furthermore, as diastolic dysfunction is physiological with advancing age, some authors have applied a correction for age [14], which was however not applied in other studies. The use of Tissue Doppler Imaging (TDI) can overcome some of this criticism, mainly because this echocardiography method is less influenced by the changes in cardiac load conditions [15]. The American Society of Echocardiography has included TDI parameters in the definition of diastolic dysfunction and these criteria have recently been updated [16]. Our study aimed at evaluating, in a selected group of cirrhotic patients, the relationship between cirrhotic cardiomiopathy evaluated by TDI and the severity of liver impairment. 2. Patients and methods Cirrhotic patients, either admitted in hospital or followed as outpatients, were considered for the study. Diagnosis of cirrhosis was established through histology and/or a combination of clinical, biochemical and instrumental findings. Age b 18 and >75 years, active alcohol abuse, surgical or radiological shunts, hepatocellular carcinoma (beyond Milan criteria) or recurrence of cirrhosis after liver transplantation were causes of exclusion. Patients with a history of past or present cardiac disease, severe arterial hypertension, chronic pulmonary disease or an abnormal 12 leads electrocardiogram were also excluded. Hospitalized patients with active complications were studied only after successful treatment. A total of 74 patients were then enrolled in this study and 26 sex and age-matched healthy subjects were studied with a similar protocol and constituted the control group. All patients were informed about the opportunity of being included in a study aimed at a more complete cardiovascular assessment and those enrolled gave a written consent. The study was approved by the Local Ethical Committee. 2.1. Clinical evalutation On the day of the study, heart rate and blood pressure were measured. Blood pressure was measured by sphygmomanometer and the mean arterial pressure (MAP) was calculated as (systolic pressure+diastolic pressure×2)/3. Patients provided a detailed clinical history and had a clinical examination and blood tests (including haematology and biochemistry profile). Liver function was quantified by Child-Pugh and MELD scores [17,18]. Therapies assumed in the last weeks were recorded. Patients were followed up until death or liver transplantation for 12 months.
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Simpson's modified biplane method. An LVEF above 50% was considered normal. Left atrial end-systolic volume was calculated with monoplane method in apical 4-chambers views using the following formula: volume = 8 (A1) 2/3π∙(L). Pulsed Doppler examination of the LV inflow was performed with the sample volume placed between the mitral leaflet tips. The following parameters were recorded and measured: peak early (E wave) and atrial (A wave) flow velocities, their ratio E⁄A, and the E-wave deceleration time. TDI was obtained from the four chamber apical view and tissue velocity were calculated. The myocardial peak systolic velocity (S′) was measured in lateral mitral annulus to define systolic function. Tissue velocities were also measured in the lateral mitral annulus during the diastole to obtain peak myocardial velocities during early (E′) and atrial filling (A′) phases. Isovolumetric Ventricular Relaxation Time (IVRT) was measured by TDI. To evaluate ventricular filling pressure also E/E’ ratio was calculated. The intra observer variation for echocardiographic measurements was b 10%. Systolic and diastolic functions were defined according to American Society of Echocardiography 2009 [16]. Diastolic dysfunction was divided in three grades of increasing severity. Mild diastolic dysfunction (grade I) was defined as mitral E/A ratio b 0.8, decTime > 200 ms, IVRT ≥ 100 ms, annular E’ b 8 cm/s and E/E′ lateral ratio b 8; moderate diastolic dysfunction (grade II) as mitral E/A ratio between 0.8 and 1.5, E/E′ lateral 9 to 12 and E′ b 8 cm/s and severe diastolic dysfunction (grade III) as E/A ≥ 2, decTimeb 160 ms, IVRT≤ 60 ms, E/E′ lateral>12. The patient's assessment, taking into consideration the patient age and heart rate, was always performed by the senior cardiologist (C.T.). 2.4. Statistical analysis All the values are reported as means±SD and p valuesb .05 were considered as significant. Data were analyzed as continuous or categorical by using the Student T test for parametric data and the Mann–Whitney U test or Wilcoxon for non-parametric data; the Chi-square test was used for the comparison of dichotomist data. Correlations were explored by means of logistic and linear regression analyses. Survival rate was calculated according to the Kaplan–Meier method and survival curves were compared with the log rank test. The software used for the analysis was NCSS (Number Cruncher Statistical System) 2007. 3. Results 3.1. Patients characteristics
2.3. Echocardiography
Seventy-four cirrhotic patients were included in the study (Table 1). The prevalent etiology of cirrhosis was post-viral, followed by postalcoholic. Age, sex distribution and severity of liver disease were similar in patients with alcoholic and viral origin of liver disease. As expected, liver dysfunction was more severe in hospitalized (49 patients) than ambulatory patients (25 patients). Twenty-three hospitalized and 2 non-hospitalized patients were studied in the presence of mild ascites. Patients were not assuming drugs potentially affecting the QT interval except 26 patients who were under beta-blockers at a dosage between 20 and 40 mg/daily. A prolonged QTc interval (>440 ms) was reported in 45% of patients with a similar prevalence in those assuming vs those not assuming beta-blockers.
Echocardiography was performed by an experienced operator in accordance with the recommendations of the American Society of Echocardiography [18], using an Aplio CV (Toshiba Industrial System 2004) system operating with a 3.5 MHz transducer. From a long axis parasternal view, the left ventricular (LV) systolic and diastolic septal wall thickness (SWST and SWDT), posterior wall thickness (PWTs and PWTd) and the LV diameter (LVESD and LVEDD) were measured in M-mode. The LV mass and LV geometry were calculated accordingly. LV volumes and LV Ejection Fraction (LVEF) were estimated using
3.1.1. Echocardiographic characteristics Left ventricular end-systolic and end-diastolic diameters were significantly increased in cirrhotic patients compared with the healthy controls (30.4 ± 6 vs 27.6 ± 4 mm, p = 0.02 and 50.4 ± 5.8 vs 44 ± 4.4 mm, p = b 0.0001, respectively), however left ventricular volumes were similar (Table 2). Left ventricular ejection fraction was always within normal limits in cirrhotic patients, while the peak systolic velocities recorded with TDI (S′) were significantly decreased. The decrease in S′ was particularly evident in post-alcoholic patients
2.2. Electrocardiographic evaluation A 12 leads electrocardiogram was done in each patient and QTc interval was estimated according to Bazett's formula: QTc=QTmax/square root of RR interval.
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Table 1 Demographic and clinical characteristics of the 74 cirrhotic patients included in the study. Age (years) Sex (M/F) Hospitalized/Ambulatory (n° patients) Diabetes (%) Mild arterial hypertension (%) Aetiology (%) Post-viral Alcohol Cryptogenic Others Child Pugh class (%) A/B/C Esophageal varices (absent/small/medium/large) % Ascites (absent/previous/present) % MELD score (mean ± SD) Therapy (%) β-blockers Furosemide Spironolactone Proton-pump inhibitors Heart rate (bpm) MAP (mmHg) QTc interval > 440 ms (%) Haemoglobin (g/dl)
58 ± 10 44/30 49/25 22 5 55 28 11 6 39/35/26 35/36/21/8 11/55/25 13 ± 5 35 37 42 65 73 ± 13 89 ± 11 45 11,7 ± 2,2
(Child-Pugh class or MELD), echocardiography parameters were similar, except for subtle E/E’ lateral difference between Child A and B/C; however, values obtained were always within normal limits (Table 3). 3.2. Electrophysiological abnormalities We found a longer QTc interval in patients with a more compromised liver function. Patients with a QTc interval>440 ms were 27% of those Child A vs 56% of those Child B/C (p=0.02), 36% of patients with MELDb 15 vs 63% of MELD>15 (p=0.03) and 35% in patients without ascites vs 62% in patients with ascites (p=0.03). 3.3. Follow-up The mortality rate was 34% after 1 year follow-up. All patients died for complications of liver disease (variceal bleeding; hepatorenal syndrome; hepatocellular carcinoma, liver failure). One patient was censored at the time of liver transplantation, which occurred 5 months after the inclusion in the study. This patient died for cardiac complications 15 days after liver transplantation. Patients with diastolic dysfunction and patients without diastolic dysfunction had a similar survival rate (64% vs 73% respectively; p = 0.3) (Suppletive Fig. 1). 4. Discussion
(S′: 10.3 ± 1.9 in post-alcoholic vs 11.8 ± 2.6 cm/s in non-alcoholic patients; p = 0.04). Cardiac mass was increased in cirrhotic patients (p b 0.001). A cardiac geometric modification was observed in 24 patients (5 concentric hypertrophy, 13 eccentric hypertrophy and 6 cardiac remodeling) [19]. With regard to diastolic function, E/A ratio and decTime were significantly decreased in cirrhotics compared to controls, although still within normal limits (Table 2). Mild diastolic dysfunction, according to the American Society of Echocardiography Guidelines, was present in 47 cirrhotic patients (64%) at rest: grade I in thirty-seven patients and grade II in ten. For technical reasons left atrial end-systolic volume could be measured only in forty patients with liver disease, and it was then indexed for body surface area. Patients with cirrhosis had larger left atrial end-systolic volume compared with healthy controls (p b 0.001). Diastolic dysfunction was more prevalent in cirrhotic patients with ascites vs those without (77% vs 56%; p = 0.04). When patients were stratified according to the degree of liver impairment
Table 2 Echocardiographic data in patients and controls. Echocardiographic parameters (mean ± SD)
Patients (n = 74)
Controls (n = 26)
p
LVEDD (mm) LVESD (mm) LVEDV (ml) SWDT (mm) PWDT (mm) LAESV (ml/m2)a Cardiac mass (g/m2) E/A ratio DT (ms) IVRT (ms) EF (%) E’ lateral (cm/s) E/ E’ lateral S’ (cm/s)
50.4 ± 5.8 30.4 ± 6 114.2 ± 34 9.2 ± 1.6 8.9 ± 1.3 32.7 ± 8.3 90.6 ± 23.7 1.0 ± 0.3 219.8 ± 38.7 74.7 ± 17.4 61.2 ± 4.8 11.6 ± 2.9 6.1 ± 2.8 11.3 ± 2.7
44 ± 4.4 27.6 ± 4 104.1 ± 23 8.8 ± 1.1 8.8 ± 1.3 24 ± 8.5 70.5 ± 22.2 1.2 ± 0.3 194.9 ± 45.6 77.7 ± 6.3 62 ± 4.2 10.7 ± 0.8 5.8 ± 1.5 13.9 ± 1.4
b0.0001 0.02 0.2 0.2 0.8 b0.0001 b0.001 0.04 0.009 0.4 0.4 0.1 0.6 b0.0001
LVEDD: Left Ventricular End Diastolic Diameter; LVESD: Left Ventricular End Systolic Diameter; LVEDV: Left Ventricular End Diastolic Volume; SWDT: Septal wall diastolic thickness; PWDT: Posterior wall diastolic thickness; LAESV: Left atrial end-systolic volume; DT: deceleration Time; IVRT: Isovolumetric Ventricular Relaxation Time; EF: Ejection Fraction. a For technical reasons left atrial end-systolic volume could be measured only in forty patients with liver disease, and it was then indexed for body surface area.
During the last years several studies have focused their attention on the presence of specific cardiac abnormalities in cirrhotic patients. The term cirrhotic cardiomiopathy was proposed in 1996 [4] and further investigation suggested that the presence of cirrhotic cardiomiopathy may favor some clinical complications of cirrhosis, such as the development of hepatorenal syndrome after spontaneous bacterial peritonitis [20,21] and may be associated with a decreased survival after trans jugular intrahepatic portosystemic shunt implantation [11]. While some authors consider cirrhotic cardiomiopathy an independent entity, others have claimed that the alteration of cardiac function in liver cirrhosis is mainly secondary to hemodynamic changes and increased blood volume, chronically present in patients with advanced liver disease [5,22]. In fact, in cirrhotic patients the decreased systemic vascular resistances and increased cardiac output and heart rate, in the setting of a hyperdynamic circulation, may be responsible for a persistent increase in cardiac work and may lead secondarily to cirrhotic cardiomyopathy [23]. It is not completely agreed how cirrhotic cardiomiopathy should be diagnosed. The 2005 World Congress of Gastroenterology's working definition included in the diagnostic criteria the presence of an impaired contractile responsiveness to stress and/or an altered diastolic relaxation with electrophysiological abnormalities, but the minimum criteria by which the diagnosis of diastolic dysfunction can be made was not fully clarified. Previous studies have in fact evaluated diastolic dysfunction only based on the classic E/A ratio, derived from bi-dimensional echocardiography [11,12]. The more recent American Society of Echocardiography Guidelines [16] have approached the diagnosis of diastolic dysfunction in a somehow different way: in particular TDI parameters have been introduced which may be less influenced by condition of overload. Furthermore the diagnosis of diastolic dysfunction is derived from the analysis of a combination of cardiac parameters which are normalized for age. In our study we found a significant increase in left ventricular diameters, but not in volumes. The apical 4-chambers view, needed for volume estimation, was however difficult to obtain in some of the patients with ascites which may explain this discrepancy. Our results are similar to those obtained by Kazankov et al. [24], who also applied the American Society of Echocardiography Guidelines. When systolic function was assessed by conventional echocardiography, based on LVEF, no significant differences were observed between patients with cirrhosis and controls. Only more complex techniques, such as TDI, were able
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Table 3 Echocardiography parameters according to the degree of liver impairment and etiology. Echocardiographic parameters (mean ± SD)
Child-Pugh A (n = 29)
Child-Pugh B/C (n = 45)
p
MELD b 15 (n = 50)
MELD > 15 (n = 24)
p
Alcholic (n = 21)
Non Alcholic (n = 53)
P
LVEDD (mm) LVESD (mm) LVEDV(ml) SWDT (mm) PWDT (mm) LAESV (ml/m2)
51 ± 5 31 ± 7 108.2 ± 29 9±2 8.8 ± 1.4 34.3 ± 10.5 (n = 11) 62 ± 5 1.1 ± 0.4 222 ± 40.7 71.5 ± 15.5 10.9 ± 1.6 7.2 ± 1.4 10.9 ± 2.6
50 ± 6 30 ± 6 118.1 ± 37 9±1 8.9 ± 1.3 32.1 ± 7.4 (n = 28) 61 ± 4 0.9 ± 0.3 218.1 ± 37.7 76.8 ± 18.4 11.9 ± 3.3 5.6 ± 3.1 11.5 ± 2.7
0.4 0.3 0.2 0.6 0.7 0.5
50.2 ± 5.2 30.6 ± 6.1 109 ± 24 9.2 ± 1.7 8.9 ± 1.3 33.4 ± 9.5 (n = 24) 61 ± 5 1.1 ± 0.34 222.1 ± 41.4 74.9 ± 17.4 10.8 ± 2 6.3 ± 2.8 10.9 ± 2.5
50.8 ± 7.2 30.2 ± 5.8 125 ± 30 9.3 ± 1.6 8.9 ± 1.3 31.6 ± 6.1 (n = 15) 62 ± 4 1 ± 0.33 214.6 ± 32 74 ± 17.9 13 ± 3.7 5.7 ± 2.8 12 ± 3
0.6 0.7 0.08 0.6 0.9 0.5
50.4 ± 6.7 31 ± 6.7 123.5 ± 36 9.5 ± 1.2 9.2 ± 1.1 33.4 ± 9.1 (n = 3) 60 ± 5.4 1 ± 0.3 226.3 ± 32.5 78.8 ± 22.5 10.6 ± 3.1 6.6 ± 3.6 10.3 ± 1.9
50.4 ± 5.5 30.3 ± 5.8 110.7 ± 33.1 9.2 ± 1.7 8.8 ± 1.4 31.5 ± 7.6 (n = 11) 61.6 ± 4.5 1.1 ± 0.4 217.2 ± 40.9 73 ± 14.8 11.8 ± 2.8 5.9 ± 2.4 11.8 ± 2.6
0.9 0.6 0.2 0.4 0.5 0.5
EF (%) E/A DT (ms) IVRT (ms) E’ lateral (cm/s) E/ E’ lateral S’ (cm/s)
0.5 0.07 0.7 0.2 0.2 0.02 0.4
0.6 0.8 0.4 0.8 0.02 0.4 0.13
0.2 0.6 0.3 0.2 0.1 0.4 0.04
LVEDD: Left Ventricular End Diastolic Diameter; LVESD: Left Ventricular End Systolic Diameter; LVEDV: Left Ventricular End Diastolic Volume; SWDT: Septal wall diastolic thickness. PWDT: Posterior wall diastolic thickness; LAESV: Left atrial end-systolic volume; DT: deceleration Time; IVRT: Isovolumetric Ventricular Relaxation Time; EF: Ejection Fraction.
to identify trivial impairment in the longitudinal peak systolic velocities (S’) or in the regional contractility and detect a sign of early damage in the LV longitudinal function in cirrhotic patients. In our study diastolic dysfunction was found to be a rather common abnormality, although generally mild in severity (grade I). In our population, E/A ratio in patients with cirrhosis moved toward a value close to 1, as for some impairment in the diastolic function, whilst in the control group it was certainly within normal range. Conversely, E/E′ which is more stable and less influenced by loading conditions [16], was not different. Supporting the hypothesis that the E/A ratio was influenced by a more severe fluid overload status, we also observed lower values in patients with vs those without ascites (0.9± 0.2 vs 1.1 ±0.3; p = 0.03). It is therefore conceivable that the alteration of E/A and decTime reported in our study and also described in literature [25], are frequently influenced by the hemodynamic overload occurring in cirrhotic patients and may in many cases reflect a “functional” diastolic dysfunction, more than a primary heart disease. On the other hand, if diastolic dysfunction was only the consequence of a progressive liver decompensation and hyperdinamic circulation one would have expected that the greater the severity of liver disease the higher the prevalence of cardiac dysfunction. Cardiac abnormalities at rest in our study were however not different in Child B/C vs Child A patients or MELD >15 vs b 15. Lastly it cannot be excluded that a small percentage of cirrhotic patients may actually develop a diastolic type cardiomyopathy, still not easily identifiable by the low sensitivity and specificity of the technique we used. Concerning electrophysiological abnormalities, in keeping to previous studies [9,26,27] QTc value was more prevalent in patients with severe liver impairment. In our study we failed to find a correlation between the presence of diastolic dysfunction and 1 year survival. The method of assessment, patients characteristics and the short follow-up may explain the reason of this discrepancy with previous studies. Limits of the present study were the small sample size and the unavailability of brain natriuretic peptide and pro-brain natriuretic peptide, which are also recognized to be important in the evaluation of diastolic dysfunction [28]. Moreover our study did not include a stress test (physical activity or pharmacological stress) which could have better evidenced a sub clinical cardiac dysfunction. It is conceivable that some of our patients, who were relatively young and did not have severe cardiovascular disease, probably died before that their subtle systo-diastolic dysfunction progressed to a higher degree of severity, due to their underlying liver disease. We also think that new sophisticated and detailed techniques are needed to better characterize the systo-diastolic cardiac status in these patients. A speckle tracking analysis may be in the future an alternate and preferred method to investigate the LV regional contractility in a populations like ours, which may have some minor degree of LV dysfunction not detectable with a simple LVEF measurement.
5. Conclusion Subtle left ventricular systo-diastolic abnormalities were found in patients with liver cirrhosis not related to the severity of liver disease. TDI parameters appeared to detect LV systolic impairment at an early stage and were generally not altered when used to evaluate the LV diastolic function in patients with cirrhosis. At variance with previous studies we underline that the alteration in cardiac load needs to be considered a relevant confounding factor in the diagnosis of diastolic dysfunction in cirrhotic patients. Further studies are needed to better characterize the diagnosis of the “cirrhotic” cardiomyopathy. Learning points • Cirrhotic cardiomyopathy is defined as a cardiac dysfunction in patients with cirrhosis in the absence of other known cardiac disease. • Cardiac alterations in cirrhotic patients may be primary or secondary to the haemodynamic changes present in liver cirrhosis such as the hyperdynamic syndrome and/or the condition of fluid retention causing an increased cardiac load. • The present study shows that the diagnosis of diastolic dysfunction is strongly influenced by fluid retention and loading conditions as is the case in cirrhotic patients with ascites. • The use of 2D-Doppler echocardiography with Tissue Doppler Imaging, a method which is less influenced by the changes in cardiac load, underlines that systo-diastolic abnormalities in patients with liver cirrhosis do not correlate with the severity of liver disease. Conflict of interests The Authors of the manuscript “Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease” have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence (bias) their work. Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.ejim.2012.08.007. References [1] Kowalski HJ, Abelmann WH. The cardiac output at rest in Laennec's cirrhosis. J Clin Invest 1953;32:1025-33. [2] Ma Z, Lee SS. Cirrhotic cardiomyopathy: getting to the heart of the matter. Hepatology 1996;24:451-9. [3] Møller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol 2010;53:179-90. [4] Zardi EM, Abbate A, Zardi DM, Dobrina A, Margiotta D, Van Tassell BW, et al. Cirrhotic cardiomyopathy. J Am Coll Cardiol 2010;10:539-49. [5] Møller S, Henriksen JH. Cardiovascular complications of cirrhosis. Gut 2008;57: 268-78.
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease☆ Manuela Merli a,⁎, Angela Calicchia b, Alessandra Ruffa a, Pierpaolo Pellicori c, Oliviero Riggio a, Michela Giusto a, Carlo Gaudio b, Concetta Torromeo b a b c
Gastroenterologia, Dipartimento Medicina Clinica, Sapienza Università di Roma, Italy Dipartimento di Scienze Cardiovascolari, Nefrologiche e Geriatriche, Sapienza Università di Roma, Italy Department of Academic Cardiology, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Kingstone upon Hull, UK
a r t i c l e
i n f o
Article history: Received 1 May 2012 Received in revised form 12 July 2012 Accepted 14 August 2012 Available online 5 September 2012 Keywords: Liver cirrhosis Diastolic dysfunction Heart Cirrhotic cardiomiopathy Cardiac load
a b s t r a c t Background: Cirrhotic cardiomiopathy is described as the presence of cardiac dysfunction in cirrhotic patients. The aim of the study was to investigate factors associated with cardiac dysfunction in cirrhotic patients. Patients and methods: Seventy-four cirrhotic patients and twenty-six controls performed a conventional echocardiography and Tissue Doppler Imaging (TDI) for systolic and diastolic function. Results were analyzed by using the Guidelines of American Society of Echocardiography. Results: In patients with cirrhosis, left ventricular end-diastolic diameter was increased (p b 0.001) , peak systolic velocities were decreased (11.3 ± 2.7 vs 13.9 ± 1.4 cm/s; p b 0.001) and left atrial volumes were increased (32.7 ± 8.3 vs 24 ± 8.5 ml, p b 0.001) as well as cardiac mass (90.6 ± 23 vs 70.5 ± 22 g/m 2, p b 0.001). Forty-seven cirrhotic patients (64%) showed diastolic dysfunction at rest: grade I in 37 and grade II in 10 patients. Systolic and/or diastolic dysfunction were not influenced by a more severe liver impairment. Diastolic dysfunction was more prevalent in patients with ascites vs those without (77% vs 56%; p = 0.04). Conclusion: A mild diastolic dysfunction at rest is frequent in cirrhotic patients but cardiac load conditions are confounding factors in this diagnosis. We did not identify an association between severity of liver disease and cardiac dysfunction. © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Historically, liver cirrhosis has not been associated with any cardiac abnormalities, despite the fact that a hyperdynamic state leading to increased cardiac output and decreased systemic vascular resistance has been described in patients with cirrhosis more than 50 years ago [1]. In the last 20 years a number of evidences suggested that cirrhosis regardless of its etiology, is associated with the development of hemodynamic changes and major cardiovascular anomalies. Overall these alterations are known as cirrhotic cardiomyopathy [2–4]. According to the 2005 World Congress of Gastroenterology, cirrhotic cardiomyopathy is defined as “a cardiac dysfunction in patients
Abbreviations: decTime, deceleration time; EF, ejection fraction; IVRT, isovolumetric ventricular relaxation time; LAESV, left atrial end-systolic volume; LVEDD, left ventricular end diastolic diameter; LVEDV, left ventricular end diastolic volume; LVESD, left ventricular end systolic diameter; MAP, mean arterial pressure; PWDT, posterior wall diastolic thickness; SWDT, septal wall diastolic thickness; SWST, septal wall systolic thickness; TDI, tissue Doppler imaging. ☆ Disclosure: The authors have nothing to disclose No conflict of interest exist. ⁎ Corresponding author at: Gastroenterologia, Dipartimento di Medicina Clinica, “Sapienza” Università di Roma, Viale dell'Università 37, 00185 Roma, Italy. Tel.: +39 0649972001; fax: +39 064453319, +39 064440806. E-mail address: [email protected] (M. Merli).
with cirrhosis characterised by impaired contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiological abnormalities in the absence of other known cardiac disease” [5]. Systolic dysfunction, in cirrhotic patients, is characterized by a blunted increase in cardiac output and decreased contractility with exercise, pharmacological stress, and volume challenge [6]. Moreover cirrhotic patients have severe chronotropic incompetence, defined as significantly reduced cardiac response to exercise due to autonomic dysfunction with blunted sensitivity to sympathetic activation [7]. Diastolic dysfunction in cirrhotic patients has been associated with increased left ventricular wall thickness, subendocardial oedema, fibrosis and altered collagen structure, ultimately leading to altered relaxation [8]. Electrophysiological abnormalities have been related to plasma membrane and fluidity changes, adrenergic and post receptor signalling pathway defects and/or ion channel dysfunction [2]. The main electrophysiological changes in cirrhosis are prolongation at electrocardiography of the QTc interval and impaired electromechanical coupling likely as a result of potassium and calcium ion channel defects [9,10]. The criteria adopted for the diagnosis of diastolic dysfunction in cirrhotic patients need, however, to be interpreted with caution. Previous studies have based the diagnosis of diastolic dysfunction mainly on 2D-Doppler echocardiography parameters [11–13]. It is however well known that the E/A ratio is strongly influenced by loading
0953-6205/$ – see front matter © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2012.08.007
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conditions, and decompensated cirrhotic patients are frequently suffering a condition of fluid retention. Moreover it has not been completely defined how many parameters need to be altered for the diagnosis of diastolic dysfunction, therefore different criteria have been utilized in different studies. Furthermore, as diastolic dysfunction is physiological with advancing age, some authors have applied a correction for age [14], which was however not applied in other studies. The use of Tissue Doppler Imaging (TDI) can overcome some of this criticism, mainly because this echocardiography method is less influenced by the changes in cardiac load conditions [15]. The American Society of Echocardiography has included TDI parameters in the definition of diastolic dysfunction and these criteria have recently been updated [16]. Our study aimed at evaluating, in a selected group of cirrhotic patients, the relationship between cirrhotic cardiomiopathy evaluated by TDI and the severity of liver impairment. 2. Patients and methods Cirrhotic patients, either admitted in hospital or followed as outpatients, were considered for the study. Diagnosis of cirrhosis was established through histology and/or a combination of clinical, biochemical and instrumental findings. Age b 18 and >75 years, active alcohol abuse, surgical or radiological shunts, hepatocellular carcinoma (beyond Milan criteria) or recurrence of cirrhosis after liver transplantation were causes of exclusion. Patients with a history of past or present cardiac disease, severe arterial hypertension, chronic pulmonary disease or an abnormal 12 leads electrocardiogram were also excluded. Hospitalized patients with active complications were studied only after successful treatment. A total of 74 patients were then enrolled in this study and 26 sex and age-matched healthy subjects were studied with a similar protocol and constituted the control group. All patients were informed about the opportunity of being included in a study aimed at a more complete cardiovascular assessment and those enrolled gave a written consent. The study was approved by the Local Ethical Committee. 2.1. Clinical evalutation On the day of the study, heart rate and blood pressure were measured. Blood pressure was measured by sphygmomanometer and the mean arterial pressure (MAP) was calculated as (systolic pressure+diastolic pressure×2)/3. Patients provided a detailed clinical history and had a clinical examination and blood tests (including haematology and biochemistry profile). Liver function was quantified by Child-Pugh and MELD scores [17,18]. Therapies assumed in the last weeks were recorded. Patients were followed up until death or liver transplantation for 12 months.
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Simpson's modified biplane method. An LVEF above 50% was considered normal. Left atrial end-systolic volume was calculated with monoplane method in apical 4-chambers views using the following formula: volume = 8 (A1) 2/3π∙(L). Pulsed Doppler examination of the LV inflow was performed with the sample volume placed between the mitral leaflet tips. The following parameters were recorded and measured: peak early (E wave) and atrial (A wave) flow velocities, their ratio E⁄A, and the E-wave deceleration time. TDI was obtained from the four chamber apical view and tissue velocity were calculated. The myocardial peak systolic velocity (S′) was measured in lateral mitral annulus to define systolic function. Tissue velocities were also measured in the lateral mitral annulus during the diastole to obtain peak myocardial velocities during early (E′) and atrial filling (A′) phases. Isovolumetric Ventricular Relaxation Time (IVRT) was measured by TDI. To evaluate ventricular filling pressure also E/E’ ratio was calculated. The intra observer variation for echocardiographic measurements was b 10%. Systolic and diastolic functions were defined according to American Society of Echocardiography 2009 [16]. Diastolic dysfunction was divided in three grades of increasing severity. Mild diastolic dysfunction (grade I) was defined as mitral E/A ratio b 0.8, decTime > 200 ms, IVRT ≥ 100 ms, annular E’ b 8 cm/s and E/E′ lateral ratio b 8; moderate diastolic dysfunction (grade II) as mitral E/A ratio between 0.8 and 1.5, E/E′ lateral 9 to 12 and E′ b 8 cm/s and severe diastolic dysfunction (grade III) as E/A ≥ 2, decTimeb 160 ms, IVRT≤ 60 ms, E/E′ lateral>12. The patient's assessment, taking into consideration the patient age and heart rate, was always performed by the senior cardiologist (C.T.). 2.4. Statistical analysis All the values are reported as means±SD and p valuesb .05 were considered as significant. Data were analyzed as continuous or categorical by using the Student T test for parametric data and the Mann–Whitney U test or Wilcoxon for non-parametric data; the Chi-square test was used for the comparison of dichotomist data. Correlations were explored by means of logistic and linear regression analyses. Survival rate was calculated according to the Kaplan–Meier method and survival curves were compared with the log rank test. The software used for the analysis was NCSS (Number Cruncher Statistical System) 2007. 3. Results 3.1. Patients characteristics
2.3. Echocardiography
Seventy-four cirrhotic patients were included in the study (Table 1). The prevalent etiology of cirrhosis was post-viral, followed by postalcoholic. Age, sex distribution and severity of liver disease were similar in patients with alcoholic and viral origin of liver disease. As expected, liver dysfunction was more severe in hospitalized (49 patients) than ambulatory patients (25 patients). Twenty-three hospitalized and 2 non-hospitalized patients were studied in the presence of mild ascites. Patients were not assuming drugs potentially affecting the QT interval except 26 patients who were under beta-blockers at a dosage between 20 and 40 mg/daily. A prolonged QTc interval (>440 ms) was reported in 45% of patients with a similar prevalence in those assuming vs those not assuming beta-blockers.
Echocardiography was performed by an experienced operator in accordance with the recommendations of the American Society of Echocardiography [18], using an Aplio CV (Toshiba Industrial System 2004) system operating with a 3.5 MHz transducer. From a long axis parasternal view, the left ventricular (LV) systolic and diastolic septal wall thickness (SWST and SWDT), posterior wall thickness (PWTs and PWTd) and the LV diameter (LVESD and LVEDD) were measured in M-mode. The LV mass and LV geometry were calculated accordingly. LV volumes and LV Ejection Fraction (LVEF) were estimated using
3.1.1. Echocardiographic characteristics Left ventricular end-systolic and end-diastolic diameters were significantly increased in cirrhotic patients compared with the healthy controls (30.4 ± 6 vs 27.6 ± 4 mm, p = 0.02 and 50.4 ± 5.8 vs 44 ± 4.4 mm, p = b 0.0001, respectively), however left ventricular volumes were similar (Table 2). Left ventricular ejection fraction was always within normal limits in cirrhotic patients, while the peak systolic velocities recorded with TDI (S′) were significantly decreased. The decrease in S′ was particularly evident in post-alcoholic patients
2.2. Electrocardiographic evaluation A 12 leads electrocardiogram was done in each patient and QTc interval was estimated according to Bazett's formula: QTc=QTmax/square root of RR interval.
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Table 1 Demographic and clinical characteristics of the 74 cirrhotic patients included in the study. Age (years) Sex (M/F) Hospitalized/Ambulatory (n° patients) Diabetes (%) Mild arterial hypertension (%) Aetiology (%) Post-viral Alcohol Cryptogenic Others Child Pugh class (%) A/B/C Esophageal varices (absent/small/medium/large) % Ascites (absent/previous/present) % MELD score (mean ± SD) Therapy (%) β-blockers Furosemide Spironolactone Proton-pump inhibitors Heart rate (bpm) MAP (mmHg) QTc interval > 440 ms (%) Haemoglobin (g/dl)
58 ± 10 44/30 49/25 22 5 55 28 11 6 39/35/26 35/36/21/8 11/55/25 13 ± 5 35 37 42 65 73 ± 13 89 ± 11 45 11,7 ± 2,2
(Child-Pugh class or MELD), echocardiography parameters were similar, except for subtle E/E’ lateral difference between Child A and B/C; however, values obtained were always within normal limits (Table 3). 3.2. Electrophysiological abnormalities We found a longer QTc interval in patients with a more compromised liver function. Patients with a QTc interval>440 ms were 27% of those Child A vs 56% of those Child B/C (p=0.02), 36% of patients with MELDb 15 vs 63% of MELD>15 (p=0.03) and 35% in patients without ascites vs 62% in patients with ascites (p=0.03). 3.3. Follow-up The mortality rate was 34% after 1 year follow-up. All patients died for complications of liver disease (variceal bleeding; hepatorenal syndrome; hepatocellular carcinoma, liver failure). One patient was censored at the time of liver transplantation, which occurred 5 months after the inclusion in the study. This patient died for cardiac complications 15 days after liver transplantation. Patients with diastolic dysfunction and patients without diastolic dysfunction had a similar survival rate (64% vs 73% respectively; p = 0.3) (Suppletive Fig. 1). 4. Discussion
(S′: 10.3 ± 1.9 in post-alcoholic vs 11.8 ± 2.6 cm/s in non-alcoholic patients; p = 0.04). Cardiac mass was increased in cirrhotic patients (p b 0.001). A cardiac geometric modification was observed in 24 patients (5 concentric hypertrophy, 13 eccentric hypertrophy and 6 cardiac remodeling) [19]. With regard to diastolic function, E/A ratio and decTime were significantly decreased in cirrhotics compared to controls, although still within normal limits (Table 2). Mild diastolic dysfunction, according to the American Society of Echocardiography Guidelines, was present in 47 cirrhotic patients (64%) at rest: grade I in thirty-seven patients and grade II in ten. For technical reasons left atrial end-systolic volume could be measured only in forty patients with liver disease, and it was then indexed for body surface area. Patients with cirrhosis had larger left atrial end-systolic volume compared with healthy controls (p b 0.001). Diastolic dysfunction was more prevalent in cirrhotic patients with ascites vs those without (77% vs 56%; p = 0.04). When patients were stratified according to the degree of liver impairment
Table 2 Echocardiographic data in patients and controls. Echocardiographic parameters (mean ± SD)
Patients (n = 74)
Controls (n = 26)
p
LVEDD (mm) LVESD (mm) LVEDV (ml) SWDT (mm) PWDT (mm) LAESV (ml/m2)a Cardiac mass (g/m2) E/A ratio DT (ms) IVRT (ms) EF (%) E’ lateral (cm/s) E/ E’ lateral S’ (cm/s)
50.4 ± 5.8 30.4 ± 6 114.2 ± 34 9.2 ± 1.6 8.9 ± 1.3 32.7 ± 8.3 90.6 ± 23.7 1.0 ± 0.3 219.8 ± 38.7 74.7 ± 17.4 61.2 ± 4.8 11.6 ± 2.9 6.1 ± 2.8 11.3 ± 2.7
44 ± 4.4 27.6 ± 4 104.1 ± 23 8.8 ± 1.1 8.8 ± 1.3 24 ± 8.5 70.5 ± 22.2 1.2 ± 0.3 194.9 ± 45.6 77.7 ± 6.3 62 ± 4.2 10.7 ± 0.8 5.8 ± 1.5 13.9 ± 1.4
b0.0001 0.02 0.2 0.2 0.8 b0.0001 b0.001 0.04 0.009 0.4 0.4 0.1 0.6 b0.0001
LVEDD: Left Ventricular End Diastolic Diameter; LVESD: Left Ventricular End Systolic Diameter; LVEDV: Left Ventricular End Diastolic Volume; SWDT: Septal wall diastolic thickness; PWDT: Posterior wall diastolic thickness; LAESV: Left atrial end-systolic volume; DT: deceleration Time; IVRT: Isovolumetric Ventricular Relaxation Time; EF: Ejection Fraction. a For technical reasons left atrial end-systolic volume could be measured only in forty patients with liver disease, and it was then indexed for body surface area.
During the last years several studies have focused their attention on the presence of specific cardiac abnormalities in cirrhotic patients. The term cirrhotic cardiomiopathy was proposed in 1996 [4] and further investigation suggested that the presence of cirrhotic cardiomiopathy may favor some clinical complications of cirrhosis, such as the development of hepatorenal syndrome after spontaneous bacterial peritonitis [20,21] and may be associated with a decreased survival after trans jugular intrahepatic portosystemic shunt implantation [11]. While some authors consider cirrhotic cardiomiopathy an independent entity, others have claimed that the alteration of cardiac function in liver cirrhosis is mainly secondary to hemodynamic changes and increased blood volume, chronically present in patients with advanced liver disease [5,22]. In fact, in cirrhotic patients the decreased systemic vascular resistances and increased cardiac output and heart rate, in the setting of a hyperdynamic circulation, may be responsible for a persistent increase in cardiac work and may lead secondarily to cirrhotic cardiomyopathy [23]. It is not completely agreed how cirrhotic cardiomiopathy should be diagnosed. The 2005 World Congress of Gastroenterology's working definition included in the diagnostic criteria the presence of an impaired contractile responsiveness to stress and/or an altered diastolic relaxation with electrophysiological abnormalities, but the minimum criteria by which the diagnosis of diastolic dysfunction can be made was not fully clarified. Previous studies have in fact evaluated diastolic dysfunction only based on the classic E/A ratio, derived from bi-dimensional echocardiography [11,12]. The more recent American Society of Echocardiography Guidelines [16] have approached the diagnosis of diastolic dysfunction in a somehow different way: in particular TDI parameters have been introduced which may be less influenced by condition of overload. Furthermore the diagnosis of diastolic dysfunction is derived from the analysis of a combination of cardiac parameters which are normalized for age. In our study we found a significant increase in left ventricular diameters, but not in volumes. The apical 4-chambers view, needed for volume estimation, was however difficult to obtain in some of the patients with ascites which may explain this discrepancy. Our results are similar to those obtained by Kazankov et al. [24], who also applied the American Society of Echocardiography Guidelines. When systolic function was assessed by conventional echocardiography, based on LVEF, no significant differences were observed between patients with cirrhosis and controls. Only more complex techniques, such as TDI, were able
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Table 3 Echocardiography parameters according to the degree of liver impairment and etiology. Echocardiographic parameters (mean ± SD)
Child-Pugh A (n = 29)
Child-Pugh B/C (n = 45)
p
MELD b 15 (n = 50)
MELD > 15 (n = 24)
p
Alcholic (n = 21)
Non Alcholic (n = 53)
P
LVEDD (mm) LVESD (mm) LVEDV(ml) SWDT (mm) PWDT (mm) LAESV (ml/m2)
51 ± 5 31 ± 7 108.2 ± 29 9±2 8.8 ± 1.4 34.3 ± 10.5 (n = 11) 62 ± 5 1.1 ± 0.4 222 ± 40.7 71.5 ± 15.5 10.9 ± 1.6 7.2 ± 1.4 10.9 ± 2.6
50 ± 6 30 ± 6 118.1 ± 37 9±1 8.9 ± 1.3 32.1 ± 7.4 (n = 28) 61 ± 4 0.9 ± 0.3 218.1 ± 37.7 76.8 ± 18.4 11.9 ± 3.3 5.6 ± 3.1 11.5 ± 2.7
0.4 0.3 0.2 0.6 0.7 0.5
50.2 ± 5.2 30.6 ± 6.1 109 ± 24 9.2 ± 1.7 8.9 ± 1.3 33.4 ± 9.5 (n = 24) 61 ± 5 1.1 ± 0.34 222.1 ± 41.4 74.9 ± 17.4 10.8 ± 2 6.3 ± 2.8 10.9 ± 2.5
50.8 ± 7.2 30.2 ± 5.8 125 ± 30 9.3 ± 1.6 8.9 ± 1.3 31.6 ± 6.1 (n = 15) 62 ± 4 1 ± 0.33 214.6 ± 32 74 ± 17.9 13 ± 3.7 5.7 ± 2.8 12 ± 3
0.6 0.7 0.08 0.6 0.9 0.5
50.4 ± 6.7 31 ± 6.7 123.5 ± 36 9.5 ± 1.2 9.2 ± 1.1 33.4 ± 9.1 (n = 3) 60 ± 5.4 1 ± 0.3 226.3 ± 32.5 78.8 ± 22.5 10.6 ± 3.1 6.6 ± 3.6 10.3 ± 1.9
50.4 ± 5.5 30.3 ± 5.8 110.7 ± 33.1 9.2 ± 1.7 8.8 ± 1.4 31.5 ± 7.6 (n = 11) 61.6 ± 4.5 1.1 ± 0.4 217.2 ± 40.9 73 ± 14.8 11.8 ± 2.8 5.9 ± 2.4 11.8 ± 2.6
0.9 0.6 0.2 0.4 0.5 0.5
EF (%) E/A DT (ms) IVRT (ms) E’ lateral (cm/s) E/ E’ lateral S’ (cm/s)
0.5 0.07 0.7 0.2 0.2 0.02 0.4
0.6 0.8 0.4 0.8 0.02 0.4 0.13
0.2 0.6 0.3 0.2 0.1 0.4 0.04
LVEDD: Left Ventricular End Diastolic Diameter; LVESD: Left Ventricular End Systolic Diameter; LVEDV: Left Ventricular End Diastolic Volume; SWDT: Septal wall diastolic thickness. PWDT: Posterior wall diastolic thickness; LAESV: Left atrial end-systolic volume; DT: deceleration Time; IVRT: Isovolumetric Ventricular Relaxation Time; EF: Ejection Fraction.
to identify trivial impairment in the longitudinal peak systolic velocities (S’) or in the regional contractility and detect a sign of early damage in the LV longitudinal function in cirrhotic patients. In our study diastolic dysfunction was found to be a rather common abnormality, although generally mild in severity (grade I). In our population, E/A ratio in patients with cirrhosis moved toward a value close to 1, as for some impairment in the diastolic function, whilst in the control group it was certainly within normal range. Conversely, E/E′ which is more stable and less influenced by loading conditions [16], was not different. Supporting the hypothesis that the E/A ratio was influenced by a more severe fluid overload status, we also observed lower values in patients with vs those without ascites (0.9± 0.2 vs 1.1 ±0.3; p = 0.03). It is therefore conceivable that the alteration of E/A and decTime reported in our study and also described in literature [25], are frequently influenced by the hemodynamic overload occurring in cirrhotic patients and may in many cases reflect a “functional” diastolic dysfunction, more than a primary heart disease. On the other hand, if diastolic dysfunction was only the consequence of a progressive liver decompensation and hyperdinamic circulation one would have expected that the greater the severity of liver disease the higher the prevalence of cardiac dysfunction. Cardiac abnormalities at rest in our study were however not different in Child B/C vs Child A patients or MELD >15 vs b 15. Lastly it cannot be excluded that a small percentage of cirrhotic patients may actually develop a diastolic type cardiomyopathy, still not easily identifiable by the low sensitivity and specificity of the technique we used. Concerning electrophysiological abnormalities, in keeping to previous studies [9,26,27] QTc value was more prevalent in patients with severe liver impairment. In our study we failed to find a correlation between the presence of diastolic dysfunction and 1 year survival. The method of assessment, patients characteristics and the short follow-up may explain the reason of this discrepancy with previous studies. Limits of the present study were the small sample size and the unavailability of brain natriuretic peptide and pro-brain natriuretic peptide, which are also recognized to be important in the evaluation of diastolic dysfunction [28]. Moreover our study did not include a stress test (physical activity or pharmacological stress) which could have better evidenced a sub clinical cardiac dysfunction. It is conceivable that some of our patients, who were relatively young and did not have severe cardiovascular disease, probably died before that their subtle systo-diastolic dysfunction progressed to a higher degree of severity, due to their underlying liver disease. We also think that new sophisticated and detailed techniques are needed to better characterize the systo-diastolic cardiac status in these patients. A speckle tracking analysis may be in the future an alternate and preferred method to investigate the LV regional contractility in a populations like ours, which may have some minor degree of LV dysfunction not detectable with a simple LVEF measurement.
5. Conclusion Subtle left ventricular systo-diastolic abnormalities were found in patients with liver cirrhosis not related to the severity of liver disease. TDI parameters appeared to detect LV systolic impairment at an early stage and were generally not altered when used to evaluate the LV diastolic function in patients with cirrhosis. At variance with previous studies we underline that the alteration in cardiac load needs to be considered a relevant confounding factor in the diagnosis of diastolic dysfunction in cirrhotic patients. Further studies are needed to better characterize the diagnosis of the “cirrhotic” cardiomyopathy. Learning points • Cirrhotic cardiomyopathy is defined as a cardiac dysfunction in patients with cirrhosis in the absence of other known cardiac disease. • Cardiac alterations in cirrhotic patients may be primary or secondary to the haemodynamic changes present in liver cirrhosis such as the hyperdynamic syndrome and/or the condition of fluid retention causing an increased cardiac load. • The present study shows that the diagnosis of diastolic dysfunction is strongly influenced by fluid retention and loading conditions as is the case in cirrhotic patients with ascites. • The use of 2D-Doppler echocardiography with Tissue Doppler Imaging, a method which is less influenced by the changes in cardiac load, underlines that systo-diastolic abnormalities in patients with liver cirrhosis do not correlate with the severity of liver disease. Conflict of interests The Authors of the manuscript “Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease” have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence (bias) their work. Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.ejim.2012.08.007. References [1] Kowalski HJ, Abelmann WH. The cardiac output at rest in Laennec's cirrhosis. J Clin Invest 1953;32:1025-33. [2] Ma Z, Lee SS. Cirrhotic cardiomyopathy: getting to the heart of the matter. Hepatology 1996;24:451-9. [3] Møller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol 2010;53:179-90. [4] Zardi EM, Abbate A, Zardi DM, Dobrina A, Margiotta D, Van Tassell BW, et al. Cirrhotic cardiomyopathy. J Am Coll Cardiol 2010;10:539-49. [5] Møller S, Henriksen JH. Cardiovascular complications of cirrhosis. Gut 2008;57: 268-78.
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